6-HETEROCYCLOALKYL-QUINAZOLINE DERIVATIVES AND USES THEREOF RELATED APPLICATIONS This application claims priority to, and the benefit of, U.S. Application Nos. 63/221,440, filed July 13, 2021, and 63/211,914, filed June 17, 2021, the entire contents of each of which are incorporated herein by reference. BACKGROUND Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal growth factor receptor (EGFR) and Erb-2, also named HER2 in humans). ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies. The present disclosure provides compositions and methods for treating cancer in patients with these oncogenic mutations without the variable reponsivenss observed when patients having these ErbB mutants are treated using the existing standard of care. SUMMARY In some aspects, the present disclosure provides a compound of Formula (I): a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W ¹ is =CR ^W1 – or =N–; R ^W1 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; X ¹ is –CH ₂ –, –NH–, –N(CH ₃ )–, or –O–; X ² is absent, –NH–, –N(CH ₃ )–, or –O–; Y is C ₃ -C ₈ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, - O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), -O-(5- to 9- membered heteroaryl), -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -O- (C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl), or -O-(C ₁ -C ₆ alkyl)-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -O-(C3- C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), -O-(5- to 9-membered heteroaryl), -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -O-(C ₁ -C ₆ alkyl)- (3- to 9-membered heterocycloalkyl), or -O-(C ₁ -C ₆ alkyl)-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 ; R ^Y1 is -CN, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen; Z is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Z ; R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen; R ¹ is C ₃ -C ₈ cycloalkyl, –HC=CH ₂ , –HC=CHR ^1a , or –C≡C–CH ₃ ; and R ^1a is -CH ₂ -N(CH ₃ ) ₂ or -CH ₂ -morpholinyl. In some aspects, the present disclosure provides a compound of Formula (I): a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W ¹ is =CR ^W1 – or =N–; R ^W1 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; X ¹ is –CH ₂ –, –NH–, –N(CH ₃ )–, or –O–; X ² is absent, –NH–, –N(CH ₃ )–, or –O–; Y is C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; R ^Y is -CN, oxo, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, - O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ - C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O- (C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl) is optionally substituted with one or more R ^Y1 ; R ^Y1 is halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen; Z is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Z ; R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen; R ¹ is C ₃ -C ₈ cycloalkyl, –HC=CH ₂ , –HC=CHR ^1a , or –C≡C–CH ₃ ; and R ^1a is -CH ₂ -N(CH ₃ ) ₂ or -CH ₂ -morpholinyl. In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Schemes 1-15). In some aspects, the present disclosure provides an isotopic derivative of a compound described. In some aspects, the present disclosure provides a method of preparing a compound described herein. In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-487). In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. In some aspects, the present disclosure provides a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor. In some aspects, the present disclosure provides a compound described herein for use in the manufacture of a medicament for the prevention or treatment of cancer. In some aspects, the present disclosure provides a compound described herein for use in the manufacture of a medicament for the inhibition of an oncogenic variant of an ErbB receptor. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION The present disclosure relates to compounds, and pharmaceutically acceptable salts and stereoisomers thereof, useful in the treatment of cancers associated with ErbB oncogenic activity, including methods of preparing the compounds, compositions comprising the compounds, and methods of using the compounds (e.g., in the treatment of cancer). Compounds of the Present Disclosure In some aspects, the present disclosure provides a compound of Formula (I): a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W ¹ is =CR ^W1 – or =N–; R ^W1 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; X ¹ is –CH ₂ –, –NH–, –N(CH ₃ )–, or –O–; X ² is absent, –NH–, –N(CH3)–, or –O–; Y is C ₃ -C ₈ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, - O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), -O-(5- to 9- membered heteroaryl), -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -O- (C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl), or -O-(C ₁ -C ₆ alkyl)-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ - C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), -O-(5- to 9-membered heteroaryl), -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -O-(C ₁ -C ₆ alkyl)- (3- to 9-membered heterocycloalkyl), or -O-(C ₁ -C ₆ alkyl)-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 ; R ^Y1 is -CN, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen; Z is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Z ; R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen; R ¹ is C3-C8 cycloalkyl, –HC=CH2, –HC=CHR ^1a , or –C≡C–CH3; and R ^1a is -CH ₂ -N(CH ₃ ) ₂ or -CH ₂ -morpholinyl. In some aspects, the present disclosure provides a compound of Formula (I): a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W ¹ is =CR ^W1 – or =N–; R ^W1 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; X ¹ is –CH ₂ –, –NH–, –N(CH ₃ )–, or –O–; X ² is absent, –NH–, –N(CH ₃ )–, or –O–; Y is C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, - O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ - C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O- (C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl) is optionally substituted with one or more R ^Y1 ; R ^Y1 is halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen; Z is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Z ; R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C1-C6 alkyl is optionally substituted with one or more OH or halogen; R ¹ is C ₃ -C ₈ cycloalkyl, –HC=CH ₂ , –HC=CHR ^1a , or –C≡C–CH ₃ ; and R ^1a is -CH ₂ -N(CH ₃ ) ₂ or -CH ₂ -morpholinyl. In some aspects, the present disclosure provides a compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: W ¹ is =CR ^W1 –, or =N–; R ^W1 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; W ² is =CR ^W2 –, or =N–; R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; X ¹ is –CH ₂ –, –NH–, –N(CH ₃ )–, or –O–; X ² is absent, –NH–, or –N(CH ₃ )–; Y is a C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O- (C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ - C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9- membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 ; R ^Y1 is halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen; Z is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Z , wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom; R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C3-C6 cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OH or halogen; R ¹ is C ₃ -C ₈ cycloalkyl, –HC=CH ₂ , –HC=CHR ^1a , or –C≡C–CH ₃ ; and R ^1a is -CH ₂ -N(CH ₃ ) ₂ or -CH ₂ -morpholinyl; provided that when X ² is absent, then a nitrogen atom of Z is attached to -C(=O)-R ¹ . It is understood that, for a compound disclosed herein, W ¹ , R ^W1 , W ² , R ^W2 , X ¹ , X ² , Y, R ^Y , R ^Y1 , Z, R ^Z , R ¹ , and R ^1a can each be, where applicable, selected from the groups described herein, and any group described herein for any of W ¹ , R ^W1 , W ² , R ^W2 , X ¹ , X ² , Y, R ^Y , R ^Y1 , Z, R ^Z , R ¹ , and R ^1a can be combined, where applicable, with any group described herein for one or more of the remainder of W ¹ , R ^W1 , W ² , R ^W2 , X ¹ , X ² , Y, R ^Y , R ^Y1 , Z, R ^Z , R ¹ , and R ^1a . Variables W ¹ , W ² , R ^W1 , and R ^W2 In some embodiments, W ¹ is =CR ^W1 –. In some embodiments, W ¹ is =CH–. In some embodiments, W ¹ is =N–. In some embodiments, R ^W1 is halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). In some embodiments, R ^W1 is H. In some embodiments, W ² is =CR ^W2 –. In some embodiments, W ² is =CH–. In some embodiments, W ² is =CF–. In some embodiments, W ² is =N–. In some embodiments, R ^W2 is halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). In some embodiments, R ^W2 is H. In some embodiments, R ^W2 is halogen. In some embodiments, R ^W2 is fluorine. In some embodiments, R ^W2 is chlorine. In some embodiments, R ^W2 is bromine. In some embodiments, R ^W2 is iodine. In some embodiments, W ¹ is =CR ^W1 - and W ² is =CR ^W2 -. In some embodiments, W ¹ is N and W ² is =CR ^W2 -. In some embodiments, W ¹ is =CR ^W1 - and W ² is N. In some embodiments, W ¹ is CH and W ² is CH. In some embodiments, W ¹ is N and W ² is CH. In some embodiments, W ¹ is N and W ² is CF. In some embodiments, W ¹ is CH and W ² is N. Variables X ¹ and X ² In some embodiments, X ¹ is –CH ₂ –, –NH–, –N(CH ₃ )–, or –O–. In some embodiments, X ¹ is –CH ₂ –. In some embodiments, X ¹ is –NH–. In some embodiments, X ¹ is –N(CH ₃ )–. In some embodiments, X ¹ is –O–. In some embodiments, X ² is absent, –NH–, –N(CH ₃ )–, or –O–. In some embodiments, X ² is absent. In some embodiments, X ² is–NH–. In some embodiments, X ² is –N(CH ₃ )–. In some embodiments, X ² is –O–. In some embodiments, X ¹ is –NH–, –N(CH ₃ )–, or –O–, and X ² is absent. In some embodiments, X ¹ is –NH–, –N(CH ₃ )–, or –O–, and X ² is –NH–. In some embodiments, X ¹ is –NH–, –N(CH ₃ )–, or –O–, and X ² is –N(CH ₃ )–. Variables R ¹ and R ^1a In some embodiments, R ¹ is C ₃ -C ₈ cycloalkyl, –HC=CH ₂ , –HC=CHR ^1a , or –C≡C–CH ₃ . In some embodiments, R ¹ is C ₃ -C ₈ cycloalkyl. In some embodiments, R ¹ is –HC=CH ₂ . In some embodiments, R ¹ is –HC=CHR ^1a . In some embodiments, R ¹ is –C≡C–CH ₃ . In some embodiments, R ¹ is C ₃ cycloalkyl. In some embodiments, R ¹ is C ₄ cycloalkyl. In some embodiments, R ¹ is C ₅ cycloalkyl. In some embodiments, R ¹ is C ₆ cycloalkyl. In some embodiments, R ¹ is C ₇ cycloalkyl. In some embodiments, R ¹ is C ₈ cycloalkyl. In some embodiments, R ^1a is -CH2-N(Me)2 or -CH2-morpholinyl. In some embodiments, R ^1a is -CH ₂ -N(Me) ₂ . In some embodiments, R ^1a is -CH ₂ -morpholinyl. Variables Y, R ^Y , R ^Y1 , Z, and R ^Z In some embodiments, Y is a C ₃ -C ₈ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ₆ - C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y . In some embodiments, Y is a C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ - C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y . In some embodiments, Y is a C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ - C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is substituted with one or more R ^Y . In some embodiments, Y is a C ₃ -C ₈ cycloalkyl optionally substituted with one or more R ^Y . In some embodiments, Y is a C ₃ -C ₈ cycloalkyl substituted with one or more R ^Y . In some embodiments, Y is a 3- to 8-membered heterocycloalkyl optionally substituted with one or more R ^Y . In some embodiments, Y is a 3- to 8-membered heterocycloalkyl substituted with one or more R ^Y . In some embodiments, Y is a C ₆ -C ₁₀ aryl optionally substituted with one or more R ^Y . In some embodiments, Y is a C ₆ -C ₁₀ aryl substituted with one or more R ^Y . In some embodiments, Y is a 5- to 9-membered heteroaryl optionally substituted with one or more R ^Y . In some embodiments, Y is a 5- to 9-membered heteroaryl substituted with one or more R ^Y . In some embodiments, Y is a C ₃ cycloalkyl. In some embodiments, Y is a C ₄ cycloalkyl. In some embodiments, Y is a C5 cycloalkyl. In some embodiments, Y is a C6 cycloalkyl. In some embodiments, Y is a C ₇ cycloalkyl. In some embodiments, Y is a C ₈ cycloalkyl. In some embodiments, Y is a 3-membered heterocycloalkyl. In some embodiments, Y is a 4-membered heterocycloalkyl. In some embodiments, Y is a 5-membered heterocycloalkyl. In some embodiments, Y is a 6-membered heterocycloalkyl. In some embodiments, Y is a 7- membered heterocycloalkyl. In some embodiments, Y is an 8-membered heterocycloalkyl. In some embodiments, Y is a C ₆ aryl. In some embodiments, Y is a C ₇ aryl. In some embodiments, Y is a C ₈ aryl. In some embodiments, Y is a C ₉ aryl. In some embodiments, Y is a C ₁₀ aryl. In some embodiments, Y is a 5-membered heteroaryl. In some embodiments, Y is a 6- membered heteroaryl. In some embodiments, Y is a 7-membered heteroaryl. In some embodiments, Y is a 8-membered heteroaryl. In some embodiments, Y is a 9-membered heteroaryl. In some embodiments, Y is cyclohexyl, phenyl, pyridinyl, benzisoxazolyl, 1,2- benzisothiazolyl, pyrazolyl, pyrimidinyl, benzo-1,4-dioxyl, indazolyl, 1,2-dihydrocinnolinyl, 2- pyridonyl, or 2-hydroxypyridinyl. In some embodiments, Y is phenyl or pyridinyl. In some embodiments, Y is phenyl. In some embodiments, Y is pyridinyl. In some embodiments, R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9- membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), -O-(5- to 9-membered heteroaryl), -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ - C6 alkyl)-(C6-C10 aryl), -O-(C1-C6 alkyl)-(3- to 9-membered heterocycloalkyl), or -O-(C1-C6 alkyl)-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), -O- (5- to 9-membered heteroaryl), -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -O-(C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl), or -O-(C ₁ -C ₆ alkyl)-(5- to 9- membered heteroaryl) is optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, 3- to 9-membered heterocycloalkyl, C6-C10 aryl, 5- to 9- membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9- membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is substituted with one or more R ^Y1 . In some embodiments, R ^Y is -CN, oxo, halogen, or -OH. In some embodiments, R ^Y is fluorine. In some embodiments, R ^Y is chlorine. In some embodiments, R ^Y is bromine. In some embodiments, R ^Y is iodine. In some embodiments, R ^Y is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxyl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxyl is optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is C ₁ alkyl. In some embodiments, R ^Y is C ₂ alkyl. In some embodiments, R ^Y is C ₃ alkyl. In some embodiments, R ^Y is C ₄ alkyl. In some embodiments, R ^Y is C ₅ alkyl. In some embodiments, R ^Y is C ₆ alkyl. In some embodiments, R ^Y is C2 alkenyl. In some embodiments, R ^Y is C3 alkenyl. In some embodiments, R ^Y is C ₄ alkenyl. In some embodiments, R ^Y is C ₅ alkenyl. In some embodiments, R ^Y is C ₆ alkenyl. In some embodiments, R ^Y is C ₂ alkynyl. In some embodiments, R ^Y is C ₃ alkynyl. In some embodiments, R ^Y is C ₄ alkynyl. In some embodiments, R ^Y is C ₅ alkynyl. In some embodiments, R ^Y is C ₆ alkynyl. In some embodiments, R ^Y is C ₁ alkoxyl. In some embodiments, R ^Y is C ₂ alkoxyl. In some embodiments, R ^Y is C ₃ alkoxyl. In some embodiments, R ^Y is C ₄ alkoxyl. In some embodiments, R ^Y is C5 alkoxyl. In some embodiments, R ^Y is C6 alkoxyl. In some embodiments, R ^Y is C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is C ₃ cycloalkyl. In some embodiments, R ^Y is C ₄ cycloalkyl. In some embodiments, R ^Y is C ₅ cycloalkyl. In some embodiments, R ^Y is C ₆ cycloalkyl. In some embodiments, R ^Y is C ₇ cycloalkyl. In some embodiments, R ^Y is C ₈ cycloalkyl. In some embodiments, R ^Y is 3-membered heterocycloalkyl. In some embodiments, R ^Y is 4-membered heterocycloalkyl. In some embodiments, R ^Y is 5-membered heterocycloalkyl. In some embodiments, R ^Y is 6-membered heterocycloalkyl. In some embodiments, R ^Y is 7- membered heterocycloalkyl. In some embodiments, R ^Y is 8-membered heterocycloalkyl. In some embodiments, R ^Y is 9-membered heterocycloalkyl. In some embodiments, R ^Y is C ₆ aryl. In some embodiments, R ^Y is C ₇ aryl. In some embodiments, R ^Y is C ₈ aryl. In some embodiments, R ^Y is C ₉ aryl. In some embodiments, R ^Y is C ₁₀ aryl. In some embodiments, R ^Y is 5-membered heteroaryl. In some embodiments, R ^Y is 6- membered heteroaryl. In some embodiments, R ^Y is 7-membered heteroaryl. In some embodiments, R ^Y is 8-membered heteroaryl. In some embodiments, R ^Y is 9-membered heteroaryl. In some embodiments, R ^Y is -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9- membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl), wherein the -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₃ cycloalkyl). In some embodiments, R ^Y is -O-(C ₄ cycloalkyl). In some embodiments, R ^Y is -O-(C ₅ cycloalkyl). In some embodiments, R ^Y is -O-(C ₆ cycloalkyl). In some embodiments, R ^Y is -O-(C ₇ cycloalkyl). In some embodiments, R ^Y is -O-(C ₈ cycloalkyl). In some embodiments, R ^Y is -O-(C ₆ aryl). In some embodiments, R ^Y is -O-(C ₇ aryl). In some embodiments, R ^Y is -O-(C ₈ aryl). In some embodiments, R ^Y is -O-(C ₉ aryl). In some embodiments, R ^Y is -O-(C ₁₀ aryl). In some embodiments, R ^Y is -O-(3-membered heterocycloalkyl). In some embodiments, R ^Y is -O-(4-membered heterocycloalkyl). In some embodiments, R ^Y is -O-(5-membered heterocycloalkyl). In some embodiments, R ^Y is -O-(6-membered heterocycloalkyl). In some embodiments, R ^Y is -O-(7-membered heterocycloalkyl). In some embodiments, R ^Y is -O-(8- membered heterocycloalkyl). In some embodiments, R ^Y is -O-( 9-membered heterocycloalkyl). In some embodiments, R ^Y is -O-(5-membered heteroaryl). In some embodiments, R ^Y is - O-(6-membered heteroaryl). In some embodiments, R ^Y is -O-(7-membered heteroaryl). In some embodiments, R ^Y is -O-(8-membered heteroaryl). In some embodiments, R ^Y is -O-(9-membered heteroaryl). In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ -C ₆ alkyl)-(C ₆ - C ₁₀ aryl), -O-(C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl), or -O-(C ₁ -C ₆ alkyl)-(5- to 9- membered heteroaryl), wherein the -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl), -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -O-(C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl), or -O-(C ₁ -C ₆ alkyl)-(5- to 9- membered heteroaryl) is optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl) optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl). In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(C ₃ -C ₈ cycloalkyl) substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl) optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl). In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl) substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl) optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl). In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(3- to 9-membered heterocycloalkyl) substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(5- to 9-membered heteroaryl) optionally substituted with one or more R ^Y1 . In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(5- to 9-membered heteroaryl). In some embodiments, R ^Y is -O-(C ₁ -C ₆ alkyl)-(5- to 9-membered heteroaryl) substituted with one or more R ^Y1 . In some embodiments, R ^Y1 is -CN, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen. In some embodiments, R ^Y1 is halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ - C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen. In some embodiments, R ^Y1 is -CN. In some embodiments, R ^Y1 is halogen or -OH. In some embodiments, R ^Y1 is fluorine. In some embodiments, R ^Y1 is chlorine. In some embodiments, R ^Y1 is bromine. In some embodiments, R ^Y1 is iodine. In some embodiments, R ^Y1 is C ₁ alkyl. In some embodiments, R ^Y1 is C ₂ alkyl. In some embodiments, R ^Y1 is C ₃ alkyl. In some embodiments, R ^Y1 is C ₄ alkyl. In some embodiments, R ^Y1 is C ₅ alkyl. In some embodiments, R ^Y1 is C ₆ alkyl. In some embodiments, R ^Y1 is C ₁ alkoxyl. In some embodiments, R ^Y1 is C ₂ alkoxyl. In some embodiments, R ^Y1 is C ₃ alkoxyl. In some embodiments, R ^Y1 is C ₄ alkoxyl. In some embodiments, R ^Y1 is C ₅ alkoxyl. In some embodiments, R ^Y1 is C ₆ alkoxyl. In some embodiments, R ^Y1 is C ₃ cycloalkyl. In some embodiments, R ^Y1 is C ₄ cycloalkyl. In some embodiments, R ^Y1 is C ₅ cycloalkyl. In some embodiments, R ^Y1 is C ₆ cycloalkyl. In some embodiments, R ^Y1 is C ₇ cycloalkyl. In some embodiments, R ^Y1 is C ₈ cycloalkyl. In some embodiments, R ^Y1 is 3-membered heterocycloalkyl. In some embodiments, R ^Y1 is 4-membered heterocycloalkyl. In some embodiments, R ^Y1 is 5-membered heterocycloalkyl. In some embodiments, R ^Y1 is 6-membered heterocycloalkyl. In some embodiments, R ^Y1 is 7- membered heterocycloalkyl. In some embodiments, R ^Y1 is 8-membered heterocycloalkyl. In some embodiments, R ^Y1 is 9-membered heterocycloalkyl. In some embodiments, R ^Y1 is C ₆ aryl. In some embodiments, R ^Y1 is C ₇ aryl. In some embodiments, R ^Y1 is C ₈ aryl. In some embodiments, R ^Y1 is C ₉ aryl. In some embodiments, R ^Y1 is C ₁₀ aryl. In some embodiments, R ^Y1 is 5-membered heteroaryl. In some embodiments, R ^Y1 is 6- membered heteroaryl. In some embodiments, R ^Y1 is 7-membered heteroaryl. In some embodiments, R ^Y1 is 8-membered heteroaryl. In some embodiments, R ^Y1 is 9-membered heteroaryl. In some embodiments, Z is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Z . In some embodiments, Z is 3- to 9-membered heterocycloalkyl substituted with one or more R ^Z . In some embodiments, Z is 3-membered heterocycloalkyl. In some embodiments, Z is 4- membered heterocycloalkyl. In some embodiments, Z is 5-membered heterocycloalkyl. In some embodiments, Z is 6-membered heterocycloalkyl. In some embodiments, Z is 7-membered heterocycloalkyl. In some embodiments, Z is 8-membered heterocycloalkyl. In some embodiments, Z is 9-membered heterocycloalkyl. In some embodiments, Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9- membered heterocycloalkyl contains at least one nitrogen atom. In some embodiments, Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9- membered heterocycloalkyl contains at least two nitrogen atoms. In some embodiments, Z is azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 1,6- diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1- azaspiro[3.3]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 1,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2,5- diazaspiro[3.4]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 4,7- diazaspiro[2.5]octyl, 2,6-diazaspiro[3.4]octan-7-one-yl, 2,6-diazaspiro[3.5]nonyl, 2,7- diazaspiro[4.4]nonan-3-one-yl. In some embodiments, R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen. In some embodiments, R ^Z is -OH, oxo, or halogen. In some embodiments, R ^Z is fluorine. In some embodiments, R ^Z is chlorine. In some embodiments, R ^Z is bromine. In some embodiments, R ^Z is iodine. In some embodiments, R ^Z is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxyl. In some embodiments, R ^Z is C ₁ alkyl. In some embodiments, R ^Z is alkyl. In some embodiments, R ^Z is C3 alkyl. In some embodiments, R ^Z is C4 alkyl. In some embodiments, R ^Z is C ₅ alkyl. In some embodiments, R ^Z is C ₆ alkyl. In some embodiments, R ^Z is C ₁ alkoxyl. In some embodiments, R ^Z is C ₂ alkoxyl. In some embodiments, R ^Z is C ₃ alkoxyl. In some embodiments, R ^Z is C ₄ alkoxyl. In some embodiments, R ^Z is C ₅ alkoxyl. In some embodiments, R ^Z is C ₆ alkoxyl. In some embodiments, R ^Z is C ₃ -C ₆ cycloalkyl or 3- to 9-membered heterocycloalkyl. In some embodiments, R ^Z is C ₃ cycloalkyl. In some embodiments, R ^Z is C ₄ cycloalkyl. In some embodiments, R ^Z is C ₅ cycloalkyl. In some embodiments, R ^Z is C ₆ cycloalkyl. In some embodiments, R ^Z is C ₇ cycloalkyl. In some embodiments, R ^Z is C ₈ cycloalkyl. In some embodiments, R ^Z is 3-membered heterocycloalkyl. In some embodiments, R ^Z is 4-membered heterocycloalkyl. In some embodiments, R ^Z is 5-membered heterocycloalkyl. In some embodiments, R ^Z is 6-membered heterocycloalkyl. In some embodiments, R ^Z is 7-membered heterocycloalkyl. In some embodiments, R ^Z is 8-membered heterocycloalkyl. In some embodiments, R ^Z is 9-membered heterocycloalkyl. In some embodiments, X ² is absent and Z is a 3- to 9-membered heterocycloalkyl containing at least one nitrogen atom, and a nitrogen atom of Z is attached to -C(=O)-R ¹ . In some embodiments, X ² is absent and Z is a 3- to 9-membered heterocycloalkyl containing at least two nitrogen atoms, and a nitrogen atom of Z is attached to -C(=O)-R ¹ . In some embodiments, Y is phenyl and Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom. In some embodiments, Y is pyridinyl and Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom. It is understood that, for a compound disclosed herein, W ¹ , R ^W1 , W ² , R ^W2 , X ¹ , X ² , Y, R ^Y , R ^Y1 , Z, R ^Z , R ¹ , and R ^1a can each be, where applicable, selected from the groups described herein, and any group described herein for any of W ¹ , R ^W1 , W ² , R ^W2 , X ¹ , X ² , Y, R ^Y , R ^Y1 , Z, R ^Z , R ¹ , and R ^1a can be combined, where applicable, with any group described herein for one or more of the remainder of W ¹ , R ^W1 , W ² , R ^W2 , X ¹ , X ² , Y, R ^Y , R ^Y1 , Z, R ^Z , R ¹ , and R ^1a . Exemplary Embodiments of the Compound In some embodiments, the compound is of formula (I-a), (I-b), or (I-c): or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound is of formula (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), or (I-j): (I-j) or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound is of formula (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), or (I-r):

(I-r) or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound is of formula (I-s), (I-t), (I-u), or (I-v):

wherein m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound is of formula (I-w), (I-x), (I-y), (I-z), (I-aa), (I-ab), (I-ac), or (I-ad):

(I-ad) or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound is selected from a compound described in Table I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound is selected from a compound described in Table I, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from a compound described in Table I. Table I.

In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of a compound disclosed herein. In some embodiments, the compound is an isotopic derivative of a compound described in Table I, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is an isotopic derivative of a compound described in Table I. It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, the isotopic derivative is a deuterium labeled compound. In some embodiments, the isotopic derivative is a deuterium labeled compound of a compound of the Formulae disclosed herein. In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I. It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%. In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium. It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent. A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the invention. Further, substitution with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group. A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. It will be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds. As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents. As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116). As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity. As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centers (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity. The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions. It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms. It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound. As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996. It is also to be understood that certain compounds of the present disclosure may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono- hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity. It is also to be understood that certain compounds of the present disclosure may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis. Compounds of the present disclosure may exist in a number of different tautomeric forms and references to compounds of the present disclosure include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. Compounds of the present disclosure containing an amine function may also form N- oxides. A reference herein to a compound disclosed herein that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Particular examples of N-oxides are the N- oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. The compounds of the present disclosure may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the sulfonylurea group in a compound of the any one of the Formulae disclosed herein. Accordingly, the present disclosure includes those compounds of the present disclosure as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of the present disclosure that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the present disclosure may be a synthetically-produced compound or a metabolically-produced compound. A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987. A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the present disclosure containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C ₁ -C ₁₀ alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C ₁ -C ₆ alkyl) ₂ carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include D-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C ₁ - ₄ alkylamine such as methylamine, a (C ₁ -C ₄ alkyl) ₂ amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C ₁ -C ₄ alkoxy-C ₂ - C ₄ alkylamine such as 2-methoxyethylamine, a phenyl-C ₁ -C ₄ alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C ₁ -C ₁₀ alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C ₁ -C ₄ alkyl)piperazin-1-ylmethyl. The in vivo effects of a compound of the present disclosure may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the present disclosure. As stated hereinbefore, the in vivo effects of a compound of the present disclosure may also be exerted by way of metabolism of a precursor compound (a prodrug). Methods of Synthesis In some aspects, the present disclosure provides a method of preparing a compound disclosed herein. In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein. In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound described herein. In some aspects, the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein. The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized. It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. Once a compound of the present disclosure has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure into another compound of the present disclosure; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof. The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art. The reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n- butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2- methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N- methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). General routes for the preparation of a compound of the application are described in Schemes 1-15.

Scheme 1 Scheme 4 Scheme 6

Scheme 7 Scheme 8 Scheme 10 Scheme 13 Scheme 15 Biological Assays Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. In some embodiments, the biological assay is described in the Examples herein. In some embodiments, the biological assay is an assay measuring cell proliferation. In some embodiments, the assay involves retroviral production wherein EGFR mutants may be subcloned. In some embodiments, retroviral expression vector retrovirus may be produced by transient transfection of cells (e.g., HEK 293T cells) with the retroviral EGFR mutant expression vector with the appropriate co-vectors. In some embodiments, the cells may be plated, incubated, and mixed with a medium (e.g., Optimem), followed by additional incubation steps and harvesting. In some embodiments, the assay involves generation of EGFR mutant stable cell lines. In some embodiments, the cells (e.g., BaF3 cells) may be infected with supplemented viral supernatant and incubated. In some embodiments, the cells may be pelleted and the supernatant removed and the cells re-infected with supplemented viral supernatant, followed by incubation. In some embodiments, the cells may be maintained and then selected for retroviral infection. In some embodiments, the resistant populations may be washed and plated to select for selective growth (e.g., IL-3 independent growth). In some embodiments, the cell proliferation assay involves resuspending cell lines (e.g., BaF3 cells) into 96 well plates and determining the effect of a compound of the present disclosure after incubation in the presence of vehicle control or a compound of the present disclosure at varying concentrations. In some embodiments, inhibition of cell growth may be determined by luminescent quantification of intracellular ATP content (e.g., using CellTiterGlo (Promega), according to the protocol provided by the manufacturer). In some embodiments, the comparison of cell number (e.g., on day 0 versus 72 hours post treatment) may be used to plot dose-response curves. In some embodiments, the number of viable cells may be determined and normalized to vehicle-treated controls. In some embodiments, the assay involves cellular protein analysis wherein the cell extracts may be prepared with detergent lysis, protease inhibitor, and phosphatase inhibitors cocktails. In some embodiments, the soluble protein concentration may be determined by micro-BSA assay. In some embodiments, the protein immunodetection may be performed by electrophoretic transfer of SDS-PAGE separated proteins to nitrocellulose, followed by incubation with an antibody, and chemiluminescent second step detection. In some embodiments, nitrocellulose membranes may be blocked and incubated with antibody. In some embodiments, the antibody may be used at a dilution (e.g., 1:1000 dilution or 1:5000 dilution). Potent Inhibition Exemplary compounds and compositions of the disclosure are potent inhibitors of one or more oncogenic variants of an EGFR. In some embodiments, exemplary compounds and compositions of the disclosure are potent inhibitors of one or more of a wild type HER-2 receptor or an oncogenic variant of a HER-2 receptor. In some embodiments, the oncogenic variant of a HER-2 receptor is an allosteric variant of a HER-2 receptor. Pharmaceutical Compositions In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table I. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts. The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β- cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β- cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β- cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β- cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof. Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl- p-hydroxybenzoate, and sorbic acid, and mixtures thereof. The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. The aqueous vehicle may also contain a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range. The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof. The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent an inflammasome related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. The size of the dose for therapeutic or prophylactic purposes of a compound of the present disclosure will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Method of Use In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering to the subject in need thereof a compound described herein. In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering to the subject in need thereof a composition described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a compound described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a compound described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a composition described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a composition described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering to the subject in need of the treatment a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering to the subject in need of the treatment a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering to the subject in need of the treatment a compound described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering to the subject in need of the treatment a compound described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering to the subject in need of the treatment a composition described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering to the subject in need of the treatment a composition described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment a therapeutically effective amount of a compound described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment a compound described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment a compound described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment a composition described herein. In some aspects, the present disclosure provides a method of treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment a composition described herein. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a composition described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a composition described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. In some aspects, the present disclosure provides a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). In some aspects, the present disclosure provides a composition described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. In some aspects, the present disclosure provides a compound described herein for use in the treatment of cancer. In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer. In some aspects, the present disclosure provides a composition described herein for use in the treatment of cancer. In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides a compound described herein for use in the treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides a composition described herein for use in the treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides a compound described herein for use in the treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides a composition described herein for use in the treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer. In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for treating cancer. In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a composition described herein in the manufacture of a medicament for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a composition described herein in the manufacture of a medicament for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a composition described herein in the manufacture of a medicament for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a composition described herein in the manufacture of a medicament for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a compound described herein for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). In some aspects, the present disclosure provides use of a compound described herein for preventing or treating cancer. In some aspects, the present disclosure provides use of a compound described herein in for treating cancer. In some aspects, the present disclosure provides use of a compound described herein for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a compound described herein for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a composition described herein for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a composition described herein for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. In some aspects, the present disclosure provides use of a compound described herein for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a compound described herein for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a composition described herein for preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some aspects, the present disclosure provides use of a composition described herein for treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. In some embodiments, cancer is a solid tumor. In some embodiments, the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof. In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR). In some embodiments, the oncogenic variant is an oncogenic variant in an ErbB receptor. In some embodiments, the oncogenic variant in the ErbB receptor is an allosteric variant. In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor. In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR). In some embodiments, the ErbB receptor is a HER2 receptor. In some embodiments, the oncogenic variant is an oncogenic variant in an epidermal growth factor receptor (EGFR). In some embodiments, the oncogenic variant in the EGFR is an allosteric variant. In some embodiments, the oncogenic variant is an oncogenic variant of a HER2 receptor. In some embodiments, the oncogenic variant in the HER2 receptor is an allosteric variant. In some embodiments, the oncogenic variant in the EGFR is an EGFR variant III (EGFR- Viii) variant. In some embodiments, the oncogenic variant in the EGFR is a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1. In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, the oncogenic variant in the EGFR is a modification of a structure of the EGFR, wherein the oncogenic variant in the EGFR is capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor. In some embodiments, the modification of the structure of the EGFR comprises a modification of one or more of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a quaternary structure. In some embodiments, the modification of the structure of the EGFR occurs within a first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR. In some embodiments, the first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and/or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant in the EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant in the EGFR removes a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant in the EGFR results into one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant in the EGFR results into one or more free or unpaired Cysteine (C) residues at a site selected from the group consisting of C190-C199, C194C207, C215C223, C219-C231, C232C240, C236-C248, C251C260, C264C291, C295C307, C311C326, C329-C333, C506-C515, C510-C523, C526- C535, C539-C555, C558-C571, C562C579, C582C591, C595C617, C620-C628 and C624C636 according to SEQ ID NO: 1. In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of C190- C199, C194C207, C215C223, C219-C231, C232C240, C236-C248, C251C260, C264C291, C295C307, C311C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558- C571, C562C579, C582C591, C595C617, C620-C628 and C624C636 according to SEQ ID NO: 1. In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, wherein a nucleotide sequence encoding the EGFR having the oncogenic variant comprises a deletion or the substitution comprises one or more amino acids that encode an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or the deletion or substitution thereof comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the lysine (K) at position 858 (K858R) of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the leucine (L) at position 858 (L858R) of SEQ ID NO: 1. In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, wherein a nucleotide sequence encoding the EGFR having the oncogenic variant comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acid sequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitution of the amino acid sequence GYN for the DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertion of the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of the amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the amino acid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) an insertion of the amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the amino acid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequence GSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the amino acid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequence GNPHVC for the VC between positions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee) an insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGP for the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP for the NP between positions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) an insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) a substitution of the amino acid sequence STLASV for the SV between positions 768 and 769 of SEQ ID NO: 1. In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, the EGFR having the oncogenic variant comprises EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR- R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR- A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR- G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR- C628Y, EGFR-C636Y, EGFR-G645C, EGFR- Δ660, EGFR- Δ768 or any combination thereof. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor, the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of a phenylalanine (F) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of a tyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of a glutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of a leucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of a methionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of an isoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of an alanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of a proline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutation in the HER2 receptor comprises a substitution of a serine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, wherein a nucleotide sequence encoding the HER2 receptor having the oncogenic variant comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C- helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCV for the G between position 776 of SEQ ID NO: 2; (j) an insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) a substitution of the amino acid sequence PS for the LRE between positions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertion of the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for the AG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the amino acid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the amino acid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (r) an insertion of the amino acid G between positions G778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertion of the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u) an insertion of the amino acid sequence YAMA between positions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) a substitution of the amino acid sequence AVCGG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution of the amino acid sequence VVVG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the amino acid sequence AVGSGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the amino acid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution of the amino acid sequence HVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (ff) a substitution of the amino acid sequence VAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the amino acid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) a substitution of the amino acid sequence VPS for the VLRE between positions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the amino acid E between positions V777 and G778 of SEQ ID NO: 2; (ll) an insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S between positions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and (oo) an insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO: 2. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the HER2 receptor having the oncogenic variant comprises HER2-Δ16, HER2C311R, HER2-S310F, p95-HER2-M611 or any combination thereof. In some embodiments, the oncogenic variant is an oncogenic variant in a HER-4 receptor. In some embodiments, the oncogenic variant in the HER-4 receptor is an allosteric variant in the HER4 receptor. In some embodiments, the oncogenic variant in the HER4 receptor results into the deletion of exon 16 (HER4-Δ16). In some embodiments, the subject or the cancer is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, and necitunumab. In some embodiments, the subject or the cancer is insensitive or resistant to treatment with one or more of crixotinib, alectinib, and ceritinib. In some embodiments, the subject or the cancer is insensitive or resistant to treatment with one or more of dabrafenib and trametinib. In some embodiments, the subject or the cancer is insensitive or resistant to treatment with crizotinib. In some embodiments, the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, tumor or cell thereof does not comprise an oncogenic variation in a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS or wherein. In some embodiments, the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, tumor or cell thereof does not comprise a marker indicating responsiveness to immunotherapy. In some embodiments, the oncogenic variant (e.g., allosteric variant) or the oncogenic mutation (e.g., allosteric mutation) is detected by a Food and Drug Administration (FDA)- approved diagnosis. In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent different from the compound of the present disclosure. In some embodiments, the subject has an adverse reaction to treatment with a Type I inhibitor. In some embodiments, the subject has an adverse reaction to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291. In some embodiments, the adverse reaction is an activation of the oncogenic variant of an EGFR and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor. In some embodiments, the adverse reaction is an activation of the oncogenic variant of a HER-2 Receptor and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor. In some embodiments, the compound is used in combination with a second therapeutically active agent. In some embodiments, the composition comprises a second therapeutically active agent. In some embodiments, the second therapeutically active agent comprises a second compound of the disclosure. In some embodiments, the second therapeutically active agent comprises a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a Type II inhibitor. In some embodiments, the Type II inhibitor comprises a small molecule inhibitor. In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the method comprises administering to the subject in need thereof a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the method comprises administering to the subject in need thereof a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. In some embodiments, the compound is used in combination with a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the compound is used in combination with a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. In some embodiments, the composition comprises a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC) or any subtype thereof. In some embodiments, the cancer comprises a glioblastoma (GBM). In some embodiments, the cancer comprises a breast cancer. In some embodiments, the cancer comprises a lung cancer. In some embodiments, the therapeutically effective amount reduces a severity of a sign or symptom of the cancer. In some embodiments, the compound reduces a severity of a sign or symptom of the cancer. In some embodiments, the sign of the cancer comprises a tumor grade and wherein a reduction of the severity of the sign comprises a decrease of the tumor grade. In some embodiments, the sign of the cancer comprises a tumor metastasis and wherein a reduction of the severity of the sign comprises an elimination of the metastasis or a reduction in the rate or extent the metastasis. In some embodiments, the sign of the cancer comprises a tumor volume and wherein a reduction of the severity of the sign comprises an elimination of the tumor or a reduction in the volume. In some embodiments, the symptom of the cancer comprises pain and wherein a reduction of the severity of the sign comprises an elimination or a reduction in the pain. In some embodiments, the therapeutically effective amount induces a period of remission. In some embodiments, the compound induces a period of remission. In some embodiments, the therapeutically effective amount improves a prognosis of the subject. In some embodiments, the compound improves a prognosis of the subject. In some embodiments, the subject is a participant or a candidate for participation in in a clinical trial or protocol thereof. In some embodiments, the subject is excluded from treatment with a Type I inhibitor. In some embodiments, the Type I inhibitor comprises gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 or AZD9291. In some embodiments, the use comprises treating the subject with a Non-Type I inhibitor. In some embodiments, the composition comprises a Non-Type I inhibitor. In some embodiments, the Non-Type I inhibitor comprises a Type II small molecule inhibitor. In some embodiments, the Type II small molecule inhibitor comprises neratinib, AST- 1306, HKI-357, or lapatinib. Exemplary Embodiments Exemplary Embodiment No. 1. A compound of Formula (I) a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W ¹ is =CR ^W1 –, or =N–; R ^W1 is H, halogen, - O(C ₁ -C ₆ alkyl), or C _{1 6} alkyl; W ² is =CR ^W2 –, or =N–; R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ - C ₆ alkyl; s absent, –NH–, –N(CH ₃ )–, or –O–; Y is C ₃ - C ₈ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y ; R ^Y is -CN, oxo, halogen, - OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 ; R ^Y1 is halogen, -OH, C1-C6 alkyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen; Z is 3- to 9- membered heterocycloalkyl optionally substituted with one or more R ^Z ; R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen; R ¹ is C3-C8 cycloalkyl, –HC=CH2, –HC=CHR ^1a , or –C≡C–CH3; and R ^1a is -CH2-N(CH3)2 or -CH ₂ -morpholinyl. Exemplary Embodiment No.2. The compound of Exemplary Embodiment 1, wherein: W ¹ is =CR ^W1 –, or =N–; R ^W1 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; W ² is =CR ^W2 –, or =N–; R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl; X ¹ is –CH ₂ –, –NH–, –N(CH ₃ )–, or –O–; X ² is absent, – , or –N(CH ₃ )–; Y is a C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; R ^Y is -CN, oxo, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, - ₈ cycloalkyl), -O- (C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ - C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9- membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 ; R ^Y1 is halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen; Z is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Z , wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom; R ^Z is -OH, oxo, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OH or halogen; R ¹ is C ₃ -C ₈ cycloalkyl, –HC=CH ₂ , –HC=CHR ^1a , or –C≡C–CH3; and R ^1a is -CH2-N(CH3)2 or -CH2-morpholinyl; provided that when X ² is absent, then a nitrogen atom of Z is attached to -C(=O)-R ¹ . Exemplary Embodiment No. 3. The compound of any one of the preceding Exemplary Embodiments, wherein W ¹ is =CR ^W1 –. Exemplary Embodiment No. 4. The compound of any one of the preceding Exemplary Embodiments, wherein R ^W1 is halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). Exemplary Embodiment No. 5. The compound of any one of the preceding Exemplary Embodiments, wherein W ¹ is =CH– or =N–. Exemplary Embodiment No. 6. The compound of any one of the preceding Exemplary Embodiments, wherein W ² is =CR ^W2 –. Exemplary Embodiment No. 7. The compound of any one of the preceding Exemplary Embodiments, wherein R ^W2 is halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). Exemplary Embodiment No. 8. The compound of any one of the preceding Exemplary Embodiments, wherein W ² is =CH– or =N–. Exemplary Embodiment No. 9. The compound of any one of the preceding Exemplary Embodiments, wherein W ¹ is =CH– and W ² is CH–. Exemplary Embodiment No. 10. The compound of any one of the preceding Exemplary Embodiments, wherein W ¹ is =N– and W ² is =CH–. Exemplary Embodiment No. 11. The compound of any one of the preceding Exemplary Embodiments, wherein W ¹ is =CH– and W ² is =N–. Exemplary Embodiment No. 12. The compound of any one of the preceding Exemplary Embodiments, wherein W ¹ is =N– and W ² are =N–. Exemplary Embodiment No. 13. The compound of any one of the preceding Exemplary Embodiments, wherein X ¹ is –NH–, –N(CH ₃ )–, or –O–, and X ² is absent. Exemplary Embodiment No. 14. The compound of any one of the preceding Exemplary Embodiments, wherein X ¹ is –NH–, –N(CH ₃ )–, or –O–, and X ² is –NH–. Exemplary Embodiment No. 15. The compound of any one of the preceding Exemplary Embodiments, wherein X ¹ is –NH–, –N(CH ₃ )–, or –O–, and X ² is –N(CH ₃ )–. Exemplary Embodiment No. 16. The compound of any one of the preceding Exemplary Embodiments, wherein R ¹ is C ₃ -C ₈ cycloalkyl. Exemplary Embodiment No. 17. The compound of any one of the preceding Exemplary Embodiments, wherein R ¹ is–HC=CH2. Exemplary Embodiment No. 18. The compound of any one of the preceding Exemplary Embodiments, wherein R ^1a is -CH ₂ -N(Me) ₂ . Exemplary Embodiment No. 19. The compound of any one of the preceding Exemplary Embodiments, wherein R ^1a is -CH ₂ -morpholinyl. Exemplary Embodiment No. 20. The compound of any one of the preceding Exemplary Embodiments, wherein Y is C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y . Exemplary Embodiment No. 21. The compound of any one of the preceding Exemplary Embodiments, wherein Y is cyclohexyl, phenyl, pyridinyl, benzisoxazolyl, 1,2-benzisothiazolyl, pyrazolyl, pyrimidinyl, benzo-1,4-dioxyl, indazolyl, 1,2-dihydrocinnolinyl, 2-pyridonyl, or 2- hydroxypyridinyl, wherein the cyclohexyl, phenyl, pyridinyl, benzisoxazolyl, 1,2- benzisothiazolyl, pyrazolyl, pyrimidinyl, benzo-1,4-dioxyl, indazolyl, 1,2-dihydrocinnolinyl, 2- pyridonyl, or 2-hydroxypyridinyl is optionally substituted with one or more R ^Y . Exemplary Embodiment No. 22. The compound of any one of the preceding Exemplary Embodiments, wherein Y is cyclohexyl, phenyl, pyridinyl, benzisoxazolyl, 1,2-benzisothiazolyl, pyrazolyl, pyrimidinyl, benzo-1,4-dioxyl, indazolyl, 1,2-dihydrocinnolinyl, 2-pyridonyl, or 2- hydroxypyridinyl. Exemplary Embodiment No. 23. The compound of any one of the preceding Exemplary Embodiments, wherein Y is cyclohexyl, phenyl, or pyridinyl, wherein the cyclohexyl, phenyl, or pyridinyl is optionally substituted with one or more R ^Y . Exemplary Embodiment No. 24. The compound of any one of the preceding Exemplary Embodiments, wherein Y is phenyl or pyridinyl. Exemplary Embodiment No. 25. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Y is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ - C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ - C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O- (C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl) is optionally substituted with one or more R ^Y1 . Exemplary Embodiment No. 26. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Y is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C ₃ - C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl). Exemplary Embodiment No. 27. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Y is -CN, oxo, halogen, or -OH. Exemplary Embodiment No. 28. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Y1 is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more halogen. Exemplary Embodiment No. 29. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Y1 is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl. Exemplary Embodiment No. 30. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Y1 is halogen or -OH. Exemplary Embodiment No. 31. The compound of any one of the preceding Exemplary Embodiments, wherein Z is 3- to 9-membered heterocycloalkyl substituted with one or more R ^Z . Exemplary Embodiment No. 32. The compound of any one of the preceding Exemplary Embodiments, wherein Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom. Exemplary Embodiment No. 33. The compound of any one of the preceding Exemplary Embodiments, wherein Z is azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 1,6- diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1- azaspiro[3.3]heptyl, 3,6-diazabicyclo[3.1.1]heptane, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 1,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2,5- diazaspiro[3.4]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 4,7- diazaspiro[2.5]octyl, 2,6-diazaspiro[3.4]octan-7-one-yl, 2,6-diazaspiro[3.5]nonyl, or 2,7- diazaspiro[4.4]nonan-3-one-yl, wherein the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 1,6- diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1- azaspiro[3.3]heptyl, 3,6-diazabicyclo[3.1.1]heptane, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 1,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2,5- diazaspiro[3.4]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 4,7- diazaspiro[2.5]octyl, 2,6-diazaspiro[3.4]octan-7-one-yl, 2,6-diazaspiro[3.5]nonyl, or 2,7- diazaspiro[4.4]nonan-3-one-yl is optionally substituted with one or more R ^Z . Exemplary Embodiment No. 34. The compound of any one of the preceding Exemplary Embodiments, wherein Z is azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 1,6- diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1- azaspiro[3.3]heptyl, 3,6-diazabicyclo[3.1.1]heptane, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 1,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2,5- diazaspiro[3.4]octyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 4,7- diazaspiro[2.5]octyl, 2,6-diazaspiro[3.4]octan-7-one-yl, 2,6-diazaspiro[3.5]nonyl, or 2,7- diazaspiro[4.4]nonan-3-one-yl. Exemplary Embodiment No. 35. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Z is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more -OH or halogen. Exemplary Embodiment No. 36. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Z is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl. Exemplary Embodiment No. 37. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Z is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl. Exemplary Embodiment No. 38. The compound of any one of the preceding Exemplary Embodiments, wherein two R ^Z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl or a 3- to 9-membered heterocycloalkyl. Exemplary Embodiment No. 39. The compound of any one of the preceding Exemplary Embodiments, wherein R ^Z is -OH, oxo, or halogen. Exemplary Embodiment No. 40. The compound of any one of the preceding Exemplary Embodiments, wherein X ² is absent and Z is a 3- to 9-membered heterocycloalkyl containing at least one nitrogen atom, and a nitrogen atom of Z is attached to -C(=O)-R ¹ . Exemplary Embodiment No. 41. The compound of any one of the preceding Exemplary Embodiments, wherein Y is phenyl and Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom. Exemplary Embodiment No. 42. The compound of any one of the preceding Exemplary Embodiments, wherein Y is pyridinyl and Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom. Exemplary Embodiment No. 43. The compound of any one of the preceding Exemplary Embodiments, being of formula (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt or stereoisomer thereof. Exemplary Embodiment No. 44. The compound of any one of the preceding Exemplary Embodiments, being of formula (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), or (I-j), or a pharmaceutically acceptable salt or stereoisomer thereof. Exemplary Embodiment No. 45. The compound of any one of the preceding Exemplary Embodiments, being of formula (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), or (I-r), or a pharmaceutically acceptable salt or stereoisomer thereof. Exemplary Embodiment No. 46. The compound of any one of the preceding Exemplary Embodiments, being of formula (I-s), (I-t), (I-u), or (I-v), wherein m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or stereoisomer thereof. Exemplary Embodiment No. 47. The compound of any one of the preceding Exemplary Embodiments, being of formula (I-w), (I-x), (I-y), (I-z), (I-aa), (I-ab), (I-ac), or (I-ad), or a pharmaceutically acceptable salt or stereoisomer thereof. Exemplary Embodiment No. 48. The compound of any one of the preceding Exemplary Embodiments, being selected from the compounds described in Table I and pharmaceutically acceptable salt or stereoisomer thereof. Exemplary Embodiment No.49. An isotopic derivative of the compound of any one of the preceding Exemplary Embodiments. Exemplary Embodiment No. 50. A method of preparing the compound of any one of the preceding Exemplary Embodiments. Exemplary Embodiment No.51. A pharmaceutical composition comprising the compound of any one of the preceding Exemplary Embodiments and one or more pharmaceutically acceptable carriers or excipients. Exemplary Embodiment No.52. A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a therapeutically effective amount of the compound of any one of the preceding Exemplary Embodiments. Exemplary Embodiment No. 53. A method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of the compound of any one of the preceding Exemplary Embodiments. Exemplary Embodiment No. 54. The compound of any one of the preceding Exemplary Embodiments for use in the prevention or treatment of cancer. Exemplary Embodiment No. 55. The compound of any one of the preceding Exemplary Embodiments for use in the inhibition of an oncogenic variant of an ErbB receptor. Exemplary Embodiment No.56. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the cancer is a solid tumor. Exemplary Embodiment No.57. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof. Exemplary Embodiment No.58. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the cancer is glioblastoma (GBM) or any subtype thereof. Exemplary Embodiment No.59. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the cancer is glioblastoma. Exemplary Embodiment No.60. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an ErbB receptor. Exemplary Embodiment No.61. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the oncogenic variant of the ErbB receptor comprises an allosteric mutation. Exemplary Embodiment No.62. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the oncogenic variant of an ErbB receptor is an allosteric variant of the ErbB receptor. Exemplary Embodiment No.63. The method or the compound of any one of the preceding Exemplary Embodiments, wherein the oncogenic variant or the oncogenic mutation is detected by a Food and Drug Administration (FDA)-approved diagnosis. Definitions Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non- operable embodiments caused by certain combinations of the options. It is to be understood that a compound of the present disclosure may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in an anionic form, it should be understood that such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound. For another example, when a compound the present disclosure is depicted in an anionic form, it should be understood that such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound. As used herein, “alkyl”, “C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ alkyl” or “C ₁ -C ₆ alkyl” is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ straight chain (linear) saturated aliphatic hydrocarbon groups and C ₃ , C ₄ , C ₅ or C ₆ branched saturated aliphatic hydrocarbon groups. For example, C ₁ -C ₆ alkyl is intends to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C ₁ -C ₆ for straight chain, C ₃ -C ₆ for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In some embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). The term “C ₂ -C ₆ ” includes alkenyl groups containing two to six carbon atoms. The term “C ₃ -C ₆ ” includes alkenyl groups containing three to six carbon atoms. As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In some embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). The term “C ₂ -C ₆ ” includes alkynyl groups containing two to six carbon atoms. The term “C ₃ -C ₆ ” includes alkynyl groups containing three to six carbon atoms. As used herein, “C ₂ -C ₆ alkenylene linker” or “C ₂ -C ₆ alkynylene linker” is intended to include C ₂ , C ₃ , C ₄ , C ₅ or C ₆ chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C ₂ -C ₆ alkenylene linker is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkenylene linker groups. As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl. As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C ₃ -C ₁₂ , C ₃ -C ₁₀ , or C ₃ -C ₈ ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic. As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. 1¸, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H- spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2- azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2- azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa- azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl). As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NoO and S(O) _p , where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, or indolizine. The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-. As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy. As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise. It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples. It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ^th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999. It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. As used herein, the term “subject” is interchangeable with the term “subject in need thereof”, both of which refer to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who has (e.g., is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that doesn't respond or hasn’t yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy. As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 ^rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 ^th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier. As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED ₅₀ (the dose therapeutically effective in 50% of the population) and LD ₅₀ (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD ₅₀ /ED ₅₀ . Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. In some embodiments, the appropriate formulation is dependent upon the route of administration chosen. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell. It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure. As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt. Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration. The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 ^th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. Sequences A wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181 qnhlgscqkc dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc 241 tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv 301 vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls inatnikhfk 361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke itgflliqaw penrtdlhaf 421 enleiirgrt kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc yantinwkkl 481 fgtsgqktki isnrgensck atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkck 541 llegeprefv enseciqchp eclpqamnit ctgrgpdnci qcahyidgph cvktcpagvm 601 genntlvwky adaghvchlc hpnctygctg pglegcptng pkipsiatgm vgalllllvv 661 algiglfmrr rhivrkrtlr rllqerelve pltpsgeapn qallrilket efkkikvlgs 721 gafgtvykgl wipegekvki pvaikelrea tspkankeil deayvmasvd nphvcrllgi 781 cltstvqlit qlmpfgclld yvrehkdnig sqyllnwcvq iakgmnyled rrlvhrdlaa 841 rnvlvktpqh vkitdfglak llgaeekeyh aeggkvpikw malesilhri ythqsdvwsy 901 gvtvwelmtf gskpydgipa seissilekg erlpqppict idvymimvkc wmidadsrpk 961 freliiefsk mardpqrylv iqgdermhlp sptdsnfyra lmdeedmddv vdadeylipq 1021 qgffsspsts rtpllsslsa tsnnstvaci drnglqscpi kedsflqrys sdptgalted 1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps rdphyqdphs tavgnpeyln 1141 tvqptcvnst fdspahwaqk gshqisldnp dyqqdffpke akpngifkgs taenaeylrv 1201 apqssefiga (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank Accession No. CAA25240). A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt lglepseeea prsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq rysedptvpl psetdgyvap ltcspqpeyv 1141 nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 1201 ggaapqphpp pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 2, corresponding to receptor tyrosine-protein kinase erbB-2 isoform a precursor [Homo sapiens] and GenBank Accession No. NP_004439). A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 thscvdlddk gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl 661 lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv 721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql mpygclldhv 781 renrgrlgsq dllnwcmqia kgmsyledvr lvhrdlaarn vlvkspnhvk itdfglarll 841 dideteyhad ggkvpikwma lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger lpqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961 nedlgpaspl dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss 1021 strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqs lpthdpsplq 1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp spregplpaa rpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnl yywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 3, corresponding to receptor tyrosine- protein kinase erbB-2 isoform b [Homo sapiens] and GenBank Accession No. NP_001005862). A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mprgswkpqv ctgtdmklrl paspethldm lrhlyqgcqv vqgnleltyl ptnaslsflq 61 diqevqgyvl iahnqvrqvp lqrlrivrgt qlfednyala vldngdplnn ttpvtgaspg 121 glrelqlrsl teilkggvli qrnpqlcyqd tilwkdifhk nnqlaltlid tnrsrachpc 181 spmckgsrcw gessedcqsl trtvcaggca rckgplptdc cheqcaagct gpkhsdclac 241 lhfnhsgice lhcpalvtyn tdtfesmpnp egrytfgasc vtacpynyls tdvgsctlvc 301 plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa gckkifgsla 361 flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw pdslpdlsvf qnlqvirgri 421 lhngaysltl qglgiswlgl rslrelgsgl alihhnthlc fvhtvpwdql frnphqallh 481 tanrpedecv geglachqlc arghcwgpgp tqcvncsqfl rgqecveecr vlqglpreyv 541 narhclpchp ecqpqngsvt cfgpeadqcv acahykdppf cvarcpsgvk pdlsympiwk 601 fpdeegacqp cpincthscv dlddkgcpae qraspltsii savvgillvv vlgvvfgili 661 krrqqkirky tmrrllqete lvepltpsga mpnqaqmril ketelrkvkv lgsgafgtvy 721 kgiwipdgen vkipvaikvl rentspkank eildeayvma gvgspyvsrl lgicltstvq 781 lvtqlmpygc lldhvrenrg rlgsqdllnw cmqiakgmsy ledvrlvhrd laarnvlvks 841 pnhvkitdfg larlldidet eyhadggkvp ikwmalesil rrrfthqsdv wsygvtvwel 901 mtfgakpydg ipareipdll ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961 fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021 apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv fdgdlgmgaa 1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdv rpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe yltpqggaap qphpppafsp 1201 afdnlyywdq dppergapps tfkgtptaen peylgldvpv (SEQ ID NO: 4, corresponding to receptor tyrosine-protein kinase erbB-2 isoform c [Homo sapiens] and GenBank Accession No. NP_001276865). A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strnm (SEQ ID NO: 5, corresponding to receptor tyrosine-protein kinase erbB-2 isoform d precursor [Homo sapiens] and GenBank Accession No. NP_001276866). A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 ths (SEQ ID NO: 6, corresponding to receptor tyrosine-protein kinase erbB-2 isoform e [Homo sapiens] and GenBank Accession No. NP_001276867). EXAMPLES For exemplary purpose, neutral compounds of Formula (I) are synthesized and tested in the examples. It is understood that the neutral compounds of Formula (I) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt). Abbreviations: ACN Acetonitrile BOC tert-butyl carbamate DAD diode array detector D ^CM _{Dichloromethane} D ^MSO _{Dimethylsulfoxide} E ^A _{ethyl acetate} E ^{S / ESI} _{electrospray ionisation} HPLC high-performance liquid chromatography I ^PA _{Isopropylalcohol} LC liquid chromatography MS mass spectrometry NMR nuclear magnetic resonance Py Pyridine RT retention time S ^FC _{supercritical fluid chromatography} T ^FA _{trifluoroacetic acid} T ^HF _{Tetrahydrofuran} TLC thin layer chromatography Preparation of common Intermediates, Anilines, and Phenols: Intermediate 1: tert-Butyl 4-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl)piperaz ine- 1-carboxylate Step 1. tert-Butyl 4-(3-cyano-4-nitrophenyl)piperazine-1-carboxylate To a solution of 5-fluoro-2-nitro-benzonitrile (1.0 g, 6.02 mmol) and tert-butyl piperazine- 1-carboxylate (1.61 g, 7.22 mmol, hydrochloric acid salt) in N-methylpyrrolidone (10 mL) was added N,N-diisopropylethylamine (1.56 g, 12.0 mmol, 2.10 mL). The mixture was stirred at 100 °C for 2 h. On completion, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-(3-cyano-4-nitrophenyl)piperazine-1-carboxylate (3.2 g, crude) as a yellow solid. NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 9.6 Hz, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.23 (dd, J = 2.8, 9.6 Hz, 1H), 3.61 - 3.55 (m, 4H), 3.31 (t, J = 7.2 Hz, 4H), 1.43 (s, 9H). Step 2. tert-Butyl 4-(4-amino-3-cyanophenyl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-cyano-4-nitrophenyl)piperazine-1-carboxylate (3.20 g, 9.63 mmol) in ethyl acetate (60 mL) was added platinum on carbon (3.0 g, 461 μmol, 3 wt. % loading). The mixture was stirred at 25 °C for 5 hr under hydrogen gas atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-(4- amino-3-cyanophenyl)piperazine-1-carboxylate (3 g, crude) as a yellow oil. Step 3. tert-Butyl 4-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl)-pipera zine- 1-carboxylate To a solution of tert-butyl 4-(4-amino-3-cyanophenyl)piperazine-1-carboxylate (3.0 g, 9.92 mmol) in toluene (40 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (3.55 g, 29.8 mmol, 3.95 mL). The mixture was stirred at 110 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl 4-(3-cyano-4-(((dimethylamino)methylene)- amino)phenyl)piperazine-1-carboxylate (0.89 g, 2.5 mmol, 41% over three steps) as a yellow oil. Intermediate 2 & Intermediate 3: 6-Chloropyrido[3,2-d]pyrimidin-4-ol & 4,6- dichloropyrido[3,2-d]pyrimidine Step 1. 3-Amino-6-chloro-pyridine-2-carboxamide To a mixture of 6-chloro-3-nitro-pyridine-2-carbonitrile (25 g, 136 mmol) in ethanol (350 mL) was added tin(II) chloride dihydrate (123 g, 545 mmol), the reaction mixture was stirred at 85 °C for 2 h. The reaction mixture was concentrated in vacuo to remove the solvent. The crude product was diluted with ethyl acetate (300 mL), adjusted to pH = 7~8 with saturated sodium carbonate and then extracted with ethyl acetate (2 L x 3). The combined organic layers were washed with brine (2 L x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-amino-6-chloro-pyridine-2-carboxamide (21 g, 122.8 mmol, 89%) as a pink solid. m/z ES+ [M+H] ⁺ 172.1. Step 2. 6-Chloropyrido[3,2-d]pyrimidin-4-ol A mixture of 3-amino-6-chloro-pyridine-2-carboxamide (21 g, 122 mmol) in triethyl orthoformate (400 mL) was stirred at 140 °C for 12 h. The reaction mixture was filtered and filter cake was dried in vacuo to give 6-chloropyrido[3,2-d]pyrimidin-4-ol (18 g, 99.4 mmol, 81%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.73 (s, 1H), 8.19 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H). Step 3. 4,6-Dichloropyrido[3,2-d]pyrimidine To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (7 g, 38.6 mmol) in toluene (100 mL) was added phosphorus oxychloride (7.68 g, 50.1 mmol) and diisopropylethylamine (24.9 g, 192 mmol). The mixture was stirred at 110 °C for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=3:1 to 2:1) to give 4,6-dichloropyrido[3,2-d]pyrimidine (6.72 g, 33.6 mmol, 87%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H); m/z ES+ [M+H] ⁺ 200.0. Intermediate 4: 6-Chloro-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e Step 1. 6-Chloro-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.5 g, 2.50 mmol) and 3,4- dichloroaniline (404 mg, 2.50 mmol) in acetonitrile (5 mL) was stirred at 25 °C for 2 h. On completion, the mixture was quenched by water (30 mL) and then stirred at 25 °C for 30 min. The mixture was filtered and concentrated in vacuo to give 6-chloro-N-(3,4- dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amine (0.7 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.74 - 10.61 (m, 1H), 8.86 - 8.82 (m, 1H), 8.42 - 8.39 (m, 1H), 8.36 - 8.31 (m, 1H), 8.09 - 8.00 (m, 2H), 7.71 - 7.65 (m, 1H); m/z ES+ [M+H] ⁺ 325.0. Intermediate 5: 6-Chloro-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrido[3,2-d] pyrimidin-4- amine Step 1. 6-Chloro-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrido[3,2-d] pyrimidin-4- amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.50 mmol) and 3-chloro-4- (difluoromethoxy)aniline (483 mg, 2.50 mmol) in acetonitrile (8.0 mL) was stirred at 80 °C for 2 hr. On completion, the reaction mixture was poured into water (10.0 mL) and the suspension was filtered. The filter cake was washed with acetonitrile (5 mL × 3), dried in vacuo to give 6-chloro- N-[3-chloro-4-(difluoromethoxy)phenyl]pyrido[3,2-d]pyrimidin -4-amine (400 mg, 1.12 mmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.23 (s, 1H), 8.94 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 2.4, 9.2 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.36 - 7.05 (m, 1H); m/z ES+ [M+H] ⁺ 357.0. Intermediate 6 & Intermediate 20: 6-Chloro-N-(3-chloro-4-(difluoromethoxy)-2- fluorophenyl)pyrido[3,2-d] pyrimidin-4-amine & 2-chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4- yl)amino)-3-fluorophenol Step 1. 2-Chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-fl uorophenol To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (1.00 g, 5.00 mmol) in acetonitrile (10 mL) was added 4-amino-2-chloro-3-fluoro-phenol (1.05 g, 6.50 mmol), the mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give 2-chloro- 4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fluoro-phen ol (2.0 g, 6.17 mmol, 98%) as a yellow solid. m/z ES+ [M+H] ⁺ 325.1. Step 2. 6-Chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri do[3,2- d]pyrimidin-4-amine To a solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fl uoro- phenol (300 mg, 922 μmol) and cesium carbonate (601 mg, 1.85 mmol) in N,N- dimethylformamide (2.8 mL) and water (0.4 mL) was added (2-chloro-2,2- difluoroacetyl)oxysodium (492 mg, 3.23 mmol), the mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were washed by brine (10 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give 6-chloro-N-[3-chloro-4-(difluoromethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (130 mg, 0.35 mmol, 33%) as a red solid. m/z ES+ [M+H] ⁺ 375.1. Intermediate 7: 6-Chloro-N-(5-chloro-6-phenoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4-amine Step 1. 6-Chloro-N-(5-chloro-6-phenoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4-amine To a solution of 4, 6-dichloropyrido[3,2-d]pyrimidine (244 mg, 1.22 mmol) in acetonitrile (10 mL) was added 5-chloro-6-phenoxy-pyridin-3-amine (270 mg, 1.22 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the mixture was filtered and the filter cake was collected. The crude product was triturated with acetonitrile (20 mL) to give 6-chloro-N-(5-chloro-6- phenoxy-3-pyridyl) pyrido [3,2-d] pyrimidin-4-amine (470 mg, 1.22 mmol, 99 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.98 - 11.04 (m, 1H), 9.01 - 8.88 (m, 1H), 8.70 - 8.43 (m, 3H), 8.27 - 8.09 (m, 1H), 7.52 - 7.41 (m, 2H), 7.33 - 7.14 (m, 3H); m/z ES+ [M+H] ⁺ 384.2. Intermediate 8: 6-Chloro-N-(2-fluoro-3-methylphenyl)pyrido[3,2-d]pyrimidin-4 -amine Step 1.6-Chloro-N-(2-fluoro-3-methylphenyl)pyrido[3,2-d]pyrimidin -4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (300 mg, 1.50 mmol) in acetonitrile (1.0 mL) was added 2-fluoro-3-methyl-aniline (225 mg, 1.80 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was filtered and washed with acetonitrile (3 mL). The filter cake was concentrated in vacuo to give 6-chloro-N-(2-fluoro-3-methyl- phenyl)pyrido[3,2-d]pyrimidin-4-amine (433 mg, 1.50 mmol, 100%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 8.86 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.22 - 7.17 (m, 1H), 2.30 (d, J = 1.4 Hz, 3H); m/z ES+ [M+H] ⁺ 288.9. Intermediate 9: N-(3-Bromo-2-fluorophenyl)-6-chloropyrido[3,2-d]pyrimidin-4- amine Step 1. N-(3-Bromo-2-fluorophenyl)-6-chloropyrido[3,2-d]pyrimidin-4- amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 599 μmol) in acetonitrile (2.0 mL) was added 3-bromo-2-fluoro-aniline (136 mg, 719 μmol). The mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give N-(3- bromo-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]pyrimidin-4-ami ne (200 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.85 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.29 (dt, J = 0.8, 8.0 Hz, 1H); m/z ES+ [M+H] ⁺ 354.9. Intermediate 10: (1S,4S)-tert-Butyl 5-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1] heptane-2-carboxylate

Step 1. 2-((1S,4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]he ptan-2-yl)-5- nitroisonicotinic acid To a solution of 2-chloro-5-nitro-pyridine-4-carboxylic acid (1.5 g, 7.41 mmol) in N- methylpyrrolidone (10.0 mL) was added diisopropylethylamine (2.87 g, 22.2 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.47 g, 7.41 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was filtered and concentrated to give 2- [(1S,4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptan -2-yl]-5-nitro-pyridine-4- carboxylic acid (1.80 g, 4.89 mmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 6.57 (s, 1H), 5.25 - 4.86 (m, 1H), 4.67 - 4.38 (m, 1H), 3.69 - 3.49 (m, 2H), 3.20 - 3.17 (m, 2H), 1.96 (d, J = 11.6 Hz, 2H), 1.39 (d, J = 17.6 Hz, 9H). Step 2. 5-Amino-2-((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[ 2.2.1]heptan-2- yl)isonicotinic acid To a solution of 2-[(1S,4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]hept an-2-yl]-5- nitro-pyridine-4-carboxylic acid (1.80 g, 4.94 mmol) in methanol (20.0 mL) was added platinum on carbon (900 mg, 3.45 mmol, 3 wt. % loading). The mixture was stirred at 25 °C for 2 hours under hydrogen (15 psi). On completion, the mixture was filtered and concentrated in vacuo to give 5-amino-2-[(1S,4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo[2. 2.1]heptan-2-yl]pyridine-4- carboxylic acid (1.00 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (s, 1H), 6.70 (s, 1H), 4.69 - 4.23 (m, 2H), 3.54 - 3.19 (m, 4H), 2.05 - 1.75 (m, 2H), 1.43 - 1.29 (m, 9H). Step 3. (1S,4S)-tert-Butyl 5-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of 5-amino-2-[(1S,4S)-5-tert-butoxycarbonyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyridine-4-carboxylic acid (800 mg, 2.39 mmol) in 2- methoxyethanol (10.0 mL) was added formimidamide acetate (498 mg, 4.79 mmol). The mixture was stirred at 140 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated to give tert-butyl (1S,4S)-5-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 8.64 (s, 1H), 7.84 (s, 1H), 6.87 (s, 1H), 4.58 - 4.55 (m, 1H), 3.66 - 3.38 (m, 5H), 2.04 - 1.90 (m, 2H), 1.44 - 1.28 (m, 9H). Step 4. (1S,4S)-tert-Butyl 5-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 1.45 mmol) in toluene (5.0 mL) was added diisopropylethylamine (935 mg, 7.25 mmol) and phosphorus oxychloride (333 mg, 1.5 mmol). The mixture was stirred at 110 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give (1S,4S)-tert-butyl 5-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 362.3. Intermediate 11: 5-(3-cyano-4-(((dimethylamino)methylene)amino) phenyl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Step 1. (1S,4S)-tert-Butyl 5-(3-cyano-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate To a mixture of 5-fluoro-2-nitro-benzonitrile (500 mg, 3.01 mmol) and tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (596 mg, 3.01 mmol) in N,N-dimethylformamide (8.00 mL) was added potassium carbonate (1.25 g, 9.03 mmol), the reaction mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1S,4S)-tert-butyl 5-(3-cyano-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-c arboxylate (1.00 g, 2.90 mmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 345.4. Step 2. (1S,4S)-tert-Butyl 5-(4-amino-3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate To a mixture of (1S,4S)-tert-Butyl 5-(3-cyano-4-nitrophenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (980 mg, 2.85 mmol) in tetrahydrofuran (10.0 mL) was added platinum on carbon (14.8 g, 1.71 mmol, 3 wt. % loading), the reaction mixture was stirred at 25 °C under hydrogen for 1 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give (1S,4S)-tert-butyl 5-(4-amino-3-cyanophenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (870 mg, 2.76 mmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 315.3. Step 3. (1S,4S)-tert-Butyl 5-(3-cyano-4-((E)-((dimethylamino)methylene)amino)phenyl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a mixture of (1S,4S)-tert-butyl 5-(4-amino-3-cyanophenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (850 mg, 2.70 mmol) in toluene (10.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (966 mg, 8.11 mmol), the reaction mixture was stirred at 100 °C for 3 hr. On completion, the reaction mixture was concentrated in vacuo to give (1S,4S)- tert-butyl 5-(3-cyano-4-((E)-((dimethylamino)methylene)amino)phenyl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate (800 mg, 2.16 mmol, 80%) as a black solid. m/z ES+ [M+H] ⁺ 370.3. Intermediate 12: tert-Butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1-carboxyl ate Step 1. tert-Butyl 4-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)piperazine-1-carboxy late To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (5.0 g, 27.5 mmol) in N- methylpyrrolidone (50 mL) was added diisopropylethylamine (17.8 g, 138 mmol) and tert-butyl piperazine-1-carboxylate (10.3 g, 55.1 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% NH ₄ OH conditions) to give tert-butyl 4-(4- hydroxypyrido[3,2-d]pyrimidin-6-yl)piperazine-1-carboxylate (5.7 g, 17.1 mmol, 59%) as a yellow solid. m/z ES+ [M+H] ⁺ 332.4. Step 2. tert-Butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1-carboxyl ate To a solution of tert-butyl 4-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate (4.9 g, 14.8 mmol) in toluene (50 mL) was added diisopropylethylamine (9.56 g, 73.9 mmol) and followed by phosphorus oxychloride (2.95 g, 19.2 mmol). The mixture was stirred at 110 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 3/1) to give tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate (5.0 g, 14.3 mmol, 86%) as a white solid. m/z ES+ [M+H] ⁺ 350.1. Intermediate 14: 2-Chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)pheno l Step 1.2-Chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)phe nol To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (400 mg, 2.00 mmol) in acetonitrile (6.00 mL) was added 4-amino-2-chloro-phenol (373 mg, 2.60 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give 2-chloro-4-[(6- chloropyrido[3,2-d]pyrimidin-4-yl)amino]phenol (610 mg, 1.99 mmol, 97%) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 2.8, 8.8 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.23 - 7.01 (m, 2H); m/z ES+ [M+H] ⁺ 307.0. Intermediate 15: 6-Bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine Step 1.6-Bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine To a solution of 3,4-dichloro-2-fluoro-aniline (14.8 g, 82.1 mmol) in acetonitrile (80 mL) was added a solution of 6-bromo-4-chloro-quinazoline (10.0 g, 41.0 mmol) in N,N- dimethylformamide (80 mL). The mixture was stirred at 20 °C for 3 h. On completion, the reaction was poured into water (500 mL). The resulting precipitate was filtered and washed with water (50 mL x 3), which was further triturated in petroleum ether/ethyl acetate (300 mL, 10/1 v/v) at 20 °C for 30 min to afford 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl) quinazolin-4-amine (15.2 g, 39.3 mmol, 93%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆₎ δ 11.10 - 10.03 (m, 1H), 8.76 (s, 1H), 8.57 (s, 1H), 8.02 (dd, J = 1.6, 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.60 - 7.46 (m, 2H); m/z ES+ [M+H] ⁺ 388.1. Intermediate 16: 6-Bromo-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-amine Step 1.6-Bromo-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-amine To a solution of 6-bromo-4-chloro-quinazoline (3.00 g, 12.3 mmol) and 3-chloro-2-fluoro- aniline (1.79 g, 12.3 mmol) in isopropanol (100 mL) was added trifluoroacetic acid (702 mg, 6.16 mmol) at 20 °C. The mixture was stirred at 20 °C for 3 hours. The mixture was filtered and the solid was washed with water (20 mL), dried under vacuum to give 6-bromo-N-(3-chloro-2-fluoro- phenyl)quinazolin-4-amine (4.00 g, 11.4 mmol, 92%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 8.77 (s, 1H), 8.568 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.525 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H). Intermediate 17: tert-Butyl 3-(4-chloroquinazolin-6-yl)piperidine-1-carboxylate Step 1. tert-Butyl 3-(4-hydroxyquinazolin-6-yl)piperidine-1-carboxylate To a solution of 6-bromoquinazolin-4-ol (500 mg, 2.22 mmol) and tert-butyl 3- bromopiperidine-1-carboxylate (586 mg, 2.22 mmol) in dimethoxyethane (10 mL) was added Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (24.9 mg, 22.2 μmol), tris(trimethylsilyl)silane (552 mg, 2.22 mmol), sodium carbonate (470 mg, 4.44 mmol) and NiCl ₂ ·dtbbpy (4.42 mg, 11.11 μmol). The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 12 hours under nitrogen. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1 to 0:1) to give tert-butyl 3-(4- hydroxyquinazolin-6-yl)piperidine-1-carboxylate (0.61 g, 1.85 mmol, 83%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H), 8.05 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 2.0, 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 4.00 - 3.90 (m, 2H), 2.93 - 2.70 (m, 3H), 1.77 - 1.65 (m, 2H), 1.43 - 1.38 (m, 9H); m/z ES+ [M+H] ⁺ 330.2. Step 2. tert-Butyl 3-(4-chloroquinazolin-6-yl)piperidine-1-carboxylate To a solution of tert-butyl 3-(4-hydroxyquinazolin-6-yl)piperidine-1-carboxylate (0.6 g, 1.82 mmol) in toluene (10 mL) was added N,N-diisopropylethylamine (706 mg, 5.46 mmol) and phosphorus oxychloride (391 mg, 2.55 mmol, 236 uL). The mixture was stirred at 110 °C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1 to 1:1) to give tert-butyl 3-(4-chloroquinazolin-6-yl)piperidine-1-carboxylate (400 mg, 1.15 mmol, 63%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.83 - 7.78 (m, 1H), 3.94 (d, J = 12.4 Hz, 2H), 2.82 (s, 2H), 2.55 - 2.51 (m, 1H), 1.93 (d, J = 10.4Hz, 1H), 1.81 - 1.64 (m, 2H), 1.54 - 1.44 (m, 1H), 1.40 (s, 9H); m/z ES+ [M+H] ⁺ 348.1. Intermediate 18: 6-Chloro-N-(4-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine Step 1. 6-Chloro-N-(4-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.50 mmol) in THF (5 mL) was added 4-phenoxyaniline (509.30 mg, 2.75 mmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether/ethyl acetate (5/1, 24 mL) to give 6-chloro-N-(4- phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (870 mg, 2.49 mmol, 99%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04 (s, 1H), 8.83 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 9.2 Hz, 2H), 7.50 – 7.40 (m, 2H), 7.20 – 7.15 (m, 1H), 7.10 – 7.00 (m, 4H); m/z ES+ [M+H] ⁺ 349.1. Intermediate 19: 6-Bromo-4-chloro-7-methoxyquinazoline Step 1. Methyl 2-amino-5-bromo-4-methoxybenzoate To a solution of methyl 2-amino-4-methoxy-benzoate (3 g, 16.5 mmol) in acetic acid (3 mL) and dichloromethane (30 mL) was added bromine (2.65 g, 16.5 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give methyl 2-amino-5-bromo-4-methoxy-benzoate (4.72 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (s, 1H), 6.46 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H). Step 2. 6-Bromo-7-methoxyquinazolin-4-ol A solution of methyl 2-amino-5-bromo-4-methoxy-benzoate (1 g, 3.84 mmol) and ammonium formate (500 mg, 7.93 mmol) in formamide (1 mL) was stirred at 165 °C for 3 h. On completion, the reaction mixture was filtered. The filter cake was washed with water (5 mL) and then dried under vacuum to give 6-bromo-7-methoxy-quinazolin-4-ol (550 mg, 2.16 mmol, 56%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.28 (br. d, J = 1.6 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.26 (s, 1H), 4.00 (s, 3H). Step 3. 6-Bromo-4-chloro-7-methoxyquinazoline To a solution of 6-bromo-7-methoxy-quinazolin-4-ol (500 mg, 1.96 mmol) in thionyl chloride (1 mL) was added dimethylformamide (14.3 mg, 196 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give 6-bromo-4-chloro-7-methoxy-quinazoline (500 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 274.9. Intermediate 21: 6-Chloro-N-(3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl )pyrido[3,2- d]pyrimidin-4-amine Step 1. 6-Chloro-N-(3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl )pyrido[3,2- d]pyrimidin-4-amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (254 mg, 1.27 mmol) and 3-chloro-4- (1-methylpyrazol-3-yl)oxy-aniline (341 mg, 1.52 mmol) in acetonitrile (7.00 mL) was stirred at 40 °C for 2 hr. On completion, the mixture was filtrated and the filter cake was concentrated to give 6-chloro-N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]pyri do[3,2-d]pyrimidin-4-amine (570 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.02 (s, 1H), 8.87 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 2.4, 9.2 Hz, 1H), 7.66 - 7.63 (m, 1H), 7.25 - 7.23 (m, 1H), 5.86 (d, J = 2.4 Hz, 1H), 3.73 (s, 3H); m/z ES+ [M+H] ⁺ 386.9. Intermediate 22: Benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[4.1.0]heptane-3-carbo xylate, potassium salt Step 1. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetr ahydropyridine To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro- 2H-pyridine-1-carboxylate (1.00 g, 3.23 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction was concentrated under reduced pressure to give 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (676 mg, crude) as a yellow oil. Step 2. Benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrop yridine- 1(2H)-carboxylate To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine (676 mg, 3.23 mmol) in tetrahydrofuran (10 mL) was added triethylamine (1.64 g, 16.2 mmol) and benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (966 mg, 3.88 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to give benzyl 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.00 g, 2.92 mmol, 90%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 - 7.29 (m, 5H), 6.66 (d, J = 14.0 Hz, 1H), 5.17 (s, 2H), 4.08 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.23 (s, 2H), 1.26 (s, 12H). Step 3. Benzyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- azabicyclo[4.1.0]heptane-3-carboxylate To a solution of diethylzinc (1 M in toluene, 23.3 mL) in dry dichloromethane (20 mL) was added diiodomethane (12.5 g, 46.6 mmol) slowly at -40 °C. The mixture was stirred at -40 °C for 1 hour. Then trifluoroacetic acid (2.66 g, 23.1 mmol) was added slowly at -40 °C and the mixture was stirred at -15 °C for 1 hour. Then benzyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.00 g, 2.91 mmol) was added slowly at -15 °C. The mixture was warmed to 20 °C and sirred for 16 hours. On completion, the mixture was quenched by sat. sodium bicarbonate solution to adjust pH = 7 and then filtered. The filtrate was extracted with dichloromethane (20 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by prep-HPLC (column: Welch Ultimate XB NH2 10u 100*30 mm; mobile phase: [Heptane-ethanol]; B%: 0%-20%, 10 min) to give benzyl 1- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4 .1.0]heptane-3-carboxylate (360 mg, 1.01 mmol, 34%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 - 7.28 (m, 5H), 5.18 - 5.06 (m, 2H), 3.93 - 3.59 (m, 2H), 3.50 - 3.36 (m, 1H), 3.10 - 3.02 (m, 1H), 1.96 (d, J = 5.2 Hz, 1H), 1.81 (s, 1H), 1.21 (s, 13H), 0.88 (dd, J = 4.0, 8.4 Hz, 1H), 0.47 - 0.42 (m, 1H). Step 4. Benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[4.1.0]heptane-3-carbo xylate, potassium salt To a solution of benzyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- azabicyclo[4.1.0]heptane-3-carboxylate (300 mg, 839 μmol) in methanol (5.0 mL) was added potassium bifluoride (459 mg, 5.88 mmol) at 20 °C. The mixture was stirred at 90 °C for 12 hours. The mixture was concentrated under reduced pressure. The mixture was triturated with petroleum ether (5.0 mL) and filtered. The solid was dissolved in warm acetonitrile (5.0 mL) and then filtered. The filtrate was concentrated under reduced pressure to give benzyl 1-(trifluoro-l4-boraneyl)-3- azabicyclo[4.1.0]heptane-3-carboxylate, potassium salt (260 mg, 0.77 mmol, 92%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42 - 7.25 (m, 5H), 5.01 (s, 2H), 3.63 (d, J = 13.4 Hz, 1H), 3.20 (s, 2H), 2.83 (s, 1H), 1.82 - 1.68 (m, 1H), 1.60 (s, 1H), 0.62 (s, 1H), 0.21 (dd, J = 2.4, 7.6 Hz, 1H), -0.31 (s, 1H). Intermediate 23: tert-Butyl 3-(3-cyano-4-(((dimethyl-l4- azaneylidene)methylene)amino)phenyl)piperidine-1-carboxylate Step 1. tert-Butyl 5-(4-amino-3-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxyl ate To a solution of 2-amino-5-bromo-benzonitrile (2.00 g, 10.2 mmol) and tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H -pyridine-1-carboxylate (3.14 g, 10.2 mmol) in dioxane (20 mL) and water (5 mL) was added Pd(dppf)Cl ₂ (371 mg, 508 μmol) and potassium carbonate (4.21 g, 30.5 mmol). The mixture was degassed and purged with nitrogen for 3 times, and then stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate 30 mL x 3. The combined organic layers were washed with brine 30 mL x 3, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 3/1) to give tert-butyl 3-(4-amino-3-cyanophenyl)-5,6-dihydropyridine-1(2H)- carboxylate (2.70 g, 9.02 mmol, 89%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 - 7.30 (m, 2H), 6.72 (d, J = 8.8 Hz, 1H), 6.08 (br. s, 1H), 4.47 (br. s, 2H), 4.17 (br. s, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.28 (br. d, J = 2.8 Hz, 2H), 1.50 (s, 9H). Step 2. tert-Butyl 3-(4-amino-3-cyanophenyl)piperidine-1-carboxylate To a solution of tert-butyl 3-(4-amino-3-cyanophenyl)-5,6-dihydropyridine-1(2H)- carboxylate (2.56 g, 8.55 mmol) in methanol (30 mL) was added palladium on activated carbon (256 mg, 241 μmol, 10% loading). The mixture was degassed and purged with hydrogen for 3 times and then stirred at 25 °C for 2 h under hydrogen (15 psi). The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 3-(4-amino-3-cyanophenyl)piperidine-1-carboxylate (2.30 g, 7.63 mmol, 89%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26 - 7.18 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.22 - 4.01 (m, 2H), 2.79 - 2.51 (m, 3H), 1.96 (br. d, J = 7.6 Hz, 1H), 1.81 - 1.70 (m, 1H), 1.64 (br. s, 2H), 1.58 - 1.51 (m, 2H), 1.47 (s, 9H). Step 3. tert-Butyl 3-(3-cyano-4-(((dimethyl-l4- azaneylidene)methylene)amino)phenyl)piperidine-1-carboxylate A solution of tert-butyl 3-(4-amino-3-cyano-phenyl)piperidine-1-carboxylate (600 mg, 1.99 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (711 mg, 5.97 mmol) in toluene (10 mL) was stirred at 115 °C for 3 hr. On completion. The mixture was concentrated in vacuo to give tert- butyl 3-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl)piperid ine-1-carboxylate (0.7 g, crude) as a brown oil. m/z ES+[M+H] ⁺ 357.4. Intermediate 24 & 27: 4,6-Dichloropyrido[3,4-d]pyrimidine & 6-Chloropyrido[3,4-d]pyrimidin- 4-ol Step 1. 6-Chloropyrido[3,4-d]pyrimidin-4-ol A mixture of 5-amino-2-chloro-pyridine-4-carboxylic acid (20 g, 116 mmol) and formamidine acetate (24.1 g, 231 mmol) was stirred at 160 °C for 30 minutes. On completion, the mixture was cooled to 20 °C and water (100 mL) was added. The mixture was then stirred at 100 °C for 30 min. The solution was filtered and the filter cake was washed with water (80 mL) and methanol (20 mL), then concentrated in vacuum to give 6-chloropyrido[3,4-d]pyrimidin-4-ol (15 g, 82.6 mmol, 71%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 - 12.45 (m, 1H), 8.90 (s, 1H), 8.24 (s, 1H), 7.97 (s, 1H). Step 2. 4,6-Dichloropyrido[3,4-d]pyrimidine To a solution of 6-chloropyrido[3,4-d]pyrimidin-4-ol (10 g, 55.1 mmol) in toluene (100 mL) was added phosphorus oxylchloride (20.2 g, 132 mmol) and diisopropylethylamine (35.6 g, 275 mmol). The mixture was stirred at 110 °C for 1.5 hr. The mixture was concentrated to give 4,6-dichloropyrido[3,4-d]pyrimidine (11 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.37 (s, 1H), 9.19 (s, 1H), 8.09 (s, 1H); m/z ES+ [M+H] ⁺ 199.9. Intermediate 25: 6-Chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,4-d]pyrimidin-4 -amine Step 1. 6-Chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,4-d]pyrimidin-4 -amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (11.0 g, 54.9 mmol) in acetonitrile (100 mL) was added 3-chloro-2-fluoro-aniline (9.61 g, 65.9 mmol). The mixture was stirred at 60 °C for 12 h. On completion, the reaction mixture was filtered and the filter cake was washed with acetonitrile (80 mL) to give 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4- amine (15 g, 88%) as a yellow solid. m/z ES+ [M+H] ⁺ 308.9. Intermediate 26: 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,4-d]pyrimid in-4-amine Step 1. 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,4-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (1.00 g, 5.00 mmol) in acetonitrile (20 mL) was added 3,4-dichloro-2-fluoro-aniline (990 mg, 5.50 mmol). The mixture was stirred at 60 °C for 2 hours. On completion, the mixture was concentrated. The residue was washed with acetonitrile (5 mL) and then dried in vacuum to give compound 6-chloro-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,4-d]pyrimidin-4-amine (1.30 g, 3.81 mmol, 73%) as a yellow solid. m/z ES+ [M+H] ⁺ 342.9. Intermediate 28: N'-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide (for alternative synthesis of intermediate 24, refer to intermediate 64) Step 1. 3-Amino-6-chloropicolinonitrile To a solution of 6-chloro-3-nitro-pyridine-2-carbonitrile (3.00 g, 16.3 mmol) in water (40 mL) and acetic acid (4.0 mL) was added sodium hydrosulfite (9.96 g, 57.2 mmol) at 20 °C. The mixture was stirred at 60 °C for 12 hours. The mixture was then filtered and the precipitate was collected. The filtrate was further extracted with ethyl acetate (40 mL x 3). The organic layers were concentrated under reduced pressure. Both the precipitate and the residue was combined to give 3-amino-6-chloropicolinonitrile (1.20 g, 7.84 mmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29 (s, 1H), 7.31 - 7.27 (m, 1H), 7.14 - 7.09 (m, 1H), 4.51 (br. s, 2H). Step 2. N'-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidamide To a solution of 3-amino-6-chloro-pyridine-2-carbonitrile (1.50 g, 9.77 mmol) in toluene (15 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (3.49 g, 29.3 mmol) at 20 °C. The mixture was stirred at 110 °C for 2 hours. The mixture was concentrated under reduced pressure to give N'-(6-chloro-2-cyano-3-pyridyl)-N,N-dimethyl-formamidine (2.00 g, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s, 1H), 7.32 (d, J = 6.0 Hz, 1H), 7.21 - 7.14 (m, 1H), 3.13 (s, 6H). Intermediate 29: 6-Chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine Step 1. 6-Chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (300 mg, 1.50 mmol) in acetonitrile (1.0 mL) was added 3-chloro-2-fluoroaniline (327 mg, 2.25 mmol). The mixture was stirred at 60 °C for 12 hrs. The reaction mixture was filtered. The filtered cake was washed with acetonitrile (50 mL) and then dried in vacuo to give 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d] pyrimidin-4-amine (280 mg, 0.91 mmol, 60%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.18 - 10.61 (m, 1H), 8.79 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.72 - 7.63 (m, 1H), 7.61 - 7.51 (m, 1H), 7.33 (dt, J = 1.2, 8.0 Hz, 1H); m/z ES+ [M+H] ⁺ 308.9. Intermediate 30 & 31: 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)-7-methoxypyrido[3,2 - d]pyrimidin-4-amine & 6-Bromo-7-fluoropyrido[3,2-d]pyrimidin-4-ol Step 1. 3-Amino-5-fluoropicolinonitrile To a solution of 2-bromo-5-fluoropyridin-3-amine (100 g, 523 mmol, 1.00 eq) in dimethyl formamide (500 mL) was added zinc cyanide (46.2 g, 392 mmol, 0.75 eq), tris(dibenzylideneacetone)dipalladium(0) (9.50 g, 10.4 mmol) and 1,1’- bis(diphenylphosphino)ferrocene (8.80 g, 15.9 mmol). The mixture was stirred at 130 °C for 3 h under nitrogen. After being cooled to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5/1 to 0/1) to give 3-amino-5-fluoropicolinonitrile (60.0 g, 437 mmol, 83%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 2.4, 11.0 Hz, 1H), 6.62 (br. s, 2H); m/z ES+ [M+H] ⁺ 138.0. Step 2. 3-Amino-5-fluoropicolinamide To a solution of 3-amino-5-fluoropicolinonitrile (60.0 g, 437 mmol, 1.00 eq) and potassium carbonate (30.0 g, 217 mmol) in dimethylsulfoxide (200 mL) was added aq. hydrogen peroxide solution (177 g, 1.56 mol, 150 mL, 30%) dropwise at 25 °C. Then the mixture was stirred at 25 °C for 2 h. The mixture was poured into water (2.00 L) brown solid was precipitated from the mixture. The solid was collected by filtration and dried under vacuum to give 3-amino-5- fluoropicolinamide (58.0 g, 374 mmol, 85%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (br. s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.34 (br. s, 1H), 7.13 (br. s, 2H), 6.96 (dd, J = 2.5, 11.3 Hz, 1H); m/z ES+ [M+H] ⁺ 157.0. Step 3. 3-Amino-6-bromo-5-fluoropicolinamide To a solution of 3-amino-5-fluoropicolinamide (58.0 g, 374 mmol) in acetonitrile (500 mL) was added N-bromosuccinimide (75.0 g, 421 mmol) portionwise. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.00 L) and washed with hydrochloric acid (1 M, 2 × 500 mL). The organic layer was separated and concentrated under reduced pressure to give 3-amino-6-bromo-5- fluoropicolinamide (78.0 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.68 (br. s, 1H), 7.44 (br. s, 1H), 7.34 - 7.18 (m, 1H), 7.12 (br. d, J = 10.1 Hz, 1H); m/z ES+ [M+H] ⁺ 233.9. Step 4. 6-Bromo-7-fluoropyrido[3,2-d]pyrimidin-4-ol A solution of 3-amino-6-bromo-5-fluoropicolinamide (78.0 g, 333 mmol) in diethoxymethoxyethane (356 g, 2.40 mol, 400 mL) was stirred at 150 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was triturated in ethyl acetate (400 mL) for 0.5 h at 25 °C. The solid was collected by filtration and dried in vacuo to give 6-bromo-7- fluoropyrido[3,2-d] pyrimidin-4-ol (65.0 g, 266 mmol, 80%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (br. s, 1H), 8.25 (s, 1H), 8.18 (br. d, J = 8.4 Hz, 1H); m/z ES+ [M+H] ⁺ 243.9. Step 5. 6-Bromo-7-methoxypyrido[3,2-d]pyrimidin-4-ol To a solution of methanol (6.73 g, 210 mmol, 8.50 mL) in dimethylsulfoxide (1.00 L) was added potassium tert-butoxide (46.0 g, 410 mmol). The mixture was stirred at 25 °C for 1 h. Then 6-bromo-7-fluoropyrido[3,2-d]pyrimidin-4-ol (50.0 g, 205 mmol) was added. The mixture was stirred at 25 °C for another 5 h. The mixture was dissolved in water (5.00 L) to give a solution which was adjusted to pH = 7 with hydrochloric acid (6 M). Yellow solid was precipitated from the mixture which was collected by filtration and dried in vacuum to give 6-bromo-7- methoxypyrido[3,2-d]pyrimidin-4-ol (40.0 g, 156 mmol, 76%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (s, 1H), 7.59 (s, 1H), 4.04 (s, 3H); m/z ES+ [M+H] ⁺ 255.9. Step 6. 4,6-Dichloro-7-methoxypyrido[3,2-d]pyrimidine To a suspension of 6-bromo-7-methoxypyrido[3,2-d]pyrimidin-4-ol (40.0 g, 156 mmol) in thionyl chloride (200 mL) was added dimethyl formamide (1.90 g, 26.0 mmol, 2.00 mL). The mixture was stirred at 100 °C for 12 h. The mixture was concentrated under reduced pressure to give 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (32.0 g, crude) as a yellow solid. Step 7. 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)-7-methoxypyrido[3,2 -d]pyrimidin-4- amine To a solution of 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (32.0 g, 139 mmol) in acetonitrile (200 mL) was added 3,4-dichloro-2-fluoro-aniline (23.0 g, 127 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was diluted with acetonitrile (200 mL) and filtered. The filter cake was collected and dried under vacuum to give 6-chloro-N-(3,4-dichloro-2- fluorophenyl)-7-methoxypyrido[3,2-d] pyrimidin-4-amine (45.0 g, 102 mmol, 73%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.93 (br. s, 1H), 8.83 (s, 1H), 7.87 (s, 1H), 7.72 - 7.63 (m, 1H), 7.66 - 7.60 (m, 1H), 4.12 (s, 3H); m/z ES+ [M+H] ⁺ 372.9. Intermediate 32: 6-Bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine Step 1. 6-Bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine To a solution of 6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (1 g, 4.10 mmol) in toluene (10 mL) was added diisopropylethylamine (1.59 g, 12.29 mmol) and phosphorus oxychloride (942.54 mg, 6.15 mmol). The mixture was stirred at 110 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. Then water (30 mL) and dichloromethane (30 mL) was added to the residue. The mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 1/1) to give 6-bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine (550 mg, 2.07 mmol, 51%) as a yellow solid. m/z ES+ [M+H] ⁺ 264.2. Intermediate 33: tert-Butyl N-[1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl]carb amate Step 1. tert-Butyl N-[1-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl]car bamate To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (1.5 g, 8.26 mmol) in N-methyl pyrrolidone (20 mL) was added tert-butyl N-(azetidin-3-yl)carbamate (1.90 g, 9.09 mmol, HCl) and diisopropylethylamine (4.27 g, 33.0 mmol), the mixture was stirred at 100 °C for 12 hr. The mixture was quenched by water (10 mL) and filtrated, the filter cake was concentrated to give tert- butyl N-[1-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl]car bamate (2 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.29 - 4.23 (m, 2H), 3.88 - 3.81 (m, 2H), 1.38 (s, 9H); m/z ES+ [M+H] ⁺ 318.0. Step 2. tert-Butyl N-[1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl]carb amate To a solution of tert-butyl N-[1-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl]carbamate (2 g, 6.30 mmol) in toluene (20 mL) was added phosphorus oxychloride (1.45 g, 9.45 mmol) and diisopropylethylamine (3.26 g, 25.2 mmol). The mixture was stirred at 115 °C for 2 hr. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to 1/1) to give tert-butyl N-[1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl]carb amate (750 mg, 2.23 mmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H), 4.50 - 4.38 (m, 3H), 4.04 - 3.99 (m, 2H); m/z ES+ [M+H] ⁺ 336.1. Intermediate 34: 6-Chloro-N-(5-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimid in-4-amine Step 1. 6-Chloro-N-(5-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 1 mmol) in acetonitrile (5 mL) was added 5-chloro-2,4-difluoro-aniline (163 mg, 1 mmol). The mixture was stirred at 20 °C for 2 hrs. On completion, the mixture was filtered and the filter cake was collected to give 6-chloro- N-(5-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (300 mg, 0.92 mmol, 92%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.77 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.99 (br. t, J = 7.6 Hz, 1H), 7.75 (br. t, J = 9.6 Hz, 1H); m/z ES+ [M+H] ⁺ 327.1. Intermediate 35: 6-Chloro-N-(5-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine Step 1. 6-Chloro-N-(5-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (1 g, 5.00 mmol) and 5-chloro-2- fluoro-aniline (800 mg, 5.50 mmol) in acetonitrile (20 mL) was stirred at 20 °C for 1 h. On completion, The mixture was quenched by water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers was washed with brine (20 mL x 3), dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1~1/1) to give compound 6-chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,2- d]pyrimidin-4-amine (1.1 g, 3.56 mmol, 71%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 7.2 Hz, 2H). Intermediate 36: 6-Chloro-N-(6-phenoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-a mine Step 1. 6-Chloro-N-(6-phenoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-a mine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.35 g, 1.75 mmol) in acetonitrile (5 mL) was added 6-phenoxypyridin-3-amine (358 mg, 1.92 mmol). The mixture was stirred at 25 °C for 2 h. On completion, the reaction was filtered and the filtered cake was washed with acetonitrile (5 mL x 2). The crude product was purified by column chromatography:(petroleum ether: ethyl acetate from 10:1 to 0:1) to afford 6-chloro-N-(6-phenoxy-3-pyridyl)pyrido[3,2- d]pyrimidin-4-amine (0.5 g, 1.43 mmol, 74%) as a yellow solid. m/z ES+ [M+H] ⁺ 350.0. Intermediate 37: 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-methoxypyrido[3,2-d]py rimidin-4- amine Step 1. 6-Bromo-4-chloro-7-methoxypyrido[3,2-d]pyrimidine To a solution of 6-bromo-7-methoxy-pyrido[3,2-d]pyrimidin-4-ol (2 g, 7.81 mmol), diisopropylethylamine (4.04 g, 31.2 mmol) in toluene (25 mL) was added phosphorus oxychloride (1.80 g, 11.7 mmol). The mixture was stirred at 110 °C for 2 h. Upon completion, the mixture was concentrated in vacuo to give 6-bromo-4-chloro-7-methoxy-pyrido[3,2-d]pyrimidine (1.4 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 275.8. Step 2. 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-methoxypyrido[3,2-d]py rimidin-4- amine A solution of 6-bromo-4-chloro-7-methoxy-pyrido[3,2-d]pyrimidine (1.2 g, 4.37 mmol), 3-chloro-2-fluoro-aniline (636 mg, 4.37 mmol) in acetonitrile (5.0 mL) was stirred at 20 °C for 3 h. Upon completion, the mixture was quenched by water (30 mL) and then stirred at 25 ^o C for 30 min. The mixture was filtered and the filter cake was collected to give 6-bromo-N-(3-chloro-2- fluoro-phenyl)-7-methoxy-pyrido[3,2-d]pyrimidin-4-amine (1.4 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 384.9. Intermediate 38: N-(6-Chloropyrido[3,2-d]pyrimidin-4-yl)-7-fluorobenzo[d]isot hiazol-6-amine Step 1. N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-7-fluorobenzo[d]isot hiazol-6-amine To a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (114 mg, 571 μmol) and 7-fluoro- 1,2-benzothiazol-6-amine (80 mg, 476 μmol) in acetonitrile (1 mL) was added N,N- diisopropylethylamine (123 mg, 951 μmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 12 hr. On completion, the mixture was concentrated under reduced pressure. The residue was triturated with water (2.0 ml) at 25 °C to give N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-7- fluoro-1,2-benzothiazol-6-amine (50 mg, 0.15 mmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.92 (s, 1H), 9.06 - 8.93 (m, 3H), 8.61 - 8.51 (m, 1H), 8.08 - 7.90 (m, 2H); m/z ES+ [M+H] ⁺ 331.9. Intermediate 39: N-(6-Chloropyrido[3,2-d]pyrimidin-4-yl)benzo[d]isothiazol-6- amine Step 1. N-(6-Chloropyrido[3,2-d]pyrimidin-4-yl)benzo[d]isothiazol-6- amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 750 μmol) in acetonitrile (3 mL) was added 1,2-benzothiazol-6-amine (113 mg, 750 μmol). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was concentrated in vacuo to give N-(6-chloropyrido[3,2- d]pyrimidin-4-yl)-1,2-benzothiazol-6-amine (230 mg, 0.73 mmol, 98%) as a yellow solid. m/z ES+ [M+H] ⁺ 313.9. Intermediate 40: 6-Chloro-N-(2,3-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e Step 1. 6-Chloro-N-(2,3-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 500 μmol) in acetonitrile (3.0 mL) was added 2,3-difluoroaniline (77.5 mg, 600 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the filter cake was washed with acetonitrile (2 mL x 3), dried in vacuo to give 6-chloro-N-(2,3-difluorophenyl)pyrido[3,2- d]pyrimidin-4-amine (134 mg, 402 μmol, 87%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 - 10.64 (m, 1H), 8.79 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.54 - 7.27 (m, 3H); m/z ES+ [M+H] ⁺ 292.9. Intermediate 41: 6-Chloro-N-(1-phenyl-1H-indazol-5-yl)pyrido[3,2-d]pyrimidin- 4-amine Step 1. 6-Chloro-N-(1-phenyl-1H-indazol-5-yl)pyrido[3,2-d]pyrimidin- 4-amine To a solution of 1-phenylindazol-5-amine (103 mg, 495 μmol) in acetonitrile (1 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (90 mg, 450 μmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by reversed- phase HPLC (0.1% FA condition) to give 6-chloro-N-(1-phenylindazol-5-yl)pyrido[3,2- d]pyrimidin-4-amine (130 mg, 349 μmol, 77%) as a yellow solid. m/z ES+ [M+H] ⁺ 373.2. Intermediate 42: 6-Chloro-N-(3-ethynyl-2-fluorophenyl)pyrido[3,2-d]pyrimidin- 4-amine Step 1. 6-Chloro-N-(3-ethynyl-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin -4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 1.00 mmol) and 3-ethynyl- 2-fluoro-aniline (135 mg, 1.00 mmol) in acetonitrile (6 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure. The residue was triturated with petroleum ether/acetonitrile (20 mL, 9:1) at 25 °C for 3 min, then filtered. The filter cake was collected to give 6-chloro-N-(3-ethynyl-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin -4-amine (280 mg, 937 μmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.78 (s, 1H), 8.99 - 8.89 (m, 2H), 8.50 (t, J = 7.6 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.48 (t, J = 6.8 Hz, 1H), 7.33 - 7.29 (m, 1H), 3.43 (s, 1H); m/z ES+ [M+H] ⁺ 299.2. Intermediate 43: 6-Chloro-N-(3-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine Step 1. 6-Chloro-N-(3-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 500 μmol) in acetonitrile (4 mL) was added 3-phenoxyaniline (139 mg, 750 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the filter cake was collected to give 6- chloro-N-(3-phenoxyphenyl) pyrido[3,2-d]pyrimidin-4-amine (150 mg, 430 μmol, 86%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.80 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.46 - 7.40 (m, 3H), 7.23 - 7.14 (m, 1H), 7.11 - 7.04 (m, 2H), 6.95 - 6.75 (m, 1H). Intermediate 44: 6-Chloro-N-(4-(neopentyloxy)phenyl)pyrido[3,2-d]pyrimidin-4- amine Step 1. 6-Chloro-N-(4-(neopentyloxy)phenyl)pyrido[3,2-d]pyrimidin-4- amine To a solution of 4-(2,2-dimethylpropoxy) aniline (200 mg, 1.12 mmol) in acetonitrile (4.0 mL) was added 4,6-dichloropyrido [3,2-d] pyrimidine (186 mg, 929 μmol). On completion, the mixture was stirred at 25 °C for 3 hr. The reaction mixture was filtered and the filter cake was concentrated in vacuo to give 6-chloro-N-[4-(2, 2-dimethylpropoxy)phenyl]pyrido[3,2- d]pyrimidin-4-amine (240 mg, 702 μmol, 75%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.22 (s, 1H), 8.86 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.72-7.30 (d, J = 8.8 Hz, 2H), 7.08 - 7.00 (m, 2H), 3.71 - 3.60 (m, 2H), 1.14 - 0.76 (m, 9H). Intermediate 45: 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4-amine Step 1. 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of N'-(6-chloro-2-cyano-3-pyridyl)-N,N-dimethyl-formamidine (700 mg, 3.35 mmol) in toluene (10 mL) and acetic acid (10 mL) was added 3,4-dichloro-2-fluoro-aniline (604 mg, 3.35 mmol). The mixture was stirred at 110 °C for 3 hr. On completion, the mixture was concentrated in vacuo. The residue was purifed by column chromatography (Petroleum ether/Ethyl acetate=3/1~1/1) to give 6-chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4- amine (400 mg, 1.16 mmol, 35%) as a yellow solid. m/z ES+ [M+H] ⁺ 343.1. Intermediate 46: 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-fluoropyrido[3,2-d]pyr imidin-4- amine Step 1. 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-fluoropyrido[3,2-d]pyr imidin-4-amine To a solution of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (0.26 g, 991 μmol) in acetonitrile (8 mL) was added 3-chloro-2-fluoro-aniline (216 mg, 1.49 mmol). The mixture was stirred at 25 °C for 16 h. On completion, the reaction was filtered and the filter cake was washed with acetonitrile (2 mL x 2) to afford 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[3,2- d]pyrimidin-4-amine (0.28 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 372.9. Intermediate 47: 6-Bromo-4-(3-chloro-2-fluorophenoxy)quinazoline Step 1. 6-Bromo-4-(3-chloro-2-fluoro-phenoxy)quinazoline To a solution of 6-bromo-4-chloro-quinazoline (500 mg, 2.05 mmol) in dichloromethane (6.0 mL) was added diisopropylethylamine (398 mg, 3.08 mmol) and 3-chloro-2-fluoro-phenol (451.4 mg, 3.08 mmol). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 6-bromo-4-(3-chloro-2-fluoro- phenoxy)quinazoline (600 mg, 1.7 mmol, 83%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 2.4, 8.8 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.63 (ddd, J = 1.6, 6.8, 8.4 Hz, 1H), 7.57 (ddd, J = 1.6, 7.2, 8.4 Hz, 1H), 7.43 - 7.37 (m, 1H); m/z ES+ [M+H] ⁺ 355.2. Intermediate 48: 4-Chloro-6-fluoropyrido[3,4-d]pyrimidine Step 1. 6-Fluoropyrido[3,4-d]pyrimidin-4-ol To a solution of 2-fluoropyridine-4-carboxylic acid (2.5 g, 17.7 mmol) in ethylene glycol (13 mL) was added sodium acetate (4.36 g, 53.2 mmol) and methanimidamide hydrochloride (5.71 g, 70.9 mmol). The mixture was stirred at 120 °C for 2 hr. On completion, the resulting precipitate was filtered. The filter cake was washed with water (40 mL x 3) and methanol (20 mL), which was further dried in vacuo to give 6-fluoropyrido[3,4-d]pyrimidin-4-ol (3.2 g, crude) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.65 (br. s, 1H), 8.78 (s, 1H), 8.18 (s, 1H), 7.66 (d, J = 3.2 Hz, 1H). Step 2. 4-Chloro-6-fluoro-pyrido[3,4-d]pyrimidine To a solution of 6-fluoropyrido[3,4-d]pyrimidin-4-ol (100 mg, 605 μmol) in thionyl chloride (1 mL) was added N,N-dimethylformamide (44.2 mg, 605 μmol). The mixture was stirred at 75 °C for 20 hr. On completion, the mixture was concentrated in vacuo to give 4-chloro-6- fluoro-pyrido[3,4-d]pyrimidine (100 mg, crude) as a yellow oil which was used into next step directly without charactarization. Intermediate 49: 6-Chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)p yrido[3,2- d]pyrimidin-4-amine Step 1. 6-Chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)p yrido[3,2- d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (180 mg, 901 μmol) in acetonitrile (2.5 mL) was added 3-chloro-4-(cyclopropylmethoxy)-2-fluoro-aniline (216 mg, 1.00 mmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the solid was collected to give 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin -4-amine (310 mg, 818 μmol, 73%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 8.76 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 7.08 (dd, J = 1.6, 9.2 Hz, 1H), 4.03 (s, 1H), 4.01 (s, 1H), 1.37 - 1.22 (m, 1H), 0.65 - 0.60 (m, 2H), 0.39 (dd, J = 1.6, 4.8 Hz, 2H); m/z ES+ [M+H] ⁺ 379.1. Intermediate 50: 6-Chloro-N-(3-chloro-4-((tetrahydrofuran-3-yl)methoxy)phenyl )pyrido[3,2- d]pyrimidin-4-amine Step 1. 6-Chloro-N-(3-chloro-4-((tetrahydrofuran-3-yl)methoxy)phenyl )pyrido[3,2- d]pyrimidin-4-amine To a solution of 3-chloro-4-(tetrahydrofuran-3-ylmethoxy)aniline (204 mg, 899 μmol) in acetonitrile (5.0 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 749 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated to give 6-chloro-N-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (300 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.85 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.15 - 8.04 (m, 2H), 7.78 (dd, J = 2.8, 8.8 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H), 4.13 - 3.97 (m, 2H), 3.85 - 3.75 (m, 2H), 3.72 - 3.64 (m, 1H), 3.58 (dd, J = 5.6, 8.4 Hz, 1H), 2.77 - 2.62 (m, 1H), 2.06 - 1.99 (m, 1H), 1.77 - 1.64 (m, 1H). Intermediate 51: 6-Chloro-N-(3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl)p yrido[3,2- d]pyrimidin-4-amine Step 1. 6-Chloro-N-(3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl)p yrido[3,2- d]pyrimidin-4-amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (733 mg, 3.67 mmol), 3-chloro-2- fluoro-4-(oxetan-3-ylmethoxy)aniline (850 mg, 3.67 mmol) in acetonitrile (20 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40mm x 15um; mobile phase: [water (0.1% trifluoroacetic acid) - acetonitrile]; B%: 28% - 58%, 11min) to give 6-chloro-N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]p yrido[3,2-d]pyrimidin-4-amine (300 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 395.1. Intermediate 52: 6-Chloro-N-(3-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimid in-4-amine Step 1. 6-Chloro-N-(3-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (380 mg, 1.90 mmol) in acetonitrile (5.0 mL) was added 3-chloro-2,4-difluoro-aniline (466 mg, 2.85 mmol). The mixture was stirred at 60 °C for 12 hrs. On completion, the reaction mixture was filtered. The filtered cake was washed with petroleum ether (30 mL) and then concentrated under reduced pressure to give 6-chloro-N- (3-chloro-2,4-difluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (595 mg, 1.83 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 - 10.69 (m, 1H), 8.80 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.67 (dt, J = 6.0, 8.8 Hz, 1H), 7.45 (dt, J = 2.0, 9.2 Hz, 1H); m/z ES+ [M+H] ⁺ 326.9. Intermediate 53: 6-Chloro-N-(5-fluoro-6-phenoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4-amine Step 1. 6-Chloro-N-(5-fluoro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimi din-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 750 μmol) in acetonitrile (3.0 mL) was added 5-fluoro-6-phenoxy-pyridin-3-amine (230 mg, 1.12 mmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was diluted with water 20 mL and filtered. The filter cake was concentrated in vacuo to give 6-chloro-N-(5-fluoro-6-phenoxy-3- pyridyl)pyrido[3,2-d]pyrimidin-4-amine (280 mg, 0.76 mmol, 92%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.73 (s, 1H), 8.54 (dd, J = 2.4, 11.2 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.15 (s, 1H), 7.14 - 7.10 (m, 2H); m/z ES+ [M+H] ⁺ 368.3. Intermediate 54: N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-chloro pyrido[3,2- d]pyrimidin-4-amine Step 1. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-chloro pyrido[3,2- d]pyrimidin-4-amine A solution of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline (1.2 g, 4.24 mmol) and 4,6- dichloropyrido[3,2-d]pyrimidine (848 mg, 4.24 mmol) in acetonitrile (20 mL) was stirred at 25 °C for 12 hr. On completion, the mixture was filtrated and the filter cake was triturated with acetonitrile (10 mL) to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 5/1~0/1) to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl)-6-chloropyrido[3,2-d]pyrimidin-4-amine (1.1 g, 2.83 mmol, 67%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.99 - 8.92 (m, 1H), 8.77 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.10 - 8.00 (m, 4H), 7.34 - 7.28 (m, 2H), 7.05 - 7.03 (m, 1H). Intermediate 55: 6-Bromo-4-methoxyquinazoline Step 1. 6-Bromo-4-methoxy-quinazoline To a solution of 6-bromo-4-chloro-quinazoline (5.00 g, 20.5 mmol) in tetrahydrofuran (100 mL) was added sodium methoxide (2.22 g, 41.1 mmol), the mixture was stirred at 25 °C for 12 h. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate and concentrated in vacuum to give compound 6-bromo-4-methoxy- quinazoline (5.00 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 241.3. Intermediate 56 & 57: tert-Butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-methoxyquinazolin-6- yl)azetidine-1-carboxylate & tert-butyl 3-(4-methoxyquinazolin-6-yl)-3-methylazetidine-1- Step 1.4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)q uinazoline To a solution of 6-bromo-4-methoxy-quinazoline (4.00 g, 16.7 mmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (5.10 g, 20.1 mmol) in dioxane (120 mL) was added Pd(dppf)Cl ₂ (1.22 g, 1.67 mmol) and potassium acetate (4.93 g, 50.1 mmol), the mixture was stirred at 100 °C for 12 h under nitrogen. On completion, the mixture was quenched by water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=3/1) to give compound 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)quinazoline (7.00 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 8.67 (s, 1H), 8.20 (dd, J = 1.2, 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 4.19 (s, 3H), 1.39 (s, 12H). Step 2. (4-Methoxyquinazolin-6-yl)boronic acid To a solution of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)qui nazoline (7.00 g, 19.6 mmol) in tetrahydrofuran (100 mL) and water (100 mL) was added sodium periodate (12.6 g, 58.7 mmol) and ammonium acetate (4.53 g, 58.7 mmol). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was quenched with aq. hydrochloric acid (1N) to pH = 3 and then filtered. The filter cake was concentrated in vacuum to give compound (4-methoxyquinazolin- 6-yl)boronic acid (3.50 g, crude) as a white solid. Step 3. tert-Butyl 3-(2-ethoxy-2-oxo-ethyl)-3-(4-methoxyquinazolin-6-yl)azetidi ne-1- carboxylate To a solution of (4-methoxyquinazolin-6-yl)boronic acid (1.00 g, 4.90 mmol) and tert- butyl 3-(2-ethoxy-2-oxo-ethylidene)azetidine-1-carboxylate (788 mg, 3.27 mmol) in dioxane (10 mL) was added chlororhodium;(1Z,5Z)-cycloocta-1,5-diene (80.5 mg, 163 μmol) and potassium hydroxide (1.5 M, 3.27 mL), the mixture was stirred at 100 °C for 10 min under microwave irradiation conditions under nitrogen. On completion, the mixture was quenched by water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=3/1) to give compound tert- butyl 3-(2-ethoxy-2-oxo-ethyl)-3-(4-methoxyquinazolin-6-yl)azetidi ne-1-carboxylate (1.50 g, 3.73 mmol, 38% yield) as a yellow solid. m/z ES+ [M+H] ⁺ 402.3. Step 4. tert-Butyl 3-(4-methoxyquinazolin-6-yl)-3-(2-oxoethyl)azetidine-1-carbo xylate To a solution of tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-3-(4-methoxyquinazolin-6- yl)azetidine-1-carboxylate (300 mg, 747 μmol) in dichloromethane (5 mL) was added DIBAL-H (1 M, 3.74 mL) dropwise at -78 °C and the mixture was stirred at -78 °C for 1 h under nitrogen. On completion, the mixture was carefully quenched with MeOH (10 mL) at -78 °C and then filtered. The filtrate was concentrated in vacuum to give compound tert-butyl 3-(4- methoxyquinazolin-6-yl)-3-(2-oxoethyl)azetidine-1-carboxylat e (300 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 358.1. Step 5. tert-Butyl 3-(4-methoxyquinazolin-6-yl)-3-methyl-azetidine-1-carboxylat e To a solution of tert-butyl 3-(4-methoxyquinazolin-6-yl)-3-(2-oxoethyl)azetidine-1- carboxylate (300 mg, 839 μmol) in toluene (5 mL) was added Rh(PPh ₃ ) ₃ Cl (776 mg, 839 μmol), the mixture was stirred at 120 °C for 4 h under nitrogen. On completion, the mixture was concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=3/1~0/1) to give compound tert-butyl 3-(4-methoxyquinazolin-6-yl)-3- methyl-azetidine-1-carboxylate (120 mg, 0.36 mmol, 43%) as a white solid. m/z ES+ [M+H] ⁺ 330.0. Intermediate 58: tert-Butyl 3-hydroxy-3-(4-methoxyquinazolin-6-yl)azetidine-1-carboxylat e Step 1. tert-Butyl 3-hydroxy-3-(4-methoxyquinazolin-6-yl)azetidine -1-carboxylate To a solution of 6-bromo-4-methoxy-quinazoline (2.70 g, 11.3 mmol) in tetrahydrofuran (10 mL) was added n-butyl lithium (2.5 M, 4.52 mL) dropwise at -78 °C. After addition, the mixture was stirred at this temperature for 0.5 h, and then a solution of tert-butyl 3-oxoazetidine- 1-carboxylate (2.32 g, 13.6 mmol) in tetrahydrofuran (5 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25°C for 1 h. On completion, the reaction mixture was quenched by water (3 mL) at 25 °C and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed- phase HPLC(0.1% NH ₃ •water condition) to give tert-butyl 3-hydroxy-3-(4-methoxyquinazolin-6- yl)azetidine -1-carboxylate (800 mg, 2.31 mmol, 21%) as a white solid; m/z ES+ [M+H] ⁺ 346.1. Intermediate 59: tert-Butyl 6-bromo-1-azaspiro[3.3]heptane-1-carboxylate Step 1. tert-Butyl 6-bromo-1-azaspiro[3.3]heptane-1-carboxylate To a solution of tert-butyl 6-hydroxy-1-azaspiro[3.3]heptane-1-carboxylate (900 mg, 4.22 mmol) in dichloromethane (3 mL) was added triphenylphosphine (1.66 g, 6.33 mmol) and tetrabromomethane (2.10 g, 6.33 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was diluted with dichloromethane (30 mL) and washed with sat. sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 50/1) to give tert-butyl 6-bromo-1-azaspiro[3.3]heptane-1- carboxylate (240 mg, 869 μmol, 21%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.65 – 4.55 (m, 1H), 3.78 (t, J = 7.2 Hz, 2H), 3.41 (dd, J = 14.0, 8.0 Hz, 2H), 2.61 (dd, J = 15.2, 4.4 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H), 1.47 (2, 9H). Intermediate 60: tert-Butyl 3-methyl-3-(4-(methylthio)quinazolin-6-yl)azetidine-1-carbox ylate Step 1. Methyl 6-bromo-4-(methylthio)quinazoline To a solution of 6-bromo-4-chloro-quinazoline (50.0 g, 205 mmol) in dimethylformamide (400 mL) was added sodium thiomethoxide (16.1 g, 226 mmol), the mixture was stirred at 0 °C for 1 hour. The mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (50 mL x 2). The combined organic layers were concentrated in vacuo. The residue was partitioned in water (500 mL) and then filtered. The filter cake was collected, concentrated in vacuo to give methyl 6-bromo-4-(methylthio)quinazoline (48.0 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 256.1. Step 2.4-(Methylthio)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)quinazoline To a solution of 6-bromo-4-methylsulfanyl-quinazoline (40.0 g, 157 mmol) in dioxane (500 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (47.8 g, 188 mmol), Pd(dppf)Cl ₂ (11.5 g, 15.7 mmol) and potassium acetate (30.8 g, 314 mmol). The mixture was stirred at 100 °C for 12 hours under nitrogen. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 1/1) to give 4-(methylthio)- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (25 g, 82.5 mmol, 49%) as a white solid. m/z ES+ [M+H] ⁺ 303.1. Step 3. (4-(Methylthio)quinazolin-6-yl)boronic acid To a solution of 4-methylsulfanyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 - yl)quinazoline (22.1 g, 73.1 mmol) in acetonitrile (220 mL) was added hydrochloric acid (1 M, 219 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was filtered and the solid was concentrated in vacuo to give (4-(methylthio)quinazolin-6-yl)boronic acid (5.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (s, 1H), 8.63 (s, 1H), 8.36 (dd, J = 0.8, 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 2.74 (s, 3H); m/z ES+ [M+3] ⁺ 223.1. Step 4. tert-Butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-(methylthio)quinazolin-6-yl)aze tidine-1- carboxylate To a solution of (4-methylsulfanylquinazolin-6-yl)boronic acid (4.50 g, 20.5 mmol) and tert-butyl 3-(2-ethoxy-2-oxo-ethylidene)azetidine-1-carboxylate (14.8 g, 61.4 mmol) in dioxane (45 mL) was added chlororhodium;(1Z,5Z)-cycloocta-1,5-diene (303 mg, 613 μmol) and potassium hydroxide (1.5 M, 13.6 mL), the mixture was strred at 100 °C for 1 hour under nitrogen. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 3/1) to give tert-butyl 3-(2-ethoxy- 2-oxoethyl)-3-(4-(methylthio)quinazolin-6-yl)azetidine-1-car boxylate (2.50 g, 5.98 mmol, 29%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 7.95 (s, 2H), 7.88 (s, 1H), 4.20 (d, J = 11.6 Hz, 4H), 3.91 (q, J = 7.2 Hz, 2H), 3.16 (s, 2H), 2.70 (s, 3H), 1.39 (s, 9H), 1.01 (t, J = 7.2 Hz, 3H); m/z ES+ [M+H] ⁺ 418.2. Step 5. tert-Butyl 3-(4-(methylthio)quinazolin-6-yl)-3-(2-oxoethyl)azetidine-1- carboxylate To a solution of tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-3-(4-methylsulfanylquinazolin-6- yl)azetidine-1-carboxylate (2.98 g, 7.14 mmol) in dichloromethane (2 mL) was added DIBAL-H (1 M, 35.7 mL) at -78 °C, the mixture was stirred at -78 °C for 1 hour. The mixture was quenched by methanol (30 mL) at -78 °C and then filtered to remove the solid. The organic phase was concentrated in vacuo to give tert-butyl 3-(4-(methylthio)quinazolin-6-yl)-3-(2- oxoethyl)azetidine-1-carboxylate (2.40 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 374.1. Step 6. tert-Butyl 3-methyl-3-(4-(methylthio)quinazolin-6-yl)azetidine-1-carbox ylate To a solution of tert-butyl 3-(4-methylsulfanylquinazolin-6-yl)-3-(2-oxoethyl)azetidine- 1-carboxylate (2.40 g, 6.43 mmol) in toluene (1 mL) was added Rh(PPh ₃ ) ₃ Cl (4.16 g, 4.50 mmol). The mixture was stirred at 110 °C for 12 hours under nitrogen. The mixture was filtered and the organic phase was concentrated in vacuo to give a residue. The residue was purified by reversed- phase HPLC (0.1% FA condition) to give tert-butyl 3-methyl-3-(4-(methylthio)quinazolin-6- yl)azetidine-1-carboxylate (0.25 g, 0.72 mmol, 10%) as a yellow oil. m/z ES+ [M+H] ⁺ 346.1. Intermediate 61: 6-Bromo-N-(3-chloro-2,4-difluorophenyl)quinazolin-4-amine Step 1. 6-Bromo-N-(3-chloro-2,4-difluorophenyl)quinazolin-4-amine To a solution of 6-bromo-4-chloro-quinazoline (2 g, 8.23 mmol) in acetonitrile (20 mL) was added 3-chloro-2,4-difluoro-aniline (1.61 g, 9.88 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was filtered and the solid was collected to give 6-bromo-N-(3-chloro-2,4- difluorophenyl)quinazolin-4-amine (3 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.84 (s, 1H), 8.24 - 8.16 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.51 - 7.45 (m, 1H); m/z ES+ [M+3] ⁺ 372.0. Intermediate 62: tert-Butyl 3-(5-cyano-4-(((dimethylamino)methylene)amino)-2- methoxyphenyl)-3-methylazetidine-1-carboxylate

Step 1. Ethyl 2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-cyano-acetate To a solution of ethyl 2-cyanoacetate (5.41 g, 47.8 mmol) in dimethyl sulfoxide (100 mL) was added potassium hydroxide (2.68 g, 47.8 mmol) at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 4 h. Then 1-bromo-5-fluoro-4-methoxy-2-nitro-benzene (9.20 g, 36.8 mmol) was added and the mixture was stirred at 25 °C for 16 hrs. On completion, the reaction mixture was quenched by addition water (40 mL) at 25 °C, and then extracted with ethyl acetate (20 mL x 4). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (80 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ethergradient @ 100 mL/min) to give compound ethyl 2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-cyano-acetate (9.50 g, 27.7 mmol, 75%) as a pink solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (s, 1H), 7.44 (s, 1H), 5.02 (s, 1H), 4.33 - 4.28 (m, 2H), 3.95 (s, 3H), 3.46 (s, 1H), 1.35 - 1.32 (m, 3H). Step 2. Ethyl 2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-cyano-propanoate To a solution of ethyl 2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-cyano-acetate (9.00 g, 26.2 mmol) in dimethyl formamide (50 mL) was added sodium hydride (2.10 g, 52.5 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred at 25 °C for 30 min. Then methyl iodide (11.2 g, 78.69 mmol) was added to the mixture at 0 °C and the mixture was stirred at 25°C for 1 h. On completion, the reaction mixture was poured into water (200 mL). The solid was collected by filtration to give compound ethyl 2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-cyano-propanoate (10.0 g, crude) as a orange solid. Step 3.3-Amino-2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-methyl-prop an-1-ol To a solution of ethyl 2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-cyano-propanoate (8.00 g, 22.4 mmol) in tetrahydrofuran (80 mL) was added borane-dimethylsulfide (10 M, 8.96 mL). The mixture was stirred at 60 °C for 3 hr under nitrogen atmosphere. On completion, the mixture was carefully quenched by addition methanol (50 mL) dropwise and then the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (FA conditon: column: 330g Flash Column Welch Ultimate XB_C18 20-40煱m; 120 A; mobile phase(water(0.1% FA)/MeCN); B%: 0-50% 50 min; 50% 20min) to give compound 3-amino-2- (5-bromo-2-methoxy-4-nitro-phenyl)-2-methyl-propan-1-ol (2.10 g, 6.58 mmol, 25%) as a red solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.74 (s, 1H), 7.57 (s, 1H), 3.94 (s, 3H), 3.90 (s, 2H), 3.28 - 3.18 (m, 2H), 1.37 (s, 3H). Step 4. tert-Butyl N-[2-(5-bromo-2-methoxy-4-nitro-phenyl)-3-hydroxy-2-methyl- propyl]carbamate To a solution of 3-amino-2-(5-bromo-2-methoxy-4-nitro-phenyl)-2-methyl-propan -1-ol (2.00 g, 6.27 mmol) in ethanol (20 mL) was added di-tert-butyl pyrocarbonate (1.50 g, 6.89 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 20 mL/min) to give compound tert- butyl N-[2-(5-bromo-2-methoxy-4-nitro-phenyl)-3-hydroxy-2-methyl-p ropyl]carbamate (2.60 g, 6.21 mmol, 98%) as an orange solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (s, 1H), 7.43 (s, 1H), 4.76 - 4.68 (m, 1H), 3.96 - 3.93 (m, 1H), 3.91 (s, 3H), 3.75 - 3.66 (m, 3H), 3.59 - 3.52 (m, 1H), 1.44 (s, 9H), 1.26 (s, 3H). Step 5. [2-(5-Bromo-2-methoxy-4-nitro-phenyl)-3-(tert-butoxycarbonyl amino)-2- methyl-propyl]methanesulfonate To a solution of tert-butyl N-[2-(5-bromo-2-methoxy-4-nitro-phenyl)-3-hydroxy-2- methyl-propyl]carbamate (2.60 g, 6.20 mmol) and triethylamine (1.88 g, 18.60 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1.07 g, 9.30 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 30 °C for 16 h. On completion, the reaction mixture was quenched by addition water (20 mL) at 20 °C, and then extracted with ethyl acetate (30 mL x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=0/1 to 1/1) to give compound [2-(5- bromo-2-methoxy-4-nitro-phenyl)-3-(tert-butoxycarbonylamino) -2-methyl-propyl] methanesulfonate (2.5 g, 5.03 mmol, 81%) as s yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (s, 1H), 7.44 (s, 1H), 4.70 (d, J = 9.6 Hz, 1H), 4.46 (d, J = 9.6 Hz, 1H), 3.96 (s, 3H), 3.76 - 3.65 (m, 1H), 3.64 - 3.53 (m, 1H), 2.96 (s, 3H), 1.47 (s, 3H), 1.42 - 1.36 (m, 9H). Step 6. tert-Butyl 3-(5-bromo-2-methoxy-4-nitro-phenyl)-3-methyl-azetidine-1- carboxylate To a solution of [2-(5-bromo-2-methoxy-4-nitro-phenyl)-3-(tert-butoxycarbonyl amino)- 2-methyl-propyl] methanesulfonate (670 mg, 1.35 mmol) in dimethylformamide (6 mL) was added sodium bis(trimethylsilyl)amide (1 M, 2.69 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. On completion, the reaction mixture was quenched by sat. ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by flash column chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ethergradient @ 40 mL/min). to give compound tert-butyl 3-(5- bromo-2-methoxy-4-nitro-phenyl)-3-methyl-azetidine-1-carboxy late (250 mg, 0.62 mmol, 46%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (s, 1H), 7.31 (s, 1H), 4.18 (d, J = 8.4 Hz, 2H), 3.91 - 3.88 (m, 5H), 1.60 (s, 3H), 1.46 (s, 9H). Step 7. tert-Butyl 3-(5-cyano-2-methoxy-4-nitro-phenyl)-3-methyl-azetidine-1- carboxylate To a solution of tert-butyl 3-(5-bromo-2-methoxy-4-nitro-phenyl)-3-methyl-azetidine-1- carboxylate (250 mg, 623 μmol) in dimethylformamide (3 mL) was added copper(I) cyanide (112 mg, 1.25 mmol). The mixture was stirred at 130 °C for 16 h under nitrogen. On completion, the mixture was filtered and the filtrate was diluted with water (10 mL), then extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (30 mL x2), dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give compound tert-butyl 3-(5-cyano-2- methoxy-4-nitro-phenyl)-3-methyl-azetidine-1-carboxylate (100 mg, 0.29 mmol, 46%) as a yellow solid. Step 8. tert-Butyl 3-(4-amino-5-cyano-2-methoxy-phenyl)-3-methyl-azetidine-1- carboxylate To a solution of tert-butyl 3-(5-cyano-2-methoxy-4-nitro-phenyl)-3-methyl-azetidine-1- carboxylate (100 mg, 288 μmol) in ethyl acetate (3 mL) was added platinum on carbon (200 mg, 3 wt. % loading). The mixture was stirred at 15 °C for 16 h under hydrogen atmosphere (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give compound tert-butyl 3-(4-amino-5-cyano-2-methoxy-phenyl)-3-methyl-azetidine-1-ca rboxylate (100 mg, crude) as a white solid. Step 9. tert-Butyl 3-[5-cyano-4-[(E)-dimethylaminomethyleneamino]-2-methoxy- phenyl]-3-methyl-azetidine-1-carboxylate To a solution of tert-butyl 3-(4-amino-5-cyano-2-methoxy-phenyl)-3-methyl-azetidine-1- carboxylate (100 mg, 315 μmol) in toluene (3 mL) was added dimethylformamide-dimethyl acetamide (112 mg, 945 μmol). The mixture was stirred at 115 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give compound tert-butyl 3-[5-cyano-4-[(E)- dimethylaminomethyleneamino]-2-methoxy-phenyl]-3-methyl-azet idine-1-carboxylate (120 mg, crude) as a yellow gum. m/z ES+ [M+H] ⁺ 372.9. Intermediate 63: 6-Chloro-N-(3-chloro-2,4-difluorophenyl)pyrido[3,4-d]pyrimid in-4-amine Step 1. 6-Chloro-N-(3-chloro-2,4-difluorophenyl)pyrido[3,4-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (1.00 g, 5.00 mmol) in acetonitrile (20 mL) was added 3-chloro-2,4-difluoro-aniline (981 mg, 6.00 mmol) in acetonitrile (20 mL). The mixture was stirred at 60 °C for 2 hrs. On completion, the mixture was filtered and the filter cake was washed with acetonitrile (10 mL x 2) and petroleum ether (20 mL x 2), then concentrated in vacuo to give 6-chloro-N-(3-chloro-2,4-difluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine (1.60 g, 4.91 mmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.88 (s, 1H), 8.78 (s, 1H), 7.60 -7.56 (m, 1H), 7.48-7.46 (m, 1H); m/z ES+ [M+H] ⁺ 326.9. Intermediate 64: (E)-N’-(6-Chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide ((for alternative synthesis of intermediate 64, refer to intermediate 24) Step 1. (E)-N’-(6-Chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide A solution of 3-amino-6-chloropicolinonitrile (2.00 g, 13.0 mmol) in N,N- dimethylformamide dimethyl acetal (4.41 mL, 32.6 mmol) was heated to 90 °C using microwave irradiation, and stirring was continued for 20 minutes. The mixture was removed from the microwave and allowed to cool to room temperature. The excess reagent was removed in vacuo to afford (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide as a crude brown solid that was carried forward without further purification (2.60 g, 12.5 mmol, 96%). m/z ES+ [M+H] ⁺ 208.9. Intermediate 65: (1S,4S)-tert-Butyl 5-(4-(methylsulfonyl)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate Step 1. 6-Chloro-4-(methylthio)pyrido[3,2-d]pyrimidine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (1.00 g, 5.00 mmol) in acetonitrile (40 mL) was added sodium thiomethoxyde (406 mg, 5.50 mmol). Stirring was continued for 18 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to afford 6-chloro-4-(methylthio)pyrido[3,2-d]pyrimidine as a (1.05 g, 99%, crude) yellow solid. m/z ES+ [M+H] ⁺ 212.2. Step 2. (1S,4S)-tert-Butyl 5-(4-(methylthio)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloro-4-(methylthio)pyrido[3,2-d]pyrimidine (1.06 g, 5.00 mmol) in dimethylsulfoxide (10 mL) was added (1S,4S)-tertbutyl-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (1.09 g, 5.50 mmol) and N,N-diisopropylethylamine (2.63 mL, 15.0 mmol). The mixture was heated to 80 ºC and stirring was continued for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate (10 mM) and acetonitrile (0- 100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford (1S,4S)- tert-butyl 5-(4-(methylthio)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyc lo[2.2.1]heptane-2- carboxylate (801 mg, 2.15 mmol, 43%) as a white solid. m/z ES+ [M+H] ⁺ 374.1. Step 3. (1S,4S)-tert-Butyl 5-(4-(methylsulfonyl)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate A solution of (1S,4S)-tert-butyl 5-(4-(methylthio)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (801 mg, 2.14 mmol) in chloroform (100 mL) was cooled to 0 °C. A solution of 3-chloroperbenzoic acid (388 mg, 2.25 mmol) in chloroform (100 mL) was added dropwise and the cooling bath was removed. Stirring was continued at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford (1S,4S)-tert-butyl 5-(4-(methylsulfonyl)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (760 mg, 1.94 mmol, 91%) as a white solid. m/z ES+ [M+H] ⁺ 390.1 Intermediate 66: But-2-ynoyl chloride Step 1. But-2-ynoyl chloride To a solution of 2-butynoic acid (13.4 mg, 160 μmol) in dichloromethane (0.640 mL) was added dimethylformamide (1.12 μL, 14.5 μmol). The solution was cooled to 0 °C, and oxalyl chloride (13.8 μL, 160 μmol) was added before the cooling bath was removed. Stirring was continued for 5 minutes and the 0.25 M solution of but-2-ynoyl chloride was used as such. Intermediate 67: 6-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,2-d ]pyrimidin-4- amine Step 1. 6-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,2-d ]pyrimidin-4- amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (400 mg, 1.92 mmol) in toluene (5 mL) was added and 1,4-benzodioxan-6-amine (235 μL, 1.92 mmol). Acetic acid (1 mL) was added and the mixture was heated to 90 °C with an oil bath. Stirring was continued for 18 hours. The mixture was cooled and diluted with methanol (5 mL). The solid was collected by vacuum filtration to afford 6-chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6- yl)pyrido[3,2-d]pyrimidin-4-amine as a beige solid (520 mg, 1.65 mmol, 86%). m/z ES+ [M+H] ⁺ 315.0. Intermediate 68: 6-Chloro-N-(2,3,4-trifluorophenyl)pyrido[3,2-d]pyrimidin-4-a mine Step 1. 6-Chloro-N-(2,3,4-trifluorophenyl)pyrido[3,2-d]pyrimidin-4-a mine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 2,3,4-trifluoroaniline (152 μL, 1.44 mmol). Acetic acid (2 mL) was added and the mixture was heated to 110 °C. Stirring was continued for 18 hours. The material was concentrated in vacuo to afford a residue that was purified using silica gel chromatography (40 g cartridge) with heptanes and ethyl acetate (10-100% gradient) as eluent. The pure fractions were collected and concentrated in vacuo to afford 6-chloro- N-(2,3,4-trifluorophenyl)pyrido[3,2-d]pyrimidin-4-amine as a beige solid (120 mg, 388 μmol, 27%). m/z ES+ [M+H] ⁺ 311.1. Intermediate 69: 6-Chloro-N-(2,4-difluoro-3-methylphenyl)pyrido[3,2-d]pyrimid in-4-amine Step 1. 6-Chloro-N-(2,4-difluoro-3-methylphenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 2,4-difluoro-3-methylaniline (162 μL, 1.44 mmol). Acetic acid (2 mL) was added and the mixture was heated to 110 °C. Stirring was continued for 18 hours. The material was concentrated in vacuo to afford a residue that was purified using silica gel chromatography (40 g cartridge) with heptanes and ethyl acetate (10-100% gradient) as eluent. The pure fractions were collected and concentrated in vacuo to afford 6-chloro- N-(2,4-difluoro-3-methylphenyl)pyrido[3,2-d]pyrimidin-4-amin e as a beige solid (380 mg, 1.24 mmol, 86%). m/z ES+ [M+H] ⁺ 307.1. Intermediate 70: 6-Chloro-N-(2,3-difluoro-4-methylphenyl)pyrido[3,2-d]pyrimid in-4-amine Step 1. 6-Chloro-N-(2,3-difluoro-4-methylphenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 2,3-difluoro-4-methylaniline (152 μL, 1.38 mmol). Acetic acid (2 mL) was added and the mixture was heated to 110 °C. Stirring was continued for 18 hours. The material was precipitated in water and methanol and filtered to afford 6-chloro-N-(2,3-difluoro-4-methylphenyl)pyrido[3,2-d]pyrimid in-4-amine (330 mg, 1.08 mmol, 75%) as a brown solid. m/z ES+ [M+H] ⁺ 307.0. Intermediate 71: (1S,4S)-tert-butyl 5-(4-((6-(cyclopropylmethoxy)pyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate Step 1. (1S,4S)-tert-butyl 5-(4-((6-(cyclopropylmethoxy)pyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of (1S,4S)-tert-butyl 5-(4-(methylsulfonyl)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (79.6 mg, 204 μmol) in dimethylsulfoxide (1 mL) was added 6-phenoxypyridin-3-amine (70.3 mg, 428 μmol). The mixture was heated to 50 °C, and stirring was continued for 18 hours. The mixture was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford (1S,4S)-tert- butyl 5-(4-((6-(cyclopropylmethoxy)pyridin-3-yl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate as a beige solid (40.0 mg, 81.6 μmol, 40%). m/z ES+ [M+H] ⁺ 490.3. Intermediate 72: (1S,4S)-tert-butyl 5-(4-(3-chloro-2-fluorophenoxy)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of (1S,4S)-tert-butyl 5-(4-(methylsulfonyl)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (70.0 mg, 180 μmol) in dimethylsulfoxide (1 mL) was added 3-chloro-2-fluorophenol (26.3 mg, 180 μmol) and potassium tert-butoxide (22.6 mg, 198 μmol). The mixture was heated to 50 °C and stirring was continued for 18 hours. The mixture was then cooled to room temperature and purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford (1S,4S)-tert-butyl 5-(4-(3-chloro-2- fluorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate as a beige solid (21 mg, 45.0 μmol, 25%). m/z ES+ [M+H] ⁺ 472.0. Intermediate 73: 6-Chloro-N-(4-chloro-2,3-difluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of (E)-N'-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidam ide (300 mg, 1.44 mmol) in toluene (2 mL) was added 3-chloro-2,4-difluoroaniline (235 mg, 1.41 mmol) and acetic acid (2 mL, 34.8 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature before being diluted with methanol (5 mL) and water (5 mL) and filtered to obtain 6-chloro-N-(4-chloro-2,3-difluorophenyl)pyrido[3,2- d]pyrimidin-4-amine as a brown solid (236 mg, 570 μmol, 50%). m/z ES+ [M+H] ⁺ 326.9. Intermediate 74: 6-Chloro-N-(4-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of (E)-N'-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidam ide (300 mg, 1.44 mmol) in toluene (2 mL) was added 4-chloro-2-fluoroaniline (209 mg, 1.41 mmol) and acetic acid (2 mL, 34.8 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature before being diluted with methanol (5 mL) and water (5 mL) and filtered to afford 6-chloro-N-(4-chloro-2-fluorophenyl)pyrido[3,2- d]pyrimidin-4-amine as a crude brown solid that was carried forward without further purification (430 mg, 1.37 mmol, 97%). m/z ES+ [M+H] ⁺ 309.0. Intermediate 75: 6-Chloro-N-(2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of (E)-N'-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidam ide (300 mg, 1.44 mmol) in toluene (2 mL) was added 2-fluoroaniline (139 μL, 1.44 mmol) and acetic acid (2 mL, 34.8 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature, filtered, and washed with methanol (1 mL) to afford 6-chloro-N-(2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine as a brown solid (290 mg, 1.05 mmol, 73%). m/z ES+ [M+H] ⁺ 274.7. Intermediate 76: 6-Chloro-N-(3-fluoro-2-methoxyphenyl)pyrido[3,2-d]pyrimidin- 4-amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 3-fluoro-2-methoxyaniline (173 μL, 1.44 mmol) and acetic acid (2.00 mL, 34.8 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature, filtered, and washed with methanol (1.00 mL) to afford 6-chloro-N-(3-fluoro-2-methoxyphenyl)pyrido[3,2-d]pyrimidin- 4- amine as a brown solid (340 mg, 1.12 mmol, 78%). m/z ES+ [M+H] ⁺ 304.9. Intermediate 77: 6-Chloro-N-(5-fluoro-6-methoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4-amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 3-amino-5-fluoro-6-methoxypyridine (163 μL, 1.44 mmol) and acetic acid (2 mL, 34.8 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature, filtered, and washed with methanol (1.00 mL) to afford 6-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)pyrido[3,2- d]pyrimidin-4-amine as a brown solid (350 mg, 1.15 mmol, 80%). m/z ES+ [M+H] ⁺ 305.8. Intermediate 78: 6-Chloro-N-(5-chloro-6-methoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4-amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 5-chloro-6-methoxypyridin-3-amine (180 μL, 1.44 mmol) and acetic acid (2 mL, 34.8 mmol. The mixture was heated to 110 °C. Stirring was continued for 18 hours. The mixture was cooled to room temperature, filtered, and washed with methanol (1 mL) to afford 6-chloro-N-(5-chloro-6-methoxypyridin-3-yl)pyrido[3,2-d]pyri midin- 4-amine as a brown solid (360 mg, 1.12 mmol, 78%). m/z ES+ [M+H] ⁺ 321.8. Intermediate 79: 6-Chloro-N-(5-chloropyridin-3-yl)pyrido[3,2-d]pyrimidin-4-am ine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 5-chloro-3-pyridinamine (146 μL, 1.44 mmol) and acetic acid (2 mL, 34.8 mmol) was added and the mixture was heated to 110 °C. Stirring was continued for 18 hours. The mixture was cooled to room temperature, filtered, and washed with methanol (1 mL) to afford 6-chloro-N-(5-chloropyridin-3-yl)pyrido[3,2-d]pyrimidin- 4-amine as a brown solid (350 mg, 1.20 mmol, 83%). m/z ES+ [M+H] ⁺ 291.8. Intermediate 80: 6-Chloro-N-(5-fluoropyridin-3-yl)pyrido[3,2-d]pyrimidin-4-am ine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.44 mmol) in toluene (2 mL) was added 3-amino-5-fluoropyridine (145 μL, 1.44 mmol) and acetic acid (2 mL, 34.8 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was filtered and washed with methanol (1 mL) to afford 6- chloro-N-(5-fluoropyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amin e as a brown solid (300 mg, 1.09 mmol, 76%). m/z ES+ [M+H] ⁺ 275.6. Intermediate 81: 3-((6-Chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluorobenzo nitrile To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (100 mg, 479 μmol) in toluene (2 mL) was added 3-amino-2-fluorobenzonitrile (118 μL, 479 μmol) and acetic acid (1 mL, 17.4 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature, diluted in water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo to afford a residue that was diluted in a minimum volume of methanol and precipitated with cold water (30 mL). The mixture was filtered to afford 3-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluorobenzo nitrile as a light brown solid (26.0 mg, 86.2 μmol, 18%). m/z ES+ [M+H] ⁺ 326.8. Intermediate 82: 6-Chloro-N-(3,5-difluoro-4-methylpyridin-2-yl)pyrido[3,2-d]p yrimidin-4- amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (200 mg, 959 μmol) in toluene (1 mL) was interadded 3,5-difluoro-4-methylpyridin-2-amine (138 mg, 911 μmol) and acetic acid (1 mL, 17.3 mmol). The mixture was heated to 110 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature, diluted in water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo to afford a crude residue that was purified using C18 reverse phase chromatography (30 g) with ammonium formate (10 mM) and acetonitrile (10-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford 6-chloro-N-(3,5-difluoro-4-methylpyridin-2-yl)pyrido[3,2-d]p yrimidin-4- amine as a white solid (100 mg, 309 μmol, 34%). m/z ES+ [M+H] ⁺ 326.8. Intermediate 83: Benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[3.1.0]hexane-3-carbox ylate, potassium salt Step 1. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H-pyrrol To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate (1.00 g, 3.39 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (660 mg, crude) as a white solid. Step 2. Benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H-pyrrole- 1-carboxylate To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H-pyrrole (661 mg, 3.39 mmol) in tetrahydrofuran (10 mL) was added triethylamine (1.71 g, 16.9 mmol) and benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.01 g, 4.07 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ethyl acetate = 10/1 to 5/1) to give benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H-pyrrole-1- carboxylate (800 mg, 2.43 mmol, 72%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 - 7.28 (m, 6H), 6.50 - 6.43 (m, 1H), 5.18 - 5.15 (m, 2H), 4.35 - 4.28 (m, 4H), 1.28 (d, J = 2.3 Hz, 12H). Step 3. Benzyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate To a solution of diethylzinc (1.0 M, 18.7 mL) in dry dichloromethane (20 mL) was added diiodomethane (10.0 g, 37.4 mmol) slowly at -40 °C, the mixture was stirred at -40 °C for 1 h. Then trifluoroacetic acid (2.13 g, 18.7 mmol) was added slowly at -40 °C and the mixture was stirred at -15 °C for 1 h. Benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydropyrrole-1-carboxylate (769 mg, 2.34 mmol) was added slowly at -15 °C, and the mixture was then stirred at 20 °C for 16 h. On completion, the reaction mixture was quenched by saturated sodium bicarbonate (10 mL) at 20 °C, and then extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ethyl acetate = 10/1 to 5/1) to give benzyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo [3.1.0]hexane-3- carboxylate (520 mg, 1.52 mmol, 65%) as a white oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 - 7.26 (m, 5H), 5.14 - 5.03 (m, 2H), 3.77 - 3.66 (m, 1H), 3.62 - 3.41 (m, 3H), 1.69 - 1.64 (m, 1H), 1.23 (s, 12H), 0.99 (dd, J = 4.2, 7.3 Hz, 1H), 0.48 - 0.37 (m, 1H). Step 4. Benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[3.1.0]hexane-3-carbox ylate, potassium salt To a solution of benzyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- azabicyclo[3.1.0] hexane-3-carboxylate (440 mg, 1.34 mmol) in methanol (8.0 mL) was added potassium bifluoride (731 mg, 9.36 mmol). The mixture was stirred at 75 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was triturated with petroleum ether (6.0 mL) at 20 °C for 2 min and then filtered. The filter cake was washed with hot acetonitrile (50 °C, 6.0 mL) and then filtered. The filtrate was concentrated in vacuo to give benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[3.1.0]hexane-3-carbox ylate, potassium salt (340 mg, 1.05 mmol, 79%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.40 - 7.27 (m, 5H), 5.00 (br. s, 2H), 3.47 - 3.37 (m, 1H), 3.26 - 3.17 (m, 3H), 0.99 (br. s, 1H), 0.39 (br. s, 1H), -0.37 (br. s, 1H). Intermediate 84: tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- hydroxypyrrolidine-1-carboxylate Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-hydro xy- pyrrolidine-1carboxylate To a mixture of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (2.00 g, 5.17 mmol) in tetrahydrofuran (20 mL) was added n-butyl lithium (2.5 M in toluene, 4.13 mL) over 30 min slowly at -60 °C under nitrogen atmosphere. The mixture was stirred at -60 °C for 30 min. Then tert-butyl 3-oxopyrrolidine-1-carboxylate (2.87 g, 15.5 mmol) in tetrahydrofuran (6 mL) was added slowly at -60 °C and the resulting mixture was stirred at -60 °C for 0.5 hr and 20 °C for 1 hr. On completion, the mixture was quenched with saturated ammonium chloride (40 mL). The aqueous phase was extracted with ethyl acetate (35 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 5/1 to 1/1] to afford tert-butyl 3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-hydroxy-pyrrolidine-1carboxylate (560 mg, 1.13 mmol, 21%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J = 12.4 Hz, 1H), 8.44 - 8.16 (m, 2H), 8.01 - 7.90 (m, 1H), 7.90 - 7.84 (m, 1H), 7.83 - 7.73 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 3.94 - 3.62 (m, 4H), 2.54 - 2.18 (m, 2H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 493.3. Intermediate 85: Benzyl 1-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate Step 1. Benzyl 1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate A mixture of (3-benzyloxycarbonyl-3-azabicyclo[3.1.0]hexan-1-yl)-trifluor o- boron;potassium hydride (223 mg, 691 μmol), 6-bromo-N-(3,4-dichloro-2-fluoro- phenyl)quinazolin-4-amine (227 mg, 587 μmol), cesium carbonate (676 mg, 2.08 mmol), [2-(2- aminophenyl) phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methan esulfonate (50.3 mg, 69.1 μmol) in toluene (0.50 mL) and water (0.05 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched by water (2.0 mL) at 20 °C, and then extracted with ethyl acetate (2.0 mL × 3). The combined organic layers were washed with brine (2.0 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ethyl acetate = 10/1 to 5/1) to give benzyl1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3 - azabicyclo[3.1.0]hexane-3-carboxylate (135 mg, 258 μmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (d, J = 14.8 Hz, 1H), 8.49 (s, 1H), 8.30 (d, J = 16.4 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.61 (s, 2H), 7.45 - 7.28 (m, 5H), 5.12 (br. s, 2H), 4.12-4.03 (m, 1H), 3.83 (d, J = 10.4 Hz, 1H), 3.75 - 3.58 (m, 2H), 2.22 (s, 1H), 1.30 - 1.24 (m, 2H). Intermediate 86: tert-Butyl 3-(4-chloroquinazolin-6-yl)pyrrolidine-1-carboxylate Step 1. tert-Butyl 3-(4-hydroxyquinazolin-6-yl)pyrrolidine-1-carboxylate To an 40 mL vial equipped with a stir bar was added 6-bromoquinazolin-4-ol (1 g, 4.44 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (1.44 g, 5.78 mmol), sodium carbonate (942 mg, 8.89 mmol), NiCl ₂ .dtbbpy (8.84 mg, 22.22 μmol), tris(trimethylsilyl)silane (1.10 g, 4.44 mmol, 1.37 mL) and Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (49.9 mg, 44.4 μmol) in 1,2-dimethoxyethane (15 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hr under nitrogen. On completion, the mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was washed with water (2 x 50 mL) and brine (2 x 50 mL), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 5/1 to 1/1) to give tert-butyl 3-(4-hydroxyquinazolin-6-yl)pyrrolidine-1- carboxylate (1.1 g, 3.49 mmol, 78%) as a light yellow solid. m/z ES+ [M+H] ⁺ 316.1; Step 2. tert-Butyl 3-(4-chloroquinazolin-6-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl 3-(4-hydroxyquinazolin-6-yl)pyrrolidine-1-carboxylate (1.00 g, 3.17 mmol) in toluene (10 mL) was added diisopropylethylamine (2.05 g, 15.8 mmol) and phosphorus oxychloride (583 mg, 3.81 mmol). The reaction mixture was stirred at 110 °C for 4 hr. The mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel. Petroleum ether/Ethyl acetate=1:2 to 1:4) to give tert-butyl 3-(4-chloroquinazolin-6- yl)pyrrolidine-1-carboxylate (700 mg, 2.10 mmol, 66%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 2.0, 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 3.76 (dd, J = 7.6, 10.0 Hz, 1H), 3.56 (dd, J = 6.4, 10.8 Hz, 1H), 3.48 (ddd, J = 2.4, 8.0, 10.8 Hz, 1H), 3.38 - 3.28 (m, 1H), 3.23 (d, J = 12.4 Hz, 1H), 2.26 (s, 1H), 2.07 - 1.94 (m, 1H), 1.41 (d, J = 2.8 Hz, 9H). Intermediate 87: N-(6-Bromoquinazolin-4-yl)-7-fluorobenzo[d]isothiazol-6-amin e Step 1. N-(6-Bromoquinazolin-4-yl)-7-fluorobenzo[d]isothiazol-6-amin e A solution of 6-bromo-4-chloro-quinazoline (1.00 g, 4.11 mmol) and 7-fluoro-1,2- benzothiazol-6-amine (0.76 g, 4.52 mmol) in acetonitrile (20 mL) was stirred at 60 °C for 1 hour. On completion, the suspension was filtered and the filter cake was washed with acetonitrile (10 mL), concentrated to give N-(6-bromoquinazolin-4-yl)-7-fluorobenzo[d]isothiazol-6-amin e (1.50 g, 4.00 mmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 375.1; Intermediate 88: 6-Bromo-4-(3,4-dichloro-2-fluorophenoxy)quinazoline Step 1. 6-Bromo-4-(3,4-dichloro-2-fluorophenoxy)quinazoline A solution of 6-bromo-4-chloro-quinazoline (672.7 mg, 2.76 mmol), 3,4-dichloro-2- fluoro-phenol (500 mg, 2.76 mmol) and potassium carbonate (763.6 mg, 5.53 mmol) in acetonitrile (5 mL) was stirred at 60 °C for 2 hrs. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was recrystallized in dimethyl sulfoxide (15 mL) and then filtered. The filter cake was collected to give 6-bromo-4-(3,4-dichloro-2- fluoro-phenoxy)quinazoline (670 mg, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 2.0, 8.8 Hz, 1H), 7.97 - 7.90 (m, 1H), 7.40 (dd, J = 2.0, 9.2 Hz, 1H), 7.23 (dd, J = 7.6, 8.8 Hz, 1H). Intermediate 89: 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-am ine Step 1. 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-am ine To a solution of 6-bromo-4-chloro-7-methoxy-quinazoline (400 mg, 1.46 mmol) in acetonitrile (6 mL) was added 3-chloro-2-fluoro-aniline (234 mg, 1.61 mmol). The mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was filtered and the filter cake was collected to give 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-methoxy-quinazolin-4- amine (500 mg, 1.31 mmol, 89%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.96 (s, 1H), 7.69 - 7.60 (m, 1H), 7.57 - 7.48 (m, 2H), 7.37 (dt, J = 1.2, 8.0 Hz, 1H), 6.94 - 6.88 (m, 1H), 6.85 - 6.80 (m, 1H), 6.76 - 6.70 (m, 1H), 4.08 (s, 3H). Intermediate 90: Benzyl 1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate Step 1. Benzyl 1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-amine (218 mg, 619 μmol) and (3-benzyloxycarbonyl-3-azabicyclo[3.1.0]hexan-1-yl)-trifluor o-boron;potassium hydride (200 mg, 618 μmol) in toluene (5 mL) and water (1 mL) was added cesium carbonate (605 mg, 1.86 mmol) and catacxium (R) A PD G3 (45.1 mg, 61.9 μmol) at 20 °C, the mixture was stirred at 110 °C for 12 hr under nitrogen. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ethyl acetate = 10/1 to 1/1) to give benzyl 1-[4-(3-chloro-2-fluoro- anilino)quinazolin-6-yl]-3-azabicyclo[3.1.0]hexane-3-carboxy late (170 mg, 347 μmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 (d, J = 14.8 Hz, 1H), 8.48 (s, 1H), 8.31 (d, J = 15.7 Hz, 1H), 7.76 - 7.64 (m, 2H), 7.53 (t, J = 7.2 Hz, 2H), 7.43 - 7.28 (m, 6H), 5.12 (s, 2H), 4.16 - 4.03 (m, 1H), 3.84 (d, J = 10.6 Hz, 1H), 3.77 - 3.56 (m, 2H), 2.28-2.17 (m, 1H), 1.33 - 1.23 (m, 1H), 1.00 - 0.91 (m, 1H). Intermediate 91: tert-Butyl 3-(6-cyano-5-(((dimethylamino)methylene)amino)pyridin-2- yl)imidazolidine-1-carboxylate Step 1. tert-Butyl 3-(6-cyano-5-nitropyridin-2-yl)imidazolidine-1-carboxylate To a solution of 6-chloro-3-nitro-pyridine-2-carbonitrile (300 mg, 1.63 mmol) in 1- methylpyrrolidin-2-one (10 mL) was added diisopropylethylamine (634 mg, 4.90 mmol) and tert-butyl imidazolidine-1-carboxylate (338 mg, 1.96 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 2:1 to 1:1) to give tert-butyl 3-(6-cyano-5-nitro-2-pyridyl)imidazolidine-1-carboxylate (1.2 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J = 9.6 Hz, 1H), 6.59 - 6.40 (m, 1H), 4.87 (s, 2H), 3.84 - 3.60 (m, 4H), 1.45 (s, 9H). Step 2. tert-Butyl 3-(5-amino-6-cyanopyridin-2-yl)imidazolidine-1-carboxylate To a solution of tert-butyl 3-(6-cyano-5-nitro-2-pyridyl)imidazolidine-1-carboxylate (300 mg, 940 μmol) in ethyl acetate (3.0 mL) was added Pt/V/C (150mg, 18.3 μmol, 3% purity) under nitrogen. The suspension was degassed and purged with hydrogen for 3 times. The mixture was stirred at 25°C for 3 hr under hydrogen (15 psi). On completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give tert-butyl 3-(5- amino-6-cyano-2-pyridyl)imidazolidine-1-carboxylate (300 mg, crude) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.23 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 5.59 (s, 2H), 4.56 (s, 2H), 3.53 (dd, J = 4.4, 17.2 Hz, 4H), 1.44 (s, 9H). Step 3. tert-Butyl 3-(6-cyano-5-(((dimethylamino)methylene)amino)pyridin-2- yl)imidazolidine-1-carboxylate To a solution of tert-butyl 3-(5-amino-6-cyano-2-pyridyl)imidazolidine-1-carboxylate (140 mg, 484 μmol) in toluene (3.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (173 mg, 1.45 mmol). The mixture was stirred at 110 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl 3-(6-cyano-5- (((dimethylamino)methylene)amino)pyridin-2-yl)imidazolidine- 1-carboxylate (200 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 345.3. Aniline-1: 4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)aniline Step 1. 4-(4-Nitrophenoxy)pyridin-2-amine To a solution of 4-nitrophenol (5.41 g, 38.9 mmol) in N-methylpyrrolidone (50 mL) was added 4-chloropyridin-2-amine (5 g, 38.9 mmol) and N,N-diisopropylethylamine (15.1 g, 116 mmol), the mixture was stirred at 140 °C for 48 hr. On completion, the mixture was quenched by addition water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL x 3), dried over sodium sulphate, filtrated and concentrated in vacuum to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 3/1~0/1) to give 4-(4-nitrophenoxy)pyridin-2-amine (5.5 g, 23.8 mmol, 61%) as a yellow solid. Step 2. N,N-Dimethyl-N'-(4-(4-nitrophenoxy)pyridin-2-yl)formimidamid e To a solution of 4-(4-nitrophenoxy)pyridin-2-amine (5 g, 21.6 mmol) in ethanol (5 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (7.73 g, 64.9 mmol), the mixture was stirred at 80 °C for 16 hr. On completion, the mixture was concentrated in vacuum to give N,N-dimethyl- N'-(4-(4-nitrophenoxy)pyridin-2-yl)formimidamide (6.2 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 287.3. Step 3. N-Hydroxy-N'-(4-(4-nitrophenoxy)pyridin-2-yl)formimidamide To a solution of N,N-dimethyl-N'-(4-(4-nitrophenoxy)pyridin-2-yl)formimidamid e (6.2 g, 21.6 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (1.81 g, 26.0 mmol), the mixture was stirred at 50 °C for 3 hr under nitrogen. On completion, the mixture was filtrated and the filter cake was concentrated in vacuum to give N-hydroxy-N'-(4-(4-nitrophenoxy)pyridin-2- yl)formimidamide (2.6 g, crude) as a yellow solid. Step 4.7-(4-Nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine To a solution of N-hydroxy-N'-[4-(4-nitrophenoxy)-2-pyridyl]formamidine (2.6 g, 9.48 mmol) in tetrahydrofuran (30 mL) was added trifluoroacetic anhydride (2.59 g, 12.3 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 6 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 3/1~0/1) to give 7-(4-nitrophenoxy)- [1,2,4]triazolo[1,5-a]pyridine (1.6 g, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (d, J = 7.6 Hz, 1H), 8.49 (s, 1H), 8.33 - 8.29 (m, 2H), 7.52 (d, J = 2.4 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.12 (dd, J = 2.4, 7.6 Hz, 1H). Step 5.4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)aniline To a solution of 7-(4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 5.85 mmol) in ethanol (20 mL) was added platinum on carbon (0.75 g, 86.19 μmol, 3 wt. % loading). The mixture was stirred at 25 °C for 1 hr under hydrogen (15 psi). On completion, the mixture was filtrated and the filtrate was concentrated in vacuum to give 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline (1.3 g, crude) as a yellow solid. Aniline-2: 5-Phenoxypyridin-2-amine Step 1. 2-Nitro-5-phenoxypyridine To a solution of phenol (2.32 g, 24.6 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (1.08 g, 27.0 mmol, 60% in mineral oil) at 0 °C and followed by addition of 5-bromo-2-nitro-pyridine (5 g, 24.6 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 25 °C for 12 hr. On completion, the mixture was poured into saturated ammonium chloride (20 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 50/1) to give 2-nitro-5-phenoxypyridine (2.5 g, 11.5 mmol, 46%) as a yellow solid. m/z ES+ [M+H] ⁺ 217.0. Step 2.5-Phenoxypyridin-2-amine To a solution of 2-nitro-5-phenoxypyridine (2 g, 9.25 mmol) in methanol (30 mL) was added Pd/C (0.2 g, 10% loading) under hydrogen, and then the mixture was stirred at 25 °C for 12 hr under hydrogen (15 psi). The resulting mixture was dissolved in methanol (20 mL) and filtered. The filtrate was concentrated to give 5-phenoxypyridin-2-amine (1.7 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (d, J = 2.8 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.22 - 7.19 (m, 1H), 7.06 - 7.04 (m, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 8.8 Hz, 1H), 4.48 (s, 2H). Aniline-3: 5-Chloro-6-phenoxypyridin-3-amine (approach #1) Step 1. 3-Chloro-5-nitro-2-phenoxypyridine To a solution of 2-bromo-3-chloro-5-nitro-pyridine (980 mg, 4.13 mmol) in dimethylsulfoxide (20 mL) was added cesium carbonate (2.69 g, 8.25 mmol) and phenol (388 mg, 4.13 mmol). The mixture was stirred at 60 °C for 12 hr. On completion, the mixture was quenched with water (20 mL) and filtered. The filter cake was collected and triturated with water (30 mL) to give 3-chloro-5-nitro-2-phenoxy-pyridine (400 mg, 1.60 mmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.95 (d, J = 4.0 Hz, 1H), 8.88 (d, J = 4.0 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.35 - 7.30 (m, 1H), 7.28 - 7.24 (m, 2H). Step 2.5-Chloro-6-phenoxypyridin-3-amine To a solution of 3-chloro-5-nitro-2-phenoxy-pyridine (400 mg, 398 μmol) in methanol (12.0 mL) was added platinum on carbon (200 mg, 505 μmol, 3 wt. % loading) in one portion at 25 °C under hydrogen. The mixture was stirred at 25 °C under hydrogen (15 psi) for 1 hr. On completion, the mixture was filtered and concentrated to give 5-chloro-6-phenoxy-pyridin-3- amine (320 mg, 362 μmol, 91%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.92 (d, J = 8.0 Hz, 2H), 5.44 (s, 2H); m/z ES+ [M+H] ⁺ 221.1. Aniline-3: 5-Chloro-6-phenoxypyridin-3-amine (approach#2) Step 1. 3-Chloro-5-nitro-2-phenoxypyridine To a solution of 2,3-dichloro-5-nitropyridine (900 mg, 4.66 mmol) in dimethylsulfoxide (10 mL) was added phenol (0.410 mL, 4.66 mmol) and N,N-diisopropylethylamine (1.62 mL, 9.33 mmol). The mixture was heated to 120 °C using an oil bath and stirring was continued for 1 hour. The mixture was removed from the oil bath and allowed to cool to room temperature before it was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulphate, filtered, and concentrated in vacuo to afford 3-chloro-5-nitro-2-phenoxypyridine as a dark solid that was carried forward without further purification. m/z ES+ [M+H] ⁺ 250.9. Step 2. 5-Chloro-6-phenoxypyridin-3-amine To a solution of 3-chloro-5-nitro-2-phenoxypyridine in a mixture of tetrahydrofuran (20 mL), methanol (10 mL), and water (10 mL) was added iron powder (315 mg, 5.59 mmol) and ammonium chloride (1.25 g, 23.3 mmol). The mixture was heated to 80 °C and stirring was continued for 18 hours. The mixture was filtered through a frit filter and diluted with water (100 mL) before the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 5-chloro-6-phenoxypyridin-3- amine as a clear oil (1.00 g, 4.53 mmol99% over two steps). m/z ES+ [M+H] ⁺ 221.0. Aniline-4: 3-Chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline Step 1. 3-(2-Chloro-4-nitrophenoxy)-1-methyl-1H-pyrazole A mixture of 2-chloro-1-fluoro-4-nitro-benzene (1.00 g, 5.70 mmol), 1-methylpyrazol-3- ol (558 mg, 5.70 mmol) and potassium carbonate (2.36 g, 17.0 mmol) in N,N-dimethylformamide (10.0 mL) was stirred at 100 °C for 1 hr. On completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-(2-chloro-4-nitro-phenoxy)-1-methyl-pyrazole (1.30 g, 5.12 mmol, 90%) as a red oil. m/z ES+ [M+H] ⁺ 254.1. Step 2.3-Chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline To a mixture of 3-(2-chloro-4-nitro-phenoxy)-1-methyl-pyrazole (1.20 g, 4.73 mmol) in ethanol (5.0 mL) and water (5.0 mL) was added iron powder (1.32 g, 23.6 mmol) and ammonium chloride (2.53 g, 47.3 mmol), the reaction mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtered and the filtrate was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-4-(1-methylpyrazol-3- yl)oxy-aniline (1.00 g, 4.46 mmol, 95%) as a yellow oil. m/z ES+ [M+H] ⁺ 224.3. Aniline-5: 4-((1,3-Dioxan-2-yl)methoxy)-3-chloroaniline Step 1. 2-(2-Chloro-4-nitrophenoxy)ethanol To a solution of 1,2-dichloro-4-nitro-benzene (10 g, 52 mmol) and ethylene glycol (6.5 g, 104 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (7.20 g, 52 mmol). The mixture was stirred at 60 °C for 12 hr. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1:1) to give 2-(2-chloro-4-nitrophenoxy)ethanol (4.2 g, 19.4 mmol, 37%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.26 (m, 1H), 8.18 (m, 1H), 7.36 (m, 1H), 4.99 (m, 1H), 4.24 (m, 2H), 3.79 (m, 2H). Step 2.2-(2-Chloro-4-nitrophenoxy)acetaldehyde To a solution of oxalyl chloride (0.29 g, 2.28 mmol) in dichloromethane (16 mL) was added dimethylsulfoxide (0.35 g, 4.41 mmol) at -78 °C under nitrogen. After being stirred for 0.5 hr, a solution of 2-(2-chloro-4-nitro-phenoxy)ethanol (0.4 g, 1.84 mmol) in anhydrous dichloromethane (4 mL) was added dropwise. The mixture was stirred at -78 °C for 0.5 hr and then triethylamine (0.93 g, 9.19 mmol) was added dropwise. After being stirred at -78 °C for 30 min, the reaction was allowed to warm to 25 °C and stirred for 1 hr. The reaction mixture was acidified with aq. hydrochloric acid (2 N) to pH = 4 and then extracted with dichloromethane (3 x 400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-chloro-4-nitrophenoxy)acetaldehyde (400 mg, crude) as a yellow solid. Step 3. 2-((2-Chloro-4-nitrophenoxy)methyl)-1,3-dioxane To a solution of 2-(2-chloro-4-nitro-phenoxy)acetaldehyde (200 mg, 0.93 mmol) in toluene (2 mL) was added p-toluenesulfonic acid (14 mg, 83.5 μmol) and propane-1,3-diol (77.5 mg, 1.02 mmol). The mixture was stirred at 100 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate =1:1) to give 2-((2-chloro-4- nitrophenoxy)methyl) -1,3-dioxane (130 mg, 0.48 mmol, 51%) as a yellow solid. Step 4.4-((1,3-Dioxan-2-yl)methoxy)-3-chloroaniline To a solution of 2-[(2-chloro-4-nitro-phenoxy)methyl]-1,3-dioxane (100 mg, 0.37 mmol) in ethanol (1 mL) and water (1 mL) was added iron powder (0.1 g, 1.83 mmol) and ammonium chloride (0.2 g, 3.65 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give 4-((1,3-dioxan-2-yl)methoxy)-3- chloroaniline (60 mg, crude) as a yellow oil. m/z ES+ [ ⁺ 244.1. Aniline-6: 2-Fluoro-4-phenoxyaniline Step 1. 2-Fluoro-1-nitro-4-phenoxybenzene To a solution of 3-fluoro-4-nitro-phenol (2.00 g, 12.7 mmol), phenylboronic acid (2.33 g, 19.1 mmol) and 4Å MS (2.00 g) in dichloromethane (60.0 mL) was added copper acetate (4.62 g, 25.46 mmol) and triethylamine (6.40 g, 63.2 mmol). The mixture was stirred at 25 °C for 6 h under oxygen (15 psi). On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 10:1) to give 2- fluoro-1-nitro-4-phenoxy-benzene (0.60 g, 2.57 mmol, 20%) as a yellow solid. Step 2.2-Fluoro-4-phenoxyaniline To a mixture of 2-fluoro-1-nitro-4-phenoxy-benzene (600 mg, 2.57 mmol) in tetrahydrofuran (6.00 mL) was added platinum on carbon (350 mg, 1.34 mmol, 3 wt. % loading). The reaction mixture was stirred at 25 °C under hydrogen (15 Psi) for 1 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give 2-fluoro-4-phenoxy-aniline (480 mg, 2.36 mmol, 92%) as a brown oil. m/z ES+ [M+H] ⁺ 204.3. Aniline-7: 3-Chloro-4-((tetrahydrofuran-3-yl)methoxy)aniline Step 1.3-((2-Chloro-4-nitrophenoxy)methyl)tetrahydrofuran To a solution of 2-chloro-1-fluoro-4-nitro-benzene (2.00 g, 11.3 mmol) and tetrahydrofuran-3-ylmethanol (1.50 g, 14.7 mmol) in N,N-dimethylformamide (20.0 mL) was added sodium hydride (902 mg, 22.5 mmol, 60% in mineral oil). The mixture was stirred at 20 °C for 4 hr. On completion, the reaction mixture was quenched by saturated ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 5/1) to give 3-[(2-chloro-4-nitro- phenoxy)methyl]tetrahydrofuran (400 mg, 1.36 mmol, 12%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 2.8 Hz, 1H), 8.16 (dd, J = 2.8, 9.2 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 4.13 - 4.04 (m, 2H), 3.99 - 3.91 (m, 2H), 3.87 - 3.75 (m, 2H), 2.91 - 2.76 (m, 1H), 2.27 - 2.12 (m, 1H), 1.89 - 1.73 (m, 1H). Step 2.3-Chloro-4-((tetrahydrofuran-3-yl)methoxy)aniline To a solution of 3-[(2-chloro-4-nitro-phenoxy)methyl]tetrahydrofuran (400 mg, 1.55 mmol) in methanol (5.0 mL) was added platinum on carbon (200 mg, 3 wt. % loading). The mixture was stirred at 20 °C for 2 hr under hydrogen (15 psi). On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 3-chloro-4-(tetrahydrofuran-3- ylmethoxy)aniline (300 mg, crude) as a black oil. m/z ES+ [M+H] ⁺ 228.0. Aniline-8: 2-Fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline Step 1. 3-(3-Fluoro-4-nitrophenoxy)-1-methyl-1H-pyrazole & 3-(5-fluoro-2- nitrophenoxy)-1-methyl-1H-pyrazole A mixture of 2,4-difluoro-1-nitro-benzene (0.5 g, 3.14 mmol), 1-methylpyrazol-3-ol (308 mg, 3.14 mmol) and potassium carbonate (1.09 g, 7.86 mmol) in N,N-dimethylformamide (5 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 1 hours under nitrogen atmosphere. On completion the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x40mm, 15 um;mobile phase: [water(0.225%FA)-ACN];B%: 28%-58%,10 min) to give 3-(5-fluoro-2-nitro-phenoxy)-1-methyl-pyrazole (110 mg, 462 μmol, 14.7%) as a yellow oil and 3-(3-fluoro-4-nitro-phenoxy)-1-methyl-pyrazole (60 mg, 253 μmol, 8.1%) as a yellow oil. 3-(5-fluoro-2-nitrophenoxy)-1-methyl-1H-pyrazole: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 - 7.99 (m, 1H), 7.32 - 7.27 (m, 1H), 7.02 - 6.98 (m, 1H), 6.91 - 6.84 (m, 1H), 5.94 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H). 3-(3-Fluoro-4-nitrophenoxy)-1-methyl-1H-pyrazole: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 - 8.07 (m, 1H), 7.35 - 7.27 (m, 1H), 7.04 - 6.96 (m, 2H), 5.93 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H). Step 2.2-Fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline To a solution of 3-(5-fluoro-2-nitro-phenoxy)-1-methyl-pyrazole (110 mg, 464 μmol) in ethyl acetate (2 mL) was added platinum on carbon (50 mg, 3 wt. % loading) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. The mixture was stirred under hydrogen (15 Psi) at 25 °C for 1 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give 4-fluoro-2-(1-methylpyrazol-3-yl)oxy-aniline (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 208.2. Aniline-9: 3-Chloro-2-fluoro-4-methoxyaniline Step 1.2-Chloro-3-fluoro-1-methoxy-4-nitrobenzene To the solution of 2-chloro-3-fluoro-4-nitro-phenol (200 mg, 1.04 mmol) and potassium carbonate (721.5 mg, 5.22 mmol) in acetone (5.0 mL) was added methyl iodide (741 mg, 5.22 mmol, 325 uL). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-3-fluoro-1- methoxy-4-nitro- benzene (200 mg, 0.98 mmol, 74%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 - 7.98 (m, 1H), 6.75 (dd, J = 1.6, 9.2 Hz, 1H), 3.97 (s, 3H). Step 2.3-Chloro-2-fluoro-4-methoxyaniline To the solution of 2-chloro-3-fluoro-1-methoxy-4-nitro-benzene (200 mg, 972 μmol) in methanol (2.0 mL) and water (2.0 mL) was added iron powder (472 mg, 8.46 mmol) and ammonium chloride (572 mg, 10.7 mmol), the mixture was stirred at 80°C for 2 hr. On completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 3- chloro- 2-fluoro-4-methoxy -aniline (180 mg, 1.02 mmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 6.83 - 6.78 (m, 1H), 6.77 - 6.73 (m, 1H), 4.98 (s, 2H), 3.83 - 3.76 (m, 3H); m/z ES+ [M+H] ⁺ 176.1. Aniline-10: 3-Chloro-4-(oxetan-3-ylmethoxy)aniline Step 1.3-((2-Chloro-4-nitrophenoxy)methyl)oxetane Sodium hydride (680 mg, 17.0 mmol, 60% in mineral oil) was added portionwise to the mixture of oxetan-3-ylmethanol (1.50 g, 17.0 mmol) in N,N-dimethylformamide (15 mL) at 0 °C. The suspension was stirred at 0 °C for 30 minutes under nitrogen atmosphere. Then 2-chloro-1- fluoro-4-nitro-benzene (2.49 g, 14.1 mmol) was added, and then the mixture was stirred at 0 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was partitioned between water (60 mL) and ethyl acetate (60 mL). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-[(2- chloro-4-nitro-phenoxy)methyl]oxetane (3.20 g, 15.8 mmol, 74%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J = 2.8 Hz, 1H), 8.26 (dd, J = 2.8, 9.2 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 4.73 (dd, J = 6.0, 8.0 Hz, 2H), 4.50 - 4.44 (m, 4H), 3.54 - 3.41 (m, 1H). Step 2.3-Chloro-4-(oxetan-3-ylmethoxy)aniline A mixture of 3-[(2-chloro-4-nitro-phenoxy)methyl]oxetane (3.10 g, 12.7 mmol) and platinum on carbon (100 mg, 1.27 mmol, 3 wt. % loading) in ethyl acetate (30 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 20 °C for 2 hr under hydrogen (15 psi) atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , pure dichloromethane) to give 3-chloro-4-(oxetan-3-ylmethoxy)aniline (1.30 g, 6.1 mmol, 48%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.90 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 6.48 (dd, J = 2.8, 8.8 Hz, 1H), 4.97 (s, 2H), 4.68 (dd, J = 6.0, 8.0 Hz, 2H), 4.42 (t, J = 6.0 Hz, 2H), 4.09 (d, J = 6.8 Hz, 2H), 3.32 - 3.22 (m, 1H); m/z ES+ [M+H] ⁺ 214.2. Aniline-11: 5-Chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline Step 1.3-(2-Chloro-5-fluoro-4-nitrophenoxy)-1-methyl-1H-pyrazole To a solution of 1-methylpyrazol-3-ol (500 mg, 5.10 mmol) in anhydrous tetrahydrofuran (20.0 mL) was added sodium hydride (245 mg, 6.13 mmol, 60% in mineral oil) at 0 °C. After addition, the mixture was stirred at this temperature for 0.2 hr, and then 1-chloro-2,4-difluoro-5- nitro-benzene (1.00 g, 5.17 mmol) was added at 0 °C. The resulting mixture was stirred at 0 °C for 1 hr. On completion, the reaction mixture was quenched by addition ammonium chloride aqueous (50 mL) at 20 °C, and then extracted with ethyl acetate (50 mL × 3). The organic layer was concentrated to give 3-(2-chloro-5-fluoro-4-nitro-phenoxy)-1-methyl-pyrazole (1.14 g, 4.2 mmol, 80%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 - 8.42 (m, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 12.4 Hz, 1H), 6.10 (d, J = 2.4 Hz, 1H), 3.79 (s, 3H); m/z ES+ [M+H] ⁺ 272.0. Step 2.5-Chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline To a solution of 3-(2-chloro-5-fluoro-4-nitro-phenoxy)-1-methyl-pyrazole (940 mg, 3.46 mmol) in tetrahydrofuran (20.0 mL) was added platinum on carbon (200 mg, 3 wt. % loading). The mixture was stirred at 20 °C for 2 hr under hydrogen (15 psi). On completion, the mixture was filtered and the filtrate was concentrated to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give 5-chloro-2-fluoro-4-(1-methylpyrazol-3- yl)oxy-aniline (300 mg, 1.24 mmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.54 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 12.0 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 5.64 (d, J = 2.4 Hz, 1H), 5.27 (s, 2H), 3.67 (s, 3H); m/z ES+ [M+H] ⁺ 242.3. Aniline-12: 1-(3-Chloro-2-fluorophenyl)ethanamine Step 1. N-(1-(3-Chloro-2-fluorophenyl)ethylidene)-2-methylpropane-2- sulfinamide To a solution of 1-(3-chloro-2-fluoro-phenyl)ethanone (5 g, 29 mmol) in tetrahydrofuran (50 mL) was added tetraethoxytitanium (16.5 g, 72.4 mmol) and 2-methylpropane-2-sulfinamide (5.27 g, 43.5 mmol). The mixture was stirred at 70 °C for 12 hr. On completion, the mixture was cooled to 0 °C. Then ethyl acetate (5 mL), saturated sodium bicarbonate solution (1 mL) and brine (1 mL) were added sequentially into the mixture. The mixture was dried over anhydrous sodium sulphate, filtrated and concentrated in vacuo to give N-(1-(3-chloro-2-fluorophenyl)ethylidene)-2- methylpropane-2-sulfinamide (9 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 275.8. Step 2. N-(1-(3-Chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfi namide To a solution of diisobutylaluminum hydride (1 M in toluene, 60.9 mL) in toluene (40 mL) was added a solution of N-[1-(3-chloro-2-fluoro-phenyl)ethylidene]-2-methyl-propane- 2-sulfinamide (4.2 g, 15.2 mmol) in toluene (40 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hr. On completion, the mixture was carefully quenched by methanol (100 mL) at -78 °C. The mixture was then warmed to 15 °C and filtered. The filtrate was concentrated in vacuo to give N- (1-(3-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfina mide (3.9 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 278.1. Step 3.1-(3-Chloro-2-fluorophenyl)ethanamine To a solution of N-[1-(3-chloro-2-fluoro-phenyl)ethyl]-2-methyl-propane-2-sul finamide (0.25 g, 900 μmol) in methanol (3 mL) was added HCl/dioxane (4 M, 675 uL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give 1-(3-chloro-2- fluorophenyl)ethanamine (0.1 g, 450 μmol, 51%, FA salt) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (s, 2H), 7.70 - 7.60 (m, 2H), 7.40 - 7.30 (m, 1H), 4.69 - 4.56 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H). Aniline-13: 3-Chloro-4-(cyclopropylmethoxy)-2-fluoroaniline Step 1.2-Chloro-1-(cyclopropylmethoxy)-3-fluoro-4-nitrobenzene To a solution of 2-chloro-3-fluoro-4-nitro-phenol (385 mg, 2.01 mmol) in N,N- dimethylformamide (1.0 mL) and acetonitrile (1.0 mL) was added sodium carbonate (305 mg, 2.21 mmol) and then the mixture was stirred at 25 °C for 0.5 hr. After that, bromomethylcyclopropane (352 mg, 2.61 mmol) was added dropwise into the mixture and the mixture was stirred at 100 °C for 16 hr. On completion, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=7/3 to 3/7) to give 2-chloro-1- (cyclopropylmethoxy)-3-fluoro-4-nitro-benzene (330 mg, 1.35 mmol, 66%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.24 (t, J = 9.2 Hz, 1H), 7.25 (dd, J = 1.6, 9.6 Hz, 1H), 4.19 (d, J = 7.2 Hz, 2H), 1.41 - 1.29 (m, 1H), 0.79 - 0.59 (m, 2H), 0.48 - 0.38 (m, 2H). Step 2.3-Chloro-4-(cyclopropylmethoxy)-2-fluoroaniline A mixture of 2-chloro-1-(cyclopropylmethoxy)-3-fluoro-4-nitro-benzene (300 mg, 1.22 mmol) and platinum on carbon (100 mg, 122 μmol, 3 wt. % loading) in methanol (5.0 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 40 °C for 2 hr under hydrogen (15 psi) atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give 3-chloro-4-(cyclopropylmethoxy)-2-fluoro-aniline (240 mg, 1.12 mmol, 65%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.51 - 6.38 (m, 2H), 4.69 (s, 2H), 3.52 (d, J = 6.8 Hz, 2H), 0.99 - 0.90 (m, 1H), 0.34 - 0.27 (m, 2H), 0.09 - 0.02 (m, 2H); m/z ES+ [M+H] ⁺ 216.1. Aniline-14: 3-Chloro-2-fluoro-4-(oxetan-3-ylmethoxy)aniline Step 1. Oxetan-3-ylmethyl methanesulfonate To a solution of oxetan-3-ylmethanol (5 g, 56.7 mmol) in dichloromethane (150 mL) was added triethylamine (11.49 g, 113 mmol) and methane sulfonyl chloride (7.80 g, 68.1 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was diluted with sat. sodium bicarbonate (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give oxetan-3-ylmethyl methanesulfonate (5 g, crude) as a white solid. Step 2.3-((2-Chloro-3-fluoro-4-nitrophenoxy)methyl)oxetane A mixture of oxetan-3-ylmethyl methanesulfonate (1.1 g, 6.62 mmol), 2-chloro-3-fluoro- 4-nitro-phenol (1.52 g, 7.94 mmol) and potassium carbonate (3.66 g, 26.4 mmol) in N,N- dimethylformamide (15 mL) was stirred at 80 °C for 4 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate = 1:1) to give 3-[(2-chloro- 3-fluoro-4-nitro-phenoxy)methyl]oxetane (1.2 g, 4.57 mmol, 69%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (t, J = 9.2 Hz, 1H), 7.28 - 7.26 (m, 1H), 4.74 - 4.70 (m, 2H), 4.53 - 4.44 (m, 4H), 3.53 - 3.42 (m, 1H). Step 3.3-Chloro-2-fluoro-4-(oxetan-3-ylmethoxy)aniline To a solution of 3-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]oxetane (1.15 g, 4.40 mmol) in ethanol (6 mL) and water (6 mL) was added iron powder (1.23 g, 21.9 mmol) and ammonium chloride (2.35 g, 43.9 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtrated and washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to give 3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)aniline (900 mg, crude) as a white solid. m/z ES+ [M-56] ⁺ 232.0. Aniline-15: 4-Chloro-5-phenoxypyridin-2-amine Step 1.5-Bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridin-2-amine Sodium hydride (12.5 g, 313 mmol, 60% in mineral oil) was added portionwise to a solution of 5-bromo-4-chloro-pyridin-2-amine (25.0 g, 121 mmol) in anhydrous tetrahydrofuran (200 mL) at 0 °C. The mixture was stirred at 0 °C for 0.25 hr. Then 1-(chloromethyl)-4- methoxybenzene (39.6 g, 253 mmol) was added to the mixture and the mixture was stirred at 0 °C for 1.5 hr. On completion, the mixture was quenched with water (200 mL) slowly at 0 °C and diluted with ethyl acetate (300 mL). The mixture is partitioned. The aqueous layer was further extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether : Ethyl acetate = 1:0 ~ 0:1) to give 5-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridin-2-amine (19.5 g, 43.7 mmol, 36%) as a pale yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 7.15 (d, J = 8.4 Hz, 4H), 6.88 (d, J = 8.4 Hz, 4H), 6.82 (s, 1H), 4.69 (s, 4H), 3.73 (s, 6H). Step 2.6-(Bis(4-methoxybenzyl)amino)-4-chloropyridin-3-ol To a solution of 5-bromo-4-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-a mine (19.4 g, 43.3 mmol) in anhydrous tetrahydrofuran (400 mL) at -70 °C was added n-BuLi (2.5 M, 54.3 mmol, 21.7 mL) dropwise. The mixture was stirred at -70 °C for 1.5 hr. Then 2-isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.1 g, 86.7 mmol) was added to the mixture and the mixture was stirred at -70 °C for another 0.75 hr. The mixture was warmed up to -10 °C in 0.5 hr. Then hydrogen peroxide (19.7 g, 173 mmol, 16.7 mL, 30%) was added slowly at -10 °C. The mixture was stirred at 15 °C for another 1 hr. On completion, the mixture was partitioned between ethyl acetate (200 mL), and saturated sodium sulfite (100 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated. The residue was purified by reversed-phase HPLC (FA condition, Instrument: Biotage Isolera One, Column: I.D.95mm*H365mm Welch Ultimate XB_C1820-40煱m; 120 A, Solvent for sample dissolution: about 30.00 grams of sample dissolved in 200 ml of methanol, Flow rate: 200ml/min, Mobile phase: acetonitrile/water, Gradient B%: 20-75% 35min; 75% 25min) to give 6-(bis(4- methoxybenzyl)amino)-4-chloropyridin-3-ol (8.00 g, 20.8 mmol, 19%) as a yellow solid. m/z ES+ [M+H] ⁺ 385.3. Step 3.4-Chloro-N,N-bis(4-methoxybenzyl)-5-phenoxypyridin-2-amine To a solution of 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-pyridin-3-ol (2.50 g, 6.50 mmol) and iodobenzene (1.33 g, 6.50 mmol) in dioxane (50 mL) was added cesium carbonate (6.35 g, 19.5 mmol) and bis[(Z)-1-methyl-3-oxo-but-1-enoxy]copper (340 mg, 1.30 mmol). The mixture was stirred at 120 °C for 16 hr under nitrogen. On completion, the solution was concentrated and purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1:0~1:1) to give 4-chloro-N,N-bis(4-methoxybenzyl)-5-phenoxypyridin-2-amine (1.7 g, 3.70 mmol, 57%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.32 - 7.30 (m, 3H), 7.19 (d, J = 8.4 Hz, 3H), 7.07 - 7.09 (m, 1H), 6.96 - 6.88 (m, 6H), 6.58 (s, 1H), 4.71 (s, 2H), 4.49 (s, 2H), 3.83 (s, 6H). Step 4.4-Chloro-5-phenoxypyridin-2-amine To a solution of 4-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-phenoxy-pyridin- 2- amine (1.70 g, 3.69 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid (13.9 g, 122 mmol). The mixture was stirred at 15 °C for 2 hr. On completion, the solution was concentrated. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give 4-chloro-5- phenoxypyridin-2-amine (0.7 g, 3.18 mmol, 86%) as a white solid. m/z ES+ [M+H] ⁺ 221.1. Aniline-16: 3-Chloro-4-(difluoromethoxy)aniline Step 1. 2-Chloro-1-(difluoromethoxy)-4-nitrobenzene To a solution of 2-chloro-4-nitro-phenol (16.0 g, 92.1 mmol) and (2-chloro-2,2-difluoro- acetyl)oxysodium (35.1 g, 230 mmol) in N,N-dimethylformamide (200 mL) and water (30.0 mL) was added cesium carbonate (60.0 g, 184 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give 2-chloro-1-(difluoromethoxy)-4-nitro-benzene (3.5 g, 15.7 mmol, 15%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J = 2.8 Hz, 1H), 8.24 (dd, J = 2.8, 9.2 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.50 - 7.25 (m, 1H). Step 2.3-Chloro-4-(difluoromethoxy)aniline To a mixture of 2-chloro-1-(difluoromethoxy)-4-nitro-benzene (3.00 g, 13.4 mmol) in methanol (40.0 mL) was added platinum on carbon (0.70 g, 2.68 mmol, 3 wt. % loading) under hydrogen. The mixture was stirred at 25 °C for 2 hr under hydrogen (15 psi). On completion, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give 3-chloro-4-(difluoromethoxy)aniline (2.6 g, 13.5 mmol, 90%) as a brown oil. m/z ES+ [M+H] ⁺ 194.1. Aniline-17: 5-Ethynyl-6-phenoxypyridin-3-amine Step 1. 3-Bromo-5-nitro-2-phenoxy-pyridine To a solution of 3-bromo-2-chloro-5-nitro-pyridine (2 g, 8.42 mmol) and phenol (721 mg, 7.66 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (4.99 g, 15.31 mmol). The mixture was stirred at 50 °C for 2 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-bromo-5-nitro-2-phenoxy-pyridine (2.18 g, 7.39 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 - 8.94 (m, 2H), 7.52 - 7.45 (m, 2H), 7.36 - 7.29 (m, 1H), 7.28 - 7.22 (m, 2H). Step 2. Trimethyl-[2-(5-nitro-2-phenoxy-3-pyridyl)ethynyl]silane A solution of 3-bromo-5-nitro-2-phenoxy-pyridine (1.00 g, 3.39 mmol), ethynyl(trimethyl)silane (332 mg, 3.39 mmol), tetrakis(triphenylphosphine)palladium (195 mg, 169 μmol), copper iodide (64.5 mg, 338 μmol) and triethylamine (1.37 g, 13.5 mmol) in N,N- dimethylformamide (1 mL) was stirred at 90 °C for 2 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition water (1 mL) at 25 °C, then diluted water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give trimethyl-[2-(5-nitro-2-phenoxy-3-pyridyl)ethynyl]silane (120 mg, 0.38 mmol, 11%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 2.8 Hz, 1H), 7.29 - 7.24 (m, 2H), 7.12 - 7.07 (m, 1H), 7.06 - 7.02 (m, 2H), 0.08 - 0.03 (m, 9H); m/z ES+ [M+H] ⁺ 313.3. Step 3. 3-Ethynyl-5-nitro-2-phenoxy-pyridine A solution of trimethyl-[2-(5-nitro-2-phenoxy-3-pyridyl)ethynyl]silane (80.0 mg, 256 μmol) and cesium fluoride (38.9 mg, 256 μmol) in methanol (1 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 3-ethynyl-5-nitro-2-phenoxy-pyridine (85.0 mg, crude) as yellow solid. m/z ES+ [M+H] ⁺ 241.1. Step 4. 5-Ethynyl-6-phenoxy-pyridin-3-amine A solution of 3-ethynyl-5-nitro-2-phenoxy-pyridine (75.0 mg, 312 μmol), ammonium chloride (83.5 mg, 1.56 mmol) and iron powder (87.1 mg, 1.56 mmol) in ethanol (4 mL) and water (1 mL) was stirred at 80 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was added tetrahydrofuran (2 ml) and filtered. The filtrate was concentrated under reduced pressure to give 5-ethynyl-6-phenoxy-pyridin-3-amine (60.0 mg, 0.29 mmol, 91%) as light yellow solid. m/z ES+ [M+H] ⁺ 211.3. Aniline-18: (4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline Step 1. 4-(2-Methyl-4-nitrophenoxy)pyridin-2-amine To a solution of 2-methyl-4-nitrophenol (9.0 g, 58.8 mmol) in N-methyl pyrrolidone (65 mL) was added diisopropylethylamine (22.8 g, 176 mmol) and 4-chloropyridin-2-amine (7.56 g, 58.8 mmol). The mixture was stirred at 135 °C for 48 hr. On completion, the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 0/1) to give 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine (1.14 g, 4.65 mmol, 8%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 2.8, 8.8 Hz, 1H), 7.87 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 8.8Hz, 1H), 6.19 (dd, J = 2.4, 5.6 Hz, 1H), 6.06 (s, 2H), 5.89 (d, J = 2.0 Hz, 1H), 2.28 (s, 3H). Step 2. N,N-Dimethyl-N'-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)for mimidamide To a mixture of 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine (1.14 g, 4.65 mmol) in ethanol (12 mL) was added dimethyl formamide dimethyl acetal (665 mg, 5.58 mmol). The mixture was stirred at 75 °C for 16 hr. On completion, the mixture was concentrated to give N,N- dimethyl-N'-(4-(2-methyl-4- nitrophenoxy)pyridin-2-yl)formimidamide (1.40 g, crude) as a brown oil. m/z ES+ [M+H] ⁺ 301.3. Step 3. N-Hydroxy-N'-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)formim idamide To a mixture of N,N-dimethyl-N'-(4-(2-methyl-4-nitrophenoxy)pyridin-2- yl)formimidamide (1.40 g, 4.66 mmol) in ethanol (12 mL) was added hydroxylamine hydrochloride (389 mg, 5.59 mmol), and the mixture was stirred at 50 °C for 3 hrs under nitrogen atmosphere. On completion, the mixture was cooled to 20 °C and filtered. The filter cake was dried under reduced pressure to give N-hydroxy-N'-(4-(2-methyl-4-nitrophenoxy) pyridin-2-yl) formimidamide (800 mg, 2.78 mmol, 60%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.36 (d, J = 10.0 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 2.8, 8.8 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.54 (dd, J = 2.0, 5.6 Hz, 1H), 2.27 (s, 3H). Step 4. 7-(2-Methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine To a solution of N-hydroxy-N'-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)formim idamide (800 mg, 2.78 mmol) in tetrahydrofuran (12 mL) was added trifluoroacetic anhydride (641 mg, 3.05 mmol) dropwise at 0 °C. The mixture was stirred at 20 ° C for 12 hr. Then trifluoroacetic anhydride (117 mg, 555 μmol) was added dropwise and the mixture wass stirred at 20 ° C for 3 hr. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 10/1 to 0/1) to give 7-(2-methyl-4-nitro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (420 mg, 1.56 mmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (d, J = 7.2 Hz, 1H), 8.47 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 2.4, 8.8 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.10 (dd, J = 2.8, 7.6 Hz, 1H), 2.35 (s, 3H). Step 5. 4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline A mixture of 7-(2-methyl-4-nitro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (420 mg, 1.55 mmol) and palladium on activated carbon (200 mg, 1.55 mmol, 10% loading) in tetrahydrofuran (10 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 40 °C for 16 hr under hydrogen atmosphere (15 psi). On completion, the cooled mixture was filtered and concentrated under reduced pressure to give 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)- 3-methylaniline (420 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J = 7.6 Hz, 1H), 8.35 (s, 1H), 6.96 (dd, J = 2.4, 7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.62 (dd, J = 2.4, 9.6 Hz, 2H), 6.56 (dd, J = 2.4, 8.4 Hz, 1H), 2.00 (s, 3H); m/z ES+ [M+H] ⁺ 241.4. Aniline-19: 7-Fluorobenzo[d]isothiazol-6-amine Step 1. 4-Bromo-2-(tert-butylthio)-3-fluorobenzaldehyde To a mixture of 4-bromo-2,3-difluoro-benzaldehyde (5.00 g, 22.6 mmol) and 2- methylpropane-2-thiol (2.24 g, 24.9 mmol) in dimethyl sulfoxide (50 mL) was added potassium carbonate (3.13 g, 22.6 mmol) at 20 °C under nitrogen atmosphere. The mixture was stirred at 60 °C for 4 hr. On completion, the mixture was poured into water (100 mL) and ethyl acetate (80 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (3 mL x 2), dried with anhydrous sodium sulfate filtered and the filtrate concentrated in vacuum. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 1/ 0 to 0/ 1) to give 4-bromo-2-(tert-butylthio)-3- fluorobenzaldehyde (6.40 g, 22.1 mmol, 97%) as a yellow oil. Step 2. (E)-4-Bromo-2-(tert-butylthio)-3-fluorobenzaldehyde oxime To a mixture of 4-bromo-2-(tert-butylthio)-3-fluorobenzaldehyde (6 g, 20.6 mmol) in water (10 mL) and isopropanol (50 mL) was added hydroxylamine hydrochloride (1.58 g, 22.6 mmol) in one portion at 20 °C under nitrogen atmosphere. The mixture was stirred at 90 °C for 2 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether / ethyl acetate = 1/ 0 to 0/ 1) to give (E)-4-bromo-2-(tert- butylthio)-3-fluorobenzaldehyde oxime (6 g, 19.7 mmol, 95%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.64 (s, 1H), 7.80 (dd, J = 7.2, 8.4 Hz, 1H), 7.66 (dd, J = 0.8, 8.8 Hz, 1H), 1.23 (s, 9H). Step 3. 6-Bromo-7-fluorobenzo[d]isothiazole To a mixture of (E)-4-bromo-2-(tert-butylthio)-3-fluorobenzaldehyde oxime (4 g, 13.1 mmol) in n-butyl alcohol (40 mL) was added benzenesulfonic acid (4.13 g, 26.1 mmol) in one portion at 20 °C under nitrogen atmosphere. The mixture was stirred at 140 °C for 4 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether / ethyl acetate = 1/ 0 to 0/ 1) to give 6-bromo-7- fluorobenzo[d]isothiazole (2.00 g, 8.66 mmol, 66%) as a yellow oil. ¹ H NMR (400 MHz, DMSO- δ 9.21 (d, J = 4.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.90 - 7.76 (m, 1H). Step 4. tert-Butyl (7-fluorobenzo[d]isothiazol-6-yl)carbamate To a mixture of 6-bromo-7-fluorobenzo[d]isothiazole (1.90 g, 8.19 mmol), tert-butyl carbamate (1.44 g, 12.3 mmol) and cesium carbonate (8.00 g, 24.6 mmol) in 1,4-dioxane (20 mL) was added Pd ₂ (dba) ₃ (750 mg, 819 μmol) and XantPhos (474 mg, 819 μmol) in one portion at 20 °C under nitrogen atmosphere. The mixture was stirred at 80 °C for 2 hr. On completion, the mixture poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (8mL x 3). The combined organic phase was washed with brine (8 mL x 2), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether / ethyl acetate = 1/ 0 to 0/ 1) to give tert-butyl (7- fluorobenzo[d]isothiazol-6-yl)carbamate (2.00 g, 7.46 mmol, 91%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 9.11 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 16.0 Hz, 1H), 1.49 (s, 10H). Step 5. 7-Fluorobenzo[d]isothiazol-6-amine To a mixture of tert-butyl (7-fluorobenzo[d]isothiazol-6-yl)carbamate (1 g, 3.73 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (4 mL) in one portion at 20 °C. The mixture was stirred at 20 °C for 2 hr. On completion, the mixture was concentrated in reduced pressure. The residue was poured into sat. sodium bicarbonate (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with brine (3 mL x 2), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether / ethyl acetate = 1/ 0 to 0/ 1) to give 7-fluorobenzo[d]isothiazol-6-amine (500 mg, 2.98 mmol, 79%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 4.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 5.92 (s, 2H). Aniline-20: 6-(Cyclopropylmethoxy)pyridin-3-amine Step 1. 2-(Cyclopropylmethoxy)-5-nitropyridine To a mixture of cyclopropylmethanol (1.42 g, 19.7 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (985 mg, 24.6 mmol, 60% in mineral oil). The mixture was stirred at 25 C for 0.5 hr. Then 2-bromo-5-nitro-pyridine (2 g, 9.85 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting mixture was stirred at 25 C for another 2 hr. On completion, the reaction mixture was quenched by addition water (10 mL), and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate =20/1 to 5/1) to give 2-(cyclopropylmethoxy)-5- nitro-pyridine (0.7 g, 3.61 mmol, 32%) as a yellow solid. Step 2.6-(Cyclopropylmethoxy)pyridin-3-amine To a solution of 2-(cyclopropylmethoxy)-5-nitro-pyridine (700 mg, 3.60 mmol) in methanol (35 mL) was added palladium on activated carbon (100 mg, 3.60 mmol, 10 wt. % loading) under nitrogen atmosphere. The mixture was stirred at 25 °C for 2 hours under hydrogen atmosphere (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 6-(cyclopropylmethoxy)pyridin-3-amine (0.5 g, 3.05 mmol, 73%) as a yellow oil. m/z ES+ [M+H] ⁺ 165.2. Aniline-21: 5-Ethynyl-2-fluoropyridin-3-amine Step 1. 5-Bromo-2-fluoropyridin-3-amine To a solution of 5-bromo-2-fluoro-3-nitro-pyridine (3 g, 13.6 mmol) in ethyl acetate (50 mL) was added platinum on carbon (883 mg, 136 μmol, 3 wt. % loading) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 Psi) at 25°C for 2 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-bromo-2- fluoropyridin-3-amine (2.4 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (t, J = 2.0 Hz, 1H), 7.21 (dd, J = 2.0, 9.2 Hz, 1H), 3.90 (s, 2H); m/z ES+ [M+H] ⁺ 191.0. Step 2. 2-Fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-amine To a solution of 5-bromo-2-fluoro-pyridin-3-amine (2 g, 10.5 mmol) and ethynyl(trimethyl)silane (3.09 g, 31.4 mmol) in N,N-dimethylformamide (20 mL) was added cuprous iodide (199 mg, 1.05 mmol), palladium(II)bis(triphenylphosphine) dichloride (735 mg, 1.05 mmol) and triethylamine (3.18 g, 31.4 mmol). The mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 8/1) to give 2- fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-amine (2 g, 9.62 mmol, 83%) as a yellow solid. m/z ES+ [M+H] ⁺ 209.4. Step 3. 5-Ethynyl-2-fluoropyridin-3-amine To a solution of 2-fluoro-5-(2-trimethylsilylethynyl) pyridin-3-amine (1.8 g, 8.64 mmol) in methanol (30 mL) was added potassium carbonate (597 mg, 4.32 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with sat. ammonium chloride (60 mL) and extracted with ethyl acetate (90 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 6/1) to give 5-ethynyl-2-fluoropyridin-3- amine (780 mg, 5.73 mmol, 63%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (t, J = 2.0 Hz, 1H), 7.16 (dd, J = 2.0, 10.0 Hz, 1H), 3.89 (s, 2H), 3.11 (s, 1H). Aniline-22: 1-Phenyl-1H-indazol-5-amine Step 1. 5-Nitro-1-phenyl-1H-indazole To a solution of 5-nitro-1H-indazole (1.00 g, 6.13 mmol) and phenylboronic acid (897 mg, 7.36 mmol) in dichloromethane (10 mL) was added copper acetate (1.67 g, 9.19 mmol) and triethylamine (1.24 g, 12.3 mmol), 4Å molecular sieves (1.00 g). The mixture was stirred at 20 °C for 16 hr under oxygen atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1/0 to 5/1) to give 5-nitro-1-phenyl-1H-indazole (400 mg, 1.67 mmol, 27%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (d, J = 2.0 Hz, 1H), 8.42 (s, 1H), 8.32 (dd, J = 2.4, 9.2 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.61 (t, J = 8.4 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H). Step 2. 1-Phenyl-1H-indazol-5-amine To a mixture of 5-nitro-1-phenyl-1H-indazole (330 mg, 1.38 mmol) and ammonium chloride (812 mg, 15.2 mmol) in methanol (5 mL) and water (5 mL) was added iron powder (674 mg, 12.1 mmol) at 20 °C. The mixture was heated to 80 °C and stirred for 1 h. On completion, the mixture was filtered and the filtrate was concentrated to afford a residue. The residue was diluted with water (10 mL) and saturated sodium carbonate (10 mL) and then stirred for 30 min. The mixture was filtered and the filter cake was redissolved in ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give 1-phenyl- 1H-indazol-5-amine (270 mg, 1.29 mmol, 90%) as a brown solid. m/z ES+ [M+H] ⁺ 210.0. Aniline-23: 5-Fluoro-6-phenoxypyridin-3-amine Step 1. 3-Fluoro-5-nitro-2-phenoxypyridine To a solution of 2-chloro-3-fluoro-5-nitro-pyridine (400 mg, 2.27 mmol) in acetonitrile (5.0 mL) was added cesium carbonate (1.48 g, 4.53 mmol) and phenol (213 mg, 2.27 mmol). The mixture was stirred at 20 °C for 12 hr. On completion, the reaction was added brine (10 mL x 3) and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether /ethyl acetate = 20/1 to 10/1) to give 3-fluoro-5-nitro-2-phenoxy-pyridine (300 mg, 1.28 mmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (d, J = 2.4 Hz, 1H), 8.21 (dd, J = 8.8, 2.4 Hz, 1H), 7.35 - 7.46 (m, 2H), 7.22 - 7.29 (m, 1H), 7.13 (d, J = 7.6 Hz, 2H). Step 2. 5-Fluoro-6-phenoxypyridin-3-amine To a solution of 3-fluoro-5-nitro-2-phenoxy-pyridine (300 mg, 1.28 mmol) in tetrahydrofuran (5.0 mL) was added palladium on activated carbon (200 mg, 1.28 mmol, 10 wt. % loading). The mixture was stirred at 50 °C for 1 hr under hydrogen atmosphere (15 Psi). On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-fluoro-6-phenoxy-pyridin-3-amine (200 mg, 979 μmol, 76%) as a yellow oil. m/z ES+ [M+H] ⁺ 205.0. Aniline-24 & 26: 3-Ethynyl-2-fluoro-aniline & 2-Fluoro-3-((trimethylsilyl)ethynyl)aniline Step 1. 2-Fluoro-3-(2-trimethylsilylethynyl)aniline To a stirred solution of 3-bromo-2-fluoro-aniline (4.5 g, 23.7 mmol) and ethynyl(trimethyl)silane (6.98 g, 71.1 mmol) in toluene (60 mL) was added palladium(II)bis(triphenylphosphine) dichloride (1.66 g, 2.37 mmol), cuprous iodide (451 mg, 2.37 mmol) and diisopropylethylamine (12.2 g, 94.7 mmol). The mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% FA condition) to give 2-fluoro-3-(2- trimethylsilylethynyl)aniline (1.4 g, 6.76 mmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.68 - 6.50 (m, 2H), 6.42 - 6.32 (m, 1H), 5.04 (s, 2H), 0.00 (s, 9H); m/z ES+ [M+H] ⁺ 207.8. Step 2. 3-Ethynyl-2-fluoro-aniline To a solution of 2-fluoro-3-(2-trimethylsilylethynyl)aniline (1.1 g, 5.31 mmol) in methanol (11 mL)/water (12 mL) was added potassium hydroxide (595mg, 10.6 mmol). The mixture was stirred at 25 °C for 4 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 20/1) to give 3-ethynyl-2-fluoro-aniline (650 mg, 4.11mmol, 86%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.98 - 6.76 (m, 2H), 6.63 (m, 1H), 5.30 (s, 2H), 4.32 (s, 1H); m/z ES+ [M+H] ⁺ 135.7. Aniline-25: 4-(Tetrahydrofuran-3-ylmethoxy) aniline Step 1. 1-(2,2-Dimethylpropoxy)-4-nitro-benzene To a solution of 2,2-dimethylpropan-1-ol (3.75 g, 42.5 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (2.83 g, 70.8 mmol, 60% in mineral oil) portionwise at 0 °C. The mixture was stirred at 0 °C for 10 min. Then 1-fluoro-4-nitro-benzene (5 g, 35.4 mmol) was added. The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was quenched by addition water (30 ml) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(2,2-dimethylpropoxy)-4-nitro-benzene (5.5 g, 26.6 mmol, 100%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.24 - 8.16 (m, 2H), 7.15 (d. J = 9.2 Hz, 2H), 3.79 (s, 2H), 1.01 (s, 9H). Step 2. 4-(2,2-Dimethylpropoxy)aniline To a solution of 1-(2,2-dimethylpropoxy)-4-nitro-benzene (5.00 g, 23.90 mmol) in ethanol (50.0 mL) was added palladium on activated carbon (500 mg, 10 wt. % loading). The mixture was stirred at 25 °C for 12 hr under hydrogen gas (15 psi). Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give 4-(2,2-dimethylpropoxy)aniline (4.00 g, 22.3 mmol, 93%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.68 - 6.59 (m, 2H), 6.50 (d. J = 8.4 Hz, 2H), 4.56 (s, 2H), 0.96 (s, 9H). Aniline-27: 2-Fluoro-5-((trimethylsilyl)ethynyl)aniline Step 1. 2-Fluoro-5-((trimethylsilyl)ethynyl)aniline A mixture of 5-bromo-2-fluoro-aniline (10.0 g, 52.6 mmol), ethynyl(trimethyl)silane (15.5 g, 158 mmol), copper iodide (1.00 g, 5.26 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (3.69 g, 5.26 mmol) and triethylamine (30 mL) in dimethylformamide (90 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 2 hrs under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (90 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give 2-fluoro-5-(2-trimethylsilylethynyl)aniline (6.30 g, 30.3 mmol, 58%) as a black oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.96 (dd, J = 8.4, 11.6 Hz, 1H), 6.84 (dd, J = 2.0, 8.8 Hz, 1H), 6.63-6.53 (m, 1H), 5.28 (s, 2H), 0.22 - 0.17 (m, 9H); m/z ES+ [M+H] ⁺ 208.1. Aniline-28: 4-Chloro-2-fluoro-3-((trimethylsilyl)ethynyl)aniline Step 1. N-(4-Chloro-2-fluorophenyl)acetamide To a solution of 4-chloro-2-fluoro-aniline (10 g, 68.7 mmol) in acetic acid (105 g, 1.75 mol) was added acetic anhydride (10.5 g, 103 mmol) and the reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was quenched with ice water (50 mL) and filtered. The filtered cake was diluted with sat. sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give N-(4-chloro-2-fluoro-phenyl)acetamide (11 g, 58.5 mmol, 81%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 7.93 (t, J = 8.8 Hz, 1H), 7.43 (dd, J = 2.4, 10.8 Hz, 1H), 7.26 - 7.17 (m, 1H), 2.08 (s, 3H); m/z ES+ [M+H]+ 188.1. Step 2. N-(4-Chloro-2-fluoro-3-iodophenyl)acetamide To a solution of N-(4-chloro-2-fluoro-phenyl)acetamide (11 g, 58.6 mmol) in tetrahydrofuran (60 mL) was added n-butyl lithium (2.5 M in toluene, 46.9 mL) dropwise at -78 °C and the reaction mixture was stirred at -78 °C for 2 hrs. Then 1,1,1-trifluoro-2-iodo-ethane (24.7 g, 117 mmol) was added dropwise at -78 °C. The mixture was slowly warmed to 25 °C and stirred at 25 °C for 3 hrs. On completion, the mixture was quenched with hydrochloric acid (3 M, 20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was triturated with acetonitrile (20 mL) at 25 ^o C for 5 min to give N-(4-chloro-2-fluoro-3-iodo- phenyl)acetamide (6 g, 19.1 mmol, 33%) as an off-white solid. m/z ES+ [M+H]+ 314.1; Step 3. 4-Chloro-2-fluoro-3-iodoaniline To a solution of N-(4-chloro-2-fluoro-3-iodo-phenyl)acetamide (5 g, 15.9 mmol) in methanol (50 mL) was added concentrated hydrochloric acid (12 M, 14.5 mL) and the mixture was heated to 75 °C and refluxed for 2 hrs. On completion, the residue was poured into ice water. The mixture was adjusted to pH = 9 with 3 M aqueous sodium hydroxide solution and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel. Petroleum ether/Ethyl acetate=1:50 to 1:10) to give 4-chloro-2- fluoro-3-iodo-aniline (4.3 g, 15.9 mmol, 99%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.07 (dd, J = 1.6, 8.8 Hz, 1H), 6.80 - 6.72 (m, 1H), 5.47 (s, 2H). Step 4. 4-Chloro-2-fluoro-3-((trimethylsilyl)ethynyl)aniline To a solution of 4-chloro-2-fluoro-3-iodo-aniline (4 g, 14.7 mmol) in dimethylformamide (10 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (206 mg, 294 μmol), copper iodide (112 mg, 589 μmol), triethylamine (7.50 g, 74.1 mmol) and ethynyl(trimethyl)silane (2.89 g, 29.4 mmol). The mixture was stirred at 100 °C for 2 hrs under nitrogen. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel. Petroleum ether/Ethyl acetate=10:1 to 3:1) to give 4-chloro-2-fluoro-3-(2-trimethylsilylethynyl)aniline (2 g, 8.26 mmol, 50%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.03 (dd, J = 1.2, 8.8 Hz, 1H), 6.78 (t, J = 9.2 Hz, 1H), 5.44 (s, 2H), 0.24 (s, 9H). Phenol-1: 3,4-Dichloro-2-fluorophenol Step 1.3,4-Dichloro-2-fluorophenol To a solution of 3-chloro-2-fluorophenol (2.00 g, 13.6 mmol) in acetonitrile (20 mL) was added N-chlorosuccinimide (1.82 g, 13.6 mmol) and trifluoroacetic acid (1.56 g, 13.6 mmol), the mixture was stirred at 15 °C for 16 hr. On completion, the mixture was diluted in water (100 mL) and filtered. The filtrate was concentrated to give a residue. The residue was purified by flash column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give compound 3,4-dichloro-2-fluorophenol (2 g, 11.05 mmol, 81%) as a yellow solid. m/z ES+ 178.9. Phenol-2: 2-Chloro-3-fluoro-4-nitrophenol Step 1.1-(Benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene To a solution of 2-chloro-1,3-difluoro-4-nitro-benzene (9.5 g, 49.0 mmol) in N,N- dimethylformamide (60 mL) was added benzyl alcohol (5.31 g, 49.0 mmol) and potassium carbonate (13.5 g, 98.1 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was poured into the water (200 mL) and extracted with ethyl acetate (100 mL ൈ 4). The organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1) to give 1-benzyloxy-2-chloro-3-fluoro-4-nitro-benzene (3 g, 10.7 mmol, 18%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (t, J = 9.2 Hz, 1H), 7.57 - 7.38 (m, 5H), 7.34 (d, J = 9.6 Hz, 1H), 5.42 (s, 2H). Step 2.2-Chloro-3-fluoro-4-nitrophenol To a solution of 1-benzyloxy-2-chloro-3-fluoro-4-nitro-benzene (3.00 g, 10.6 mmol) in dichloromethane (30 mL) was added boron tribromide (5.34 g, 21.3 mmol). The mixture was stirred at 0 °C for 2 hr. On completion, the mixture was added saturated sodium bicarbonate solution to adjust pH = 7 and extracted with ethyl acetate (100 mL ൈ 2). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1) to give 2-chloro- 3-fluoro-4-nitro-phenol (900 mg, 4.71 mmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.90 - 12.07 (m, 1H), 8.13 (t, J = 9.2 Hz, 1H), 7.03 (d, J = 9.6 Hz, 1H). Intermediate 92 & Intermediate 93: tert-Butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate & tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate tert-butyl Step 1. tert-Butyl (1S,4S)-5-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (26 g, 143 mmol) in 1- methylpyrrolidin-2-one (250 mL) was added diisopropylethylamine (55.5 g, 429 mmol) and tert- butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (49.7 g, 250 mmol), the mixture was stirred at 120 °C for 12 h. The mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5- (4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate (33 g, 96.1 mmol, 67%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.25 - 12.00 (m, 1H), 7.87 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.11 (br s, 1H), 4.94 (br s, 1H), 4.52 - 4.45 (m, 1H), 3.61 - 3.53 (m, 1H), 3.48 - 3.22 (m, 2H), 3.21 - 3.15 (m, 1H), 1.43 - 1.30 (m, 9H); m/z ES+ [M+H] ⁺ 344.3. Step 2. tert-Butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (30 g, 87.4 mmol) in toluene (600 mL) was added diisopropylethylamine (56.5 g, 436 mmol) and phosphorus oxychloride (40.2 g, 262 mmol), the mixture was stirred at 110 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether : ethyl acetate =20:1 to 1:1) to give tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (28.4 g, 78.5 mmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 362.1. Step 3. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)pyrid o[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (2.00 g, 5.53 mmol) and 4-amino-2-chloro-3-fluoro- phenol (946 mg, 5.86 mmol) in acetonitrile (20.0 mL) was stirred at 60 °C for 1 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (2.30 g, 4.72 mmol, 81%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04 (br s, 1H), 10.83 - 10.38 (m, 1H), 8.66 (s, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.74 - 7.18 (m, 2H), 6.96 (br d, J = 8.8 Hz, 1H), 5.69 - 4.87 (m, 1H), 4.68 - 4.46 (m, 1H), 3.75 - 3.56 (m, 4H), 2.15 - 1.84 (m, 2H), 1.49 - 1.26 (m, 9H). Intermediate 94 & Intermediate 95: 6-Chloropyrimido[5,4-d]pyrimidin-4-ol & 2,8- dichloropyrimido[5,4-d]pyrimidine

Step 1. Ethyl 5-amino-2-chloropyrimidine-4-carboxylate To a solution of palladium on activated carbon (10 g, 5% loading) in dioxane (10 mL) was added ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (10 g, 37.0 mmol) and magnesium oxide (7.57 g, 187 mmol) under nitrogen atmosphere and the mixture was stirred at 20 °C for 16 hr under hydrogen atmosphere (50 psi). On completion, the mixture was filtered and the layer was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give ethyl 5-amino-2-chloropyrimidine-4-carboxylate (820 mg, 4.08 mmol, 11%) as a brown solid. Step 2. 5-Amino-2-chloropyrimidine-4-carboxamide To a solution of ammonia (1.39 g, 80 mmol) in methanol (10 mL) was added ethyl 5- amino-2-chloropyrimidine-4-carboxylate (820 mg, 4 mmol). The reaction mixture was heated to 100 °C for 2 days in a sealed tube. On completion, the mixture was concentrated under reduced pressure to give 5-amino-2-chloropyrimidine-4-carboxamide (900 mg, crude) as a yellow solid. Step 3. 6-Chloropyrimido[5,4-d]pyrimidin-4-ol A mixture of 5-amino-2-chloro-pyrimidine-4-carboxamide (900 mg, 5 mmol) in diethoxymethoxyethane (3.6 mL) was stirred at 150 °C for 2 hr. On completion, the mixture was filtered and the cake was collected to give 6-chloropyrimido[5,4-d]pyrimidin-4-ol (625 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.36 - 12.58 (m, 1H), 9.31 (s, 1H), 8.30 (s, 1H); m/z ES+ [M+H] ⁺ 182.6. Step 4. 2,8-Dichloropyrimido[5,4-d]pyrimidine To a solution of 6-chloropyrimido[5,4-d]pyrimidin-4-ol (520 mg, 2.86 mmol) in sulfur dichloride (6 mL) was added N,N-dimethylformamide (20.8 mg, 2.86 mmol) dropwise and the mixture was stirred at 90 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 2,8-dichloropyrimido[5,4-d]pyrimidine (600 mg, crude) as a yellow solid. Intermediate 96: tert-Butyl 6-(4-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate Step 1. 2-Chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-fl uorophenol To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (1.00 g, 5.00 mmol) in acetonitrile (10 mL) was added 4-amino-2-chloro-3-fluoro-phenol (888 mg, 5.50 mmol). The mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was filtered and the filtered cake was collected to give 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fl uoro-phenol (1.64 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99 - 10.62 (m, 2H), 8.72 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 6.92 (dd, J = 1.6, 8.8 Hz, 1H); m/z ES+ [M+H]+ 324.9. Step 2. tert-Butyl 6-(4-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fl uoro- phenol (1.60 g, 4.92 mmol) in N-methylpyrrolidone (10 mL) was added diisopropylethylamine (1.91 g, 14.7 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (1.07 g, 5.41 mmol). The mixture was stirred at 100 °C for 2 hours. On completion, the reaction mixture was partitioned between water 60 mL and ethyl acetate 60 mL. The organic phase was separated, washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2-d]pyrim idin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (2.30 g, 4.72 mmol, 81%) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 1H), 8.32 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.76 (t, J = 8.8 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 6.88 (dd, J = 1.6, 8.8 Hz, 1H), 5.76 (s, 1H), 4.65 - 4.52 (m, 2H), 4.36 - 4.25 (m, 2H), 3.78 - 3.68 (m, 2H), 2.25 - 2.13 (m, 1H), 2.02 - 1.79 (m, 1H), 1.38 (s, 9H); m/z ES+ [M+1]+ 487.1. Intermediate 97: tert-Butyl (1S,4S)-5-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te Step 1. 4-Amino-2-chloro-5-fluorophenol To a solution of 2-chloro-5-fluoro-4-nitro-phenol (2 g, 10.44 mmol), ammonium chloride (5.59 g, 104 mmol) in ethanol (20 mL) and water (4 mL) was added iron powder (2.92 g, 52.2 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was filtered and the layer was concentrated in vacuo to give 4-amino-2-chloro-5-fluoro-phenol (1.5 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1 H), 6.77 (s, 1 H), 4.75 (s, 1 H) Step 2. 2-Chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-fl uorophenol A solution of 4-amino-2-chloro-5-fluoro-phenol (484 mg, 3.00 mmol) and 4,6- dichloropyrido[3,2-d]pyrimidine (0.2 g, 999 μmol) in acetonitrile (3 mL) was stirred at 25 °C for 16 hr. On completion, the mixture was filtered and the filtered cake was concentrated in vacuo to give 2-chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-fl uorophenol (0.3 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 324.9. Step 3. tert-Butyl (1S,4S)-5-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-5-fl uoro-phenol (0.3 g, 922 μmol), tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (182 mg, 922 μmol) and diisopropylethylamine (238 mg, 1.85 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 100 °C for 16 hr. On completion, the reaction mixture was quenched by addition water (10 mL) at 25 °C, and thern extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-(5-chloro-2-fluoro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (0.3 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 487.3. Intermediate 98: 2-oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate

Step 1. (3,3-Dimethoxycyclobutane-1,1-diyl)dimethanol To a solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (10 g, 34.68 mmol) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (3.95 g, 104 mmol) portion-wise at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with tetrahydrofuran (100 mL) and then carefully quenched by dropwise addition of water (4 mL), 15% sodium hydroxide (4 mL) and water (12 mL). The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5/1 to 0/1) to give (3,3-dimethoxycyclobutane-1,1- diyl)dimethanol (3.89 g, 22.08 mmol, 64%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.47 (t, J = 5.4 Hz, 2H), 3.35 (d, J = 5.5 Hz, 4H), 3 (s, 6H), 1.77 (s, 4H). Step 2. (3,3-Dimethoxycyclobutane-1,1-diyl)bis(methylene) bis(4- methylbenzenesulfonate) To a solution of [1-(hydroxymethyl)-3,3-dimethoxy-cyclobutyl]methanol (3.89 g, 22.08 mmol) in pyridine (40 mL) was added 4-methylbenzenesulfonyl chloride (12.6 g, 66.23 mmol) at 0 °C. The mixture was stirred at 0 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 1/1) to give (3,3-dimethoxycyclobutane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (4.5 g, 12.13 mmol, 55%) as a white solid. NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (d, J = 8.2 Hz, 4H), 7.49 (d, J = 8.1 Hz, 4H), 3.93 (s, 4H), 2.89 (s, 6H), 2.43 (s, 6H), 1.85 (s, 4H). Step 3. (3-Oxocyclobutane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) To a solution of (3,3-dimethoxycyclobutane-1,1-diyl)bis(methylene) bis(4- methylbenzenesulfonate) (1.06 g, 2.19 mmol) in acetonitrile (7 mL) was added hydrogen chloride/dioxane (4 M, 2.73 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (3-oxocyclobutane-1,1-diyl)bis(methylene) bis(4- methylbenzenesulfonate) (860 mg, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (d, J = 8.2 Hz, 4H), 7.55 (d, J = 8.1 Hz, 4H), 4.23 (s, 4H), 2.92 (s, 4H), 2.49 (s, 6H). Step 4. (3-Hydroxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylben zenesulfonate) To a solution of (3-oxocyclobutane-1,1-diyl)bis(methylene) bis(4- methylbenzenesulfonate) (860 mg, 1.96 mmol) in tetrahydrofuran (10 mL) was added sodium borohydride (148 mg, 3.92 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into sat. ammonium chloride (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3/1 to 1/1) to give (3- hydroxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylbenzen esulfonate) (790 mg, 1.79 mmol, 91%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (t, J = 7.6 Hz, 4H), 7.48 (d, J = 8.0 Hz, 4H), 5.09 (d, J = 6.4 Hz, 1H), 4.01 - 3.95 (m, 1H), 3.90 (d, J = 17.6 Hz, 4H), 2.43 (s, 6H), 1.99 - 1.93 (m, 2H), 1.64 - 1.57 (m, 2H). Step 5. 2-Oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate To a solution of (3-hydroxycyclobutane-1,1-diyl)bis(methylene)bis(4- methylbenzenesulfonate) (790 mg, 1.79 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (215 mg, 5.38 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into sat. ammonium chloride (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5/1 to 1/1) to give 2-oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate (140 mg, 490 umol, 27%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.54 (s, 1H), 4.30 (s, 2H), 3.57 (s, 2H), 2.47 (s, 3H), 1.75 (d, J = 5.0 Hz, 2H), 1.56 - 1.52 (m, 2H). Intermediate 99: 1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexane To a solution of (3-methylenecyclobutyl)methanol (500 mg, 5.09 mmol) in methyl tert- butyl ether (5 mL) and water (2.5 mL) was added iodine (2.59 g, 10.2 mmol) and sodium bicarbonate (856 mg, 10.2 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was quenched by sodium thiosulfate (30 mL) at 25 °C, then diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20:1 to 10:1) to give 1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane (813 mg, 3.63 mmol, 71%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.84 (s, 2H), 3.48 (s, 2H), 2.85 (t, J = 3.2 Hz, 1H), 1.82 - 1.73 (m, 2H), 1.55 (dd, J = 1.6, 4.4 Hz, 2H). Intermediate 100 & Intermediate 101: tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate & 4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2,3-difluorop henol Step 1. 4-((6-Chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2,3-difluorop henol A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.50 mmol), 4-amino-2,3- difluoro-phenol (363 mg, 2.50 mmol) in acetonitrile (5 mL) was stirred at 25 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give 4-((6-chloropyrido[3,2-d]pyrimidin-4- yl)amino)-2,3-difluorophenol (800 mg, crude) as a yellow solid without further purification. m/z ES+ [M+H] ⁺ 308.7. Step 2. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-hydroxyphenyl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A mixture of 4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-2,3-difluoro- phenol (500 mg, 1.62 mmol), tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (321.15 mg, 1.62 mmol), diisopropylethylamine (418.71 mg, 3.24 mmol) in 1-methylpyrrolidin-2-one (10 mL) was stirred at 100 °C for 16 hr. On completion, the reaction mixture was directly purified by reversed-phase HPLC (0.1% formic acid conditions) to give tert-butyl (1S,4S)-5-(4-((2,3-difluoro- 4-hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaza bicyclo[2.2.1]heptane-2- carboxylate (600 mg, 1.13 mmol, 70%) as a yellow solid. m/z ES+ [M+H] ⁺ 470.9. Intermediate 102: tert-Butyl 7-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]o ctane- 4-carboxylate Step 1. tert-Butyl 7-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5] octane- 4-carboxylate To a solution of 6-fluoropyrido[3,4-d]pyrimidin-4-ol (570 mg, 3.45 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (1.10 g, 5.18 mmol) in 1-methylpyrrolidin-2-one (20 mL) was added diisopropylethylamine (2.23 g, 17.2 mmol). The mixture was stirred at 100 °C for 12 hr. On completion, the crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl 7-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5] octane- 4-carboxylate (900 mg, 2.51 mmol, 69%) as a yellow solid; m/z ES+ [M+1] ⁺ 358.1. Step 2. tert-Butyl 7-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]o ctane-4- carboxylate To a solution of tert-butyl 7-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 559 μmol) in toluene (1 mL) was added phosphorus oxychloride (111 mg, 727 μmol) and diisopropylethylamine (361 mg, 2.80 mmol). The mixture was stirred at 110 °C for 1.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate 3:1) to give tert-butyl 7-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]o ctane-4-carboxylate (170 mg, 0.44 mmol, 80%) as a yellow solid. m/z ES+ [M+1] ⁺ 376.0. Intermediate 103: tert-Butyl (1S,4S)-5-[4-(2,5-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te Step 1: tert-Butyl (1S,4S)-5-[4-(2,5-difluoro-4-hydroxy-anilino)pyrido[3,2-d]py rimidin- 6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.4 g, 1.1 mmol) in acetonitrile (4 mL) was added 4- amino-2,5-difluoro-phenol (0.18 g, 1.2 mmol). The mixture was stirred at 40 °C for 2 h. On completion, the mixture was filtered and the filtered cake was collected to give tert-Butyl (1S,4S)- 5-[4-(2,5-difluoro-4-hydroxy-anilino)pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.5 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 471.0. Intermediate 104: tert-Butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro-pyrid o[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te Step 1. 6-Bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine To a solution of 6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (3.00 g, 12.3 mmol) in toluene (50 mL) was added phosphorus oxychloride (2.83 g, 18.4 mmol) and diisopropylethylamine (7.94 g, 61.5 mmol). The mixture was stirred at 110 °C for 1.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 5/1) to give 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (2.03 g, 7.73 mmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H); m/z ES+[M+H] ⁺ 261.8. Step 2. 4-[(6-Bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-yl)amino]-2,3- difluoro-phenol A mixture of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (1.90 g, 7.24 mmol) and 4-amino-2,3-difluoro-phenol (1.16 g, 7.96 mmol) in acetonitrile (25 mL) was stirred at 25 °C for 12 hr. On completion, the reaction mixture was filtered. The filtered cake was washed with acetonitrile (100 mL) and dried in vacuo to give 4-[(6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4- yl)amino]-2,3-difluoro-phenol (2.95 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 - 10.30 (m, 2H), 8.67 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.10 - 7.05 (m, 1H), 6.90 - 6.84 (m, 1H); m/z ES+[M+H] ⁺ 370.8. Step 3. tert-Butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro-pyrid o[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 4-[(6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-yl)amino]-2,3- difluoro- phenol (2.59 g, 6.98 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.66 g, 8.37 mmol) in N-methyl pyrrolidone (25 mL) was added diisopropylethylamine (4.51 g, 34.9 mmol), the mixture was stirred at 100 °C for 4 hr. On completion, the reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The crude product was triturated with petroleum ether/ethyl acetate (2/1, 100 mL) at 25 ^o C for 30 min to give tert-butyl (1S,4S)-5-[4-(2,3-difluoro- 4-hydroxy-anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate (2.54 g, 5.20 mmol, 75%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.92 - 9.80 (m, 1H), 9.40 - 9.02 (m, 1H), 8.27 (s, 1H), 7.75 (d, J = 13.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 6.83 (t, J = 8.4 Hz, 1H), 5.24 (d, J = 14.0 Hz, 1H), 4.65 - 4.35 (m, 1H), 3.82 (s, 1H), 3.67 (d, J = 14.0 Hz, 1H), 3.40 (s, 2H), 1.93 (s, 2H), 1.38 (d, J = 18.0 Hz, 9H); m/z ES+[M+H] ⁺ 489.0. Intermediate 105: 6-Bromo-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-5- fluoroquinazolin-4-amine Step 1. N'-(4-Bromo-2-cyano-3-fluorophenyl)-N,N-dimethylformimidamid e To a solution of 6-amino-3-bromo-2-fluoro-benzonitrile (3.00 g, 14.0 mmol) in toluene (20 mL) was added N, N-dimethylformamide dimethyl acetal (4.99 g, 41.9 mmol). The mixture was stirred at 110 °C for 2 hr. On completion, the mixture was filtered and concentrated under reduced pressure to give N'-(4-bromo-2-cyano-3-fluorophenyl)-N,N-dimethylformimidamid e (1.6 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 270.3; Step 2. 6-Bromo-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-5-fl uoroquinazolin- 4-amine To a solution of N'-(4-bromo-2-cyano-3-fluoro-phenyl)-N,N-dimethyl-formamidin e (500 mg, 1.85 mmol) in toluene (5 mL) was added acetic acid (5.25 g, 87.4 mmol) and 3-chloro-4- (difluoromethoxy)-2-fluoroaniline (391 mg, 1.85 mmol). The mixture was stirred at 110 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate =20:1 to 1:1) to give 6-bromo-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-5- fluoroquinazolin-4-amine (300 mg, 627 μmol, 75%) as a yellow solid. m/z ES+ [M+H] ⁺ 438.0. Intermediate 106: tert-Butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate Step 1. tert-Butyl (1S,4S)-5-(8-hydroxypyrimido[5,4-d]pyrimidin-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloropyrimido[5,4-d]pyrimidin-4-ol (500 mg, 1 eq) in 1- methylpyrrolidin-2-one (6 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (815 mg, 1.5 eq) and diisopropylethylamine (708 mg, 2 eq), and the mixture was stirred at 100 °C for 1 h. On completion, the mixture was directly purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(8-hydroxypyrimido[5,4-d]pyrimidin-2- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (750 mg, 2.18 mmol, 80%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (s, 1H), 7.91 (s, 1H), 5.33 - 5.06 (m, 1H), 4.74 - 4.54 (m, 1H), 3.90 - 3.57 (m, 2H), 3.57 - 3.25 (m, 2H), 2.01 - 1.94 (m, 2H), 1.51 - 1.39 (m, 9H); m/z ES+ [M+H] ⁺ 344.8. Step 2. tert-Butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(8-hydroxypyrimido[5,4-d]pyrimidin-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (600 mg, 1.74 mmol) and diisopropylethylamine (675 mg, 5.23 mmol) in toluene (6 mL) was added phosphorus oxychloride (320 mg, 2.09 mmol), and the mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ethergradient @ 40 mL/min) to give tert-butyl (1S,4S)-5-(4- chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (150 mg, 0.34 mmol, 20% yield) as a yellow solid. m/z ES+ [M+H] ⁺ 362.8. Intermediate 107: tert-butyl (1S,4S)-5-[4-(3-bromo-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te Step 1. tert-Butyl (1S,4S)-5-[4-(3-bromo-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 1.38 mmol) and 4-amino-2-bromo-3-fluoro- phenol (398 mg, 1.93 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 1 hr. The mixture was then stirred at 25 °C for 15 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was triturated with ethyl acetate (20 mL) at 25 °C for 30 min to give tert-butyl (1S,4S)-5-[4-(3-bromo-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (822 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H), 8.14 - 7.95 (m, 2H), 7.69 (dd, J = 2.8, 9.2 Hz, 1H), 7.49 (s, 2H), 7.39 (d, J = 2.8 Hz, 1H), 5.49 (dd, J = 2.4, 10.0 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 3.75 - 3.63 (m, 1H), 2.14 - 2.08 (m, 1H), 2.02 - 1.95 (m, 2H), 1.78 - 1.64 (m, 1H), 1.61 - 1.51 (m, 2H); m/z ES+ [M+H] ⁺ 496.2. Intermediate 108: tert-Butyl 7-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate Step 1. tert-Butyl 7-(4-hydroxypyrimido[5,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of 6-chloropyrimido[5,4-d]pyrimidin-4-ol (500 mg, 2.74 mmol) and tert- butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (872 mg, 4.11 mmol) in N-methyl pyrrolidone (5 mL) was added diisopropylethylamine (1.06 g, 8.22 mmol), the mixture was stirred at 100 °C for 0.5 h. On completion, the mixture was diluted with aq. citric acid solution (40 mL). The crude product was triturated with water (40 mL) and then filtered. The filtered cake was collected to give tert-butyl 7-(4-hydroxypyrimido[5,4-d]pyrimidin-6-yl)-4,7-diazaspiro[2. 5]octane-4-carboxylate (680 mg, 1.90 mmol, 69%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 11.04 - 10.47 (m, 1H), 9.13 - 8.61 (m, 1H), 7.80 (s, 1H), 3.63 - 3.53 (m, 2H), 2.29 (s, 1H), 1.42 (s, 9H), 1.00 - 0.89 (m, 2H), 0.87 - 0.81(m, 2H). Step 2. tert-Butyl 7-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5 ]octane- 4-carboxylate To a solution of tert-butyl 7-(4-hydroxypyrimido[5,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (600 mg, 1.67 mmol) in toluene (20 mL) was added phosphorus oxychloride (513 mg, 3.35 mmol) and diisopropylethylamine (1.30 g, 10.0 mmol), the mixture was stirred at 110 °C for 5 hr. On completion, the reaction mixture was quenched with saturated ammonium chloride solution to adjust pH = 8. Then the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 5/1) to give tert-butyl 7-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (400 mg, 1.06 mmol, 63%) as a yellow solid. m/z ES+ [M+H] ⁺ 377.0. Intermediate 109: 6-Bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7-f luoro- pyrido[3,2-d]pyrimidin-4-amine Step 1.6-Bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7 -fluoro-pyrido[3,2- d]pyrimidin-4-amine A solution of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (500 mg, 1.91 mmol) and 3-chloro-4-(difluoromethoxy)-2-fluoroaniline (450 mg, 2.13 mmol) in acetonitrile (10 mL) was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated to give 6- bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7-flu oro-pyrido[3,2-d]pyrimidin-4- amine (480 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.52 - 10.26 (m, 1H), 8.68 - 8.55 (m, 1H), 8.40 - 8.25 (m, 1H), 7.72 - 7.63 (m, 1H), 7.58 - 7.19 (m, 2H); m/z ES+ [M+H] ⁺ 439.0. Intermediate 110: tert-Butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate Step 1. tert-Butyl (1S,4S)-5-(7-fluoro-4-hydroxy-pyrido[3,2-d]pyrimidin-6-yl)-2 ,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of 6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (10.0 g, 41.0 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (10.0 g, 50.4 mmol) in 1- methylpyrrolidin-2-one (100 mL) was added diisopropylethylamine (10.6 g, 82.0 mmol, 14.3 mL). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was poured into brine (600 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert- butyl (1S,4S)-5-(7-fluoro-4-hydroxy-pyrido[3,2-d]pyrimidin-6-yl)-2 ,5- diazabicyclo[2.2.1]heptane-2-carboxylate (14.0 g, 35.3 mmol, 86%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.31-10.88 (m, 1H), 7.92 (s, 1H), 7.71 (d, J = 13.2 Hz, 1H), 4.93 (s, 1H), 4.55- 4.36 (m, 1H), 3.75 (d, J = 10.0 Hz, 2H), 3.54-3.42(m , 2H), 1.90 (d, J = 11.6 Hz, 2H), 1.36 (d, J = 20.0 Hz, 9H); m/z ES+ [M+H] ⁺ 361.9. Step 2. tert-Butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(7-fluoro-4-hydroxy-pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (7.50 g, 20.8 mmol) in toluene (80.0 mL) was added diisopropylethylamine (16.1 g, 125 mmol, 21.7 mL). Then the mixture was added phosphorus oxychloride (6.36 g, 41.5 mmol, 3.86 mL) and stirred at 110 °C for 1 hr under nitrogen atmosphere. On completion, the mixture was quenched with saturated sodium bicarbonate solution to adjust pH = 7~8. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (3.20 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H), 8.03 (d, J = 13.2 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.52 (d, J = 18.0 Hz, 1H), 3.87 (d, J = 10.0 Hz, 2H), 3.74 - 3.65 (m, 2H), 1.97 (d, J = 10.8 Hz, 2H), 1.38 (d, J = 18.0 Hz, 9H); m/z ES+ [M+H] ⁺ 380.1. Intermediate 111: tert-Butyl 7-(8-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)pyrimido[5,4- d]pyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate Step 1. tert-Butyl 7-(8-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)pyrimido[5,4- d]pyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (180 mg, 478 μmol) in acetonitrile (10 mL) was added 4- amino-2-chloro-3-fluoro-phenol (92.60 mg, 573 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the mixture was diluted with ethyl acetate (2 mL) and further triturated with ethyl acetate (10 mL) for 10 min. The mixture was filtered and the filtered cake was collected to give tert-butyl 7-(8-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)pyrimido[5,4- d]pyrimidin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (235 mg, 468 μmol, 98%) as a yellow solid. m/z ES+ [M+H] ⁺ 502.3. Intermediate 112: tert-Butyl 7-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate Step 1. tert-Butyl 7-(7-fluoro-4-hydroxy-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of 6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (300 mg, 1.23 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (391 mg, 1.84 mmol) in 1-methylpyrrolidin-2- one (1 mL) was added diisopropylethylamine (318 mg, 2.46 mmol, 428 μL). The mixture was stirred at 110 °C for 1 hr. On completion, the reaction mixture was poured into brine (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give tert-butyl 7-(7-fluoro-4-hydroxy-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (480 mg, 1.02 mmol, 83%) as a brown solid. m/z ES+ [M+H] ⁺ 376.1. Step 2. tert-Butyl 7-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(7-fluoro-4-hydroxy-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 266 μmol) in toluene (1 mL) was added phosphorus oxychloride (81.7 mg, 533 μmol, 49.5 μL) and diisopropylethylamine (207 mg, 1.60 mmol, 278 μL). The mixture was stirred at 110 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was added into saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 7-(4-chloro-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octane-4-car boxylate (100 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 394.3. Aniline-29: 3-Chloro-4-(difluoromethoxy)-2-fluoroaniline Step 1. 2-Cloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-fluorophenol To a solution of 4-amino-2-chloro-3-fluoro-phenol (2.00 g, 12.3 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (282 mg, 2.48 mmol) and hexane-2,5- dione (1.70 g, 14.9 mmol). The reaction was stirred at 20 °C for 2 hr. On completion, the reaction mixture was concentrated to give 2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (3.00 g, 12.5 mmol, 91%) as a black oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 7.16 (t, J = 8.8 Hz, 1H), 6.92 (dd, J = 1.6, 8.8 Hz, 1H), 5.79 (s, 2H), 1.90 (s, 6H). Step 2. 1-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-2,5-dimethyl -1H-pyrrole A solution of 2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (3.00 g, 12.5 mmol), (2-chloro-2,2-difluoro-acetyl)oxysodium (6.70 g, 43.9 mmol) and cesium carbonate (8.00 g, 24.5 mmol) in N,N-dimethylformamide (24 mL) and water (4 mL) was stirred at 100 °C for 4 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[3-chloro-4- (difluoromethoxy)-2-fluoro-phenyl]-2,5-dimethyl-pyrrole (3.60 g, crude) as a black oil. Step 3.3-Chloro-4-(difluoromethoxy)-2-fluoroaniline To a solution of 1-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-2,5-dimethy l-pyrrole (3.60 g, 12.4 mmol) in ethanol (120 mL) and water (20.0 mL) was added hydroxylammonium chloride (25.1 g, 361 mmol) and trimethylamine (5.09 g, 50.3 mmol). The reaction was stirred at 80 °C for 12 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether : ethyl acetate = 4 ˖1 under UV 254 nm) to give 3-chloro-4-(difluoromethoxy)-2-fluoroaniline (1.40 g, 6.64 mmol, 50%) as a red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.03 (t, J = 74.0 Hz, 1H), 6.95 – 6.90 (m, 1H), 6.73 (t, J = 9.2 Hz, 1H), 5.47 (s, 2H). Aniline-30: 1-(4-Amino-2-chloro-3-fluoro-phenyl)cyclopropanecarbonitrile Step 1. 1-(4-Bromo-3-chloro-2-fluoro-phenyl)-2,5-dimethyl-pyrrole To a mixture of 4-bromo-3-chloro-2-fluoro-aniline (2.00 g, 8.91 mmol) and hexane-2,5- dione (2.03 g, 17.8 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (101 mg, 891 μmol), the reaction mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was then partitioned between water (30 mL) and ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether:ethyl acetate=100:1 to 4:1) to give 1-(4-bromo-3-chloro-2-fluoro-phenyl)-2,5-dimethyl- pyrrole (2.60 g, 8.59 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 - 7.54 (m, 1H), 7.11 - 7.06 (m, 1H), 5.95 (s, 2H), 2.02 (s, 6H). Step 2. 1-[2-Chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro- phenyl]cyclopropanecarbonitrile To a mixture of 1-(4-bromo-3-chloro-2-fluoro-phenyl)-2,5-dimethyl-pyrrole (1.3 g, 4.30 mmol), cyclopropanecarbonitrile (288 mg, 4.30 mmol), (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'- binaphthyl (535 mg, 859 μmol) and tris(dibenzylideneacetone)dipalladium (393 mg, 430 μmol) in tetrahydrofuran (15 mL) was added bistrimethylsilyllithiumamino (1 M in tetrahydrofuran, 8.59 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 12 hr under nitrogen. The reaction mixture was quenched by hydrochloric acid (1 N, 5 mL) and then the mixture was partitioned between water (40 mL) and ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 3/2) to give 1-[2-chloro- 4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenyl]cyclopropanecarb onitrile (200 mg, 692 μmol, 16%) as a yellow solid. m/z ES+ [M+H] ⁺ 289.1. Step 3. 1-(4-Amino-2-chloro-3-fluoro-phenyl)cyclopropanecarbonitrile To a solution of 1-[2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro- phenyl]cyclopropanecarbonitrile (160 mg, 554 μmol) in ethanol (1.6 mL) was added hydroxylamine hydrochloride (385 mg, 5.54 mmol) and water (0.8 mL). The mixture was stirred at 120 °C for 0.6 hr unde microwave irridiation. The reaction mixture was quenched by addition water 10 mL and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5/1 to 1/1) to give 1-(4-amino-2-chloro-3-fluoro-phenyl)cyclopropanecarbonitrile (50 mg, 214 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.97 (dd, J = 1.6, 8.4 Hz, 1H), 6.72 (t, J = 8.4 Hz, 1H), 1.67 - 1.62 (m, 2H), 1.34 - 1.29 (m, 2H); m/z ES+ [M+H] ⁺ 211.0 Aniline-31: 1-(4-Amino-2-chloro-3-fluoro-phenyl)cyclobutanecarbonitrile Step 1.1-[2-Chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenyl]cy clobutanecarbonitrile To a solution of 1-(4-bromo-3-chloro-2-fluoro-phenyl)-2,5-dimethyl-pyrrole (1 g, 3.31 mmol), cyclobutanecarbonitrile (536 mg, 6.61 mmol), (6-diphenylphosphanyl-10H-phenoxazin- 4-yl)-diphenyl-phosphane (182 mg, 330 μmol) and tris(dibenzylideneacetone)dipalladium (302 mg, 330 μmol) in anhydrous tetrahydrofuran (10 mL) was added lithium;bis(trimethylsilyl)azanide (1 M in tetrahydrofuran, 4.63 mL). The mixture was stirred at 80 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was quenched with ammonium chloride solution (50 mL). The mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 15/1) to give 1-[2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro- phenyl]cyclobutanecarbonitrile (800 mg, 2.59 mmol, 78%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25 - 7.14 (m, 2H), 5.96 (s, 2H), 3.06 - 2.95 (m, 2H), 2.80 - 2.68 (m, 2H), 2.08 - 2.03 (m, 7H); m/z ES+ [M+H] ⁺ 302.8. Step 2.1-(4-Amino-2-chloro-3-fluoro-phenyl)cyclobutanecarbonitril e A solution of 1-[2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro- phenyl]cyclobutanecarbonitrile (800 mg, 2.64 mmol) and hydroxylamine hydrochloride (3.67 g, 52.84 mmol) in ethanol (5 mL) and water (2.5 mL) was stirred at 100 °C for 16 hr. On completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 4/1) to give 1-(4-amino-2-chloro-3-fluoro- phenyl)cyclobutanecarbonitrile (300 mg, 1.30 mmol, 49%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.75 (d, J = 8.6 Hz, 1H), 6.67 - 6.58 (m, 1H), 2.87 - 2.76 (m, 2H), 2.59 - 2.47 (m, 2H), 2.46 - 2.33 (m, 1H), 1.99 - 1.84 (m, 1H); m/z ES+ [M+H] ⁺ 225.1. Aniline-32: 3-Chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline Step 1. 3-Chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)aniline To a solution of 4-bromo-3-chloro-2-fluoro-aniline (5.5 g, 24.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (12.4 g, 49.0 mmol) in N,N- dimethylformamide (50 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.79 g, 2.45 mmol) and potassium acetate (4.81 g, 49.0 mmol), the mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 20:1 to 3:1) to give 3-chloro-2- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilin e (5 g, 17.5 mmol, 71%) as a white solid. m/z ES+ [M+H] ⁺ 272.4. Step 2. 3-Chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline To a solution of 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)aniline (2.5 g, 9.21 mmol) and 1,1,1-trifluoro-2-iodo-ethane (11.6 g, 55.2 mmol) in dioxane (40 mL) and water (10 mL) was added (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl- phosphane (532 mg, 0.92 mmol), cesium carbonate (12.0 g, 36.8 mmol) and tris(dibenzylideneacetone)dipalladium (421 mg, 0.46 mmol), the mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The mixture was purified by column chromatography (petroleum ether : ethyl acetate = 20:1 to 1:1) to give 3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline (0.2 g, 0.87 mmol, 9.5%) as a white solid. m/z ES+ [M+H] ⁺ 228.3. Aniline-33: 3-Chloro-4-(2,2-difluoroethyl)-2-fluoroaniline

Step 1. tert-Butyl (4-bromo-3-chloro-2-fluorophenyl)carbamate To a solution of 4-bromo-3-chloro-2-fluoroaniline (2 g, 8.91 mmo), triethylamine (1.80 g, 17.8 mmol) in tetrahydrofuran (20 mL) was added di-tert-butyl dicarbonate (2.92 g, 13.37 mmol). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 10/1) to give tert-butyl (4-bromo-3-chloro-2- fluorophenyl)carbamate (2.3 g, 7.09 mmol, 79%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (t, J = 8.4 Hz, 1H), 7.29 (dd, J = 2.0, 9.2 Hz, 1H), 6.62 (s, 1H), 1.46 (s, 9H). Step 2. tert-Butyl (3-chloro-2-fluoro-4-vinylphenyl)carbamate A solution of tert-butyl (4-bromo-3-chloro-2-fluorophenyl)carbamate (1.00 g, 3.08 mmol), potassium;trifluoro(vinyl)boranuide (453 mg, 3.39 mmol), triethylamine (623 mg, 6.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (112 mg, 154 μmol) in ethanol (10 mL) was stirred at 80 °C for 16 h undet nitrogen. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 10/1) to give tert- butyl (3-chloro-2-fluoro-4-vinylphenyl)carbamate (700 mg, 2.58 mmol, 83%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 7.92 (t, J = 8.2 Hz, 1H), 7.26 (dd, J = 2.0, 8.8 Hz, 1H), 6.92 (dd, J = 11.0, 17.5 Hz, 1H), 6.63 (s, 1H), 5.65 (dd, J = 0.8, 17.6 Hz, 1H), 5.29 (d, J = 11.0 Hz, 1H), 1.46 (s, 9H). Step 3. tert-Butyl (3-chloro-2-fluoro-4-(2-hydroxyethyl)phenyl)carbamate To a solution of tert-butyl (3-chloro-2-fluoro-4-vinylphenyl)carbamate (200 mg, 736 μmol) in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran complex (1 M, 1.1 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h. Then aqueous sodium hydroxide solution (1 M, 2 mL) and hydrogen peroxide (1.3 mL, 30%) was added. The mixture was stirred at 70 °C for 16 h. On completion, the mixture was poured into sat. sodium sulfite solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were dried by sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 3/1) to give tert- butyl (3-chloro-2-fluoro-4-(2-hydroxyethyl)phenyl)carbamate (150 mg, 517 μmol, 70%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.15 - 9.01 (m, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.11 (dd, J = 1.6, 8.4 Hz, 1H), 4.74 (t, J = 5.4 Hz, 1H), 3.65 - 3.52 (m, 2H), 2.83 (t, J = 6.8 Hz, 2H), 1.44 - 1.44 (m, 1H), 1.45 (s, 9H). Step 4. tert-Butyl (3-chloro-2-fluoro-4-(2-oxoethyl)phenyl)carbamate To a solution of tert-butyl N-[3-chloro-2-fluoro-4-(2-hydroxyethyl)phenyl]carbamate (1.2 g, 4.14 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (2.64 g, 6.21 mmol) dropwise. The mixture was stirred at 25 °C for 16 h. On completion, the mixture was poured into sat. sodium sulfite solution (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=3/1 ) to give tert-butyl (3-chloro-2-fluoro-4-(2-oxoethyl)phenyl)carbamate (0.9 g, 3.13 mmol, 75%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.65 (t, J = 1.7 Hz, 1H), 6.92 (dd, J = 1.6, 8.6 Hz, 1H), 6.67 (s, 1H), 3.74 (s, 2H), 3.73 - 3.71 (m, 1H), 1.46 (s, 9H). Step 5. tert-Butyl (3-chloro-4-(2,2-difluoroethyl)-2-fluorophenyl)carbamate To a solution of tert-butyl (3-chloro-2-fluoro-4-(2-oxoethyl)phenyl)carbamate (0.9 g, 3.13 mmol) in dichloromethane (1 mL) was added (diethylamino)sulfur trifluoride (1.51 g, 9.38 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 16 h. On completion, the mixture was poured into sat. sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were dried by sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 5/1) to give tert-butyl (3-chloro-4-(2,2-difluoroethyl)-2- fluorophenyl)carbamate (250 mg, 807 μmol, 25%) as a yellow oil. Step 6. 3-Chloro-4-(2,2-difluoroethyl)-2-fluoroaniline A solution of tert-butyl (3-chloro-4-(2,2-difluoroethyl)-2-fluorophenyl)carbamate (200 mg, 645 μmol) in hydrochloric acid/dioxane (4 M, 10 mL) was stirred at 25 °C for 10 min. On completion, the mixture was concentrated under reduced pressure. The residue was diluted with aqueous ammonium hydroxide (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were dried by sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 5/1) to give 3-chloro-4-(2,2-difluoroethyl)-2-fluoroaniline (110 mg, 524 μmol, 81%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.82 (d, J = 8.4 Hz, 1H), 6.70 - 6.53 (m, 1H), 6.05 - 5.64 (m, 1H), 3.14 (dt, J = 4.6, 16.4 Hz, 2H). Aniline-34: 3-Chloro-2-fluoro-4-((1-fluorocyclopropyl)methoxy)aniline Step 1. (1-Fluorocyclopropyl)methanol To a solution of 1-fluorocyclopropanecarboxylic acid (11 g, 105 mmol) in anhydrous tetrahydrofuran (80 mL) was added lithium aluminum hydride (5.21 g, 137 mmol) portionwise at 0 °C under nitrogen atmosphere, the mixture was stirred at 25 °C for 2 hr. On completion, the mixture was quenched with 1N hydrogen chloride (1000 mL) and extracted with ethyl acetate (700 mLx 3). The combined organic layers were washed with brine (4000 mL), dried and concentarted in vacuo to give (1-fluorocyclopropyl)methanol (5 g, crude) as a white oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.88 - 3.67 (m, 2H), 1.09 - 0.97 (m, 2H), 0.66 -0.63 (m, 2H). Step 2. (1-Fluorocyclopropyl)methyl methanesulfonate To a solution of (1-fluorocyclopropyl) methanol (5 g, 55.5 mmol) in dichloromethane (30 mL) was added methylsulfonylmethanesulfonate (19.3 g, 110 mmol) and triethylamine (22.4 g, 221 mmol) at 0 °C, the mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixtrue was diluted with dichloromethane (200 mL), and the organic layers were washed with water (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (1-fluorocyclopropyl)methyl methanesulfonate (8 g, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.56 - 4.41 (m, 2H), 3.11 (s, 3H), 1.27 - 1.21 (m, 2H), 0.91 - 0.82 (m, 2H). Step 3. 2-Chloro-3-fluoro-1-((1-fluorocyclopropyl)methoxy)-4-nitrobe nzene To a solution of 2-chloro-3-fluoro-4-nitro-phenol (300 mg, 1.57 mmol) and cesium carbonate (1.02 g, 3.13 mmol) in N,N-dimethylformamide (5 mL) was added (1- fluorocyclopropyl)methyl methanesulfonate (658 mg, 3.92 mmol). The mixture was stirred at 80 °C for 16 hours. On completion, the mixture was washed with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified with column chromatograph (petroleum ether: ethyl acetate =1:0 to 5:1) to give 2-chloro-3-fluoro-1-[(1-fluorocyclopropyl)methoxy]-4-nitro-b enzene (280 mg, 1.06 mmol, 68%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 – 8.04 (m, 1H), 6.89 – 6.86 (m, 1H), 4.50 – 4.40 (m, 2H), 1.32 – 1.24 (m, 2H), 1.0 – 0.82 (m, 2H). Step 4. 3-Chloro-2-fluoro-4-((1-fluorocyclopropyl)methoxy)aniline To a solution of 2-chloro-3-fluoro-1-[(1-fluorocyclopropyl)methoxy]-4-nitro-b enzene (280 mg, 1.06 mmol) and ammonium chloride (284 mg, 5.31 mmol) in ethanol (4 mL) and water (1 mL) was added iron powder (296 mg, 5.31 mmol). The mixture was stirred at 80 °C for 1 h. On completion, the mixtrue was filtered and the filtrate was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried and concentrated in vacuo to give a residue. The residue was purified with column chromatography (petroleum ether : ethyl acetate=8:1 to 3:1) and then re-purified with reversed-phase HPLC [0.1% FA in water/ACN] to give 3-chloro-2-fluoro-4-((1-fluorocyclopropyl)methoxy)aniline (600 mg, 2.36 mmol, 48%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.71 – 6.60 (m, 2H), 4.25 – 4.05 (m, 2H), 1.16 – 1.07 (m, 2H), 0.80 – 0.65 (m, 2H). Aniline-35: 3-Chloro-4-(cyclopropoxy)-2-fluoro-aniline Step 1.2-Chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol To a mixture of 4-amino-2-chloro-3-fluoro-phenol (1 g, 6.19 mmol) and hexane-2,5-dione (1.06 g, 9.28 mmol, 1.09 mL) in dichloromethane (10 mL) was added trifluoroacetic acid (70.5 mg, 619 μmol, 45.8 μL) in one portion. The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give 2-chloro- 4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (1.2 g, 4.84 mmol, 78%) as a yellow oil. m/z ES+ [M+H] ⁺ 240.1. Step 2.1-[3-Chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-2,5-dimethyl -pyrrole To a solution of 2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (0.2 g, 834 μmol) in N,N-dimethylformamide (2 mL) and bromocyclopropane (3.03 g, 25.0 mmol) was added potassium carbonate (231 mg, 1.67 mmol) The mixture was stirred at 180 °C for 10 hr under microwave irradiation. On completion, the reaction mixture was quenched by addition water 20 mL at 25 °C, and then diluted with ethyl acetate 20 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 1/1) to give 1-[3-chloro-4- (cyclopropoxy)-2-fluoro-phenyl]-2,5-dimethyl-pyrrole (0.15 g, 515 μmol, 62%) as a yellow oil. m/z ES+ [M+H] ⁺ 280.1. Step 3.3-Chloro-4-(cyclopropoxy)-2-fluoro-aniline To a mixture of 1-[3-chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-2,5-dimethyl-p yrrole (0.15 g, 536 μmol) in ethanol (5 mL) and water (1 mL) was added hydroxylamine hydrochloride (745 mg, 10.7 mmol) and triethylamine (271 mg, 2.68 mmol) in one portion. The mixture was then heated to 100 °C and stirred for 24 hr. On completion, the reaction mixture was quenched by addition sodium bicarbonate solution 5 mL at 25 °C, and then diluted with dichloromethane (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-4-(cyclopropoxy)-2-fluoro-aniline (0.12 g, 476 μmol, 89%) as a yellow oil. m/z ES+ [M+H] ⁺ 202.1. Aniline-36: 4-(Cyclopropoxy)-2,3-difluoro-aniline Step 1.4-(2,5-Dimethylpyrrol-1-yl)-2,3-difluoro-phenol To a mixture of 4-amino-2,3-difluoro-phenol (1 g, 6.89 mmol) and hexane-2,5-dione (1.18 g, 10.3 mmol, 1.21 mL) in dichloromethane (10 mL) was added trifluoroacetic acid (78.6 mg, 689 μmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 1/1) to give 4-(2,5- dimethylpyrrol-1-yl)-2,3-difluoro-phenol (1.2 g, 5.38 mmol, 78%) as a yellow oil. m/z ES+ [M+H] ⁺ 224.2. Step 2.1-[4-(Cyclopropoxy)-2,3-difluoro-phenyl]-2,5-dimethyl-pyrr ole To a solution of 4-(2,5-dimethylpyrrol-1-yl)-2,3-difluoro-phenol (0.4 g, 1.79 mmol) in N,N-dimethylformamide (4 mL) and bromocyclopropane (6.50 g, 53.8 mmol) was added potassium carbonate (495 mg, 3.58 mmol). The mixture was stirred at 180 °C for 10 hr under microwave irradiation. On completion, the reaction mixture was quenched by addition water 20 mL at 25 °C, and then diluted with ethyl acetate 20 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue.The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 1-[4-(cyclopropoxy)-2,3-difluoro- phenyl]-2,5-dimethyl-pyrrole (0.2 g, 744 μmol, 42%) as a yellow oil. m/z ES+ [M+H] ⁺ 264.2. Step 3.4-(Cyclopropoxy)-2,3-difluoro-aniline To a mixture of 1-[4-(cyclopropoxy)-2,3-difluoro-phenyl]-2,5-dimethyl-pyrrol e (0.2 g, 760 μmol) in ethanol (5 mL) and water (1 mL) was added triethylamine (384 mg, 3.80 mmol) and hydroxylamine hydrochloride (1.06 g, 15.2 mmol) in one portion. The mixture was then heated to 100 °C and stirred for 24 hr. On completion, the reaction mixture was quenched by addition water 5 mL at 25 °C, and then diluted with dichloromethane 5 mL and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-(cyclopropoxy)-2,3-difluoro- aniline (120 mg, 544 μmol, 72%) as a yellow oil. m/z ES+ [M+H] ⁺ 186.2. Aniline-37: 2,3-Difluoro-4-(1-methylcyclobutoxy)aniline Step 1.2-Chloro-3-fluoro-4-(1-methylcyclobutoxy)-1-nitrobenzene To a solution of 1-methylcyclobutanol (1.4 g, 16.2 mmol) in anhydrous tetrahydrofuran (20 mL) was added sodium hydride (620 mg, 15.5 mmol, 60% in mineral oil) at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 0 ℃ for 0.5 hr. Then 2-chloro-3,4-difluoro-1-nitrobenzene (2 g, 10.3 mmol) was added. The mixture was stirred at 20 ℃ for 1.5 hr. The reaction mixture was quenched by addition saturated ammonium chloride solution 40 mL at 0 ℃, and then extracted with ethyl acetate (6 mL x 3). The combined organic layers were washed with brine 10 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 10/1) to give 2-chloro-3-fluoro-4-(1-methylcyclobutoxy)-1-nitrobenzene (2.4 g, 9.24 mmol, 89%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (dd, J = 1.2, 9.2 Hz, 1H), 6.78 (t, J = 8.4 Hz, 1H), 2.57 - 2.47 (m, 2H), 2.30 - 2.22 (m, 2H), 1.96 - 1.86 (m, 1H), 1.77 (m, J = 9.6 Hz, 1H), 1.61 (s, 3H). Step 2.2,3-Difluoro-1-(1-methylcyclobutoxy)-4-nitrobenzene To a solution of 2-chloro-3-fluoro-4-(1-methylcyclobutoxy)-1-nitrobenzene (400 mg, 1.54 mmol) in dimethylsulfoxide (8 mL) was added cesium fluoride (500 mg, 3.29 mmol). The mixture was stirred at 140 ℃ for 16 hr. The reaction mixture was quenched by addition water 30 mL at 0 ℃, and then extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine 40 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate = 10:1) to give 2,3-difluoro-1-(1-methylcyclobutoxy)-4- nitrobenzene (200 mg, 822 μmol, 53%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 - 7.79 (m, 1H), 6.69 - 6.40 (m, 1H), 2.53 (q, J = 10.2 Hz, 2H), 2.33 - 2.20 (m, 2H), 1.99 - 1.85 (m, 1H), 1.84 - 1.68 (m, 1H), 1.62 (s, 3H). Step 3.2,3-Difluoro-4-(1-methylcyclobutoxy)aniline To a solution of 2,3-difluoro-1-(1-methylcyclobutoxy)-4-nitrobenzene (100 mg, 411 μmol) in ethyl acetate (2 mL) was added Pt/V/C (33 mg, 5.07 μmol, 3% loadidng). The mixture was degassed and purged with hydrogen for 3 times, and then stirred at 25 ℃ for 1 hr under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether : ethyl acetate = 3:1) to give 2,3-difluoro-4-(1-methylcyclobutoxy)aniline (42 mg, 197 μmol, 48%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.60 - 6.52 (m, 1H), 6.47 - 6.38 (m, 1H), 3.95 - 3.02 (m, 2H), 2.44 - 2.33 (m, 2H), 2.00 (tt, J = 2.8, 8.8 Hz, 2H), 1.78 - 1.67 (m, 1H), 1.65 - 1.54 (m, 1H), 1.47 (s, 3H); m/z ES+ [M+H] ⁺ 214.2. Aniline-38: 3-Chloro-2-fluoro-4-(trifluoromethoxy)aniline Step 1.1-[4-[Bromo(difluoro)methoxy]-3-chloro-2-fluoro-phenyl]-2, 5-dimethyl-pyrrole To a solution of 2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (2.00 g, 8.34 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (5.77 g, 41.7 mmol) and dibromo(difluoro)methane (8.75 g, 41.7 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 20/1) to give 1-[4-[bromo(difluoro)methoxy]-3-chloro-2-fluoro-phenyl]-2,5- dimethyl-pyrrole (450 mg, 1.16 mmol, 14%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.36 - 7.32 (m, 1H), 7.25 - 7.21 (m, 1H), 4.16 – 4.10 (m, 2H), 1.56 (s, 3H), 1.29 - 1.25 (m, 3H); m/z ES+ [M+H] ⁺ 369.9. Step 2.1-[3-Chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-2,5-dimet hyl-pyrrole To a solution of 1-[4-[bromo(difluoro)methoxy]-3-chloro-2-fluoro-phenyl]-2,5- dimethyl- pyrrole (250 mg, 678 μmol) in dichloromethane (2.5 mL) was added silver tetrafluoroborate (264 mg, 1.36 mmol). The mixture was stirred at 25 °C for 3 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, fltered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 10/1) to give 1-[3-chloro- 2-fluoro-4-(trifluoromethoxy)phenyl]-2,5-dimethyl-pyrrole (90.0 mg, 283 μmol, 42%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 - 7.24 (m, 2H), 5.96 (s, 2H), 2.03 (s, 6H); m/z ES+ [M+H] ⁺ 308.0. Step 3.3-chloro-2-fluoro-4-(trifluoromethoxy)aniline To a solution of 1-[3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-2,5-dimethy l-pyrrole (100 mg, 325 μmol) in ethanol (5 mL) and water (1 mL) was added triethylamine (164 mg, 1.63 mmol) and hydroxylammonium chloride (677 mg, 9.75 mmol). The mixture was stirred at 110 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate=5:1) to give 3-chloro-2-fluoro-4- (trifluoromethoxy)aniline (20.0 mg, 73.5 μmol, 22%) as a yellow solid. m/z ES+ [M+H] ⁺ 229.9. Aniline-39: 3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-aniline Step 1. 2-Chloro-1-(2,2-difluoroethoxy)-3-fluoro-4-nitrobenzene To a mixture of 2-chloro-3-fluoro-4-nitro-phenol (2.50 g, 13.0 mmol) and 2,2- difluoroethyl trifluoromethanesulfonate (3.35 g, 15.6 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (5.41 g, 39.1 mmol), then the mixture was stirred at 80 °C for 2 hr. On completion, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (25 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-1-(2,2- difluoroethoxy)-3-fluoro-4-nitro-benzene (4.50 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 – 8.05 (m, 1H), 6.38 – 6.01 (m,1H), 6.38 - 6.01 (m, 1H), 4.42 - 4.34 (m, 2H); m/z ES+ [M+H] ⁺ 255.9. Step 2. 3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-aniline To a mixture of 2-chloro-1-(2,2-difluoroethoxy)-3-fluoro-4-nitro-benzene (4.00 g, 15.6 mmol) and ammonium chloride (4.19 g, 78.2 mmol) in ethanol (80 mL) and water (15 mL) was added iron powder (4.37 g, 78.2 mmol), then the mixture was stirred at 60 °C for 1 hr. On completion, the mixture was filtered and the filtrate was quenched with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=15/1 to 5/1) to give 3- chloro-4-(2,2-difluoroethoxy)-2-fluoro-aniline (2.10 g, 7.54 mmol, 48%) as a yellow oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.68 - 6.64 (m, 1H), 6.64 - 6.61 (m, 1H), 6.26 - 5.95 (m, 1H), 4.17 - 4.13 (m, 2H), 3.92 - 3.53 (m, 2H); m/z ES+ [M+H] ⁺ 226.0. Aniline-40: 3-Chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-anilin e Step 1. (3,3-Difluorocyclobutyl)methyl methanesulfonate To a solution of (3,3-difluorocyclobutyl)methanol (4.00 g, 32.7 mmol) and triethylamine (9.94 g, 98.2 mmol, 13.6 mL) in dichloromethane (40 mL) was added methylsulfonyl methanesulfonate (8.56 g, 49.1 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was diluted with dichloromethane (50 mL) and then washed with water (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (3,3-difluorocyclobutyl)methyl methanesulfonate (6.60 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.28 (d, J = 6.4 Hz, 2H), 3.05 (s, 3H), 2.84 - 2.64 (m, 2H), 2.64 - 2.54 (m, 1H), 2.52 - 2.33 (m, 2H); m/z ES+ [M+H] ⁺ 201.0. Step 2.2-Chloro-1-[(3,3-difluorocyclobutyl)methoxy]-3-fluoro-4-ni tro-benzene To a solution of 2-chloro-3-fluoro-4-nitro-phenol (200 mg, 1.04 mmol) and (3,3- difluorocyclobutyl)methyl methanesulfonate (313 mg, 1.57 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (432 mg, 3.13 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate=1:1) to give 2-chloro-1-[(3,3- difluorocyclobutyl)methoxy]-3-fluoro-4-nitro-benzene (160 mg, 541 μmol, 51%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 – 8.03 (m, 1H), 6.85 – 6.76 (m, J = 1.6, 9.4 Hz, 1H), 4.23 – 4.17 (m, 2H), 2.88 - 2.69 (m, 3H), 2.66 - 2.52 (m, 2H); m/z ES+ [M+H] ⁺ 296.0. Step 3.3-Chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-anil ine To a solution of 2-chloro-1-[(3,3-difluorocyclobutyl)methoxy]-3-fluoro-4-nitr o-benzene (160 mg, 541 μmol) in ethanol (3 mL) and water (0.6 mL) was added ammonium chloride (289 mg, 5.41 mmol) and iron powder (151 mg, 2.71 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtered to give a residue. The residue was partitioned between ethyl acetate (20 mL × 3) and water (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 3-chloro-4-[(3,3- difluorocyclobutyl)methoxy]-2-fluoro-aniline (120 mg, crude) as a black brown oil. m/z ES+ [M+H] ⁺ 266.0. Aniline-41: 3-chloro-4-(cyclobutoxy)-2-fluoro-aniline Step 1. 1-(3-Chloro-4-cyclobutoxy-2-fluorophenyl)-2,5-dimethyl-1H-py rrole To a solution of 2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (500 mg, 2.09 mmol) in N,N-dimethylformamide (3 mL) and bromocyclobutane (1.13 g, 8.34 mmol, 788 μL) was added cesium carbonate (1.36 g, 4.17 mmol). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was poured into brine (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[3-chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-2,5- dimethyl-pyrrole (840 mg, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.32 (t, J = 8.8 Hz, 1H), 6.95 (dd, J = 9.2, 2.4 Hz, 1H), 5.81 (s, 2H), 4.90 – 4.80 (m, 1H), 2.55 – 2.45 (m, 2H), 2.20 – 2.05 (m, 2H), 1.90 (s, 6H), 1.86 – 1.80 (m, 1H), 1.73 – 1.60 (m, 1H); m/z ES+ [M+H] ⁺ 294.4. Step 2. 3-Chloro-4-(cyclobutoxy)-2-fluoro-aniline To a solution of 1-[3-chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-2,5-dimethyl-py rrole (840 mg, 2.86 mmol) in ethanol (5 mL) and water (1 mL) was added triethylamine (1.45 g, 14.3 mmol, 1.99 mL) and hydroxylamine hydrochloride (3.97 g, 57.2 mmol). The mixture was stirred at 120 °C for 12 hr. On completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give 3- chloro-4-(cyclobutoxy)-2-fluoro-aniline (250 mg, 951 μmol, 33%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.69 - 6.62 (m, 1H), 6.61 - 6.55 (m, 1H), 4.92 (s, 2H), 4.56 (q, J = 7.2 Hz, 1H), 2.39 - 2.29 (m, 2H), 2.07 - 1.98 (m, 2H), 1.82 - 1.67 (m, 1H), 1.65 - 1.49 (m, 1H); m/z ES+ [M+H] ⁺ 215.8. Aniline-42: 4-(Difluoromethoxy)-2,3-difluoro-aniline Step 1. 1-(Difluoromethoxy)-2,3-difluoro-4-nitrobenzene To a solution of 2,3-difluoro-4-nitro-phenol (1.00 g, 5.71 mmol) and sodium carbonate (1.82 g, 17.1 mmol) in N,N-dimethylformamide (10 mL) was added (2-chloro-2,2-difluoro- acetyl)oxysodium (2.61 g, 17.1 mmol). The mixture was stirred at 100 °C for 1 hr. The mixture was washed with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1-(difluoromethoxy)-2,3-difluoro-4-nitro-benzene (1.20 g, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 - 7.76 (m, 1H), 7.26 - 7.19 (m, 1H), 6.66 (t, J = 72.8 Hz, 1H). Step 2. 4-(Difluoromethoxy)-2,3-difluoro-aniline To a solution of 1-(difluoromethoxy)-2,3-difluoro-4-nitro-benzene (600 mg, 2.67 mmol) in water (4 mL) and ethanol (12 mL) was added iron powder (744 mg, 13.3 mmol) and ammonium chloride (713 mg, 13.3 mmol). The mixture was stirred at 60 °C for 1.5 hr. On completion, the mixture was filtered through Celite and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 4/1) to give 4- (difluoromethoxy)-2,3-difluoro-aniline (400 mg, 1.97 mmol, 74%) as a brown oil. m/z ES+ [M+H] ⁺ 196.3. Example 1. Preparation of 1-(4-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 74) Step 1. 6-Bromo-4-(3,4-dichloro-2-fluorophenoxy)quinazoline To a solution of 3,4-dichloro-2-fluoro-phenol, (2.00 g, 11.1 mmol) and 6-bromo-4-chloro- quinazoline (2.69 g, 11.1 mmol) in acetonitrile (5 mL) was added potassium carbonate (3.05 g, 22.1mmol) and stirred at 60 °C for 2 h. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give 6-bromo-4-(3,4-dichloro-2-fluorophenoxy)quinazoline (4.0 g, 8.56 mmol, 77%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 - 8.74 (m, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.06 - 7.99 (m, 1H), 7.97 - 7.90 (m, 1H), 7.43 - 7.36 (m, 1H), 7.25 - 7.20 (m, 1H). Step 2. tert-Butyl 4-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)piperazin e-1- carboxylate To a solution of 6-bromo-4-(3,4-dichloro-2-fluoro-phenoxy)quinazoline (200 mg, 515 μmol) and tert-butyl piperazine-1-carboxylate (105 mg, 567 μmol) in toluene (4.0 mL) was added Pd ₂ (dba) ₃ (47.2 mg, 51.5 μmol), BINAP (64.2 mg, 103 μmol) and cesium carbonate (336 mg, 1.03 mmol) under nitrogen, then the reaction was stirred at 100 °C for 1 h under nitrogen by microwave irradiation. On completion, the reaction was quenched by brine (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether /Ethyl acetate = 1/1) to give tert-butyl 4-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)piperazine-1-carboxylate (160 mg, 0.33 mmol, 60%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.68 (dd, J = 2.8, 9.2 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.39 (dd, J = 2.0, 8.8 Hz, 1H), 7.26 - 7.19 (m, 1H), 3.69 - 3.65 (m, 4H), 3.40 - 3.31 (m, 4H), 1.51 (s, 9H). Step 3. 4-(3,4-Dichloro-2-fluorophenoxy)-6-(piperazin-1-yl)quinazoli ne To a solution of tert-butyl 4-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)piperazine-1-carboxylate (140 mg, 284 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol, 0.2 mL), then the reaction was stirred at 25 °C for 16 hr. On completion, the reaction mixture was concentrated by blowing nitrogen to give 4-(3,4-dichloro- 2-fluoro-phenoxy)-6-piperazin-1-yl-quinazoline (110 mg, 256 μmol, 99%, hydrochloric acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 393.1. Step 4. 1-(4-(4-(3,4-Dichloro-2-fluorophenoxy)quinazolin-6-yl)pipera zin-1-yl)prop-2- en-1-one To a solution of 4-(3,4-dichloro-2-fluoro-phenoxy)-6-piperazin-1-yl-quinazoli ne (110 mg, 279 μmol) in saturated sodium bicarbonate solution (0.5 mL) and tetrahydrofuran (0.5 mL) was added prop-2-enoyl chloride (25.3 mg, 279 μmol) at 0 °C, then the mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 x 40 mm x 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30% - 50%, 8 min) to give 1-[4-[4- (3,4-dichloro-2-fluoro-phenoxy)quinazolin-6-yl]piperazin-1-y l]prop-2-en-1-one (14.0 mg, 31.3 μmol , 11.1%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 7.96 - 7.89 (m, 2H), 7.71 - 7.65 (m, 1H), 7.64 - 7.57 (m, 1H), 7.46 (d, J = 2.4 Hz, 1H), 6.90 - 6.82 (m, 1H), 6.15 (dd, J = 2.4, 16.8 Hz, 1H), 5.73 (dd, J = 2.4, 10.8 Hz, 1H), 3.77 - 3.73 (m, 4H), 3.45 - 3.41 (m, 4H); m/z ES+ [M+H] ⁺ 446.9. Example 2. Preparation of 1-(4-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 198)

Step 1. tert-Butyl 4-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)piperaz ine-1- carboxylate A solution of tert-butyl 4-(3-cyano-4- (((dimethylamino)methylene)amino)phenyl)piperazine-1-carboxy late (3.60 g, 10.1 mmol) and 3- chloro-2-fluoro-aniline (1.61 g, 11.1 mmol) in toluene (20 mL) and acetic acid (20 mL) was stirred at 110 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 4/1 to 1/1) to give tert-butyl 4-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)piperaz ine-1- carboxylate (2.40 g, 5.24 mmol, 47%) as a yellow oil. m/z ES+ [M+H] ⁺ 458.2. Step 2. N-(3-Chloro-2-fluorophenyl)-6-(piperazin-1-yl)quinazolin-4-a mine A solution of tert-butyl 4-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)piperazine-1-carboxylate (300 mg, 655 μmol) in trifluoroacetic acid (0.4 mL) and dichloromethane (2.0 mL) was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-2-fluorophenyl)-6-(piperazin-1-yl)quinazolin-4-a mine (310 mg, trifluoroacetic acid salt, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 358.1. Step 3. 1-(4-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6-yl)pipe razin-1-yl)prop-2- en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-piperazin-1-yl-quinazolin-4-a mine (310 mg, 866 μmol) in water (1.5 mL) and tetrahydrofuran (1.5 mL) was added sodium bicarbonate (218 mg, 2.60 mmol). Then prop-2-enoyl chloride (78.4 mg, 866 μmol, 70.6 μL) was added at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Gemini-NX C1875 x 30 mm x 3 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 12% - 42%, 7 min) to give 1-[4-[4-(3-chloro-2-fluoro-anilino)quinazolin-6- yl]piperazin-1-yl] prop-2-en-1-one (76.7 mg, 187 μmol, 21%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.76 - 7.63 (m, 3H), 7.50 (q, J = 7.2 Hz, 2H), 7.32 - 7.25 (m, 1H), 6.90 (dd, J = 10.4, 16.8 Hz, 1H), 6.17 (dd, J = 2.4, 16.8 Hz, 1H), 5.77 - 5.69 (m, 1H), 3.77 (d, J = 10.4 Hz, 4H), 3.35 (s, 4H); m/z ES+ [M+H]+ 412.4. Example 3. Preparation of 1-(4-(4-((5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 263) Step 1. tert-Butyl 4-(4-((5-phenoxypyridin-2-yl)amino)quinazolin-6-yl)piperazin e-1- carboxylate To a solution of tert-butyl 4-(3-cyano-4- (((dimethylamino)methylene)amino)phenyl)piperazine-1-carboxy late (250 mg, 699 μmol) in acetic acid (5 mL) and toluene (5 mL) was added 5-phenoxypyridin-2-amine (149 mg, 804 μmol). The mixture was stirred at 110 °C for 12 hr. On completion, the mixture was concentrated and purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 4-(4-((5-phenoxypyridin- 2-yl)amino)quinazolin-6-yl)piperazine-1-carboxylate (100 mg, 0.2 mmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.8 Hz, 1H), 7.89 - 7.87 (m, 1H), 7.55 - 7.51 (m, 3H), 7.40 (t, J = 8.0 Hz, 3H), 7.18 (t, J = 8.0 Hz, 2H), 7.07 - 7.05 (m, 3H), 3.64 - 3.58 (m, 4H), 3.56 - 3.47 (m, 4H), 1.51 (s, 9H). Step 2. N-(5-Phenoxypyridin-2-yl)-6-(piperazin-1-yl)quinazolin-4-ami ne To a solution of tert-butyl 4-(4-((5-phenoxypyridin-2-yl)amino)quinazolin-6-yl) piperazine-1-carboxylate (80 mg, 160 μmol) in dichloromethane (2 mL) was added hydrogen chloride /dioxane (4 M, 0.4 ml). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-(5-phenoxypyridin-2-yl)-6-(piperazin-1-yl)quinazolin-4- amine (63 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 399.1. Step 3. 1-(4-(4-((5-Phenoxypyridin-2-yl)amino)quinazolin-6-yl)pipera zin-1-yl)prop-2- en-1-one To a solution of N-(5-phenoxypyridin-2-yl)-6-(piperazin-1-yl)quinazolin-4-ami ne (63 mg, 144 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (97 mg, 1.16 mmol) and prop-2-enoyl chloride (10 mg, 115 μmol, 9 μL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C18 75 x 30 mm x 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 20% - 50%, 5 min) to give 1-(4-(4-((5- phenoxypyridin-2-yl)amino)quinazolin-6-yl)piperazin-1-yl)pro p-2-en-1-one (30 mg, 66.2 μmol, 46%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H), 7.68 (s, 2H), 7.59 (s, 1H), 7.51 - 7.48 (m, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.86 - 6.79 (m, 1H), 6.28 - 6.23 (m, 1H), 5.80 - 5.77 (m, 1H), 3.85 (s, 4H), 3.41 (s, 4H); m/z ES+ [M+H] ⁺ 453.4. Example 4. Preparation of 1-(4-(4-((6-phenoxypyridin-3-yl)amino)quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 264) Step 1. tert-Butyl 4-(4-((6-phenoxypyridin-3-yl)amino)quinazolin-6-yl)piperazin e-1- carboxylate To a solution of tert-butyl 4-[3-cyano-4- (dimethylaminomethyleneamino)phenyl]piperazine-1-carboxylate (250 mg, 699 μmol) in acetic acid (2 mL) and toluene (2 mL) was added 6-phenoxypyridin-3-amine (149 mg, 804 μmol). The mixture was stirred at 110 °C for 12 hr. On completion, the mixture was concentrated and the residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 4-(4-((6- phenoxypyridin-3-yl)amino)quinazolin-6-yl)piperazine-1-carbo xylate (200 mg, 0.40 mmol, 57%) as a yellow solid. m/z ES+ [M+H] ⁺ 499.2. Step 2. N-(6-Phenoxypyridin-3-yl)-6-(piperazin-1-yl)quinazolin-4-ami ne To a solution of tert-butyl 4-(4-((6-phenoxypyridin-3-yl)amino)quinazolin-6- yl)piperazine-1-carboxylate (160 mg, 320 μmol) in dichloromethane (4 mL) was added hydrochloric acid/dioxane (4 M, 802 μL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-(6-phenoxypyridin-3-yl)-6-(piperazin-1-yl)quinazolin-4- amine (127 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 399.1. Step 3. 1-(4-(4-((6-Phenoxypyridin-3-yl)amino)quinazolin-6-yl)pipera zin-1-yl)prop-2- en-1-one To a solution of N-(6-phenoxypyridin-3-yl)-6-(piperazin-1-yl)quinazolin-4-ami ne (127 mg, 292 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (196 mg, 2.34 mmol) and prop-2-enoyl chloride (21 mg, 233 μmol, 19 μL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated and the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 x 30 mm x 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 15%-45%, 5 min) to give 1-(4-(4-((6-phenoxypyridin-3- yl)amino)quinazolin-6-yl)piperazin-1-yl)prop-2-en-1-one (17 mg, 37.5 μmol, 12%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (d, J = 2.8 Hz, 1H), 8.39 (s, 1H), 8.28 - 8.25 (m, 1H), 7.71 (s, 2H), 7.63 (s, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.14 - 7.12 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 10.4, 16.8 Hz, 1H), 6.26 (dd, J = 1.6, 16.8 Hz, 1H), 5.79 (dd, J = 2.0, 10.8 Hz, 1H), 3.88 (s, 4H), 3.42 (s, 4H); m/z ES+ [M+H] ⁺ 453.5. Example 5. Preparation of 1-(4-(4-((2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperazin-1-yl)prop-2-en -1-one (Compound 271)

Step 1. tert-Butyl 4-(4-((2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl) piperazine-1-carboxylate (300 mg, 839 μmol) and 2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)aniline (209 mg, 1.01 mmol) in toluene (2.0 mL) and acetic acid (2.0 mL) was stirred at 110 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1) to give tert-butyl 4-(4-((2-fluoro-4- ((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperazine-1-carboxylate (300 mg, 577 μmol, 63%) as an off-white solid. m/z ES+ [M+H] ⁺ 520.2. Step 2. N-(2-Fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe razin-1- yl)quinazolin-4-amine A solution of tert-butyl 4-(4-((2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)amin o) quinazolin-6-yl)piperazine-1-carboxylate (150 mg, 289 μmol) in hydrochloric acid/ethyl acetate (4 M, 2.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6- (piperazin-1- yl)quinazolin-4-amine (132 mg, crude, hydrochloric acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 420.0. Step 3. 1-(4-(4-((2-Fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)a mino)quinazolin- 6-yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-(2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe razin-1- yl) quinazolin-4-amine (132 mg, 315 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (79.3 mg, 944 μmol) and prop-2-enoyl chloride (28.48 mg, 314.69 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. Then another bacth of prop-2-enoyl chloride (14.2 mg, 157 μmol) was added and the mixture was stirred at 0 °C for another 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition;column: Phenomenex luna C18150 x 25 mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 8% - 38%, 10 min) to give 1-(4-(4-((2-fluoro-4-((1- methyl-1H-pyrazol-3-yl)oxy)phenyl)amino)quinazolin-6-yl)pipe razin-1-yl)prop-2-en-1-one (57.6 mg, 121 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.31 (s, 1H), 7.74 - 7.66 (m, 4H), 7.46 (t, J = 8.8 Hz, 1H), 7.09 (dd, J = 2.4, 11.6 Hz, 1H), 6.99 - 6.87 (m, 2H), 6.18 (dd, J = 2.4, 16.8 Hz, 1H), 5.96 (d, J = 2.4 Hz, 1H), 5.74 (dd, J = 2.4, 10.4 Hz, 1H), 3.81 - 3.74 (m, 7H), 3.46 - 3.41 (m, 4H); m/z ES+ [M+H] ⁺ 474.4. Example 6. Preparation of 1-(4-(4-((5-ethynyl-6-phenoxypyridin-3-yl)amino)quinazolin-6 - Step 1. tert-Butyl 4-(4-((5-ethynyl-6-phenoxypyridin-3-yl)amino)quinazolin-6- yl)piperazine-1-carboxylate To a solution of tert-Butyl 4-(3-cyano-4- (((dimethylamino)methylene)amino)phenyl)piperazine-1-carboxy late (250 mg, 699 μmol) in toluene (4 mL) was added 5-ethynyl-6-phenoxypyridin-3-amine (147 mg, 699 μmol) and acetic acid (4.20 g, 69.9 mmol, 4 mL) at 25 °C. The mixture was stirred at 110 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl 4-(4-((5-ethynyl- 6-phenoxypyridin-3-yl)amino)quinazolin-6-yl)piperazine-1-car boxylate (165 mg, 315 μmol, 45%) as a yellow oil. m/z ES+ [M+H] ⁺ 523.3. Step 2. N-(5-Ethynyl-6-phenoxypyridin-3-yl)-6-(piperazin-1-yl)quinaz olin-4-amine To a solution of tert-butyl 4-(4-((5-ethynyl-6-phenoxypyridin-3-yl)amino)quinazolin-6- yl)piperazine-1-carboxylate (165 mg, 315 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (616 mg, 0.40 mL). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(5-ethynyl-6- phenoxypyridin-3-yl)-6-(piperazin-1-yl)quinazolin-4-amine (169 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 423.3. Step 3. 1-(4-(4-((5-Ethynyl-6-phenoxypyridin-3-yl)amino)quinazolin-6 -yl)piperazin-1- yl)prop-2-en-1-one To a solution of N-(5-ethynyl-6-phenoxypyridin-3-yl)-6-(piperazin-1-yl)quinaz olin-4- amine (168 mg, trifluoroacetic acid salt) in tetrahydrofuran (2 mL) and water (0.40 mL) was added potassium carbonate (173 mg, 1.25 mmol) and acryloyl chloride (28.3 mg, 313 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [ water (10 mM NH ₄ HCO ₃ )-CAN]; B%: 35% - 65%, 7 min) to give 1-(4-(4-((5-ethynyl-6-phenoxypyridin-3-yl)amino)quinazolin-6 -yl)piperazin-1-yl)prop-2-en-1- one (24.6 mg, 48.5 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 8.58 - 8.39 (m, 3H), 7.89 - 7.60 (m, 3H), 7.50-7.40 (m, 2H), 7.29 - 7.13 (m, 3H), 6.99 - 6.89 (m, 1H), 6.25-6.15 (m, 1H), 5.80-5.70 (m, 1H), 4.57 (s, 1H), 3.85-3.75 (m, 4H), 3.43 - 3.36 (m, 4H); m/z ES+ [M+H] ⁺ 477.4. Example 7. Preparation of 1-(4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 7) Step 1. tert-Butyl 4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip erazine- 1-carboxylate A mixture of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (590 mg, 1.52 mmol), tert-butyl piperazine-1-carboxylate (679 mg, 3.05 mmol, hydrochloric acid salt), 1,4- diazabicyclo[2.2.2]octane (308 mg, 2.74 mmol), Ir(ppy) ₂ (dtbbpy)PF ₆ (27.86 mg, 30.49 μmol) and NiBr ₂ .glyme (23.5 mg, 76.2 μmol) in dimethyl acetamide (15 mL) was degassed with nitrogen for three times. The reaction vial was then sealed with parafilm, placed 2 cm away from one blue LED, and irradiated at 55 °C for 14 hr under nitrogen. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 4/1 to 1/1) to give tert-butyl 4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip erazine-1- carboxylate (540 mg, 1.10 mmol, 72%) as a yellow oil. m/z ES+ [M+H] ⁺ 492.1. Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(piperazin-1-yl)quinazolin -4-amine To a solution of tert-butyl 4-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]piperazi ne- 1 -carboxylate (490 mg, 995 μmol) in dichloromethane (4.0 mL) and trifluoroacetic acid (0.8 mL) was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3,4-dichloro-2-fluoro-phenyl)-6-piperazin-1-yl-quinazolin -4-amine (504 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 392.0. Step 3. 1-(4-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6-yl) piperazin-1- yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-piperazin-1-yl-quinazolin -4-amine (504 mg, 1.28 mmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (323 mg, 3.84 mmol). The mixture was added prop-2-enoyl chloride (116 mg, 1.28 mmol, 0.104 mL) at 0 °C and stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 x 50 mm x 15 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 20%-50%, 10 min) to give 1-[4-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]piper azin- 1-yl]prop-2-en-1-one (128 mg, 287 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.85 (s, 1H), 8.38 (s, 1H), 7.73 (q, J = 9.2 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.60 (s, 2H), 6.91 (dd, J = 10.4, 16.8 Hz, 1H), 6.18 (dd, J = 2.4, 16.8 Hz, 1H), 5.78 - 5.71 (m, 1H), 3.84 - 3.72 (m, 4H), 3.55 - 3.39 (m, 4H); m/z ES+ [M+H]+ 446.3. Example 8. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)prop-2-en-1-one (Compound 326) Step 1. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate A mixture of (1S,4S)-tert-butyl 5-(3-cyano-4-((E)- ((dimethylamino)methylene)amino)phenyl)-2,5-diazabicyclo[2.2 .1]heptane-2-carboxylate (200 mg, 541 μmol) and 3-chloro-4-(1-methylpyrazol-3-yl)oxy-aniline (133 mg, 595 μmol) in toluene (2.0 mL) and acetic acid (2.0 mL) was stirred at 110 °C for 3 hr. On completion, the mixture was added saturated sodium bicarbonate solution to adjust pH to 7~8, and then the residue was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 0:1) to give (1S,4S)-tert-butyl5-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (180 mg, 328 μmol , 61%) as a yellow solid. m/z ES+ [M+H] ⁺ 548.2. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -((1-methyl-1H- pyrazol-3-yl)oxy)phenyl)quinazolin-4-amine To a mixture of (1S,4S)-tert-butyl 5-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (160 mg, 291 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -((1- methyl-1H-pyrazol-3-yl)oxy)phenyl)quinazolin-4-amine (130 mg, 0.29 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 448.1. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)prop-2-en-1-one To a mixture of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -((1- methyl-1H-pyrazol-3-yl)oxy)phenyl)quinazolin-4-amine (130 mg, 290 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (24.3 mg, 290 μmol) and prop-2- enoyl chloride (26.2 mg, 290 μmol, 24 μL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 11% - 41%, 10 min) to give 1- ((1S,4S)-5-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)ph enyl)amino)quinazolin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (56.8 mg, 113 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.37 (s, 1H), 8.09 - 8.07 (m, 1H), 7.76 (s, 1H), 7.72 - 7.63 (m, 2H), 7.42 - 7.38 (m, 2H), 7.30 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 0.8, 9.2 Hz, 1H), 6.83 - 6.35 (m, 1H), 6.15 - 6.09 (m, 1H), 5.74 - 5.58 (m, 1H), 5.06 - 4.78 (m, 2H), 3.81 (s, 3H), 3.76 - 3.64 (m, 2H), 3.56 - 3.48 (m, 1H), 3.27 - 3.17 (m, 1H), 2.14 - 1.99 (m, 2H); m/z ES+ [M+H] ⁺ 502.1. Example 9. Preparation of 1-(4-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperazin-1-yl)prop-2-en -1-one (Compound 340) Step 6-Bromo-N-(3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl) quinazolin-4- amine To a solution of 3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline (275 mg, 1.23 mmol) in acetonitrile (10 mL) was added 6-bromo-4-chloroquinazoline (300 mg, 1.23 mmol), the mixture was stirred at 25 °C for 4 hr. On completion, the mixture was filtered and the filter cake was triturated with acetonitrile (20 mL) and dichloromethane (20 mL) to give 6-bromo-N-[3-chloro-4- (1-methylpyrazol-3-yl) oxy-phenyl] quinazolin-4-amine (0.50 g, 1.17 mmol, 94%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.90 (s, 1H), 9.32 (d, J = 4.0 Hz, 1H), 8.99 (s, 1H), 8.32 - 8.22 (m, 1H), 8.03 (d, J = 4.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 5.90 (d, J = 2.4 Hz, 1H), 3.74 (s, 3H). Step 2. tert-Butyl 4-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperazine-1-carboxylate To a mixture of 6-bromo-N-(3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)quinazolin-4-amine (300 mg, 696 μmol), tert-butyl piperazine-1-carboxylate (387 mg, 1.74 mmol, hydrochloric acid salt) and sodium tert-butoxide (468 mg, 4.88 mmol) in dioxane (5.0 mL) was added Pd-PEPPSI-I-Hept (30.0 mg) at 25 °C under nitrogen. The mixture was stirred at 100 °C for 12 hr under nitrogen. On completion, the mixture was concentrated and purified by reversed-phase HPLC (0.05% FA conditions) to give tert-butyl 4-[4-[3-chloro-4-(1- methylpyrazol-3-yl)oxy-anilino]quinazolin-6-yl] piperazine-1-carboxylate (160 mg, 299 μmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.46 (s, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.69 (s, 3H), 7.63 (d, J = 4.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.81 (d, J = 8.0 Hz, 1H), 3.72 (s, 3H), 3.57 - 3.51 (m, 4H), 3.32 (s, 4H), 1.44 (s, 9H). Step 3. N-(3-Chloro-4-((1-Methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe razin-1- yl)quinazolin-4-amine To a solution of tert-butyl 4-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperazine-1-carboxylate (140 mg, 261 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.8 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-[3-chloro-4-(1- methylpyrazol-3-yl)oxy-phenyl]-6-piperazin-1-yl-quinazolin-4 -amine (143 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 436.1. Step 4. 1-(4-(4-((3-Chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)a mino)quinazolin- 6-yl)piperazin-1-yl)prop-2-en-1-one To a mixture of N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-piperazin- 1-yl- quinazolin-4-amine (143 mg, 260 μmol, trifluoroacetic acid salt) and sodium bicarbonate (109 mg, 1.30 mmol) in tetrahydrofuran (0.40 mL) and water (0.40 mL) was added prop-2-enoyl chloride (23.5 mg, 260 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 12% - 42%, 11.5 min) to give 1-[4-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-anilino]quinaz olin- 6-yl]piperazin-1-yl]prop-2-en-1-one (92.7 mg, 189 μmol, 72%) as a yellow solid. NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.52 (s, 1H), 8.06 (d, J = 4.0 Hz, 1H), 7.76 - 7.69 (m, 4H), 7.64 (d, J = 4.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.94 - 6.86 (m, 1H), 6.20 - 6.14 (m, 1H), 5.83 (d, J = 8.0 Hz, 1H), 5.77 - 5.71 (m, 1H), 3.78 (d, J = 12.0 Hz, 4H), 3.73 (s, 3H), 3.38 (s, 4H); m/z ES+ [M+H] ⁺ 490.2. Example 10. Preparation of 1-(4-(4-((4-((1,3-dioxan-2-yl)methoxy)-3- chlorophenyl)amino)quinazolin-6-yl)piperazin-1-yl)prop-2-en- 1-one (Compound 330) Step 1. tert-Butyl 4-(4-((4-((1,3-dioxan-2-yl)methoxy)-3- chlorophenyl)amino)quinazolin-6-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-[3-cyano-4- (dimethylaminomethyleneamino)phenyl]piperazine- 1-carboxylate (75 mg, 0.21 mmol) and 3- chloro-4-(1,3-dioxan-2-ylmethoxy)aniline (51 mg, 0.21 mmol) in toluene (1 mL) was added acetic acid (1 mL). The reaction mixture was stirred at 110 °C for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1:1) to give tert-butyl 4-(4-((4- ((1,3-dioxan-2-yl)methoxy) -3-chlorophenyl)amino)quinazolin-6-yl)piperazine-1-carboxyla te (50 mg, 89.9 μmol, 28%) as a yellow solid. m/z ES+ [M+H] ⁺ 556.2. Step 2. N-(4-((1,3-Dioxan-2-yl)methoxy)-3-chlorophenyl)-6-(piperazin -1-yl)quinazolin- 4-amine To a solution of tert-butyl 4-[4-[3-chloro-4-(1,3-dioxan-2-ylmethoxy)anilino]quinazolin- 6-yl]piperazine-1-carboxylate (50 mg, 90 μmol) in dichloromethane (0.5 mL) was added zinc bromide (202 mg, 0.9 mmol). The reaction mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-(4-((1,3-dioxan-2- yl)methoxy) -3-chlorophenyl)-6-(piperazin-1-yl)quinazolin-4-amine (40 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 456.1. Step 3. 1-(4-(4-((4-((1,3-Dioxan-2-yl)methoxy)-3-chlorophenyl)amino) quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(1,3-dioxan-2-ylmethoxy)phenyl]-6-piperazin-1- yl- quinazolin -4-amine (40 mg, 87 μmol) and sodium bicarbonate (22 mg, 0.26 mmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added prop-2-enoyl chloride (4 mg, 43.9 μmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 x 30 mm x 3 um; mobile phase: [water (10 mM NH4HCO3)- acetonitrile]; B%: 24%-54%, 8 min) to give 1-(4-(4-((4-((1,3-dioxan-2-yl)methoxy)-3- chlorophenyl)amino)quinazolin-6-yl)piperazin-1-yl)prop-2-en- 1-one (11 mg, 21.6 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.71 (s, 2H), 7.65 - 7.56 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 16.8, 10.4 Hz, 1H), 6.27 (d, J = 10.8 Hz, 1H), 5.83 - 5.78 (m, 1H), 5.00 (t, J = 4.4 Hz, 1H), 4.15 (dd, J = 4.4, 10.2 Hz, 2H), 4.06 (d, J = 4.4 Hz, 2H), 3.94 - 3.86 (m, 6H), 3.42 (s, 4H), 2.13 - 2.05 (m, 1H), 1.47 - 1.40 (m, 1H); m/z ES+ [M+H] ⁺ 510.1. Example 11. Preparation of 1-(4-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 344)

Step 1. tert-Butyl 4-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-cyano-4- (((dimethylamino)methylene)amino)phenyl)piperazine-1-carboxy late (145.8 mg, 407.8 μmol) in toluene (1 mL) and acetic acid (360 μL) was added 4-chloro-5-phenoxy-pyridin-2-amine (60 mg, 271.9 μmol). The mixture was stirred at 110 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give tert-butyl 4-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperazine-1-carboxylate (80 mg, 150 μmol, 55%) as a white solid. m/z ES+ [M+H] ⁺ 533.2. Step 2. N-(4-Chloro-5-phenoxypyridin-2-yl)-6-(piperazin-1-yl)quinazo lin-4-amine To a solution of tert-butyl 4-[4-[(4-chloro-5-phenoxy-2-pyridyl)amino]quinazolin-6- yl]piperazine-1-carboxylate (80 mg, 150 μmol) in dichloromethane (1.5 mL) and trifluoroacetic acid (800 μL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(4-chloro-5-phenoxypyridin-2-yl)-6-(piperazin-1-yl)quinazo lin- 4-amine (80 mg, 146 μmol, 97%, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 433.3. Step 3. 1-(4-(4-((4-Chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperazin-1- yl)prop-2-en-1-one To a solution of N-(4-chloro-5-phenoxypyridin-2-yl)-6-(piperazin-1-yl)quinazo lin-4- amine (80 mg, 146 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (20.22 mg, 146 μmol) and prop-2-enoyl chloride (11.91 mg, 132 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated and the residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 33%-63%, 10 min) to give 1-(4-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperazin-1-yl)prop-2-en-1-one (26.05 mg, 52.8 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.84 (s, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.75 (s, 2H), 7.41 - 7.39 (m, 2H), 7.15 - 7.10(m, 1H), 7.02 (d, J = 7.6 Hz, 2H), 6.91 - 6.80 (m, 1H), 6.17 - 6.10(m, 1H), 5.74 -5.65(m, 1H), 3.84 - 3.69 (m, 4H), 3.41 -3.35(m, 4H); m/z ES+ [M+H] ⁺ 487.2. Example 12. Preparation of 1-(4-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one (Compound 33) Step 1. 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.50 mmol) in acetonitrile (5 mL) and dimethylsulfoxide (3 mL) was added 3,4-dichloro-2-fluoro-aniline (495 mg, 2.75 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 3/1 to 0/1) to give 6-chloro-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (180 mg, 522 μmol, 21%) as a white solid. m/z ES+ [M+H] ⁺ 345.0. Step 2. tert-Butyl 4-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperazine-1-carboxylate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (86 mg, 250 μmol) and tert-butyl piperazine-1-carboxylate (83.62 mg, 375 μmol, hydrochloric acid salt) in N-methylpyrrolidone (1 mL) was added diisopropylethylamine (97.05 mg, 751 μmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give tert-butyl 4-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]piperazine-1-carboxylate (104 mg, 211 μmol, 84%) as a white solid. m/z ES+ [M+H] ⁺ 493.2. Step 3. N-(3,4-Dichloro-2-fluorophenyl)-6-(piperazin-1-yl)pyrido[3,2 -d]pyrimidin-4- amine To a solution of tert-butyl 4-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]piperazine-1-carboxylate (80 mg, 162.15 μmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.08 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give N-(3,4-dichloro-2-fluoro-phenyl)-6-piperazin-1-yl- pyrido[3,2-d]pyrimidin-4-amine (80 mg, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 393.2. Step 4. 1-(4-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-piperazin-1-yl-pyrido[3,2 - d]pyrimidin-4-amine (80 mg, 158 μmol, trifluoroacetic acid salt) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (40 mg, 473 μmol) in water (0.8 mL) and prop-2-enoyl chloride (16 mg, 173 μmol) in tetrahydrofuran (0.3 mL) at 0 °C. The mixture was stirred at 0 °C for 0.25 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 38%-68%, 11 min) to give 1-[4-[4-(3,4- dichloro-2-fluoro-anilino)pyrido[3,2-d] pyrimidin-6-yl]piperazin-1-yl]prop-2-en-1-one (39.2 mg, 87.5 μmol, 53%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.41 (s, 1H), 8.13 (t, J = 8.8 Hz, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.63 - 7.57 (m, 2H), 6.89 (dd, J = 10.4, 16.8 Hz, 1H), 6.16 (dd, J = 2.4, 16.8 Hz, 1H), 5.73 (dd, J = 2.4, 10.4 Hz, 1H), 3.83 (s, 4H), 3.72 (d, J = 16.6 Hz, 4H); m/z ES+ [M+H] ⁺ 447.1. Example 13. Preparation of 1-(4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 49) Step 1. tert-Butyl 4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1-carboxylate To a solution of 6-chloro-N-(4-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (75 mg, 215 μmol) in N-methylpyrrolidone (1 mL) was added N,N-diisopropylethylamine (83.37 mg, 645 μmol) and tert-butyl piperazine-1-carboxylate (71.84 mg, 322 μmol, hydrochloric acid salt). The mixture was stirred at 100 °C for 12 hr. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 2/1 to 1/1) to give tert-butyl 4-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]piperazin e-1-carboxylate (90 mg, 180 μmol, 84%) as a yellow solid. m/z ES+ [M+H] ⁺ 499.4 Step 3. N-(4-Phenoxyphenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin -4-amine To a solution of tert-butyl 4-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl] piperazine-1-carboxylate (80 mg, 160 μmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(4-phenoxyphenyl)-6-piperazin-1-yl-pyrido[3,2-d]pyrimidin- 4-amine (82 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 399.1. Step 4. 1-(4-(4-((4-Phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) piperazin-1- yl)prop-2-en-1-one To a solution of N-(4-phenoxyphenyl)-6-piperazin-1-yl-pyrido[3,2-d]pyrimidin- 4-amine (80 mg, 156 μmol, trifluoroacetic acid salt) and sodium bicarbonate (39.34 mg, 468 μmol) in water (1 mL) was added prop-2-enoyl chloride (15.54 mg, 14 μL) in tetrahydrofuran (1 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 x 30 mm x 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 35%-65%, 8 min) to give 1-[4-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]pipera zin-1-yl]prop-2-en-1-one (23 mg, 44.86 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.64 - 8.58 (m, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.38 - 7.32 (m, 2H), 7.29 (s, 1H), 7.14 - 7.07 (m, 3H), 7.04 (d, J = 8.0 Hz, 2H), 6.64 (dd, J = 10.4, 16.8 Hz, 1H), 6.39 (dd, J = 1.6, 16.8 Hz, 1H), 5.80 (dd, J = 1.6, 10.4 Hz, 1H), 3.92 (s, 2H), 3.81 (s, 6H); m/z ES+ [M+H] ⁺ 453.2. Example 14. Preparation of 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazin-1-y l)prop-2-en-1-one (Compound 90) Step 1. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-chloro pyrido[3,2- d]pyrimidin-4-amine A solution of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline (1.2 g, 4.24 mmol) and 4,6- dichloropyrido[3,2-d]pyrimidine (848 mg, 4.24 mmol) in acetonitrile (20 mL) was stirred at 25 °C for 12 hr. On completion, the mixture was filtered, and the filter cake was triturated with acetonitrile (10 mL) to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 5/1~0/1) to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl)-6-chloropyrido[3,2-d]pyrimidin-4-amine (1.1 g, 2.83 mmol, 67%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.99 - 8.92 (m, 1H), 8.77 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.10 - 8.00 (m, 4H), 7.34 - 7.28 (m, 2H), 7.05 - 7.03 (m, 1H). Step 2. tert-Butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-chloro pyrido[3,2- d]pyrimidin-4-amine (100 mg, 256 μmol) and tert-butyl piperazine-1-carboxylate (52.5 mg, 282 μmol) in N-methylpyrrolidone (3 mL) was added N,N-diisopropylethylamine (132 mg, 1.03 mmol), the mixture was stirred at 100 °C for 12 hr. On completion, the mixture was quenched by water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers was washed with brine (5 mL x 3) and dried over sodium sulphate, filtered and concentrated in vacuum to give tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)amino )pyrido[3,2-d]pyrimidin- 6-yl)piperazine-1-carboxylate (150 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 19.2 Hz, 2H), 8.16 - 8.06 (m, 2H), 7.98 - 7.91 (m, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.08 - 6.97 (m, 2H), 3.89 - 3.77 (m, 4H), 3.50 (br. s, 4H), 1.44 (s, 9H). Step 3. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-(piper azin-1- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 4-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]piperazine-1-carbo xylate (150 mg, 277 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum to give 6- piperazin-1-yl-N-[4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)p henyl]pyrido[3,2-d]pyrimidin-4- amine (150 mg, crude, trifluoroacetic acid salt) as a yellow solid. Step 4. 1-(4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)phenyl)am ino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one To a solution of 6-piperazin-1-yl-N-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (150 mg, 271 μmol, trifluoroacetic acid salt) and sodium bicarbonate (91 mg, 1.08 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added prop-2-enoyl chloride (26.9 mg, 298 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum and the residue was purified by prep- HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 30% - 50%, 10 min) to give 1-[4-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]piperazin-1-yl] prop-2-en-1-one (31 mg, 62.7 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 16.4 Hz, 2H), 8.15 - 8.06 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.03 (dd, J = 2.4, 7.6 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 10.4, 16.4 Hz, 1H), 6.17 (dd, J = 2.0, 16.4 Hz, 1H), 5.77 - 5.72 (m, 1H), 3.90 - 3.85 (m, 4H), 3.78 - 3.68 (m, 4H); m/z ES+ [M+H] ⁺ 494.4. Example 15. Preparation of 1-(4-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazin-1-yl)prop-2-en-1-one (Compound 259) Step 1. tert-Butyl 4-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1-carboxylate To a solution of 6-chloro-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (0.15 g, 460 μmol) and tert-butyl piperazine-1-carboxylate (171 mg, 921 μmol) in N-methylpyrrolidone (3 mL) was added diisopropylethylamine (178 mg, 1.38 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was quenched by addition water (30 mL) and stirred at 25 °C for 0.5 h. The mixture was filtered and the filter cake was concentrated in vacuo to give tert-butyl 4-[4-(3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl] piperazine-1-carboxylate (0.2 g, crude) as a yellow solid. m/z ES+ [M+1] ⁺ 475.2. Step 2. N-(3,4-Dichlorophenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimi din-4-amine To a solution of tert-butyl 4-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1-carboxylate (0.19 g, 399 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (438 mg, 3.85 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give N-(3,4-dichlorophenyl)-6-piperazin-1- yl-pyrido[3,2-d]pyrimidin-4-amine (0.15 g, crude) as a yellow solid. Step 3. 1-(4-(4-((3,4-Dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazin-1- yl)prop-2-en-1-one To a solution of N-(3,4-dichlorophenyl)-6-piperazin-1-yl-pyrido[3,2-d]pyrimid in-4- amine (0.15 g, 399 μmol) and sodium bicarbonate (100 mg, 1.20 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (36.1 mg, 399 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo and purified by prep-HPLC (column: 3_Phenomenex Luna C1875 x 30 mm x 3 um; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; B%: 26% - 46%, 6.5 min) to give 1-[4-[4-(3,4- dichloroanilino)pyrido [3,2-d]pyrimidin-6-yl]piperazin-1-yl]prop-2-en-1-one (22 mg, 51.3 μmol, 12%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.81 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.89 (dd, J = 2.4, 8.8 Hz, 1H), 7.80 - 7.71 (m, 2H), 6.90 (dd, J = 10.4, 16.8 Hz, 1H), 6.18 (dd, J = 2.4, 16.8 Hz, 1H), 5.82 - 5.68 (m, 1H), 3.94 (d, J = 5.2 Hz, 4H), 3.73 (d, J = 14.4 Hz, 4H); m/z ES+ [M+1] ⁺ 429.1. Example 16. Preparation of 1-(4-(4-((2-fluoro-4-phenoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one (Compound 269) Step 1. tert-Butyl 4-(4-((2-fluoro-4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)piperazine-1-carboxylate A solution of tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1-carboxyl ate (200 mg, 571 μmol) and 2-fluoro-4-phenoxyaniline (116 mg, 571 μmol) in acetonitrile (10 mL) was stirred at 60 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give tert- butyl 4-(4-((2-fluoro-4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)piperazine-1- carboxylate (300 mg, crude) as a yellow oil. m/z ES+ [M+1] ⁺ 517.4. Step 2. N-(2-Fluoro-4-phenoxyphenyl)-6-(piperazin-1-yl)pyrido[3,2-d] pyrimidin-4- amine To a solution of tert-butyl 4-[4-(2-fluoro-4-phenoxy-anilino)pyrido[3,2-d]pyrimidin-6- yl]piperazine-1-carboxylate (220 mg, 425 umo) in dichloromethane (2 mL) was added trifluoroacetic acid (11.2 g, 99.0 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give N-(2-fluoro-4-phenoxy-phenyl)-6-piperazin-1-yl- pyrido[3,2-d]pyrimidin-4-amine (180 mg, crude) as a yellow oil. m/z ES+ [M+1] ⁺ 417.4. Step 3. 1-(4-(4-((2-Fluoro-4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-(2-fluoro-4-phenoxy-phenyl)-6-piperazin-1-yl-pyrido[3,2- d]pyrimidin-4-amine (180 mg, 432 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (36.3 mg, 432 μmol) to adjust the pH of the mixture to 7 - 8. Then the mixture was added prop-2-enoyl chloride (39.1 mg, 432 μmol) and stirred at 0 °C for 15 min. On completion, the residue was concentrated in vacuo and purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - acetonitrile]; B%: 42% - 72%, 9 min) to give 1-[4-[4-(2-fluoro-4-phenoxy-anilino)pyrido[3,2-d]pyrimidin-6 -yl]piperazin- 1-yl]prop-2-en-1-one (5 mg, 10.6 μmol, 2.0%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1 H), 8.35 (s, 1 H), 7.96 - 7.91 (m, 2 H), 7.59 (d, J = 9.6 Hz, 1 H), 7.46 - 7.42 (m, 2 H), 7.21 - 7.20 (m, 1 H), 7.11 - 7.05 (m, 3 H), 6.94 - 6.86 (m, 2 H), 6.19 - 6.14 (m, 1 H), 5.75 - 5.72 (m, 1 H), 3.84 - 3.70 (m, 8 H); m/z ES+ [M+1] ⁺ 471.4. Example 17. Preparation of 1-(4-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one (Compound 254)

Step 1. tert-Butyl 4-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyr imidin- 6-yl)piperazine-1-carboxylate To a mixture of tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate (200 mg, 571 μmol) and 5-chloro-6-phenoxypyridin-3-amine (126 mg, 571 μmol) in isopropanol (2.0 mL) was added trifluoroacetic acid (19.5 mg, 171 μmol, 12.7 μL). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl 4-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyr imidin-6- yl)piperazine-1-carboxylate (280 mg, 524 μmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 534.4. Step 2. N-(5-Chloro-6-phenoxypyridin-3-yl)-6-(piperazin-1-yl)pyrido[ 3,2-d]pyrimidin-4- amine To a mixture of tert-butyl 4-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazine-1-carboxylate (260 mg, 486 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(5-chloro-6- phenoxypyridin-3-yl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidi n-4-amine (200 mg, 461 μmol, 95%) as a yellow solid. m/z ES+ [M+H] ⁺ 434.4. Step 3. 1-(4-(4-((5-Chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6- yl)piperazin-1-yl)prop-2-en-1-one To a mixture of N-(5-chloro-6-phenoxy-3-pyridyl)-6-piperazin-1-yl-pyrido[3,2 - d]pyrimidin-4-amine (200 mg, 460 μmol) in tetrahydrofuran (1.50 mL) and water (1.50 mL) was added sodium bicarbonate (38.7 mg, 460 μmol) and prop-2-enoyl chloride (41.7 mg, 460 μmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 27%-69%, 14 min) to give 1-(4-(4-((5-chloro-6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazin-1-yl)prop-2-e n-1-one (134 mg, 0.27 mmol, 59%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.68 - 8.66 (m, 2H), 8.44 (s, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 9.4 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.26 - 7.19 (m, 1H), 7.17 - 7.12 (m, 2H), 6.89 (dd, J = 10.4, 16.4 Hz, 1H), 6.16 (dd, J = 2.4, 16.8 Hz, 1H), 5.77 - 5.69 (m, 1H), 3.91 - 3.84 (m, 4H), 3.75 - 3.65 (m, 4H); m/z ES+ [M+H] ⁺ 488.4. Example 18. Preparation of 1-(4-(4-((2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazin-1- yl)prop-2-en-1-one (Compound 277) Step 1. tert-Butyl 4-(4-((2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1 -carboxylate To a solution of 2-fluoro-4-(1-methylpyrazol-3-yl)oxy-aniline (47.3 mg, 228 μmol) in acetonitrile (2 mL) was added tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate (80.0 mg, 228 μmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was added water (20 mL) and filtered. The filter cake was washed with water (5 mL) and petroleum ether (5 mL), then concentrated under reduced pressure to give tert-butyl4-(4- ((2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)amino)pyr ido[3,2-d]pyrimidin-6- yl)piperazine-1-carboxylate (95.0 mg, 182 μmol, 79%) as a yellow solid. m/z ES+ [M+H] ⁺ 521.2. Step 2. N-(2-Fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe razin-1- yl)pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl 4-[4-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy-anilino]pyrido[3, 2-d] pyrimidin-6-yl]piperazine-1-carboxylate (95.0 mg, 182 μmol) in trifluoroacetic acid (752 mg, 6.60 mmol) and dichloromethane (2 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[2-fluoro-4-(1- methylpyrazol-3- yl)oxy-phenyl]-6-piperazin-1-yl-pyrido[3,2-d]pyrimidin-4-ami ne (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 421.2. Step 3. 1-(4-(4-((2-Fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)a mino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-piperazin- 1-yl- pyrido[3, 2-d]pyrimidin-4-amine (90.0 mg, 214 μmol) and sodium bicarbonate (17.9 mg, 214 μmol) in tetrahydrofuran (4 mL) and water (1 mL) was added prop-2-enoyl chloride (17.4 mg, 192 μmol) in tetrahydrofuran (4 mL) at 0 °C. Then the mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - acetonitrile]; B%: 30% - 60%, 10 min) to give 1-[4-[4-[2-fluoro-4 -(1-methylpyrazol-3-yl)oxy-anilino]pyrido[3,2- d]pyrimidin-6-yl]piperazin-1-yl]prop-2-en-1-one (30.65 mg, 64.5 μmol, 30%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.32 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.85 (t, J = 8.8 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.13 - 7.08 (m, 1H), 7.01 - 6.96 (m, 1H), 6.95 - 6.84 (m, 1H), 6.19 - 6.12 (m, 1H), 5.92 (d, J = 2.4 Hz, 1H), 5.76 - 5.70 (m, 1H), 3.83 (s, 4H), 3.76 (s, 3H), 3.72 (d, J = 16.0 Hz, 4H); m/z ES+ [M+H] ⁺ 475.4. Example 19. Preparation of 1-(4-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin - 6-yl)piperazin-1-yl)prop-2-en-1-one (Compound 279) Step 1. tert-Butyl 4-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate (200 mg, 572 μmol) in dimethylsulfoxide (4 mL) was added potassium tert-butoxide (96.2 mg, 858 μmol) and 5-phenoxypyridin-2-amine (117mg, 629 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was added water (25 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 1/1) to give tert-butyl 4-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1- carboxylate (150 mg, 0.30 mmol, 47%) as a yellow solid. m/z ES+ [M+H] ⁺ 500.2. Step 2. N-(5-Phenoxypyridin-2-yl)-6-(piperazin-1-yl)pyrido[3,2-d]pyr imidin-4-amine A solution of tert-butyl 4-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1-carboxylate (130 mg, 260 μmol) in dichloromethane (4 mL) and trifluoroacetic acid (616 mg, 5.40 mmol) was stirred at 25 °C for 1 hr. On completion, The reaction mixture was concentrated under reduced pressure to give N-(5-phenoxypyridin-2-yl)-6-(piperazin-1- yl)pyrido[3,2-d]pyrimidin-4-amine (133 mg, crude, trifluoroacetic acid salt) as a white solid. m/z ES+ [M+H] ⁺ 400.2. Step 3.1-(4-(4-((5-Phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimid in-6-yl)piperazin-1- yl)prop-2-en-1-one To a solution of N-(5-phenoxy-2-pyridyl)-6-piperazin-1-yl-pyrido[3,2-d]pyrimi din-4- amine (133 mg, 259 μmol) in tetrahydrofuran (3 mL) and water (1 mL) was added sodium bicarbonate (21.8 mg, 259 μmol) and followed by prop-2-enoyl chloride (28.1 mg, 311 μmol) at 0 °C. The mixture was stirred at 0 ~ 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 31% - 61%, 10 min) to give 1-[4-[4-[(5-phenoxy-2-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]piperazin-1-yl]prop-2-en-1-one (32.71 mg, 72 μmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.67 (d, J = 9.2 Hz, 1H), 8.56 (s, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.74 - 7.59 (m, 2H), 7.45 - 7.36 (m, 2H), 7.21 - 7.13 (m, 1H), 7.10 - 7.01 (m, 2H), 6.96 - 6.82 (m, 1H), 6.24 - 6.11 (m, 1H), 5.81 - 5.69 (m, 1H), 3.88 - 3.72 (m, 8H); m/z ES+ [M+H] ⁺ 454.4. Example 20. Preparation of 1-(4-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin - 6-yl)piperazin-1-yl)prop-2-en-1-one (Compound 274) Step 1. tert-Butyl 4-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate (150 mg, 429 μmol) in isopropanol (2.0 mL) was added 6-phenoxypyridin-3-amine (87.8 mg, 472 μmol) and trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl 4-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperazine-1- carboxylate (314 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 500.5. Step 2. N-(6-Phenoxypyridin-3-yl)-6-(piperazin-1-yl)pyrido[3,2-d]pyr imidin-4-amine To a solution of tert-butyl 4-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin- 6-yl)piperazine-1-carboxylate (314 mg, 629 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (489 mg, 4.29 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(6-phenoxypyridin-3-yl)-6-(piperazin- 1-yl)pyrido[3,2-d]pyrimidin-4-amine (185 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 400.1. Step 3.1-(4-(4-((6-Phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimid in-6-yl)piperazin-1- yl)prop-2-en-1-one To a solution of N-(6-phenoxypyridin-3-yl)-6-(piperazin-1-yl)pyrido[3,2-d]pyr imidin-4- amine (135 mg, 338 μmol) in tetrahydrofuran (2.0 mL) was added a solution of sodium bicarbonate (227 mg, 2.70 mmol) in water (0.6 mL), and then a solution of prop-2-enoyl chloride (30.6 mg, 338 μmol) in tetrahydrofuran (2.0 mL) was dropwise added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Shim-pack C18150 x 25, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 23% - 43%, 10 min) to give 1- (4-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6 -yl)piperazin-1-yl)prop-2-en-1- one (68.6 mg, 151 μmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.35 (dd, J = 2.4, 8.8 Hz, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.25 - 7.17 (m, 1H), 7.16 - 7.08 (m, 3H), 6.89 (dd, J = 10.4, 16.4 Hz, 1H), 6.16 (dd, J = 2.4, 16.8 Hz, 1H), 5.81 - 5.67 (m, 1H), 3.93 - 3.82 (m, 4H), 3.79 - 3.66 (m, 4H); m/z ES+ [M+H] ⁺ 454.4. Example 21. Preparation of 1-(4-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pi perazin-1-yl)prop-2-en-1- one (Compound 347) Step 1. tert-Butyl 4-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazine-1-carboxylate To a solution of 6-chloro-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrido[3,2- d]pyrimidin-4-amine (100 mg, 280 μmol) and tert-butyl piperazine-1-carboxylate (83.4 g, 448 μmol) in N-methylpyrrolidone (1.5 mL) was added N,N-diisopropylethylamine (144 mg, 1.12 mmol). The mixture was stirred at 100 °C for 5 hr. On completion, the mixture was poured into water (2.0 mL) and the suspension was filtered. The filter cake was washed with water (1.5 mL), dried in vacuum to give tert-butyl 4-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazine-1-carboxylate (130 mg, 256 μmol, 72%) as a brown solid. m/z ES+ [M+H] ⁺ 507.2. Step 2. N-(3-Chloro-4-(difluoromethoxy)phenyl)-6-(piperazin-1-yl)pyr ido[3,2- d]pyrimidin-4-amine A solution of tert-butyl 4-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazine-1-carboxylate (100 mg, 197 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 40 minutes. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-(3-chloro-4- (difluoromethoxy)phenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyri midin-4-amine (80.0 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 407.1. Step 3. 1-(4-(4-((3-Chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3, 2-d]pyrimidin-6- yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-4-(difluoromethoxy)phenyl)-6-(piperazin-1-yl)pyr ido[3,2- d]pyrimidin-4-amine (80.0 mg, 196 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (66.0 mg, 786 μmol) and followed by prop-2-enoyl chloride (8.90 mg, 98.3 μmol). The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 24% - 54%, 10 min) to give 1-(4-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pi perazin-1-yl)prop-2-en-1-one (24.6 mg, 53.3 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 2.4, 8.8 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.6 Hz, 1H), 7.46 - 7.37 (m, 1H), 7.24 - 7.06 (s, 1H), 6.90 (dd, J = 10.4, 16.8 Hz, 1H), 6.18 (dd, J = 2.4, 16.8 Hz, 1H), 5.81 - 5.62 (m, 1H), 3.88 (d, J = 5.2 Hz, 4H), 3.75 (d, J = 6.4 Hz, 4H); m/z ES+ [M+H] ⁺ 461.1. Example 22. Preparation of 1-(4-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazin-1-y l)prop-2-en-1-one (Compound 369) Step 1. 6-Chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)p yrido[3,2- d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (180 mg, 901 μmol) in acetonitrile (2.5 mL) was added 3-chloro-4-(cyclopropylmethoxy)-2-fluoro-aniline (216 mg, 1.00 mmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the solid was collected to give 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin -4-amine (310 mg, 818 μmol, 73%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 8.76 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 7.08 (dd, J = 1.6, 9.2 Hz, 1H), 4.03 (s, 1H), 4.01 (s, 1H), 1.37 - 1.22 (m, 1H), 0.65 - 0.60 (m, 2H), 0.39 (dd, J = 1.6, 4.8 Hz, 2H); m/z ES+ [M+H] ⁺ 379.1. Step 2. tert-Butyl 4-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate To a solution of 6-chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 395 μmol) in N-methylpyrrolidone (2.0 mL) was added diisopropylethylamine (153 mg, 1.19 mmol), followed by tert-butyl piperazine-1- carboxylate (147 mg, 791 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was poured into water (2 mL) and the suspension was filtered. The filter cake was washed with water (1.5 mL), dried in vacuum to give tert-butyl 4-(4-((3-chloro-4-(cyclopropylmethoxy)- 2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine- 1-carboxylate (200 mg, 378 μmol, 78%) as a yellow solid. m/z ES+ [M+H] ⁺ 529.2. Step 3. N-(3-Chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)-6-(pipera zin-1- yl)pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl 4-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]piperazine-1-carboxylate (150 mg, 283 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-4- (cyclopropylmethoxy)-2-fluorophenyl)-6-(piperazin-1-yl)pyrid o[3,2-d]pyrimidin-4-amine (120 mg, crude, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 429.2. Step 4. 1-(4-(4-((3-Chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)ami no)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-pipera zin-1-yl- py rido[3,2-d]pyrimidin-4-amine (120 mg, 279 μmol) in tetrahydrofuran (0.3 mL) and water (0.3 mL) was added sodium bicarbonate (70.5 mg, 839 μmol), followed by prop-2-enoyl chloride (20.2 mg, 223 μmol, 18.2 μL). The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25 mm 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - acetonitrile]; B%: 39% - 69%, 11 min) to give 1-[4-[4-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin -6-yl]piperazin-1-yl]prop-2-en-1- one (42.2 mg, 87.4 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.31 (s, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.71 (t, J = 8.8 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.06 (dd, J = 1.2, 9.2 Hz, 1H), 6.90 (dd, J = 10.4, 16.8 Hz, 1H), 6.17 (dd, J = 2.4, 16.8 Hz, 1H), 5.79 - 5.66 (m, 1H), 4.00 (d, J = 7.2 Hz, 2H), 3.85 (s, 4H), 3.77 - 3.68 (m, 4H), 1.36 - 1.20 (m, 1H), 0.66 - 0.56 (m, 2H), 0.44 - 0.35 (m, 2H); m/z ES+ [M+H] ⁺ 483.1. Example 23. Preparation of 1-(4-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazin-1- yl)prop-2-en-1-one (Compound 333) Step 1. tert-Butyl 4-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1 -carboxylate To a solution of 6-chloro-N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]pyri do[3,2- d]pyrimidin-4-amine (90.0 mg, 232 μmol) and tert-butyl piperazine-1-carboxylate hydrochloride (51.8 mg, 232 μmol) in N-methylpyrrolidone (2.0 mL) was added diisopropylethylamine (120 mg, 930 μmol, 162 μL). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was added water (5 mL) and filtered. The filter cake was dried to give tert-butyl 4-[4-[3-chloro-4-(1- methylpyrazol-3-yl)oxy-anilino]pyrido[3,2-d]pyrimidin-6-yl]p iperazine-1-carboxylate (110 mg, 205 μmol, 79%) as a yellow solid. m/z ES+ [M+H] ⁺ 537.2. Step 2. N-(3-Chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe razin-1- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 4-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]piperazine-1-carboxylate (90.0 mg, 168 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-[3-chloro-4-(1- methylpyrazol-3-yl)oxy-phenyl]-6-piperazin-1-yl-pyrido[3,2-d ]pyrimidin-4- amine (70 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 437.2. Step 3. 1-(4-(4-((3-Chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)a mino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-piperazin- 1-yl- pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, 160 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (13.5 mg, 160 μmol) to adjust the pH to 8. After that, prop-2- enoyl chloride (14.5 mg, 160 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 0.25 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 15% - 45%, 10 min) to give 1-[4-[4-[3-chloro-4-(1-methylpyrazol-3- yl)oxy-anilino]pyrido[3,2-d]pyrimidin-6-yl]piperazin-1-yl]pr op-2-en-1-one (17.3 mg, 35.2 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.45 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.63 - 7.57 (m, 2H), 7.23 (d, J = 8.8 Hz, 1H), 6.89 (dd, J = 10.4, 16.8 Hz, 1H), 6.17 (dd, J = 2.4, 16.8 Hz, 1H), 5.80 - 5.70 (m, 2H), 3.88 (s, 4H), 3.77 - 3.69 (m, 7H); m/z ES+ [M+H] ⁺ 491.4. Example 24. Preparation of 1-(4-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one (Compound 353)

Step 1. tert-Butyl 4-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyr imidin- 6-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidin-6-yl)piperazine-1- carboxylate (206 mg, 589 μmol) in dimethylsulfoxide (2 mL) was added potassium tert-butoxide (1 M, 1.77 mL), followed by 4-chloro-5-phenoxy-pyridin-2-amine (130 mg, 589 μmol). The mixture was stirred at 25 °C for 2 hr. On completion the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give tert-butyl 4-[4-[(4-chloro-5-phenoxy-2-pyridyl)amino]quinazolin-6- yl]piperazine-1-carboxylate (80 mg, 318 μmol, 55%) as a yellow oil. m/z ES+ [M+H] ⁺ 534.2. Step 2. N-(4-Chloro-5-phenoxypyridin-2-yl)-6-(piperazin-1-yl)pyrido[ 3,2-d]pyrimidin-4- amine To a solution of tert-butyl 4-[4-[(4-chloro-5-phenoxy-2-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]piperazine-1-carboxylate (150 mg, 281 μmol) in dichloromethane (3 mL) was added hydrochloric acid/dioxane (4 M, 1.5 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(4-chloro-5- phenoxy-2-pyridyl)-6-piperazin-1-yl-pyrido[3,2-d]pyrimidin-4 -amine (130 mg, 277 μmol, 98%, hydrochloric acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 434.3. Step 3. 1-(4-(4-((4-Chloro-5-phenoxypyridin-2-yl)amino)pyrido[3,2-d] pyrimidin-6- yl)piperazin-1-yl)prop-2-en-1-one To a solution of N-(4-chloro-5-phenoxy-2-pyridyl)-6-piperazin-1-yl-pyrido[3,2 - d]pyrimidin-4-amine (120 mg, 255 μmol, hydrochloric acid salt) in tetrahydrofuran (2 mL) and water (1 mL) was added potassium carbonate (35.26 mg, 255 μmol) and followed by prop-2-enoyl chloride (20.78 mg, 230 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 50%-80%, 10 min) to give 1-[4-[4-[(4-chloro-5-phenoxy- 2-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]piperazin-1-yl]p rop-2-en-1-one (20.33 mg, 41.0 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 10.4 Hz, 1H), 6.18 - 6.10 (m, 1H), 5.74 (dd, J = 10.4, 2.4 Hz, 1H), 3.94 - 3.66 (m, 8H); m/z ES+ [M+H] ⁺ 488.2. Example 25. Preparation of 1-(7-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-4 ,7-diazaspiro[2.5]octan-4- yl)prop-2-en-1-one (Compound 407) Step 1. tert-Butyl 7-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(difluoromethoxy)phenyl]pyrido[3,2-d] pyrimidin-4- amine (200 mg, 560 μmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (154 mg, 728 μmol) in N-methylpyrrolidone (3.5 mL) was added N,N-diisopropylethylamine (217 mg, 1.68 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was poured into water (8.0 mL) and the suspension was filtered. The filter cake was washed with water (5 mL x 3), dried in vacuum to give tert-butyl 7-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2- d]pyrimidin-6-yl]-4,7-diaza spiro[2.5]octane-4-carboxylate (220 mg, 413 μmol, 44%) as a yellow oil. m/z ES+ [M+H] ⁺ 533.2. Step 2. N-(3-Chloro-4-(difluoromethoxy)phenyl)-6-(4,7-diazaspiro[2.5 ]octan-7- yl)pyrido[3,2-d]pyrimidin-4-amine To a mixture of tert-butyl 7-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2-d]pyrim idin-6- yl]-4,7-diazaspiro[2.5]octane-4-carboxylate (120 mg, 225 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4- (difluoromethoxy)phenyl]-6-(4,7-diazaspiro[2.5]octan-7-yl)py rido[3,2-d]pyrimidin-4-amine (97 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 433.1. Step 3. 1-(7-(4-((3-Chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3, 2-d]pyrimidin-6- yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-6-(4,7-diazaspiro[2.5 ]octan-7- yl)pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, 138 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (11.6 mg, 138 μmol) at 0 °C. Then prop-2-enoyl chloride (12.5 mg, 138 μmol) in tetrahydrofuran (0.2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 30 mm x 5 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 28%-58%, 10 min) to give 1-[7-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2-d]py rimidin-6-yl]-4,7- diazaspiro[2.5]octan-4-yl]prop-2-en-1-one (16.2 mg, 33.2 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.47 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.03 (dd, J = 2.4, 9.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.29 - 7.03 (m, 1H), 7.01 - 6.83 (m, 1H), 6.18 (dd, J = 2.0, 16.8 Hz, 1H), 5.75 (d, J = 11.2 Hz, 1H), 4.12 - 3.62 (m, 6H), 1.17 - 0.85 (m, 4H); m/z ES+ [M+H] ⁺ 487.4. Example 26. Preparation of 1-(7-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-4,7-diazaspi ro[2.5]octan-4-yl)prop-2-en- 1-one (Compound 425)

Step 1. tert-Butyl 7-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-4,7-diazaspi ro[2.5]octane-4-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]pyr ido[3,2- d]pyrimidin-4-amine (110 mg, 293 μmol) in N-methylpyrrolidone (0.5 mL) was added N,N- diisopropylethylamine (113 mg, 879 μmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (74.7 mg, 351 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was added water (2 mL) and filtered. The filter cake was concentrated in vacuo to give tert-butyl 7-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]pyrido[3 ,2-d]pyrimidin-6-yl]-4,7- diazaspiro[2.5]octane-4-carboxylate (130 mg, 236 μmol, 68%) as a brown solid. m/z ES+ [M+H] ⁺ 551.3. Step 2. N-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-6-(4,7-diaza spiro[2.5]octan-7- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 7-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octa ne-4-carboxylate (70.0 mg, 127 μmol) in dichloromethane (1 0 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-(4,7-diaz aspiro[2.5]octan-7- yl)pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, 111 μmol, 78%) as a yellow solid. m/z ES+ [M+H] ⁺ 451.1. Step 3. 1-(7-(4-((3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one To a solution of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, 110 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (32.6 mg, 388 μmol) to adjust pH = 8. Then prop-2-enoyl chloride (5.02 mg, 55.4 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 20%-50%, 8 min) to give 1-[7-[4-[3- chloro-4-(difluoromethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyr imidin-6-yl]-4,7- diazaspiro[2.5]octan-4-yl]prop-2-en-1-one (7.22 mg, 14.3 μmol, 12%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.36 (s, 1H), 8.14 - 7.87 (m, 2H), 7.61 - 7.53 (m, 1H), 7.52- 7.02 (m, 2H), 7.01-6.89 (m,1H), 6.17 (dd, J = 2.2, 16.0 Hz, 1H), 5.75 (m, 1H), 3.93 - 3.78 (m, 4H), 3.74 (s, 2H), 1.18 - 0.94 (m, 4H); m/z ES+ [M+H] ⁺ 505.2. Example 27. Preparation of 1-(7-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one (Compound 430) Step 1. tert-Butyl 7-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyr imidin- 6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of 6-chloro-N-(5-chloro-6-phenoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4- amine (350 mg, 910 μmol) in N-methylpyrrolidone (1.0 mL) was added N,N- diisopropylethylamine (353 mg, 2.73 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4- carboxylate (386 mg, 1.82 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was diluted with water (20 mL) and filtered. The filter cake was collected, triturated with water (20 mL) and petroleum ether (20 mL) to give tert-butyl 7-[4-[(5-chloro-6-phenoxy-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro [2.5]octane-4-carboxylate (400 mg, 714 μmol, 78%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.64 (d, J = 4.0 Hz, 2H), 8.42 (s, 1H), 7.92 (d, J = 12.0 Hz, 1H), 7.54 (d, J = 12.0 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.26 - 7.19 (m, 1H), 7.15 (d, J = 8.0 Hz, 2H), 3.86 (br. s, 2H), 3.66 - 3.61 (m, 2H), 3.61 - 3.56 (m, 2H), 1.43 (s, 9H), 0.96 - 0.92 (m, 2H), 0.91 - 0.86 (m, 2H). Step 2. N-(5-Chloro-6-phenoxypyridin-3-yl)-6-(4,7-diazaspiro[2.5]oct an-7- yl)pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl 7-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 357 μmol) in dichloromethane (2.0 mL) and trifluoroacetic acid (3.0 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-(5-chloro-6-phenoxypyridin-3-yl)-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine (164 mg, 285 μmol, 99%, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 460.2. Step 3. 1-(7-(4-((5-Chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6-yl)- 4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1-one To a mixture of N-(5-chloro-6-phenoxy-3-pyridyl)-6-(4,7-diazaspiro[2.5]octan -7- yl)pyrido[3,2-d]pyrimidin-4-amine (164 mg, 285 μmol, trifluoroacetic acid salt) and sodium bicarbonate (120 mg, 1.43 mmol) in tetrahydrofuran (3.0 mL) and water (3.0 mL) was added prop- 2-enoyl chloride (25.8 mg, 285 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by Prep- HPLC (column: Waters xbridge 150 x 25 mm 10 um; mobile phase: [water (10 mM NH4HCO3)- acetonitrile]; B%: 40%-70%, 11 min) to give 1-(7-(4-((5-chloro-6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]oct an-4-yl)prop-2-en-1-one (17.8 mg, 34.6 μmol, 12%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.70 - 8.61 (m, 2H), 8.43 (s, 1H), 7.94 (d, J = 12.0 Hz, 1H), 7.55 (d, J = 12.0 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.26 - 7.20 (m, 1H), 7.18 - 7.12 (m, 2H), 7.02 - 6.84 (m, 1H), 6.21 - 6.11 (m, 1H), 5.75 (d, J = 12.0 Hz, 1H), 4.08 - 3.60 (m, 6H), 1.15 - 0.94 (m, 4H); m/z ES+ [M+H] ⁺ 514.3. Example 28. Preparation of 1-((1S,4S)-5-(4-((5-(trifluoromethyl)pyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 435)

Step 1. 6-Chloro-N-(5-(trifluoromethyl)pyridin-3-yl)pyrido[3,2-d]pyr imidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.20g, 1.00 mmol) in acetonitrile (2.5 mL) was added 5-(trifluoromethyl)pyridin-3-amine (0.19 g, 1.20 mmol). The mixture was stirred at 40 °C for 4 hr. On completion, the reaction mixture was filtered and washed with acetonitrile (3 mL). The filter cake was concentrated in vacuo to give 6-chloro-N-[5- (trifluoromethyl)-3-pyridyl]pyrido[3,2-d]pyrimidin-4-amine (180 mg, 552 μmol, 49%) as a white solid. m/z ES+ [M+H] ⁺ 326.1. Step . (1S,4S)-tert-Butyl 5-(4-((5-(trifluoromethyl)pyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 6-chloro-N-[5-(trifluoromethyl)-3-pyridyl]pyrido[3,2-d]pyrim idin-4- amine (160 mg, 491 μmol) in N-methylpyrrolidone (1 mL) was added N,N-diisopropylethylamine (190 mg, 1.47 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (116 mg, 589 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the reaction mixture was added water (3.0 mL) and filtered. The filter cake was concentrated in vacuo to give tert-butyl (1S,4S)-5-[4-[[5-(trifluoromethyl)-3-pyridyl]amino]pyrido[3, 2-d]pyrimidin-6-yl]- 2,5diazabicyclo[2.2.1]heptane-2-carboxylate (210 mg, 430 μmol, 76%) as a black solid. m/z ES+ [M+H] ⁺ 488.3. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-(trifluo romethyl)pyridin-3- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[[5-(trifluoromethyl)-3-pyridyl]amino]pyrido[3, 2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (190 mg, 389 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 3 hr. On completion, the reaction mixture was concentrated in vacuo to give 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[5-(trifluoro methyl)-3-pyridyl]pyrido[3,2- d]pyrimidin-4-amine (300 mg, 773 μmol, 96%) as a black solid. m/z ES+ [M+H] ⁺ 388.1. Step 4.1-((1S,4S)-5-(4-((5-(Trifluoromethyl)pyridin-3-yl)amino)py rido[3,2-d]pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[5-(trifluo romethyl)-3- pyridyl]pyrido[3,2-d]pyrimidin-4-amine (140 mg, 361 μmol) in tetrahydrofuran (0.75 mL) and water (0.75 mL) was added sodium bicarbonate (151 mg, 1.81 mmol). Then prop-2-enoyl chloride (45.8 mg, 505 μmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 20 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 22% - 52%, 11min) to give 1-[(1S,4S)-5-[4-[[5- (trifluoromethyl)-3-pyridyl]amino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.1]heptan- 2-yl]prop-2-en-1-one (12.2 mg, 27.6 μmol, 7%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.84 - 9.59 (m, 1H), 9.51 - 9.49 (m, 1H), 8.92 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.02 - 7.90 (m, 1H), 7.38 - 7.14 (m, 1H), 6.86 - 6.40 (m, 1H), 6.19 - 6.12 (m, 1H), 5.73 - 5.64 (m, 1H), 5.03 (d, J = 56.8 Hz, 1H), 3.79 - 3.44 (m, 5H), 2.10 - 2.03 (m, 2H); m/z ES+ [M+H] ⁺ 442.3. Example 29. Preparation of 1-(7-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one (Compound 409) Step 1. tert-Butyl 7-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of 6-chloro-N-(2-fluoro-3-methyl-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 346 μmol) in N-methylpyrrolidone (1.0 mL) was added N,N-diisopropylethylamine (134 mg, 1.04 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (95.6 mg, 450 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was diluted with water (10.0 mL) and filtered. The filter cake was concentrated in vacuo to give tert-butyl 7-[4-(2-fluoro-3- methyl-anilino)pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2 .5]octane-4-carboxylate (160 mg, 344 μmol, 90%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.38 (s, 1H), 8.00 (t, J = 7.2 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.17 - 7.09 (m, 2H), 3.79 - 3.78 (m, 2H), 3.62 - 3.58 (m, 4H), 2.30 (d, J = 1.6 Hz, 3H), 1.44 (s, 9H), 0.96 - 0.94 (m, 2H), 0.88 - 0.84 (m, 2H); m/z ES+ [M+H] ⁺ 465.3. Step 2. N-(2-Fluoro-3-methylphenyl)-6-(4,7-diazaspiro[2.5]octan-7-yl )pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 7-[4-(2-fluoro-3-methyl-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 4,7-diazaspiro[2.5]octane-4-carboxylate (160 mg, 344 μmol) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6-(4,7-diazaspiro[2.5]octan-7-yl)-N-(2-fluoro-3- methyl-phenyl)pyrido[3,2-d]pyrimidin-4-amine (129 mg, crude, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 365.1. Step 3. 1-(7-(4-((2-Fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one To a solution of 6-(4,7-diazaspiro[2.5]octan-7-yl)-N-(2-fluoro-3-methyl- phenyl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, 329 μmol) in tetrahydrofuran (0.30 mL) was added sodium bicarbonate (138 mg, 1.65 mmol) in water (0.30 mL) dropwise at 0 °C over 5 minutes and then prop-2-enoyl chloride (26.8 mg, 296 μmol) in tetrahydrofuran (0.30 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 5 minutes. On completion, the solution was concentrated to give a residue. The residue was purified by Prep- HPLC (column: Phenomenex Luna C18150 x 25mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 23% - 53%, 10 min) to give 1-[7-[4-(2-fluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1- one (96.9 mg, 232 μmol, 70%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.39 (s, 1H), 8.01 (t, J = 7.2 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.17 - 7.08 (m, 2H), 6.95 - 6.92 (m, 1H), 6.17 (dd, J = 2.4, 16.8 Hz, 1H), 5.74 (d, J = 12.0 Hz, 1H), 3.83 (s, 4H), 3.72 (s, 2H), 2.30 (d, J = 1.6 Hz, 3H), 1.13 - 0.95 (m, 4H); m/z ES+ [M+H] ⁺ 419.5. Example 30. Preparation of (E)-4-(dimethylamino)-1-((1S,4S)-5-(4-((2-fluoro-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)but- 2-en-1-one (Compound 421) Step 1. (1S,4S)-tert-Butyl 5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 6-chloro-N-(2-fluoro-3-methyl-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (230 mg, 797 μmol) in N-methylpyrrolidone (4.00 mL) was added N,N-diisopropylethylamine (309 mg, 2.39 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (205 mg, 1.04 mmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was quenched with water (10 mL) and filtered. The filter cake was concentrated in vacuo to give tert- butyl (1S,4S)-5-[4-(2-fluoro-3-methyl-anilino)pyrido[3,2-d]pyrimid in-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (340 mg, 754 μmol, 81%) as a red solid. m/z ES+ [M+H] ⁺ 451.2. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(2-fluoro-3 - methylphenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-(2-fluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (100 mg, 222 μmol) in dichloromethane (1.00 mL) was added hydrochloric acid/dioxane (0.10 mL, 4 M). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(2-fluoro-3-m ethyl-phenyl)pyrido[3,2- d]pyrimidin-4-amine (80.0 mg, crude, hydrochloric acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 351.1. Step 3. (E)-4-(Dimethylamino)-1-[(1S,4S)-5-[4-(2-fluoro-3-methyl-ani lino) pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]but-2-e n-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(2-fluoro-3 -methyl- phenyl)pyrido[3,2-d]pyrimidin-4-amine (77.8 mg, 222 μmol), (E)-4-(dimethylamino)but-2-enoic acid; hydrochloride (33.1 mg, 200 μmol) and N,N-diisopropylethylamine (86.1 mg, 666 μmol) in N,N-dimethylformamide (1.0 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate(V) (110 mg, 289 μmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was purified by prep-HPLC (column: Phenomenex Synergi Polar-RP 100 x 25mm, 4um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 7% - 37%, 8min) to give (E)-4-(dimethylamino)-1-[(1S,4S)-5-[4-(2-fluoro-3-methyl- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]but-2-en-1-one (20.6 mg, 44.6 μmol, 18%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.27 - 9.24 (m, 1H), 8.41 (s, 1H), 8.18 - 8.18 (m, 1H), 7.93 (dd, J = 3.2, 9.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 6.4 Hz, 1H), 6.65 - 6.19 (m, 2H), 5.03 - 4.92 (m, 1H), 3.76 - 3.68 (m, 3H), 3.08 (d, J = 4.4 Hz, 2H), 2.99 (d, J = 6.4 Hz, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H), 2.09 -2.01 (m, 2H); m/z ES+ [M+H] ⁺ 462.4. Example 31. Preparation of 1-((1S,4S)-5-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 335) Step 1. (1S,4S)-tert-Butyl 5-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of N-(3-bromo-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 282 μmol) in N-methylpyrrolidone (1.0 mL) was added N,N-diisopropylethylamine (109 mg, 848 μmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (61.6 mg, 311 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was filtered and the filter cake was concentrated to give tert-butyl (1S,4S)-5-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (128 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 515.3. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-bromo-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (110 mg, 213 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give 6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N-(3-bromo-2-fluorophenyl)py rido[3,2-d]pyrimidin-4-amine (88.0 mg, crude, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 415.2. Step 3. 1-((1S,4S)-5-(4-((3-Bromo-2-fluorophenyl)amino)pyrido[3,2-d] pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of N-(3-bromo-2-fluoro-phenyl)-6-[(1S,4S)-2,5-diazabicyclo[2.2. 1]heptan- 2-yl]pyrido[3,2-d]pyrimidin-4-amine (88.0 mg, 211 μmol) in tetrahydrofuran (1.0 mL) was added sodium bicarbonate (53.4 mg, 635 μmol) and water (1.0 mL). Then prop-2-enoyl chloride (19.1 mg, 211 μmol) was added at 0 °C and the mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was purified by Prep-HPLC (FA condition column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 23% - 53%, 11.5 min) to give 1-[(1S,4S)-5-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrim idin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (32 mg, 68.2 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.40 (d, J = 3.6 Hz, 1H), 8.33 - 8.17 (m, 1H), 7.93 (dd, J = 4.0, 9.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.49 - 7.22 (m, 2H), 6.78 - 6.41 (m, 1H), 6.17 – 6.12 (m, 1H), 5.71 - 5.63 (m, 1H), 5.44 - 5.13 (m, 1H), 5.10 - 4.91 (m, 1H), 3.75 - 3.52 (m, 4H), 2.14 - 1.96 (m, 2H); m/z ES+ [M+H] ⁺ 469.0. Example 32. Preparation of 1-(4-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperazin-1-yl)prop-2-en-1-one (Compound 334)

Step 1. tert-Butyl 4-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6 - yl)piperazine-1-carboxylate To a solution of N-(3-bromo-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]pyrimidin- 4-amine (200 mg, 565 μmol) in N-methylpyrrolidone (1.0 mL) was added N,N-diisopropylethylamine (292 mg, 2.26 mmol) and tert-butyl piperazine-1-carboxylate;hydrochloride (138 mg, 622 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was filtered and concentrated to give tert-butyl 4-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]p iperazine-1- carboxylate (250 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.39 (s, 1H), 8.12 - 8.04 (m, 1H), 7.96 (d, J = 9.6 Hz, 1H), 7.59 (d, J = 9.6 Hz, 1H), 7.53 - 7.51 (m, 1H), 7.26 - 7.24 (m, 1H), 3.83 - 3.75 (m, 4H), 3.56 - 3.45 (m, 4H), 1.44 (s, 9H). Step 2. N-(3-Bromo-2-fluorophenyl)-6-(piperazin-1-yl)pyrido[3,2-d]py rimidin-4-amine To a solution of tert-butyl 4-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]piperazine-1-carboxylate (240 mg, 476 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.23 g, 10.8 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-(3-bromo-2-fluoro-phenyl)-6-piperazin-1-yl-pyrido[3,2- d]pyrimidin-4-amine (190 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 405.0. Step 3.1-(4-(4-((3-Bromo-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)piperazin- 1-yl)prop-2-en-1-one To a solution of N-(3-bromo-2-fluoro-phenyl)-6-piperazin-1-yl-pyrido[3,2-d]py rimidin- 4-amine (190 mg, 471 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (39.5 mg, 471 μmol). Then prop-2-enoyl chloride (42.6 mg, 471 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the solution was concentrated and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 26% - 56%, 11.5 min) to give 1-[4-[4-(3- bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]piperazin -1-yl]prop-2-en-1-one (36 mg, 78.8 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.41 (s, 1H), 8.19 - 8.09 (m, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.62 (d, J = 9.4 Hz, 1H), 7.53 - 7.52 (m, 1H), 7.27 - 7.22 (m, 1H), 6.90 (dd, J = 10.4, 16.8 Hz, 1H), 6.17 (dd, J = 2.4, 16.8 Hz, 1H), 5.75 - 5.72 (m, 1H), 3.84 (s, 4H), 3.76 - 3.71 (m, 4H); m/z ES+ [M+H] ⁺ 456.9. Example 33. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4- methoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 412) Step 1. 6-Chloro-N-(3-chloro-2-fluoro-4-methoxyphenyl)pyrido[3,2-d]p yrimidin-4- amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (160 mg, 799 μmol) and 3-chloro-2- fluoro-4-methoxy-aniline (154 mg, 879 μmol) in acetonitrile (2.0 mL) was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered. The filter cake was concentrated in vacuo to give 6-chloro-N-(3-chloro-2-fluoro-4-methoxy-phenyl)pyrido[3,2-d] pyramidin-4-amine (180 mg, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.61 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 8.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H); m/z ES+ [M+H] ⁺ 339.1. Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-2-fluoro-4-methoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To the solution of 6-chloro-N-(3-chloro-2-fluoro-4-methoxy-phenyl)pyrido[3,2-d] pyrimidin-4- amine (160 mg, 471 μmol) in N-methylpyrrolidone (2.0 mL) was added N,N- diisopropylethylamine (182 mg, 1.42 mmol, 246 μL) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (121 mg, 613 μmol), the mixture was stirred at 100 °C for 2 hr. On completion, the mixture was added water (5 mL) and filtered. The filter cake was concentrated in vacuo to give tert-butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (130 mg, 259 μmol, 55%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 - 9.23 (m, 1H), 8.41 - 8.28 (m, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.91 - 7.82 (m, 1H), 7.48 - 7.25 (m, 1H), 7.15 (d, J = 9.2 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 4.00 (s, 3H), 3.75 - 3.63 (m, 1H), 3.55 - 3.44 (m, 2H), 3.34 - 3.29 (m, 2H), 2.10 - 1.91 (m, 2H), 1.55 - 1.36 (m, 9H); m/z ES+ [M+H] ⁺ 501.3. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4- methoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine To the solution of tert-butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-methoxy- anilino)pyrido[3,2 -d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate (110 mg, 219 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3 -chloro-2-fluoro-4-methoxy-phenyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (80.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 401.1. Step 4. 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-methoxyphenyl)amino)py rido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-(3-chloro-2-fluoro-4-methoxy-phenyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2. 1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, crude, trifluoroacetic acid salt) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (58.6 mg, 698 μmol) to adjusted pH = 8 at 0 °C, then prop-2-enoyl chloride (9.03 mg, 99.8 μmol) was added. The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column:Phenomenex Synergi Polar-RP 100 x 25mm x 4um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 20% - 50%, 8 min) to give 1-[(1S,4S)-5-[4-(3-chloro-2-fluoro-4-methoxy-anilino)pyrido[ 3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (19.5 mg, 42.9 μmol, 20%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 - 9.12 (m, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.91 (dd, J = 3.6, 9.2 Hz, 1H), 7.86 - 7.77 (m, 1H), 7.39 - 7.18 (m, 1H), 7.14 - 7.02 (m, 1H), 6.85 -6.40 (m, 1H), 6.18 - 6.12 (m, 1H), 5.72 - 5.66 (m, 1H), 5.08 - 4.94 (m, 1H), 3.93 (s, 3H), 3.74 - 3.66 (m, 2H), 3.60 - 3.51 (m, 2H), 3.44 - 3.40 (m, 1H), 2.08 - 1.99 (m, 2H); m/z ES+ [M+H] ⁺ 455.3. Example 34. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 413) Step 1. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]pyr ido[3,2- d]pyrimidin-4-amine (140 mg, 373 μmol) and tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane - 2-carboxylate (96.1 mg, 485 μmol) in N-methylpyrrolidone (1.0 mL) was added N,N- diisopropylethylamine (144 mg, 1.12 mmol, 195 μL). Then the mixture was stirred at 80 °C for 16 hr. On completion, the reaction mixture was added water (3 mL) and filtered. The filter cake was concentrated in vacuo to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (130 mg, 242 μmol, 51%) as a brown solid. m/z ES+ [M+H] ⁺ 537.2. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-am ine To a solution of tert-butyl(1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluor o- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (110 mg, 204 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (847.00 mg, 7.43 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (80.0 mg, 183 μmol, 67%) as a brown oil. m/z ES+ [M+H] ⁺ 437.1. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (80.0 mg, 183 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (46.1 mg, 549 μmol) to adjusted the pH = 8 at 0 °C, then prop-2-enoyl chloride (9.95 mg, 109.8 μmol) was added to the mixture .The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Polar-RP 100 x 25mm x 4um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 30% - 60%, 8 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2- fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo [2.2.1]heptan-2-yl]prop-2-en-1-one (23.1 mg, 47.0 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 - 9.32 (m, 1H), 8.39 - 8.35 (m, 1H), 8.19 - 8.03 (m, 1H), 7.94-7.93 (m, 1H),7.75 - 7.15 (m, 3H), 6.82 - 6.32 (m, 1H), 6.32 - 6.15 (m, 1H), 5.68 (m, 1H), 5.01 (m, 1H), 3.82 - 3.65 (m, 2H), 3.62 - 3.50 (m, 2H), 3.44 ( d, J = 1.6 Hz, 1H), 2.09 (m, 2H); m/z ES+ [M+H] ⁺ 491.3. Example 35. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (Compound 350) Step 1. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 6-chloro-N-[3-chloro-4-(difluoromethoxy)phenyl]pyrido[3,2- d]pyrimidin-4-amine (100 mg, 280 μmol) in N-methylpyrrolidone (1.0 mL) was added N,N- diisopropylethylamine (180 mg, 1.40 mmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (61.0 mg, 308 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was filtered and concentrated to give tert-butyl (1S,4S)-5- [4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2-d]pyrimid in-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (120 mg, 231 μmol, 82%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.41 - 7.04 (m, 2H), 4.55 (d, J = 13.6 Hz, 1H), 3.66 - 3.64 (m, 1H), 3.32 - 3.26 (m, 4H), 2.26 - 2.08 (m, 2H), 1.45 - 1.33 (m, 9H). Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (100 mg, 192 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give 1-[(1S,4S)-5-[4- (3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-d iazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one (32.0 mg, 59.5 μmol, 31%) as a yellow oil. m/z ES+ [M+H] ⁺ 419.1. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-4-(difluoromethoxy)phenyl)amino)p yrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (80.0 mg, 191 μmol) in water (0.5 mL) and tetrahydrofuran (0.5 mL) was added sodium bicarbonate (16.0 mg, 191 μmol). Then prop-2-enoyl chloride (17.2 mg, 191 μmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 25% - 55%, 11.5 min) to give 1-[(1S,4S)-5-[4-[3- chloro-4-(difluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo [2.2.1]heptan-2-yl]prop-2-en-1-one (40.0 mg, 84.6 μmol, 44%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.45 (s, 1H), 8.39 - 8.30 (m, 1H), 8.10 - 7.99 (m, 1H), 7.91 (dd, J = 2.8, 9.2 Hz, 1H), 7.54 - 7.04 (m, 3H), 6.84 - 6.38 (m, 1H), 6.17 - 6.11 (m, 1H), 5.71- 5.62 (m, 1H), 5.01 (d, J = 56.0 Hz, 1H), 3.82 - 3.63 (m, 2H), 3.59 - 3.32 (m, 3H), 2.10 - 1.97 (m, 2H); m/z ES+ [M+H] ⁺ 473.1. Example 36. Preparation of 1-((1S,4S)-5-(4-((4-chloro-3- (cyclopropylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl )-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (Compound 410) Step 1. 1-Chloro-2-(cyclopropylmethoxy)-4-nitrobenzene To a solution of 2-chloro-5-nitro-phenol (5.00 g, 28.8 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (11.9 g, 86.4 mmol) and bromomethylcyclopropane (15.5 g, 115 mmol). The mixture was stirred at 80 °C for 12 hours. On completion, the mixture was quenched with water (3.0 mL). The resulting precipitate was filtered and collected. The crude product was triturated with water (30 mL) for 5 mins to give 1-chloro-2-(cyclopropylmethoxy)-4- nitro-benzene (6.00 g, 26.3 mmol, 91%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 - 7.78 (m, 2H), 7.75 - 7.69b(m, 1H), 4.07 (d, J = 7.0 Hz, 2H), 1.34 - 1.20 (m, 1H), 0.66 - 0.56 (m, 2H), 0.44 - 0.33 (m, 2H). Step 2. 4-Chloro-3-(cyclopropylmethoxy)aniline To a solution of 4-chloro-3-(cyclopropylmethoxy)aniline (4.00 g, 17.5 mmol) in methanol (120 mL) was added platinum on carbon (2.00 g, 20.2 mmol, 3 wt. % loading) in one portion at 25 °C under hydrogen gas atmosphere. The mixture was stirred at 25 °C for 2 hours under hydrogen (15 psi). On completion, the mixture was filtered and the filtrate was concentrated to give 4-chloro-3-(cyclopropylmethoxy)aniline (3.40 g, 17.2 mmol, 97%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.96 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 4.0 Hz, 1H), 6.20 - 6.07 (m, 1H), 5.18 (s, 2H), 3.76 (d, J = 6.8 Hz, 2H), 1.30 - 1.15 (m, 1H), 0.63 - 0.52 (m, 2H), 0.39 - 0.28 (m, 2H). Step 3. 6-Chloro-N-(4-chloro-3-(cyclopropylmethoxy)phenyl)pyrido[3,2 -d]pyrimidin-4- amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (400 mg, 2.00 mmol) in acetonitrile (12 mL) was added 4-chloro-3-(cyclopropylmethoxy)aniline (395 mg, 2.00 mmol). The mixture was stirred at 60 °C for 12 hr. On completion, the mixture was filtered and the filter cake was collected. The crude product was triturated with acetonitrile (20 mL) at 25 °C to give 6-chloro-N- [4-chloro-3-(cyclopropylmethoxy)phenyl]pyrido[3,2-d] pyrimidin-4-amine (700 mg, 1.94 mmol, 96%) as a yellow solid. Step 4. (1S,4S)-tert-Butyl 5-(4-((4-chloro-3- (cyclopropylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl )-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloro-N-[4-chloro-3-(cyclopropylmethoxy)phenyl]pyrido[3,2 - d]pyrimidin-4-amine (500 mg, 1.38 mmol) in N-methylpyrrolidone (1 mL) was added N,N- diisopropylethylamine (536 mg, 4.15 mmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (548 mg, 2.77 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was quenched with water (20 mL) and filtered. The filter cake was collected. The crude product was triturated with water (20 mL) and petroleum ether (20 mL) at 25 ^o C to give tert-butyl (1S,4S)-5-[4-[4-chloro-3-(cyclopropylmethoxy)anilino]pyrido[ 3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (700 mg, 1.34 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.42 (s, 1H), 7.97 - 7.81 (m, 2H), 7.75 - 7.63 (m, 1H), 7.46 - 7.12 (m, 2H), 4.55 (d, J = 16.0 Hz, 1H), 3.96 (d, J = 8.0 Hz, 2H), 3.74 - 3.54 (m, 3H), 2.01 - 1.91 (m, 2H), 1.45 - 1.31 (m, 10H), 0.94 (d, J = 8.0 Hz, 2H), 0.66 - 0.56 (m, 2H), 0.46 - 0.34 (m, 2H). Step 5. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(4-chloro-3 - (cyclopropylmethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-chloro-3- (cyclopropylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate (300 mg, 573 μmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (65.4 mg, 573 μmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-[4-chloro-3-(cyclopropylmethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (307 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 423.3. Step 6. 1-((1S,4S)-5-(4-((4-Chloro-3-(cyclopropylmethoxy)phenyl)amin o)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a mixture of N-[4-chloro-3-(cyclopropylmethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (307 mg, 571 μmol, trifluoroacetic acid) and sodium bicarbonate (240 mg, 2.86 mmol) in tetrahydrofuran (3.0 mL) and water (3.0 mL) was added prop-2-enoyl chloride (51.7 mg, 571 μmol, 46.6 μL) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The crude product was purified by Prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 45% - 75%, 11 min) to give 1-[(1S,4S)-5-[4-[4-chloro-3-(cyclopropylmethoxy)anilino]pyri do[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (120 mg, 252 μmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 - 9.15 (m, 1H), 8.52 - 8.36 (m, 1H), 7.97 - 7.79 (m, 2H), 7.74 - 7.63 (m, 1H), 7.43 – 7.08 (m, 2H), 6.85 – 6.37 (m, 1H), 6.23 - 6.09 (m, 1H), 5.72 - 5.62 (m, 1H), 5.10 - 4.92 (m, 1H), 3.96 (d, J = 6.8 Hz, 2H), 3.82 - 3.63 (m, 2H), 3.59 - 3.52 (m, 1H), 3.44 - 3.34 (m, 2H), 2.11 - 1.98 (m, 2H), 1.37 - 1.23 (m, 1H), 0.68 - 0.55 (m, 2H), 0.46 - 0.35 (m, 2H); m/z ES+ [M+H] ⁺ 477.3. Example 37. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2- en-1-one (Compound 433)

Step 1. 6-Chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)p yrido[3,2- d]pyrimidin-4-amine To a solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fl uoro- phenol (1.6 g, 4.92 mmol) in acetonitrile (15 mL) was added potassium carbonate (2.04 g, 14.76 mmol). Then bromomethylcyclopropane (2.66 g, 19.6 mmol) was added into the mixture. The mixture was stirred at 80 °C for 4 hr. On completion, the reaction mixture was filtered. The filter cake was concentrated in vacuo to give a residue. The residue was poured into water (100 mL) and extracted with ethyl acetate (200 mL). The organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (940 mg, 2.48 mmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.56 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.51 (t, J = 8.8 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 4.00 (d, J = 6.8 Hz, 2H), 1.35 - 1.25 (m, 1H), 0.63 - 0.61 (m, 2H), 0.40 - 0.38 (m, 2H); m/z ES+ [M+H] ⁺ 379.2. Step 2. tert-Butyl 5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (180 mg, 474 μmol) in N-methylpyrrolidone (1.5 mL) was added N,N-diisopropylethylamine (184 mg, 1.42 mmol). And then tert-butyl 2,5- diazabicyclo[2.2.2]octane-2-carboxylate (151 mg, 712 μmol) was added into the mixture. The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was poured into water (6.0 mL) and then filtered. The filter cake was washed with water (1.0 mL) and dried in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 1/1) to give tert-butyl 5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (250 mg, 0.45 mmol, 93%) as a yellow solid. m/z ES+ [M+H] ⁺ 555.3. Step 3. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate & (1R,4R)-tert-butyl 5-(4-((3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e The compound tert-butyl 5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate (250 mg, 0.45 mmol) was purified by SFC (column: DAICEL CHIRALPAK IG (250mm x 30mm, 10um); mobile phase: [0.1% NH3 water Ethanol]; B%: 70% - 70%, 6; 50min) to give (1S,4S)-tert- butyl 5-(4-((3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)amino) pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (90 mg, 162 μmol, 36%) and (1R,4R)-tert-butyl5- (4-((3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)amino)py rido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (110 mg, 198 μmol, 44%) as yellow solids. m/z ES+ [M+H] ⁺ 555.1. m/z ES+ [M+H] ⁺ 555.1. Step 4. 6-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (cyclopropylmethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (60 mg, 108 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.2] octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (45 mg, 98.9 μmol, 89%) as a yellow oil. m/z ES+ [M+H] ⁺ 455.2. Step 5. 1-((1S,4S)-5-(4-((3-Chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2-en- 1-one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (45.0 mg, 98.9 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (24.9 mg, 296 μmol). Then prop-2-enoyl chloride (9.9 mg, 108 μmol) was added into the mixture. The mixture was stirred at 0 °C for 10 minutes. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition: column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 40% - 70%, 10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octan-2-yl]prop-2-en-1-one (29.4 mg, 57.8 μmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 - 9.14 (m, 1H), 8.28 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.81 - 7.59 (m, 1H), 7.40 - 7.13 (m, 1H), 7.06 (d, J = 9.2 Hz, 1H), 6.94 - 6.50 (m, 1H), 6.28 - 6.05 (m, 1H), 5.85 - 5.60 (m, 1H), 4.81 - 4.60 (m, 1H), 3.99 (d, J = 7.2 Hz, 2H), 3.90 - 3.79 (m, 2H), 3.78 - 3.68 (m, 2H), 3.62 (s, 1H), 2.01 - 1.90 (m, 4H), 1.33 - 1.26 (m, 1H), 0.63 - 0.60 (m, 2H), 0.40 - 0.38 (m, 2H); m/z ES+ [M+H] ⁺ 509.3. Example 38. Preparation of 1-((1R,4R)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2- en-1-one (Compound 432) Step 1. 6-((1R,4R)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (cyclopropylmethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl (1R,4R)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (80.0 mg, 144 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 30 minutes. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1R,4 R)-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (60 mg, 132 μmol, 86%) as a yellow oil. m/z ES+ [M+H] ⁺ 455.2. Step 2. 1-((1R,4R)-5-(4-((3-Chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2-en- 1-one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1R,4 R)-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, 131 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (33.2 mg, 395 μmol). Then prop-2-enoyl chloride (13.1 mg, 145 μmol) was added into the mixture. The mixture was stirred at 0 °C for 10 minutes. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition: column: Phenomenex Gemini 150 x 25mm, 10 um; mobile phase: [water (0.05% NH ₃ water) - acetonitrile]; B%: 40% - 70%, 10 min) to give 1-[(1R,4R)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octan-2-yl]prop-2-en-1-one (26.6 mg, 52.2 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 - 9.22 (m, 1H), 8.33 - 8.23 (m, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.71 (s, 1H), 7.42 - 7.12 (m, 1H), 7.06 (d, J = 9.2 Hz, 1H), 6.93 - 6.56 (m, 1H), 6.23 - 6.17 (m, 1H), 5.75 - 5.68 (m, 1H), 4.81 - 4.60 (m, 1H), 4.00 (d, J = 6.8 Hz, 2H), 3.95 - 3.79 (m, 2H), 3.78 - 3.66 (m, 2H), 3.62 (s, 1H), 2.01 - 1.91 (m, 4H), 1.32 - 1.26 (m, 1H), 0.64 - 0.60 (m, 2H), 0.40 - 0.38 (m, 2H); m/z ES+ [M+H] ⁺ 509.3. Example 39. Preparation of 1-((1S,4S)-5-(4-((4-chloro-2-fluoro-5- methoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 408)

Step 1.1-Chloro-5-fluoro-2-methoxy-4-nitrobenzene To a solution of 2-chloro-4-fluoro-5-nitro-phenol (1.00 g, 5.22 mmol) in acetone (20.0 mL) was added potassium carbonate (3.61 g, 26.1 mmol) and methyl iodide (3.71 g, 26.1 mmol). The mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was quenched with cold saturated aqueous ammonium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-chloro-5-fluoro-2-methoxy-4-nitro- benzene (1.10 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.10 (d, J = 3.2 Hz, 1H), 6.53 (s, 1H), 5.30 (s, 2H), 3.73 (s, 3H). Step 2. 4-Chloro-2-fluoro-5-methoxyaniline To a solution of 1-chloro-5-fluoro-2-methoxy-4-nitro-benzene (800 mg, 3.89 mmol) in methanol (8 mL) and water (8 mL) was added iron powder (869 mg, 15.5 mmol) and ammonium chloride (2.08 g, 38.9 mmol). The mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was filtered. The filtrate was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2-fluoro-5-methoxy-aniline (500 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 176.1. Step 3. 6-Chloro-N-(4-chloro-2-fluoro-5-methoxyphenyl)pyrido[3,2-d]p yrimidin-4- amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (273 mg, 1.37 mmol) and 4-chloro-2- fluoro-5-methoxy-aniline (300 mg, 1.71 mmol) in acetonitrile (5.0 mL) was stirred at 80 °C for 2 hr. On completion, the mixture was poured into acetonitrile (3 mL) and filtered. The filter cake was washed with acetonitrile (2 mL × 3), dried in vacuum to give 6-chloro-N-(4-chloro-2-fluoro- 5-methoxy-phenyl)pyrido[3,2-d]pyrimidin-4-amine (450 mg, 70%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 6.8 Hz, 1H), 3.85 (s, 3H). Step 4. (1S,4S)-tert-Butyl 5-(4-((4-chloro-2-fluoro-5-methoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 6-chloro-N-(4-chloro-2-fluoro-5-methoxy-phenyl)pyrido[3,2- d]pyrimidin-4-amine (400 mg, 1.18 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (280 mg, 1.42 mmol) in N-methylpyrrolidone (5.0 mL) was added N,N- diisopropylethylamine (457 mg, 3.54 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the solution was purified by reversed-phase HPLC (0.1% FA conditions) to give tert- butyl (1S,4S)-5-[4-(4-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2 -d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (260 mg, 519 μmol, 40%) as a yellow solid. m/z ES+ [M+H] ⁺ 501.2. Step 5. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-chloro-2 -fluoro-5- methoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-(4-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (120 mg, 239 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (369 mg, 3.24 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(4-chloro-2-fluoro-5-methoxy-phenyl)-6-[(1S,4S)-2,5-diazab icyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (96 mg, 239 μmol, 89%) as a s yellow oil. m/z ES+ [M+H] ⁺ 401.1. Step 6. 1-((1S,4S)-5-(4-((4-chloro-2-fluoro-5-methoxyphenyl)amino)py rido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-(4-chloro-2-fluoro-5-methoxy-phenyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (95.0 mg, 237 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (19.9 mg, 237 μmol) at 0 °C. Then prop-2-enoyl chloride (17.1 mg, 189 μmol) in tetrahydrofuran (0.2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 22%-52%, 10 min) to give 1-[(1S,4S)-5-[4-(4-chloro-2-fluoro-5-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one (38.5 mg, 84.6 μmol, 33%) as a s yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) = δ 9.33 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.22 - 8.20 (m, 1H), 7.99 (dd, J = 3.2, 9.2 Hz, 1H), 7.62 (d, J = 10.0 Hz, 1H), 7.53 - 7.22 (m, 1H), 6.95 - 6.41 (m, 1H), 6.24 - 6.22 (m, 1H), 5.81 - 5.64 (m, 1H), 5.43 - 5.18 (m, 1H), 5.16 - 4.97 (m, 1H), 3.95 (s, 3H), 3.85 - 3.70 (m, 2H), 3.69 - 3.56 (m, 2H), 3.49 (d, J = 10.8 Hz, 1H), 2.20 - 2.02 (m, 2H); m/z ES+ [M+H] ⁺ 455.4. Example 40. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(2,2,2- trifluoroethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2, 5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one (Compound 429) Step 1. 6-Chloro-N-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)pyrido[ 3,2-d]pyrimidin-4- amine To a solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]pheno l (150 mg, 488 μmol) in N,N-dimethylformamide (1.00 mL) was added potassium carbonate (202 mg, 1.47 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (136 mg, 586 μmol). The mixture was stirred at 80 °C for 1 hr. On completion, the mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 2:1) to give 6-chloro-N-[3-chloro-4-(2,2,2- trifluoroethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (160 mg, 411 μmol, 83%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 8.69 (s, 1H), 8.33 - 8.16 (m, 2H), 8.03 - 7.85 (m, 2H), 7.32 (d, J = 9.2 Hz, 1H), 4.90- 4.84 (m, 2H); m/z ES+ [M+H] ⁺ 388.9. Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(2,2,2- trifluoroethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-[3-chloro-4-(2,2,2-trifluoroethoxy)phenyl]pyrido[ 3,2- d]pyrimidin-4-amine (130 mg, 334 μmol) in N-methylpyrrolidone (1.00 mL) was added N,N- diisopropylethylamine (130 mg, 1.00 mmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (86.1 mg, 434 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the reaction was added water (3 mL) and filtered. The filter cake was concentrated to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(2,2,2- trifluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (170 mg, 309 μmol, 80%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.41 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.02 - 7.82 (m, 2H), 7.32 - 7.15 (m, 2H), 4.94 - 4.77 (m, 2H), 4.55 (d, J = 14.4 Hz, 1H), 3.66 - 3.62 (m, 1H), 3.44 (t, J = 10.8 Hz, 1H), 3.31 - 3.25 (m, 2H), 2.24 - 2.11 (m, 1H), 1.99 - 1.88 (m, 2H), 1.47 - 1.28 (m, 9H); m/z ES+ [M+H] ⁺ 551.2. Step 3.6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -4-(2,2,2- trifluoroethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(2,2,2- trifluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (170 mg, 309 μmol) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-4-(2,2,2-trifluoroethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (139 mg, 308 μmol, 90%) as a red oil. m/z ES+ [M+H] ⁺ 451.1. Step 4.1-((1S,4S)-5-(4-((3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl )amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[3-chloro-4-(2,2,2-trifluoroethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (139 mg, 308 μmol) in tetrahydrofuran (0.30 mL) and water (0.30 mL) was added sodium bicarbonate (77.7 mg, 925 μmol) at 0 °C. Then prop-2-enoyl chloride (25.1 mg, 278 μmol) in tetrahydrofuran (0.3 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 5 minutes. On completion, the solution was concentrated to give a residue. The residue was purified by Prep- HPLC (column: Phenomenex luna C18150 x 25mm x 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 22% - 52%, 10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(2,2,2- trifluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-dia zabicyclo [2.2.1]heptan-2-yl]prop-2- en-1-one (92.2 mg, 183 μmol, 59%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 - 9.27 (m, 1H), 8.41 (s, 1H), 8.22 (dd, J = 2.8, 5.6 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.90 - 7.89 (m, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.31 - 7.10 (m, 1H), 6.86 - 6.37 (m, 1H), 6.17 - 6.12 (m, 1H), 5.72 - 5.62 (m, 1H), 5.08 - 4.93 (m, 1H), 4.86 (q, J = 8.8 Hz, 2H), 3.79 - 3.65 (m, 2H), 3.62 - 3.48 (m, 2H), 3.46 - 3.38 (m, 1H), 2.09 - 1.99 (m, 2H); m/z ES+ [M+H] ⁺ 505.2. Example 41. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 403) Step 1. (R)-3-Chloro-4-((tetrahydrofuran-3-yl)methoxy)aniline & (S)-3-Chloro-4- ((tetrahydrofuran-3-yl)methoxy)aniline 3-Chloro-4-(tetrahydrofuran-3-ylmethoxy)aniline (800 mg, 3.51 mmol) was separated by SFC (column: DAICEL CHIRALCEL OJ (250mmx30mm,10um); mobile phase: [0.1% NH ₃ H ₂ O IPA]; B%: 25%-25%, 2.8. 70 min) to give 3-chloro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]aniline (300 mg, 1.32 mmol, 37%, 100% ee) as a yellow oil and 3-chloro-4-[[(3S)- tetrahydrofuran-3-yl]methoxy]aniline (300 mg, 1.32 mmol, 37%, 95% ee) as a yellow oil. Step 2. (R)-6-Chloro-N-(3-chloro-4-((tetrahydrofuran-3-yl)methoxy)ph enyl)pyrido[3,2- d]pyrimidin-4-amine To a solution of 3-chloro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]aniline (300 mg, 1.32 mmol) in acetonitrile (5.0 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (289 mg, 1.45 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated under reduced pressure to give (R)-6-chloro-N-(3-chloro-4- ((tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin -4-amine (500 mg, 1.28 mmol, 93%) as a yellow solid. m/z ES+ [M+H] ⁺ 391.0. Step 3. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (500 mg, 1.28 mmol) and tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (253 mg, 1.28 mmol) in N-methylpyrrolidone (5.0 mL) was added N,N-diisopropylethylamine (495 mg, 3.83 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was concentrated under reduced pressure to give (1S,4S)-tert-butyl5-(4-((3-chloro-4- (((R)-tetrahydrofuran-3-yl)methoxy)phenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (700 mg, 1.28 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 553.6. Step 4. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(((R)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (600 mg, 1.08 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (400 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 453.4. Step 5. 1-((1S,4S)-5-(4-((3-Chloro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of N-[3-chloro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]-6- [(1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- amine (300 mg, 662 μmol) in tetrahydrofuran (4.00 mL) and water (2 mL) was added sodium bicarbonate (166 mg, 1.99 mmol) at 0 °C. Then prop-2-enoyl chloride (59.9 mg, 662 μmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm, 10um; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 28% - 58%, 10 min) to give 1-((1S,4S)-5-(4-((3-chloro-4-(((R)-tetrahydrofuran-3-yl)meth oxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (200 mg, 394 μmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 - 9.10 (m, 1H), 8.39 (s, 1H), 8.15 (dd, J = 2.4, 5.6 Hz, 1H), 7.89 (dd, J = 2.8, 9.6 Hz, 2H), 7.21 (d, J = 9.6 Hz, 2H), 6.87 - 6.36 (m, 1H), 6.18 - 6.15 (m, 1H), 5.73 - 5.61 (m, 1H), 5.09 - 4.91 (m, 1H), 4.07 - 3.93 (m, 2H), 3.84 - 3.66 (m, 5H), 3.61 - 3.52 (m, 4H), 2.71 - 2.66 (m, 1H), 2.15 - 1.95 (m, 3H), 1.79 - 1.61 (m, 1H); m/z ES+ [M+H] ⁺ 507.4. Example 42. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 404) Step 1. (S)-6-Chloro-N-(3-chloro-4-((tetrahydrofuran-3-yl)methoxy)ph enyl)pyrido[3,2- d]pyrimidin-4-amine To a solution of 3-chloro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]aniline (300 mg, 1.32 mmol) in acetonitrile (5.0 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (289 mg, 1.45 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated under reduced pressure to give (S)-6-chloro-N-(3-chloro-4- ((tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin -4-amine (500 mg, 1.28 mmol, 93%) as a yellow solid. m/z ES+ [M+H] ⁺ 391.1. Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of (S)-6-chloro-N-(3-chloro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (500 mg, 1.28 mmol) and tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (253 mg, 1.28 mmol) in N-methylpyrrolidone (5.0 mL) was added N,N-diisopropylethylamine (495 mg, 3.83 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give (1S,4S)-tert-butyl 5-(4-((3-chloro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (700 mg, 1.27 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 553.6. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(((S)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of (1S,4S)-tert-butyl 5-(4-((3-chloro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (600 mg, 1.08 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(((S)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine (400 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 453.4. Step 4. 1-((1S,4S)-5-(4-((3-Chloro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(((S)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine (300 mg, 662 μmol) in tetrahydrofuran (4.00 mL) and water (4 mL) was added sodium bicarbonate (166 mg, 1.99 mmol) at 0 °C. Then prop-2-enoyl chloride (59.9 mg, 662 μmol) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was purified by Prep-HPLC (column: Phenomenex Gemini 150 x 25mm, 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 28%-58%, 10 min) to give 1-((1S,4S)-5-(4-((3-chloro-4-(((S)-tetrahydrofuran- 3-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-d iazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (200 mg, 394 μmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 - 9.10 (m, 1H), 8.39 (s, 1H), 8.15 - 8.13 (m, 1H), 7.90 - 7.87 (m, 2H), 7.21 (d, J = 9.6 Hz, 2H), 6.87 - 6.36 (m, 1H), 6.17 - 6.11(m, 1H), 5.73 - 5.61 (m, 1H), 5.09 - 4.91 (m, 1H), 4.07 - 3.93 (m, 2H), 3.84 - 3.66 (m, 5H), 3.60 - 3.51 (m, 4H), 2.70 - 2.66(m, 1H), 2.15 - 1.95 (m, 3H), 1.79 - 1.61 (m, 1H); m/z ES+ [M+H]+ 507.4. Example 43. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(oxetan-3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaz abicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 338) Step 1. 6-Chloro-N-(3-chloro-4-(oxetan-3-ylmethoxy)phenyl)pyrido[3,2 -d]pyrimidin-4- amine To a solution of 3-chloro-4-(oxetan-3-ylmethoxy)aniline (430 mg, 2.01 mmol) in acetonitrile (10 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (442 mg, 2.21 mmol). The mixture was stirred at 20 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated to give 6-chloro-N-[3-chloro-4-(oxetan-3-ylmethoxy)phenyl]pyrido[3,2 - d]pyrimidin-4-amine (0.65 g, 1.72 mmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.82 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.10 - 8.04 (m, 2H), 7.82 (dd, J = 2.8, 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 4.75 - 4.72 (m, 2H), 4.50 - 4.46 (m, 2H), 4.34 - 4.32 (m, 2H), 3.46 - 3.43 (m, 1H); m/z ES+ [M+H] ⁺ 377.1. Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(oxetan-3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaz abicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-[3-chloro-4-(oxetan-3-ylmethoxy)phenyl]pyrido[3,2 - d]pyrimidin-4-amine (600 mg, 1.59 mmol) in N-methylpyrrolidone (12 mL) was added N,N- diisopropylethylamine (616 mg, 4.77 mmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (630 mg, 3.18 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the solution was added water (2 mL) and filtered. The filter cake was concentrated and the residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(oxetan-3-ylmethoxy)anilino]pyrido[ 3,2-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (270 mg, 501 μmol, 27%) as a yellow solid. m/z ES+ [M+H] ⁺ 539.5. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(oxetan-3- ylmethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (200 mg, 371 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 20 °C for 20 minutes. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (150 mg, 342 μmol, 92%) as a brown oil. m/z ES+ [M+H] ⁺ 439.0. Step 4. 1-((1S,4S)-5-(4-((3-Chloro-4-(oxetan-3-ylmethoxy)phenyl)amin o)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[3-chloro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(1S,4S)-2,5-dia zabicyclo [2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (150 mg, 341 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (28.7 mg, 341 μmol) to adjust pH = 8. Then prop-2-enoyl chloride (24.7 mg, 273 μmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 15 minutes. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition. column: Phenomenex luna C18150 x 25mm,10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 12%-42%, 10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(oxetan-3-ylmethoxy)anilino]pyri do[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (20.9 mg, 42.4 μmol, 12%) as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 - 9.31 (m, 1H), 8.40 (s, 1H), 8.17 - 8.15 (m, 1H), 7.94 - 7.89 (m, 2H), 7.25 (d, J = 9.2 Hz, 2H), 6.93 - 6.31 (m, 1H), 6.18 - 6.13 (m, 1H), 5.78 - 5.56 (m, 1H), 5.08 - 4.95 (m, 1H), 4.73 (dd, J = 6.0, 8.0 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 4.30 (d, J = 6.8 Hz, 2H), 3.88 - 3.63 (m, 2H), 3.60 - 3.52 (m, 1H), 3.50 - 3.38 (m, 2H), 2.10 - 1.99 (m, 2H); m/z ES+ [M+H] ⁺ 493.3. Example 44. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 368) Step 1. 6-Chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)p yrido[3,2- d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (180 mg, 901 μmol) in acetonitrile (2.5 mL) was added 3-chloro-4-(cyclopropylmethoxy)-2-fluoro-aniline (216 mg, 1.00 mmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered. The filter cake was concentrated to give 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4 -amine (310 mg, 818 μmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 8.76 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 4.03 - 4.01 (m, 2H), 1.32 - 1.28 (m, 1H), 0.65 - 0.60 (m, 2H), 0.40 - 0.39 (m, 2H); m/z ES+ [M+H] ⁺ 379.1. Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (90 mg, 237 μmol) in N-methylpyrrolidone (1 mL) was added diisopropylethylamine (92.0 mg, 712 μmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (94.1 mg, 474 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was added water (4 mL) and filtered. The filter cake was concentrated to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (100 mg, 185 μmol, 58%) as a brown solid. m/z ES+ [M+H] ⁺ 541.2. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino] pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (80 mg, 147 μmol) in dichloromethane (0.42 mL) was added trifluoroacetic acid (985 mg, 8.64 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, The reaction mixture was concentrated in vacuo to give N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrid o[3,2-d]pyrimidin-4-amine (80.0 mg, crude, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 441.2. Step 4. 1-((1S,4S)-5-(4-((3-Chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrid o[3,2-d]pyrimidin-4-amine (80 mg, 181 μmol, trifluoroacetic acid salt) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (45.7 mg, 544 μmol) to adjust pH = 8. Then prop-2-enoyl chloride (4.93 mg, 54.4 μmol) was added to the mixture solution at 0 °C. The mixture was stirred at 0 °C for 15 minutes. On completion, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition. column: Waters xbridge 150 x 25mm, 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 35% - 65%, 11min) to give 1-[(1S,4S)-5-[4-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin -6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (23.0 mg, 46.5 μmol, 23%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 - 9.19 (m, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.92 - 7.89 (m, 1H), 7.84 - 7.72 (m, 1H), 7.43 - 7.13 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.81 - 6.43 (s, 1H), 6.18 - 6.13 (m, 1H), 5.78 - 5.60 (m, 1H), 5.49 - 5.20 (m, 1H), 5.13 - 4.88 (m, 1H), 3.99 (d, J = 6.8 Hz, 2H), 3.81 - 3.38 (m, 4H), 2.16 - 1.93 (m, 2H), 1.35 - 1.22 (m, 1H), 0.68 - 0.55 (m, 2H), 0.45 - 0.33 (m, 2H); m/z ES+ [M+H] ⁺ 495.2. Example 45. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(2,2- difluoroethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 434) Step 1. 6-Chloro-N-(3-chloro-4-(2,2-difluoroethoxy)phenyl)pyrido[3,2 -d]pyrimidin-4- amine A solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]pheno l (150 mg, 488 μmol), 2,2-difluoroethyl trifluoromethanesulfonate (150 mg, 700 μmol) and potassium carbonate (250 mg, 1.81 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether:Ethyl acetate = 1:1) to give 6-chloro-N-[3-chloro-4- (2,2-difluoroethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (95 mg, 256 μmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 8.68 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 2.4, 8.8 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 6.43 (dt, J = 3.6, 54.4 Hz, 1H), 4.46 - 4.38 (m, 2H); m/z ES+ [M+H] ⁺ 371.1. Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-(2,2- difluoroethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate A solution of 6-chloro-N-[3-chloro-4-(2,2-difluoroethoxy)phenyl]pyrido[3,2 - d]pyrimidin-4-amine (85.0 mg, 229 μmol), tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (50.0 mg, 252 μmol) and N,N-diisopropylethylamine (88.8 mg, 687 μmol) in N- methylpyrrolidone (1.00 mL) was stirred at 80 °C for 12 hr. On completion, the reaction mixture was concentrated to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(2,2- difluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diaz abicyclo[2.2.1]heptane-2- carboxylate (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 533.2. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(2,2- difluoroethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(2,2-difluoroethoxy)anilino]pyrido[ 3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (100 mg, 187 μmol) in trifluoroacetic acid (1.71 g, 15.0 mmol, 1.11 mL) and dichloromethane (2.0 mL) was stirred at 20 °C for 1 hr. On completion, the reaction mixture was concentrated to give N-[3-chloro-4-(2,2- difluoroethoxy)phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]hep tan-2-yl]pyrido[3,2-d]pyrimidin -4- amine (80.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 433.2. Step 4. 1-((1S,4S)-5-(4-((3-Dhloro-4-(2,2-difluoroethoxy)phenyl)amin o)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[3-chloro-4-(2,2-difluoroethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (80.0 mg, 184 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (54.3 mg, 646 μmol, 25.1 μL) at 0 °C until pH = 8. Then prop-2-enoyl chloride (18.0 mg, 198 μmol, 16.2 μL) was added to the mixture solution at 0 °C. The mixture was stirred at 0 °C for 0.25 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The reaction was purified by Prep-HPLC (column: Phenomenex luna C18150 x 25mm,10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 18%-48%, 10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(2,2- difluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diaz abicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (23.1 mg, 47.4 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.40 (s, 1H), 8.18 (dd, J = 2.4, 5.2 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.28 (d, J = 9.2 Hz, 2H), 6.86 - 6.28 (m, 2H), 6.18 - 6.12 (m, 1H), 5.72 - 5.62 (m, 1H), 5.01 (d, J = 53.6 Hz, 1H), 4.45 - 4.37 (m, 2H), 3.79 - 3.63 (m, 2H), 3.62 - 3.34 (m, 3H), 2.09 - 1.98 (m, 2H); m/z ES+ [M+H] ⁺ 487.2. Example 46. Preparation of 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 424) Step 1.2-Chloro-5-fluoro-4-nitrophenol To a solution of 2-chloro-5-fluoro-phenol (15.0 g, 102.3 mmol) in dichloromethane (200 mL) was added nitric acid (10.5 g, 117 mmol, 7.50 mL, 70%) at 0 °C. The mixture was stirred at 25 °C for 0.25 hours. On completion, the mixture was quenched with water (200 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was purified by reversed- phase HPLC (0.1% FA condition) and further purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5:1 to 2:1) to give 2-chloro-5-fluoro-4-nitro-phenol (5.81 g, 30.4 mmol, 29%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 11.6 Hz, 1H), 6.34 (s, 1H). Step 2. 3-((2-Chloro-5-fluoro-4-nitrophenoxy)methyl)tetrahydrofuran To a solution of 2-chloro-5-fluoro-4-nitro-phenol (500 mg, 2.61 mmol) and tetrahydrofuran-3-ylmethanol (400 mg, 3.92 mmol, 377 uL) in tetrahydrofuran (9.00 mL) was added triphenylphosphine (822 mg, 3.13 mmol) and diisopropyl (E)-diazene-1,2-dicarboxylate (581 mg, 2.87 mmol, 558 uL) under nitrogen gas atmosphere. The mixture was stirred at 60 °C for 2 hours. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5:1 to 1:1) to give 3-[(2-chloro- 5-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran (1.13 g, crude) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 13.6 Hz, 1H), 4.18 (dd, J = 7.2, 13.6 Hz, 2H), 3.81 - 3.76 (m, 2H), 3.71 - 3.66 (m, 1H), 3.55 (dd, J = 5.2, 8.8 Hz, 1H), 2.74 - 2.70 (m, 1H), 2.07 - 2.01 (m, 1H), 1.71 - 1.67 (m, 1H). Step 3. 5-Chloro-2-fluoro-4-((tetrahydrofuran-3-yl)methoxy)aniline To a solution of 3-[(2-chloro-5-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran (1.13 g, 4.10 mmol) in methanol (6.00 mL) and water (6.00 mL) was added iron powder (916 mg, 16.4 mmol) and ammonium chloride (2.19 g, 41.0 mmol). The mixture was stirred at 80 °C for 1 hour. On completion, the mixture was filtered. The filtrate was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 5- chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline (1.00 g, 3.70 mmol, 90%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 - 8.68 (m, 1H), 7.13 - 6.70 (m, 1H), 5.00 - 4.71 (m, 2H), 3.88 - 3.67 (m, 2H), 2.07 - 1.92 (m, 1H), 1.80 - 1.45 (m, 2H), 1.21 - 1.14 (m, 4H); m/z ES+ [M+H] ⁺ 246.1. Step 4. 6-Chloro-N-(5-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine A solution of 5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline (200 mg, 814 μmol) and 4,6-dichloropyrido[3,2-d]pyrimidine (148 mg, 740 μmol) in acetonitrile (3.0 mL) was stirred at 40 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated to give 6-chloro-N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (170 mg, 41.6 μmol, 51%) as a yellow solid. m/z ES+ [M+H] ⁺ 408.9. Step 5. (1S,4S)-tert-Butyl 5-(4-((5-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (170 mg, 415 μmol) and tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (107 mg, 540 μmol) in N-methylpyrrolidone (2.0 mL) was added N,N-diisopropylethylamine (161 mg, 1.25 mmol). The mixture was stirred at 100 °C for 14 hr. On completion, the mixture was added water (10 mL) and filtered. The filter cake was concentrated to give tert-butyl (1S,4S)-5-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (220 mg, 385 μmol, 79%) as a yellow solid. m/z ES+ [M+H] ⁺ 571.3. Step 6. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-2 -fluoro-4- ((tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin -4-amine To a solution of tert-butyl (1S,4S)-5-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (190 mg, 333 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol, 2.0 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6-[(1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- amine (150 mg, 318 μmol, 88%) as a brown oil. m/z ES+ [M+H] ⁺ 471.2. Step 7. 1-((1S,4S)-5-(4-((5-Chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (150 mg, 318 μmol) in tetrahydrofuran (0.75 mL) and water (0.75 mL) was added sodium bicarbonate (26.8 mg, 318 μmol, 12.4 μL) at 0 °C until pH stabilized at 8. Then prop-2-enoyl chloride (28.8 mg, 318 μmol, 26.0 μL) was added to the mixture solution at 0 °C. The mixture was stirred at 0 °C for 0.25 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150 x 25mm x 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 20%-50%, 10 min) to give 1-[(1S,4S)-5-[4-[5-chloro-2-fluoro-4- (tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (70.1 mg, 134 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 - 9.10 (m, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 7.91 (dd, J = 3.2, 9.2 Hz, 1H), 7.31 (d, J = 12.4 Hz, 2H), 6.85 - 6.37 (m, 1H), 6.17 - 6.11 (m, 1H), 5.73 - 5.60 (m, 1H), 5.48 - 5.14 (m, 1H), 5.08 - 4.92 (m, 1H), 4.10 - 3.99 (m, 2H), 3.84 - 3.77 (m, 2H), 3.76 - 3.65 (m, 3H), 3.59 - 3.50 (m, 3H), 2.75 - 2.68 (m, 1H), 2.09 - 1.99 (m, 3H), 1.74 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 525.3. Example 47. Preparation of 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 319) Step 1. 6-Chloro-N-(3-chloro-4-((tetrahydrofuran-3-yl)methoxy)phenyl )pyrido[3,2- d]pyrimidin-4-amine To a solution of 3-chloro-4-(tetrahydrofuran-3-ylmethoxy)aniline (204 mg, 899 μmol) in acetonitrile (5.0 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 749 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated to give 6-chloro-N-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (300 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.85 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.15 - 8.04 (m, 2H), 7.78 (dd, J = 2.8, 8.8 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H), 4.13 - 3.97 (m, 2H), 3.85 - 3.75 (m, 2H), 3.72 - 3.64 (m, 1H), 3.58 (dd, J = 5.6, 8.4 Hz, 1H), 2.77 - 2.62 (m, 1H), 2.06 - 1.99 (m, 1H), 1.77 - 1.64 (m, 1H). Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (100 mg, 255 μmol) and tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (55.7 mg, 281 μmol) in N-methylpyrrolidone (3.0 mL) was added N,N-diisopropylethylamine (66.0 mg, 511 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (1S,4S)-5-[4-[3-chloro-4- (tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.70 (s, 2H), 8.48 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.65 - 7.59 (m, 2H), 6.95 - 6.86 (m, 2H), 3.97 - 3.81 (m, 6H), 3.78 - 3.65 (m, 3H), 1.76 - 1.67 (m, 6H), 1.44 - 1.34 (m, 9H). Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -((tetrahydrofuran- 3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy) anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (60.0 mg, 108 μmol) in dichloromethane (0.5 mL) was added hydrochloric acid/dioxane (4 M, 0.3 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N- [3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-[(1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (40 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 453.2. Step 4. 1-((1S,4S)-5-(4-((3-Chloro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-[(1S,4S )-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (40.0 mg, 88.3 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (22.2 mg, 264 μmol). Then prop-2-enoyl chloride (7.99 mg, 88.3 μmol) was added at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1] heptan-2-yl]prop-2-en- 1-one (15 mg, 29.6 μmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.39 (s, 1H), 8.15 (dd, J = 2.8, 5.2 Hz, 1H), 7.89 (dd, J = 2.8, 9.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 6.91 - 6.33 (m, 1H), 6.18 - 6.12 (m, 1H), 5.73 - 5.58 (m, 1H), 5.14 - 4.89 (m, 1H), 4.09 - 3.92 (m, 2H), 3.85 - 3.75 (m, 3H), 3.72 - 3.64 (m, 2H), 3.62 - 3.54 (m, 2H), 3.53 - 3.33 (m, 2H), 2.78 - 2.63 (m, 1H), 2.13 - 1.96 (m, 3H), 1.77 - 1.62 (m, 1H); m/z ES+ [M+H] ⁺ 507.2. Example 48. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 339) Step 1. (1S,4S)-tert-Butyl 5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg, 469 μmol) in acetonitrile (3.0 mL) was added 3-chloro-2-fluoro-aniline (75.2 mg, 516. μmol). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated to give tert-butyl (1S,4S)- 5-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (200 mg, 425 μmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 471.1. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 - fluorophenyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (110 mg, 233 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N-(3-chloro-2- fluoro-phenyl)-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl ]pyrido[3,4-d]pyrimidin-4-amine (86.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 371.1. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,4-d ]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(1S,4S)-2,5-diazabicyclo[2.2 .1]heptan- 2-yl]pyrido[3,4-d]pyrimidin-4-amine (86.0 mg, 231 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (58.4 mg, 695 μmol). Then prop-2-enoyl chloride (20.9 mg, 231 μmol) was added at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase:[water (0.225% FA) - acetonitrile]; B%: 26% - 56%, 11.5 min) to give 1-[(1S,4S)-5-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyri midin- 6-yl]-2,5-diazabicyclo[2.2.1]heptn-2-yl]prop-2-en-1-one (50.0 mg, 118 μmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.85 (s, 1H), 8.31 (s, 1H), 7.60 - 7.48 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 3.6 Hz, 1H), 6.87 - 6.36 (m, 1H), 6.18 - 6.09 (m, 1H), 5.72 - 5.60 (m, 1H), 5.05 (d, J = 13.2 Hz, 1H), 4.93 (s, 1H), 3.77 - 3.35 (m, 4H), 2.17 - 1.94 (m, 2H); m/z ES+ [M+H] ⁺ 425.2. Example 49. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 318) Step 1. (1S,4S)-tert-Butyl 5-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]pyri do[3,2- d]pyrimidin-4-amine (570 mg, 1.47 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (380 mg, 1.92 mmol) in N-methylpyrrolidone (10.0 mL) was added N,N- diisopropylethylamine (571 mg, 4.42 mmol). The mixture was stirred at 100 °C for 14 hr. On completion, the mixture was added water (30 mL) and filtered. The filter cake was concentrated to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-anilino]p yrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (740 mg, 1.35 mmol, 83%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.42 (s, 1H), 8.30 - 8.23 (m, 1H), 7.91 - 7.89 (m, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.30 - 7.15 (m, 2H), 5.78 (d, J = 2.0 Hz, 1H), 4.55 (d, J = 13.6 Hz, 1H), 3.72 (s, 3H), 2.69 (s, 2H), 2.20 - 2.15 (m, 1H), 2.02 - 1.86 (m, 4H), 1.42 - 1.34 (m, 9H); m/z ES+ [M+H] ⁺ 549.2. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -((1-methyl-1H- pyrazol-3-yl)oxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (740 mg, 1.35 mmol) in dichloromethane (8.00 mL) was added trifluoroacetic acid (12.3 g, 108 mmol, 8.00 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N- [3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-[(1S,4S)-2,5 -diazabicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (600 mg, crude, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 449.3. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-[(1S,4S)-2 ,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (600 mg, 1.34 mmol, trifluoroacetic acid salt) in tetrahydrofuran (4.00 mL) and water (4.00 mL) was added sodium bicarbonate (1.12 g, 13.4 mmol) at 0 °C. After that, prop-2-enoyl chloride (121 mg, 1.34 mmol) was added in one portion at 0 °C. The mixture was stirred at 0 °C for 0.25 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18250 x 50mm, 7um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 20% - 50%, 10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-anilin o]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (234 mg, 465 μmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.42 (s, 1H), 8.26 (t, J = 2.8 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.86 - 6.38 (m, 1H), 6.18 - 6.11 (m, 1H), 5.78 (d, J = 2.4 Hz, 1H), 5.72 - 5.62 (m, 1H), 5.08 - 4.93 (m, 1H), 3.78 - 3.65 (m, 6H), 3.62 - 3.49 (m, 2H), 3.41 (d, J = 11.2 Hz, 1H), 2.08 - 1.99 (m, 2H); m/z ES+ [M+H] ⁺ 503.5. Example 50. Preparation of 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-((1-methyl-1H-pyrazol- 3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 400) Step 1. 6-Chloro-N-(5-chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine A solution of 5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy-aniline (110 mg, 455 μmol) and 4,6-dichloropyrido[3,2-d]pyrimidine (91.0 mg, 455 μmol) in acetonitrile (3.0 mL) was stirred at 40 °C for 2 hr. On completion, the mixture was filtered and the filter cake was concentrated to give 6-chloro-N-[5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy-ph enyl]pyrido[3,2-d]pyrimidin- 4-amine (156 mg, 385 μmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.72 - 10.57 (m, 1H), 8.77 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 11.2 Hz, 1H), 5.97 (s, 1H), 3.75 (s, 3H); m/z ES+ [M+H] ⁺ 405.0. Step 2. (1S,4S)-tert-Butyl 5-(4-((5-chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloro-N-[5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy- phenyl]pyrido[3,2-d]pyrimidin-4-amine (126 mg, 311 μmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (80.1 mg, 404 μmol) in N-methylpyrrolidone (3.0 mL) was added N,N-diisopropylethylamine (120 mg, 933 μmol, 162 μL). The mixture was stirred at 100 °C for 14 hr. On completion, the mixture was added water (5 mL) and filtered. The filter cake was concentrated to give tert-butyl (1S,4S)-5-[4-[5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (290 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 - 9.22 (m, 1H), 8.40 (s, 1H), 8.37 - 8.28 (m, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 11.2 Hz, 2H), 5.90 (d, J = 2.4 Hz, 1H), 4.54 (d, J = 16.8 Hz, 1H), 3.74 (s, 3H), 3.65 (t, J = 8.0 Hz, 1H), 3.49 - 3.39 (m, 2H), 3.25 (m, 1H), 2.69 (s, 2H), 1.92 - 1.90 (m, 1H), 1.41 - 1.34 (m, 9H); m/z ES+ [M+H] ⁺ 567.4. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-2 -fluoro-4-((1- methyl-1H-pyrazol-3-yl)oxy)phenyl)pyrido[3,2-d]pyrimidin-4-a mine To a solution of tert-butyl (1S,4S)-5-[4-[5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (290 mg, 511 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N- [5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-[(1 S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (200 mg, 428 μmol, 75%) as a yellow oil. m/z ES+ [M+H] ⁺ 467.2. Step 4. 1-((1S,4S)-5-(4-((5-Chloro-2-fluoro-4-((1-methyl-1H-pyrazol- 3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-[ (1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- amine (200 mg, 428 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (0.36 g, 4.28 mmol) at 0 °C. After that, prop-2-enoyl chloride (38.8 mg, 428 μmol) was added in one portion. The mixture was stirred at 0 °C for 0.25 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 20% - 50%, 10 min) to give 1- [(1S,4S)-5-[4-[5-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy -anilino]pyrido[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo [2.2.1]heptan-2-yl]prop-2-en-1-one (43.7 mg, 83.9 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 - 9.17 (m, 1H), 8.43 - 8.29 (m, 2H), 7.93 (dd, J = 3.6, 9.2 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 11.2 Hz, 2H), 6.85 - 6.37 (m, 1H), 6.17 - 6.11 (m, 1H), 5.94 - 5.89 (m, 1H), 5.73 - 5.61 (m, 1H), 5.44 - 5.15 (m, 1H), 5.08 - 4.92 (m, 1H), 3.74 (s, 3H), 3.71 - 3.65 (m, 2H), 3.63 - 3.49 (m, 2H), 3.47 - 3.37 (m, 1H), 2.10 - 1.99 (m, 2H); m/z ES+ [M+H] ⁺ 521.5. Example 51. Preparation of 1-((1S,4S)-5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-e n-1-one (Compound 423) Step 1. tert-Butyl 5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 2,5-diazabicyclo[2.2.2]octane-2-carboxylate To a solution of 6-chloro-N-(2-fluoro-3-methyl-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (130 mg, 450.28 μmol) and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (172 mg, 810 μmol) in N-methylpyrrolidone (2.0 mL) was added N,N-diisopropylethylamine (174 mg, 1.35 mmol). The mixture was stirred at 80 °C for 14 hr. On completion, the mixture was added water (5 mL) and filtered. The solid was concentrated to give tert-butyl 5-(4-((2-fluoro-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate (250 mg, crude) as a brown solid. m/z ES+ [M+H] ⁺ 465.1. Step 2. (1S,4S)-tert-Butyl 5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e & (1R,4R)-tert-Butyl 5-(4-((2- fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.2]octane-2- carboxylate tert-Butyl 5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (250 mg, 0.54 mmol) was purified by SFC (column: Phenomenex-Cellulose-2 (250mm x 30mm x 10um); mobile phase: [0.1% NH ₃ water methanol]; B%: 55% - 55%, 2; 30min) to give tert-butyl (1S,4S)-5-[4-(2-fluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (64.0 mg, 138 μmol, 30%) as a yellow solid and tert-butyl (1R,4R)-5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (54 mg, 116 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.38 (s, 1H), 8.24 - 8.02 (m, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.46 - 7.21 (m, 1H), 7.17 - 7.12 (m, 1H), 7.10 - 7.02 (m, 1H), 4.36 - 4.25 (m, 1H), 3.76 - 3.62 (m, 2H), 3.60 - 3.44 (m, 3H), 2.30 (d, J = 1.2 Hz, 3H), 2.20 - 2.15 (m, 4H), 1.41 (d, J = 9.6 Hz, 9H); m/z ES+ [M+H] ⁺ 465.1. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-N-(2-fluoro-3- methylphenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-(2-fluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (54 mg, 116.3 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give 6-[(1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl]-N-(2-fluoro-3-methyl-phenyl)p yrido[3,2-d]pyrimidin-4-amine (40.0 mg, 110 μmol, 92%) as a brown oil. m/z ES+ [M+H] ⁺ 365.4. Step 4. 1-((1S,4S)-5-(4-((2-Fluoro-3-methylphenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl]-N-(2-fluoro-3- methyl- phenyl)pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, 110 μmol) in tetrahydrofuran (0.25 mL) and water (0.25 mL) was added sodium bicarbonate (92 mg, 1.1 mmol) at 0 °C. After that, prop-2- enoyl chloride (9.93 mg, 110 μmol) was added in one portion. The mixture was stirred at 0 °C for 0.25 hr. On completion, the mixture was concentrated to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm x 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 18% - 48%, 10 min) to give 1-[(1S,4S)-5-[4-(2-fluoro-3- methyl-anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo [2.2.2]octan-2-yl]prop-2-en-1-one (27.89 mg, 66.6 μmol, 60%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 - 9.15 (m, 1H), 8.39 (s, 1H), 8.29 - 8.02 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.62 - 7.21 (m, 1H), 7.19 - 7.11 (m, 1H), 7.10 - 7.03 (m, 1H), 6.93 - 6.56 (m, 1H), 6.22 – 6.17 (m, 1H), 5.74 - 5.68 (m, 1H), 4.82 - 4.62 (m, 1H), 3.92 - 3.82 (m, 1H), 3.81 - 3.67 (m, 2H), 3.63 (s, 1H), 3.30 (s, 1H), 2.30 (d, J = 1.6 Hz, 3H), 2.04 - 1.85 (m, 4H); m/z ES+ [M+H] ⁺ 419.4. Example 52. Preparation of 1-((1R,4R)-5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-e n-1-one (Compound 422) Step 1. 6-((1R,4R)-2,5-Dazabicyclo[2.2.2]octan-2-yl)-N-(2-fluoro-3- methylphenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1R,4R)-5-[4-(2-fluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (44.0 mg, 94.7 μmol) in dichloromethane (0.50 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give 6-[(1R,4R)-2,5- diazabicyclo[2.2.2]octan-2-yl]-N-(2-fluoro-3-methyl-phenyl)p yrido[3,2-d]pyrimidin-4-amine (34.0 mg, 93.1 μmol, 90%) as a brown oil. m/z ES+ [M+H] ⁺ 365.2. Step 2. 1-((1R,4R)-5-(4-((2-Fluoro-3-methylphenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-onee To a solution of 6-[(1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl]-N-(2-fluoro-3- methyl- phenyl)pyrido[3,2-d]pyrimidin-4-amine (34.0 mg, 93.3 μmol) in tetrahydrofuran (0.25 mL) and water (0.25 mL) was added sodium bicarbonate (78.4 mg, 933 μmol) at 0 °C. After that, prop-2- enoyl chloride (8.44 mg, 93.3 μmol) was added in one portion. The mixture was stirred at 0 °C for 0.25 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 18% - 48%, 10 min) to give 1-[(1R,4R)-5-[4-(2-fluoro-3-methyl- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octan-2-yl]prop-2-en-1-one (18.9 mg, 45.1 μmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 8.39 (s, 1H), 8.27 - 8.01 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.56 - 7.21 (m, 1H), 7.18 - 7.11 (m, 1H), 7.10 - 7.03 (m, 1H), 6.92 - 6.55 (m, 1H), 6.18 (dt, J = 2.4, 17.2 Hz, 1H), 5.77 - 5.65 (m, 1H), 4.86 - 4.57 (m, 1H), 3.92 - 3.74 (m, 3H), 3.63 (s, 1H), 3.30 (s, 1H), 2.30 (d, J = 1.6 Hz, 3H), 2.03 - 1.86 (m, 4H); m/z ES+ [M+H] ⁺ 419.4. Example 53. Preparation of 1-(7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2 - d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one (Compound 428) Step 1.6-Bromo-7-methoxypyrido[3,2-d]pyrimidin-4-ol To a solution of methanol (10 mL) and dimethylsulfoxide (60 mL) was added potassium tert-butoxide (2.76 g, 24.6 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 hr. Then 6- bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (2 g, 8.2 mmol) was added into the reaction mixture. The mixture was stirred at 25 °C for 4 hr. On completion, the solution was added 1M hydrochloric acid solution until pH = 7~8. The mixture was concentrated in vacuo to remove methanol. Then water (60 mL) was added into the mixture. The resulting precipitate was filtered and collected to give 6-bromo-7-methoxypyrido[3,2-d]pyrimidin-4-ol (1.8 g, crude) as a brown solid. m/z ES+ [M+H] ⁺ 258.0. Step 2. tert-Butyl 7-(4-hydroxy-7-methoxypyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of 6-bromo-7-methoxy-pyrido[3,2-d]pyrimidin-4-ol (0.2 g, 781 μmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (182 mg, 859 μmol) in acetonitrile (2 mL) was added triethylamine (158 mg, 1.56 mmol), the mixture was stirred at 60 °C for 48 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 7-(4-hydroxy-7-methoxypyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (0.17 g, 438 μmol, 55%) as a colorless oil. m/z ES+ [M+H] ⁺ 388.1. Step 3. tert-Butyl 7-(4-chloro-7-methoxypyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(4-hydroxy-7-methoxy-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (0.16 g, 413 μmol) in toluene. (2 mL) was added N,N- diisopropylethylamine (160 mg, 1.24 mmol) and followed by phosphorus oxychloride (95 mg, 619 μmol). The mixture was stirred at 110 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give tert-butyl 7-(4-chloro-7-methoxypyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (0.17 g, crude) as a black oil. m/z ES+ [M+H] ⁺ 406.0. Step 4. N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-(4,7-diazaspiro[2.5] octan-7- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 7-(4-chloro-7-methoxy-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (167 mg, 411 μmol) in acetonitrile (2 mL) was added 3- chloro-2-fluoro-aniline (89.8 mg, 617 μmol). The mixture was stirred at 60 °C for 12 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6- (4,7-diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amin e (85 mg, 206 μmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.24 (s, 1H), 8.45 (s, 1H), 8.14 (s, 1H), 7.44 (s, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.90 - 3.55 (m, 6H), 1.37 (s, 1H), 0.93 - 0.61 (m, 3H). Step 5. 1-(7-(4-((3-Chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2 -d]pyrimidin-6- yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-(4,7-diazaspiro[2.5]octan-7-y l)-7- methoxy-pyrido[3,2-d]pyrimidin-4-amine (85 mg, 205 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (68.9 mg, 820 μmol) and followed by prop-2-enoyl chloride (13 mg, 143 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.2 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 49%-79%, 8 min) to give 1-(7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2 - d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one (35.88 mg, 76.8 μmol, 36%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.44 (s, 1H), 8.11 (t, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.00 - 6.80 (m, 1H), 6.16 (dd, J = 2.0, 16.8 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.98 (s, 3H), 3.94 - 3.77 (m, 2H), 3.68 (s, 2H), 3.55 (s, 2H), 1.12 - 0.92 (m, 4H); m/z ES+ [M+H] ⁺ 469.1. Example 54. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaz abicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 386) Step 1. 6-Chloro-N-(3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl)p yrido[3,2- d]pyrimidin-4-amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (733 mg, 3.67 mmol), 3-chloro-2- fluoro-4-(oxetan-3-ylmethoxy)aniline (850 mg, 3.67 mmol) in acetonitrile (20 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40mm x 15um; mobile phase: [water (0.1% trifluoroacetic acid) - acetonitrile]; B%: 28% - 58%, 11min) to give 6-chloro-N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]p yrido[3,2-d]pyrimidin-4-amine (300 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 395.1. Step 2. (1S,4S)-tert-Butyl 5-(4-((3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaz abicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-[3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (800 mg, 2.02 mmol) in N-methylpyrrolidone (4 mL) was added N,N-diisopropylethylamine (1.31 g, 10 mmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (802 mg, 4.05 mmol). The mixture was stirred at 70 °C for 6 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate) to give tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilin o]pyrido[3,2-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 898 μmol, 44%) as a white solid. m/z ES+ [M+H] ⁺ 557.3. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-(oxetan- 3-ylmethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (480 mg, 861 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 0 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(1S,4S )-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (400 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 457.2. Step 4. 1-((1S,4S)-5-(4-((3-Chloro-2-fluoro-4-(oxetan-3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaz abicyclo[2.2.1]heptan-2-yl)prop- 2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(1S,4S )-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (380 mg, 831 μmol) in dichloromethane (6 mL) was added triethylamine (252 mg, 2.50 mmol) and prop-2-enoyl chloride (75.2 mg, 831 μmol) at 0 ^o C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combine organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by perp-HPLC (column: Waters Xbridge C18150 x 50mm x 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - acetonitrile]; B%: 26%-56%, 11 min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)ani lino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (100 mg, 196 μmol, 22%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 - 9.22 (m, 1H), 8.31 (d, J = 3.2 Hz, 1H), 7.96 - 7.78 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.84 - 6.35 (m, 1H), 6.18 - 6.12 (m, 1H), 5.76 - 5.61 (m, 1H), 5.12 - 4.89 (m, 1H), 4.76 - 4.72 (m, 2H), 4.52 - 4.46 (m, 2H), 4.36 (d, J = 6.4 Hz, 2H), 3.77 - 3.43 (m, 6H), 2.10 - 2.00 (m, 2H); m/z ES+ [M+H] ⁺ 511.0. Example 55. Preparation of 1-[4-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (Compound 5) Step 1. tert-Butyl 4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip eridine- 1-carboxylate To a mixture of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (0.35 g, 904 μmol) and tert-butyl 4-bromopiperidine-1-carboxylate (239 mg, 904 μmol) in dimethoxyethane (5 mL) was added Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ , NiCl ₂ ·dtbbpy (90.4 μmol), Lutidine (194 mg, 1.81 mmol) in one portion at 25 °C under nitrogen. The mixture was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 5 h. On completion, the reaction mixture was quenched by water (20 mL) at 20 °C, and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give compound tert-butyl 4-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]piperidi ne-1- carboxylate (0.28 g, 0.57 mmol, 59%) as a yellow solid. m/z ES+ [M+H] ⁺ 491.2. Step 2. N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-4-yl)quinazolin -4-amine A mixture of tert-butyl 4-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]piperidi ne-1- carboxylate (260 mg, 529 μmol) in HCl/ethyl acetate (4 M, 5 mL) was stirred at 20 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound N- (3,4-dichloro-2-fluoro-phenyl)-6-(4-piperidyl)quinazolin-4-a mine (0.2 g, 0.51 mmol, 89%) as a yellow solid. m/z ES+ [M+H] ⁺ 391.2. Step 3. 1-(4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl) piperidin-1- yl)prop-2-en-1-one To a mixture of N-(3,4-dichloro-2-fluoro-phenyl)-6-(4-piperidyl)quinazolin-4 -amine (100 mg, 256 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added sodium bicarbonate (85.9 mg, 1.02 mmol) at 20 °C. The mixture was then cooled to 0 °C and prop-2-enoyl chloride (23.1 mg, 256 μmol) was added dropwise. The mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was quenched by water (5 mL) at 20 °C, and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25 mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%: 21%-51%, 10 min) to give compound 1-[4-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-1-piperidyl]prop-2-en-1-one (38.4 mg, 0.086 mmol, 34%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 8.49 (s, 1H), 8.31 (d, J = 17.6 Hz, 1H), 7.84 - 7.66 (m, 2H), 7.59 (s, 2H), 6.92 – 6.85 (m, 1H), 6.15 (dd, J = 2.4, 16.8 Hz, 1H), 5.70 (dd, J = 2.4, 10.0 Hz, 1H), 4.66 (d, J = 10.8 Hz, 1H), 4.25 (d, J = 12.8 Hz, 1H), 3.22 - 3.00 (m, 2H), 2.80 - 2.74 (m, 1H), 1.99 - 1.95 (m, 2H), 1.68 - 1.64 (m, 2H); m/z ES+ [M+H] ⁺ 445.2. Example 56. Preparation of 1-[3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (Compound 3) Step 1. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-5, 6- dihydropyridine-1(2H)-carboxylate To a solution of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (0.5 g, 1.29 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H- pyridine-1-carboxylate (599 mg, 1.94 mmol) in dioxane (10 mL) and water (3 mL) were added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (105.50 mg, 129.19 μmol) and potassium carbonate (536 mg, 3.88 mmol). The mixture was stirred at 80 °C for 2 h under nitrogen. On completion, the mixture was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate from 10/1 to 1/1) to give tert-butyl 5-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxyla te (0.6 g, 1.23 mmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 489.2. Step 2. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip eridine- 1-carboxylate To a solution of tert-butyl 5-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] -3,6- dihydro-2H-pyridine-1-carboxylate (50.0 mg, 102 μmol) in ethanol (5 mL) was added platinum dioxide (4.64 mg, 20.4 μmol). The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was then stirred at 50 °C for 2 h under hydrogen gas atmosphere (15 psi). On completion, the reaction mixture was filtered and concentrated under reduced pressure to give compound tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]piperidine-1-carboxylate (40.0 mg, 0.081 mmol, 72%) as a yellow solid. m/z ES+ [M+H] ⁺ 491.1. Step 3. N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl)quinazolin -4-amine A mixture of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] piperidine-1- carboxylate (80.0 mg, 163 μmol) in ethyl acetate (2 mL) was added HCl/ethyl acetate (4 M, 3.2 mL) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound N-(3,4-dichloro-2-fluoro- phenyl)-6-(3-piperidyl)quinazolin-4-amine (50.0 mg, 0.13 mmol, 77%) as a yellow solid. m/z ES+ [M+H] ⁺ 391.2. Step 4. 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl) piperidin-1- yl)prop-2-en-1-one A mixture of N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-piperidyl)quinazolin-4 -amine (50.0 mg, 128 μmol) in tetrahydrofuran (1 mL), water (1 mL) was added sodium bicarbonate (37.6 mg, 447 μmol), prop-2-enoyl chloride (11.6 mg, 128 μmol) in one portion at 0 °C under nitrogen. The mixture was then stirred at 20 °C for 2 h. On completion, the reaction mixture was quenched by water 2 mL at 20 °C, and then extracted with ethyl acetate (2 mL x 3). The combined organic layers were washed with water (2 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5um; mobile phase:[water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 43%-73%, 10 min) to give compound 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one (20.2 mg, 0.045 mmol, 36%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 7.85 - 7.77 (m, 2H), 7.58 (s, 2H), 6.92 - 6.85 (m, 1H), 6.64 - 6.57 (m, 1H), 6.11 (dd, J = 1.2, 8.4 Hz, 1H), 5.68 (t, J = 10.8 Hz, 1H), 4.64 - 4.53 (m, 1H), 4.18 - 4.15 (m, 1H), 3.17 - 3.14 (m, 1H), 2.81 - 2.66 (m, 2H), 2.05 (m, 1H), 1.87 - 1.85 (m, 2H), 1.52 (s, 1H); m/z ES ⁺ [M+H] ⁺ 445.2. Example 57. Preparation of (R)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6 - yl)piperidin-1-yl)prop-2-en-1-one (Compound 20) Step 1. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip eridine- 1-carboxylate To a 40 mL vial equipped with a stir bar was added 6-bromo-N-(3,4-dichloro-2-fluoro- phenyl)quinazolin-4-amine (1.50 g, 3.88 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (1.33 g, 5.04 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (43.5 mg, 38.8 μmol), NiCl ₂ .dtbbpy (77.1 mg, 194 μmol), tris(trimethylsilyl)silane (9.64 mg, 38.8 μmol), sodium carbonate (822 mg, 7.75 mmol) in dimethoxyethane (10 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 h under nitrogen. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip eridine-1-carboxylate (780 mg, 1.59 mmol, 41%) as a yellow solid. m/z ES+ [M+H] ⁺ 491.2. Step 2. (R)-tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl) piperidine-1-carboxylate tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]piperidi ne-1-carboxylate (780 mg, 1.59 mmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mmx30 mm, 10 um); mobile phase: [0.1% NH3 water-methanol]; B%: 45%-45%; 60 min) to give (S)-tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip eridine-1-carboxylate (400 mg, 0.81 mmol, 51%) as a yellow solid and (R)-tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino) quinazolin-6-yl)piperidine-1-carboxylate (370 mg, 0.75 mmol, 47%) as a yellow solid. m/z ES+ [M+H] ⁺ 491.2. Step 3. (R)-N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl)quinaz olin-4-amine To a solution of tert-butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]piperidine-1-carboxylate (400 mg, 814 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.6 mL), it was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give (S)-N-(3,4-dichloro-2-fluorophenyl)-6- (piperidin-3-yl)quinazolin-4-amine (400 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 391.2. Step 4. (R)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6 -yl)piperidin-1- yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3R)-3-piperidyl]quinazo lin-4- amine (300 mg, 594 μmol, trifluoroacetic acid salt) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (53.7 mg, 594 μmol) and sodium bicarbonate (249 mg, 2.97 mmol), it was stirred at 0°C for 10 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was prep-HPLC (column: Phenomenex Gemini-NX C18, 75x30 mm, 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 22%-52%, 7 min) to give (R)-1-(3-(4-((3, 4-dichloro-2-fluorophenyl) amino) quinazolin-6- yl) piperidin-1-yl)prop-2-en-1-one (147 mg, 0.33 mmol, 55%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.50 (s, 1H), 8.45 - 8.35 (m, 1H), 7.85 - 7.77 (m, 2H), 7.60 (s, 2H), 6.92 - 6.85 (m, 1H), 6.13 (dd, J = 16.8 Hz, 1H), 5.68 (t, J = 12.4 Hz, 1H), 4.64 - 4.53 (m, 1H), 4.18 - 4.15 (m, 1H), 3.17 - 3.14 (m, 1H), 2.81 - 2.66 (m, 2H), 2.05 (m, 1H), 1.87 - 1.85 (m, 2H), 1.60 – 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 445.2. Example 58. Preparation of (S)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6 - yl)piperidin-1-yl)prop-2-en-1-one (Compound 19) Step 1. (S)-N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl) quinazolin-4-amine To a solution of tert-butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]piperidine-1-carboxylate (400 mg, 814 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.6 mL), it was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give (S)-N-(3,4-dichloro-2-fluorophenyl)-6- (piperidin-3-yl)quinazolin-4-amine (400 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 391.2. Step 2. (S)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6 -yl)piperidin-1- yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3S)-3-piperidyl]quinazo lin-4- amine (400 mg, 792 μmol, trifluoroacetic acid salt) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (71.7 mg, 792 μmol) and sodium bicarbonate (333 mg, 3.96 mmol), it was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30 mmx3 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 22%-52%, 7 min) to give (S)-1-(3-(4-((3, 4-dichloro-2- fluorophenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2-en- 1-one (134 mg, 0.30 mmol, 37%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 7.93 - 7.72 (m, 2H), 7.60 (s, 2H), 6.89 (dd, J = 10.0, 16.4 Hz, 1H), 6.13 (d, J = 16.4 Hz, 1H), 5.60 - 5.75 (m, 1H), 4.75 - 4.50 (m, 1H), 4.25 - 4.08 (m, 1H), 3.17 - 3.06 (m, 1H), 2.82 - 2.68 (m, 2H), 2.07 - 2.05 (m, 1H), 1.95 - 1.75 (m, 2H), 1.62 - 1.47 (m, 1H); m/z ES+ [M+H] ⁺ 445.2. Example 59. Preparation of (S)-1-(3-((4-((1H-benzo[d]imidazol-5-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (Compound 52) Step 1. Benzyl 1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[4.1.0]heptane-3-carboxylate To a solution of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (206 mg, 533 μmol) and benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[4.1.0]heptane-3-carbo xylate, potassium salt (200 mg, 593 μmol) in toluene (5.0 mL) and water (0.50 mL) was added cesium carbonate (773 mg, 2.37 mmol) and catacxium(R) A PD G3 (43.2 mg, 59.3 μmol) at 20 °C. The mixture was stirred at 110 °C for 12 hours under nitrogen. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give benzyl 1-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-azabicyclo[4.1.0]heptane-3-carbox ylate (180 mg, 0.34 mmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 7.86 - 7.81 (m, 1H), 7.79 - 7.74 (m, 1H), 7.60 (s, 2H), 7.35 (d, J = 19.2 Hz, 5H), 5.12 (s, 2H), 4.30 - 4.10 (m, 1H), 3.86 - 3.60 (m, 2H), 3.23 - 3.14 (m, 1H), 2.20 - 2.12 (m, 1H), 1.85 - 1.78 (m, 1H), 1.53 (s, 1H), 1.18 (s, 1H), 0.78 (s, 1H). Step 2. 6-(3-Azabicyclo[4.1.0]heptan-1-yl)-N-(3,4-dichloro-2-fluoro- phenyl)quinazolin- 4-amine Benzyl 1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-azabi cyclo[4.1.0]heptane- 3-carboxylate (150 mg, 279 μmol) was dissolved in trifluoroacetic acid (2.0 mL) and the mixture was stirred at 60 °C for 2 hours. On completion, the mixture was dried by blowing nitrogen gas to give 6-(3-azabicyclo[4.1.0]heptan-1-yl)-N-(3,4-dichloro-2-fluoro- phenyl)quinazolin-4-amine (112 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 403.0. Step 3. (S)-1-(3-((4-((1H-benzo[d]imidazol-5-yl)amino)pyrido[3,2-d]p yrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one To a solution of 6-(3-azabicyclo[4.1.0]heptan-1-yl)-N-(3,4-dichloro-2-fluoro- phenyl) quinazolin-4-amine (112 mg, 278 μmol) in tetrahydrofuran (3.0 mL) and water (0.60 mL) was added sodium bicarbonate (93.3 mg, 1.11 mmol) and prop-2-enoyl chloride (20.1 mg, 222 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was added methanol (1.0 mL) and filtered. The filtrate was dried by blowing nitrogen gas. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875x30 mmx3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 35%-60%, 6 min) to give 1-[1-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-azabicyclo[4.1.0]heptan-3-yl]prop -2-en-1-one (33.0 mg, 0.072 mmol, 26%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 10.07 - 10.01 (m, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 7.95 - 7.73 (m, 2H), 7.60 (s, 2H), 6.90 - 6.74 (m, 1H), 6.15 (d, J = 16.8 Hz, 1H), 5.74 - 5.65 (m, 1H), 4.56 - 4.32 (m, 1H), 4.03 - 3.63 (m, 2H), 3.38 - 2.96 (m, 1H), 2.25 - 2.11 (m, 1H), 1.82 (s, 1H), 1.55 (s, 1H), 1.21 (d, J = 13.2 Hz, 1H), 0.77 - 0.63 (m, 1H); m/z ES+ [M+H] ⁺ 457.0. Example 60. Preparation of 1-[1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[4.1.0]heptan-3-yl]prop-2-en-1-one (Compound 75) Step 1. Benzyl 1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[4.1.0]heptane-3-carboxylate To a solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-amine (209 mg, 593 μmol) and Benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[4.1.0]heptane-3-carbo xylate, potassium salt (200 mg, 593 μmol) in toluene (5.0 mL) and water (1.0 mL) was added cesium carbonate (579 mg, 1.78 mmol) and catacxium (R) A PD G3 (43.2 mg, 59.3 μmol) at 20 °C. The mixture was stirred at 110 °C for 12 hours. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give benzyl 1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[4.1.0]heptane-3-carboxylate (170 mg, 57%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.48 (s, 1H), 8.34 (br. s, 1H), 7.88 - 7.71 (m, 2H), 7.52 (t, J = 7.4 Hz, 2H), 7.41 - 7.29 (m, 6H), 5.13 (s, 2H), 4.22 (br. s, 1H), 3.86 - 3.54 (m, 2H), 3.16 (br. s, 1H), 2.20 - 2.12 (m, 1H), 1.87 - 1.73 (m, 1H), 1.54 (s, 1H), 1.24 - 1.17 (m, 1H), 0.84 - 0.72 (m, 1H). Step 2. 6-(3-Azabicyclo[4.1.0]heptan-1-yl)-N-(3-chloro-2-fluoro-phen yl)quinazolin-4- amine Benzyl 1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azabicycl o[4.1.0]heptane-3- carboxylate (170 mg, 338 μmol) was dissolved in trifluoroacetic acid (2.0 mL) and the mixture was stirred at 60 °C for 2 hours. The mixture was dried by blowing nirogen gas to give 6-(3- azabicyclo[4.1.0]heptan-1-yl)-N-(3-chloro-2-fluoro-phenyl)qu inazolin-4-amine (124 mg, crude) as a brown oil. Step 3. 1-[1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azabic yclo[4.1.0]heptan-3- yl]prop-2-en-1-one To a solution of 6-(3-azabicyclo[4.1.0]heptan-1-yl)-N-(3-chloro-2-fluoro- phenyl)quinazolin-4-amine (124 mg, 336 μmol) in tetrahydrofuran (3.0 mL) and water (0.60 mL) was added sodium bicarbonate (113 mg, 1.34 mmol) and prop-2-enoyl chloride (27.4 mg, 302 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was added methanol (1.0 mL) and filtered. The filtrate was dried by blowing nitrogen gas. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875x30 mm, 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 20%-50%, 8 min) to give 1-[1-[4-(3-chloro-2-fluoro- anilino)quinazolin-6-yl]-3-azabicyclo[4.1.0]heptan-3-yl]prop -2-en-1-one (42.2 mg, 0.10 mmol, 30%) as a white solid. ¹ H NMR (DMSO-d ₆ ) δ 10.0 - 9.86 (m, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 7.95 - 7.73 (m, 2H), 7.60 (s, 2H), 7.32 - 7.28 (m, 1H), 6.90 - 6.74 (m, 1H), 6.15 (d, J = 16.8 Hz, 1H), 5.74 - 5.65 (m, 1H), 4.56 (d, J = 13.2 Hz, 0.5H), 4.32 (d, J = 13.2 Hz, 0.5H), 4.03 - 3.74 (m, 1.5H), 3.63 (d, J = 13.2 Hz, 0.5H), 3.38 - 3.36 (m, 0.5H), 3.08 - 2.96 (m, 0.5H), 2.25 - 2.11 (m, 1H), 1.82 (s, 1H), 1.55 (s, 1H), 1.21 (s, 1H), 0.77 - 0.63 (m, 1H); m/z ES+ [M+H] ⁺ 423.1. Example 61. Preparation of 1-[(3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (Compound 80) Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperidine-1 - carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-N-(3-chloro-2-fluoro- phenyl)quinazolin-4-amine (500 mg, 1.42 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (486 mg, 1.84 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (15.9 mg, 14.1 μmol), NiCl ₂ .dtbbpy (2.82 mg, 7.09 μmol), tris(trimethylsilyl)silane (352 mg, 1.42 mmol), sodium carbonate (300 mg, 2.84 mmol) in dimethoxyethane (10 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 h under nitrogen. On completion, the reaction mixture was diluted with water 20 mL and extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were washed with brine 270 mL (90 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 3/1 to 1/1) to give tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperidine-1 - carboxylate (330 mg, 722 μmol, 51%) as a white solid. Step 2. tert-Butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperid ine-1- carboxylate tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperidine-1 -carboxylate (330 mg, 722 μmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 um); mobile phase: [0.1% NH ₃ water-ethanol]; B%: 40%-40%, 2.7. 40 min) to give tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperid ine-1-carboxylate (130 mg, 0.29 mmol, 39%) and tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperid ine-1- carboxylate (130 mg, 0.29 mmol, 39%) as a white solid. m/z ES+ [M+H] ⁺ 457.1. Step 3. N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-3-piperidyl]quinazolin- 4-amine To a solution of tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl] piperidine-1-carboxylate (120 mg, 262 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-3- piperidyl]quinazolin-4-amine (120 mg, 0.34 mmol, 97%, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 357.1. Step 4. 1-[(3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-1-p iperidyl]prop-2-en- 1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-3-piperidyl]quinazolin- 4-amine (120 mg, 254 μmol, trifluoroacetic acid) in tetrahydrofuran (4 mL) was added prop-2-enoyl chloride (25.3 mg, 280 μmol) and sodium bicarbonate (85.6 mg, 1.02 mmol) in water (4 mL), the mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 40%- 70%, 10 min) to give 1-[(3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-1-p iperidyl]prop- 2-en-1-one (79.0 mg, 0.19 mmol, 75%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (br. s, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.91 - 7.74 (m, 2H), 7.59 - 7.46 (m, 2H), 7.30 (t, J = 8.0 Hz, 1H), 6.89 (dd, J = 11.2, 16.8 Hz, 1H), 6.13 (d, J = 17.6 Hz, 1H), 5.69 (t, J = 11.6 Hz, 1H), 4.70 - 4.51 (m, 1H), 4.26 - 4.12 (m, 1H), 3.21 - 3.05 (m, 1H), 2.92 - 2.71 (m, 2H), 2.07 (d, J = 11.6 Hz, 1H), 1.95 - 1.80 (m, 2H), 1.62 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 411.1. Example 62. Preparation of 1-[(3S)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (Compound 92)

Step 1. 6-Bromo-N-(6-phenoxy-3-pyridyl)quinazolin-4-amine To a solution of 6-bromo-4-chloro-quinazoline (500 mg, 2.05 mmol) in acetonitrile (20 mL) was added 6-phenoxypyridin-3-amine (420 mg, 2.26 mmol). The mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was filtered and the solid was collected to give 6-bromo-N-(6-phenoxy-3-pyridyl)quinazolin-4-amine (800 mg, 2,04 mmol, 99%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (d, J = 2.0 Hz, 1H), 8.98 - 8.92 (m, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.26 (dd, J = 2.0, 8.8 Hz, 1H), 8.19 (dd, J = 2.8, 8.7 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.28 - 7.21 (m, 1H), 7.20 - 7.15 (m, 3H). Step 2. tert-Butyl 3-(4-((6-phenoxypyridin-3-yl)amino)quinazolin-6-yl)piperidin e-1- carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-N-(6-phenoxy-3- pyridyl)quinazolin-4-amine (500 mg, 1.27 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (436 mg, 1.65 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (14.2 mg, 12.7 μmol), NiCl2.dtbbpy (2.53 mg, 6.36 μmol), tris(trimethylsilyl)silane (316 mg, 1.27 mmol), sodium carbonate (269 mg, 2.54 mmol) in dimethoxyethane (10 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 h under nitrogen. On completion, the reaction mixture was diluted with water 20 mL and extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were washed with brine 270 mL (90 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate= 8/1 to 1/1) to give tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperidine- 1-carboxylate (320 mg, 0.64 mmol, 47%) as a white solid. m/z ES+ [M+H] ⁺ 498.2. Step 3. tert-Butyl (3S)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]piperi dine-1- carboxylate tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperidine-1 -carboxylate (320 mg, 700 μmol) was separated by SFC (column: DAICEL CHIRALPAK AS(250mmx30mm,10um); mobile phase: [0.1% NH3 water ethanol]; B%: 40%-40%,3 min;30 min) to give tert-butyl (3S)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]piperi dine-1- carboxylate (45 mg, 0.09 mmol, 14%) as a white solid and tert-butyl (3R)-3-[4-[(6-phenoxy-3- pyridyl)amino]quinazolin-6-yl]piperidine-1-carboxylate (45 mg, 0.09 mmol, 14%) as a white solid. Step 4. N-(6-phenoxy-3-pyridyl)-6-[(3S)-3-piperidyl]quinazolin-4-ami ne To a solution of tert-butyl (3S)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl] piperidine-1-carboxylate (31.0 mg, 62.3 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-(6-phenoxy-3-pyridyl)-6-[(3S)-3- piperidyl]quinazolin-4-amine (24.0 mg, 0.06 mmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 398.2. Step 5. 1-[(3S)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]-1- piperidyl]prop-2- en-1-one To a solution of N-(6-phenoxy-3-pyridyl)-6-[(3S)-3-piperidyl]quinazolin-4-ami ne (24.0 mg, 60.3 μmol) in tetrahydrofuran (4 mL) was added prop-2-enoyl chloride (6.01 mg, 66.4 μmol) and sodium bicarbonate (20.2 mg, 242 μmol) in water (4 mL), the mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30 mm, 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-60%, 8 min) to give 1-[(3S)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (18.2 mg, 0.04 mmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 8.56 - 8.45 (m, 2H),8.37 (s, 1H), 8.29 - 8.21 (m, 1H), 7.88 - 7.71 (m, 2H), 7.48 - 7.38 (m, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 10.4, 16.8 Hz, 1H), 6.13 (d, J = 16.8 Hz, 1H), 5.73 - 5.64 (m, 1H), 4.68 - 4.53 (m, 1H), 4.24 - 4.12 (m, 1H), 3.18 - 3.08 (m, 1H), 2.90 - 2.65 (m, 2H), 2.06 (d, J = 13.6 Hz, 1H), 1.95 - 1.82 (m, 2H), 1.61 - 1.48 (m, 1H); m/z ES+ [M+H] ⁺ 452.2. Example 63. Preparation of 1-[(3R)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (Compound 93) Step 1. N-(6-phenoxy-3-pyridyl)-6-[(3R)-3-piperidyl]quinazolin-4-ami ne To a solution of tert-butyl (3R)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl] piperidine-1-carboxylate (31.0 mg, 62.3 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-(6-phenoxy-3-pyridyl)-6-[(3R)-3- piperidyl]quinazolin-4-amine (24.0 mg, 0.06 mmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 398.2. Step 2. 1-[(3R)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]-1- piperidyl]prop-2- en-1-one To a solution of N-(6-phenoxy-3-pyridyl)-6-[(3R)-3-piperidyl]quinazolin-4-ami ne (24.0 mg, 60.3 μmol) in tetrahydrofuran (4 mL) was added prop-2-enoyl chloride (6.01 mg, 66.4 μmol) and sodium bicarbonate (20.2 mg, 241.5 μmol) in water (4 mL), the mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30 mm, 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-60%, 8 min) to give 1-[(3R)-3-[4-[(6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (8.94 mg, 0.020 mmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 8.56 - 8.47 (m, 2H), 8.37 (s, 1H), 8.31 - 8.20 (m, 1H), 7.88 - 7.79 (m, 1H), 7.79 - 7.73 (m, 1H), 7.46 - 7.40 (m, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 10.4, 16.8 Hz, 1H), 6.13 (d, J = 16.4 Hz, 1H), 5.75 - 5.62 (m, 1H), 4.68 - 4.51 (m, 1H), 4.25 - 4.11 (m, 1H), 3.21 - 3.05 (m, 1H), 2.93 - 2.66 (m, 2H), 2.06 (d, J = 13.2 Hz, 1H), 1.97 - 1.81 (m, 2H), 1.60 - 1.46 (m, 1H); m/z ES+ [M+H] ⁺ 452.2. Example 64. Preparation of 1-[(3S)-3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin - 6-yl]-1-piperidyl]prop-2-en-1-one (Compound 94) Step 1. 6-Bromo-N-(5-chloro-6-phenoxy-3-pyridyl)quinazolin-4-amine To a solution of 6-bromo-4-chloro-quinazoline (1.10 g, 4.52 mmol) in acetonitrile (20 mL) was added 5-chloro-6-phenoxy-pyridin-3-amine (1.10 g, 4.97 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (25 mL) at 25 ^o C to give compound 6-bromo-N-(5-chloro-6-phenoxy-3-pyridyl)quinazolin-4-amine (2.00 g, 4.66 mmol, 95%) as a yellow solid ¹ H NMR (400 MHz, DMSO-d6) δ 12.11 - 11.53 (m, 1H), 9.19 (d, J = 1.6 Hz, 1H), 8.98 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.27 - 8.21 (m, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.29 - 7.23 (m, 1H), 7.20 (d, J = 7.6 Hz, 2H); m/z ES+ [M+H] ⁺ 429.0. Step 2. tert-butyl 3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin-6- yl]piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-N-(5-chloro-6-phenoxy-3- pyridyl)quinazolin-4-amine (800 mg, 1.87 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (494 mg, 1.87 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (209 mg, 187 μmol), NiCl2.dtbbpy (3.72 mg, 9.35 μmol), tris(trimethylsilyl)silane (465 mg, 1.87 mmol), sodium carbonate (396 mg, 3.74 mmol). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 1.5 hr under nitrogen. On completion, the reaction mixture was diluted with water 25 mL and extracted with ethyl acetate 75 mL (25 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate=0/1 to 1/1) to give compound tert-butyl 3- [4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]pipe ridine-1-carboxylate (450 mg, 0.85 mmol, 43%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.11 (d, J = 4.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.45 - 7.38 (m, 2H), 7.24 - 7.19 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 4.11 - 3.72 (m, 2H), 3.46 - 3.03 (m, 2H), 2.99 - 2.84 (m, 2H), 2.08 (s, 1H), 1.71 - 1.51 (m, 2H), 1.45 (s, 9H); m/z ES+ [M+H] ⁺ 532.0. Step 3. tert-Butyl (3S)-3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin-6- yl]piperidine-1-carboxylate tert-Butyl 3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin-6-yl]pi peridine-1- carboxylate (400 mg, 751 μmol) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm,10 um); mobile phase: [0.1% NH ₃ water-methanol]; B%: 45%-45%, 3.5. 80min) to give compound tert-butyl (3S)-3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin-6- yl]piperidine-1-carboxylate (120 mg, 0.23 mmol, 29%) as a white solid. Step 4. N-(5-chloro-6-phenoxy-3-pyridyl)-6-[(3S)-3-piperidyl]quinazo lin-4-amine To a solution of tert-butyl (3S)-3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin-6- yl]piperidine-1-carboxylate (100 mg, 187 μmol) in ethyl acetate (3 mL) was added HCl/ethyl acetate (4 M, 47.0 μL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give compound N-(5-chloro-6-phenoxy-3- pyridyl)-6-[(3S)-3-piperidyl]quinazolin-4-amine (120 mg, crude) as a red solid. m/z ES+ [M+H] ⁺ 432.1. Step 5. 1-[(3S)-3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin -6-yl]-1- piperidyl]prop-2-en-1-one To a solution of N-(5-chloro-6-phenoxy-3-pyridyl)-6-[(3S)-3-piperidyl]quinazo lin-4- amine (105 mg, 243 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (61.2 mg, 729 μmol) and prop-2-enoyl chloride (17.6 mg, 194 μmol). The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25 mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 25%-55%, 10 min) to give compound 1-[(3S)-3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]quinazolin -6-yl]-1- piperidyl]prop-2-en-1-one (23.1 mg, 0.048 mmol, 19%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.60 (s, 2H), 8.48 (s, 1H), 8.37 (s, 1H), 7.94 - 7.82 (m, 1H), 7.81 - 7.76 (m, 1H), 7.50 - 7.38 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H), 6.93 - 6.84 (m, 1H), 6.13 (d, J = 15.6 Hz, 1H), 5.75 - 5.61 (m, 1H), 4.70 - 4.49 (m, 1H), 4.25 - 4.09 (m, 1H), 3.18 - 3.09 (m, 1H), 2.93 - 2.76 (m, 2H), 2.11 - 2.00 (m, 1H), 1.94 - 1.79 (m, 2H), 1.62 - 1.44 (m, 1H); m/z ES+ [M+H] ⁺ 486.2. Example 65. Preparation of (R)-1-(3-(4-((5-fluoro-6-phenoxypyridin-3- yl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 108) Step 1. 6-Bromo-5-fluoro-pyridin-3-amine To a solution of 5-fluoropyridin-3-amine (0.5 g, 4.46 mmol) in N,N-dimethylformamide (5.0 mL) was added N-bromosuccinimide (793 mg, 4.46 mmol) and the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by water (3.0 ml) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 10/1 to 1/1) to give 6-bromo-5-fluoro-pyridin-3-amine (0.4 g, 2.11 mmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 2.8, 9.2 Hz, 1H), 3.92 (s, 2H), 2.98 (s, 1H), 2.90 (s, 1H). Step 2. 5-Fluoro-6-phenoxy-pyridin-3-amine. A suspension of 6-bromo-5-fluoro-pyridin-3-amine (0.4 g, 2.09 mmol), phenol (236 mg, 2.51 mmol), cesium carbonate (2.05 g, 6.28 mmol) and bis[(Z)-1-methyl-3-oxo-but-1- enoxy]copper (54.8 mg, 209 μmol) in dioxane (15 mL) was stirred at 120 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by water (3.0 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate=10/1 to 0/1) to give 5-fluoro-6-phenoxy-pyridin-3-amine (0.35 g, 1.72 mmol, 81%) as a yellow solid. Step 3. tert-Butyl 3-[4-[(5-fluoro-6- phenoxy-3-pyridyl)amino]quinazolin-6- yl]piperidine-1-carboxylate To a solution of (E)-tert-butyl 3-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl) piperidine-1-carboxylate (0.35 g, 981 μmol) in toluene (3.0 mL) was added acetic acid (3.0 mL) and 5-fluoro-6-phenoxy-pyridin-3-amine (200 mg, 981 μmol). The mixture was stirred at 110 °C for 3 hr. On completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-[(5-fluoro-6- phenoxy-3- pyridyl)amino]quinazolin-6-yl]piperidine-1-carboxylate (0.25 g, 0.49 mmol, 49%) as a yellow solid. m/z ES+ [M+H] ⁺ 516.2. Step 4. tert-Butyl (3S)-3-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]quinazolin-6- yl]piperidine-1-carboxylate tert-Butyl 3-(4-((5-fluoro-6-phenoxypyridin-3-yl)amino)quinazolin-6-yl) piperidine-1- carboxylate (200 mg) was purified by SFC (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 um); mobile phase: [0.1% NH3 water-methanol]; B%: 35%-35%, 4.5 min; 70 min) to give tert-butyl (3R)-3-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]quinazolin-6- yl]piperidine-1- carboxylate (0.1 g, 0.19 mmol, 50%) as a yellow solid. m/z ES+ [M+H] ⁺ 516.2. Step 5. N-(5-Fluoro-6-phenoxy-3-pyridyl)-6-[(3R)-3-piperidyl]quinazo lin-4-amine A solution of tert-butyl (3R)-3-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]quinazolin-6- yl] piperidine-1-carboxylate (0.1 g, 193 μmol) in HCl/ethyl acetate (4 M, 6.67 mL) was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give N-(5-fluoro-6- phenoxy-3-pyridyl)-6-[(3R)-3-piperidyl]quinazolin-4-amine (0.08 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 416.3. Step 6. 1-[(3R)-3-[4-[(5-fluoro-6-phenoxy-3- pyridyl)amino]quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one To a solution of (R)-N-(5-fluoro-6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)qui nazolin-4- amine (0.08 g, 192 μmol), sodium bicarbonate (48.5 mg, 577 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added prop-2-enoyl chloride (17.4 mg, 192 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 40%-70%, 9 min) to give 1-[(3R)-3-[4-[(5-fluoro-6- phenoxy-3- pyridyl)amino]quinazolin-6-yl]-1-piperidyl]prop-2-en-1-one (0.022 g, 0.047 mmol, 24%) as a yellow solid. (400 MHz, DMSO-d ₆ ) δ 10.17 - 9.90 (m, 1H), 8.61 (s, 1H), 8.49 (d, J = 11.6 Hz, 1H), 8.42 - 8.32 (m, 2H), 7.87 (d, J = 9.6 Hz, 1H), 7.83 - 7.77 (m, 1H), 7.48 - 7.40 (m, 2H), 7.26 - 7.15 (m, 3H), 6.90 (dd, J = 10.4, 16.8 Hz, 1H), 6.14 (d, J = 16.8 Hz, 1H), 5.77 - 5.62 (m, 1H), 4.75 - 4.48 (m, 1H), 4.27 - 4.11 (m, 1H), 3.31 - 3.09 (m, 1H), 2.94 - 2.69 (m, 2H), 2.06 (d, J = 14.4 Hz, 1H), 1.96 - 1.80 (m, 2H), 1.62 - 1.44 (m, 1H); m/z ES+ [M+H] ⁺ 470.2. Example 66. Preparation of (S)-1-(3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazoli n- 6-yl)piperidin-1-yl) prop-2-en-1-one (Compound 151) Step 1. 2-Fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-amine To a solution of 5-bromo-2-fluoro-pyridin-3-amine (3.00 g, 15.7 mmol) and ethynyl(trimethyl)silane (4.63 g, 47.1 mmol) in N,N-dimethylformamide (30 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (1.10 g, 1.57 mmol) and copper iodide (299 mg, 1.57 mmol), triethylamine (4.77 g, 47.1 mmol). The mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/ethyl acetate=20/1 to 5/1) to give 2-fluoro-5- ((trimethylsilyl)ethynyl)pyridin-3-amine (2.5 g, 12.02 mmol, 69%) as a brown solid. m/z ES+ [M+H] ⁺ 209.5. Step 2. 6-Bromo-N-(2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-yl) quinazolin-4-amine To a solution of 2-fluoro-5-(2-trimethylsilylethynyl)pyridin-3-amine (2.17 g, 10.4 mmol) in acetonitrile (19 mL) was added 6-bromo-4-chloro-quinazoline (1.95 g, 8.01 mmol). The mixture was stirred at 60 °C for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/ethyl acetate = 5/1 to dichloromethane/methanol = 20/1) to give 6-bromo-N-(2-fluoro-5- ((trimethylsilyl)ethynyl)pyridin-3-yl)quinazolin-4-amine (3.00 g, 7.21 mmol, 86%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.79 (s, 1H), 8.34 - 8.10 (m, 3H), 7.85 (d, J = 8.8 Hz, 1H), 0.26 (s, 9H); m/z ES+ [M+H] ⁺ 417.1. Step 3. tert-Butyl 3-(4-((2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3- yl)amino)quinazolin-6-yl) piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-N-[2-fluoro-5-(2- trimethylsilylethynyl)-3-pyridyl]quinazolin-4-amine (300 mg, 722 μmol), tert-butyl 3- bromopiperidine-1-carboxylate (248 mg, 939 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (8.10 mg, 7.22 μmol), NiCl ₂ .dtbbpy (1.44 mg, 3.61 μmol), tris(trimethylsilyl)silane (180 mg, 722 μmol), sodium carbonate (153 mg, 1.44 mmol) in dimethoxyethane (6 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hr under nitrogen. On completion, the reaction mixture was filtered. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-((2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-yl)amin o)quinazolin-6-yl)piperidine-1- carboxylate (200 mg, 0.38 mmol, 40%) as a yellow oil. m/z ES+ [M+H] ⁺ 520.3. Step 4. tert-Butyl 3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6-yl) piperidine-1-carboxylate A solution of tert-butyl 3-[4-[[2-fluoro-5-(2-trimethylsilylethynyl)-3- pyridyl]amino]quinazolin-6-yl] piperidine-1-carboxylate (260 mg, 500 μmol) in tetrabutylammonium fluoride (1 M in THF, 5.0 mL) was stirred at 25 °C for 20 min. On completion, the reaction mixture was diluted with water 30 mL and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/ethyl acetate=5/1 to 3/1) to give tert-butyl 3-(4-((5-ethynyl-2- fluoropyridin-3-yl)amino)quinazolin-6-yl) piperidine-1-carboxylate (160 mg, 0.36 mmol, 68%) as a colorless oil. m/z ES+ [M+H] ⁺ 448.3. Step 5. (S)-tert-Butyl 3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6-yl) piperidine-1-carboxylate tert-Butyl 3-[4-[(5-ethynyl-2-fluoro-3-pyridyl)amino]quinazolin-6-yl]pi peridine-1- carboxylate (160 mg, 358 μmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm x30 mm, 10 um); mobile phase: [0.1% NH3 water-IPA]; B%: 30%-30%, 4.8.75 min) to give (S)-tert-butyl 3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6-yl) piperidine-1- carboxylate (60 mg, 0.13 mmol, 36%) as a colorless oil and (R)-tert-butyl 3-(4-((5-ethynyl-2- fluoropyridin-3-yl) amino) quinazolin-6-yl) piperidine-1-carboxylate (70 mg, 0.16 mmol, 42%) as a colorless oil. m/z ES+ [M+H] ⁺ 448.1. Step 6. (S)-N-(5-ethynyl-2-fluoropyridin-3-yl)-6-(piperidin-3-yl) quinazolin-4-amine To a solution of tert-butyl (3S)-3-[4-[(5-ethynyl-2-fluoro-3-pyridyl)amino]quinazolin-6- yl] piperidine-1-carboxylate (60.0 mg, 134 μmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.2 mL), it was stirred at 25 °C for 20 min. On completion, the reaction mixture was concentrated under reduced pressure to give (S)-N-(5-ethynyl-2-fluoropyridin-3-yl)- 6-(piperidin-3-yl) quinazolin-4-amine (50.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 348.2. Step 7. (S)-1-(3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazoli n-6-yl) piperidin-1- yl)prop-2-en-1-one To a solution of prop-2-enoyl chloride (9.81 mg, 108 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (27.3 mg, 325 μmol) and N-(5-ethynyl-2- fluoro-3-pyridyl)-6-[(3S)-3-piperidyl] quinazolin-4-amine (50.0 mg, 108 μmol, trifluoroacetic acid salt). The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by methanol 0.5 mL and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25 mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 15%-45%, 10 min) to give (S)- 1-(3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one (18.6 mg, 0.046 mmol, 42%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 - 9.58 (m, 1H), 8.48 (s, 1H), 8.38 - 8.12 (m, 3H), 7.94 - 7.70 (m, 2H), 6.88 (dd, J = 10.4, 16.4 Hz, 1H), 6.13 (d, J = 16.4 Hz, 1H), 5.81 - 5.60 (m, 1H), 4.74 - 4.48 (m, 1H), 4.47 (s, 1H), 4.24 - 4.07 (m, 1H), 3.18 - 3.07 (m, 1H), 2.82 (d, J = 8.0 Hz, 2H), 2.06 (d, J = 12.0 Hz, 1H), 1.87 (d, J = 9.6 Hz, 2H), 1.67 - 1.43 (m, 1H); m/z ES+ [M+H] ⁺ 402.3. Example 67. Preparation of 1-[(1S)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo [4.1.0]heptan-3-yl] prop-2-en-1-one (Compound 162) Step 1. Benzyl 1-[4-[[(1Z)-3-chloro-2-fluoro-1-methyl-buta-1,3- dienyl]amino]quinazolin-6-yl] -3-azabicyclo[4.1.0]heptane-3-carboxylate To a solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-amine (298 mg, 845 μmol), 3-benzyloxycarbonyl-3-azabicyclo[4.1.0]heptan-1-yl)-trifluor o-boron;potassiumhydride (300 mg, 889 μmol) in Toluene (8 mL) and water (0.8 mL) was added catacxium (R) A PD G3 (64.8 mg, 89.0 μmol) and cesium carbonate (870 mg, 2.67 mmol). The mixture was stirred at 90 °C for 12 h. The reaction mixture was quenched by water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/ethyl acetate=10/1 to 5/1) to give benzyl 1-[4-[[(1Z)-3-chloro-2-fluoro-1-methyl-buta-1,3-dienyl]amino ]quinazolin-6-yl]-3- azabicyclo[4.1.0]heptane-3-carboxylate (160 mg, 0.32 mmol, 36%) as a yellow solid. m/z ES+ [M+H] ⁺ 503.0. Step 2. Benzyl (1S)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[4.1.0]heptane-3-carboxylate & Benzyl (1R)-1-[4-(3-chloro-2-fluoro- anilino)quinazolin-6-yl]-3-azabicyclo[4.1.0]heptane-3-carbox ylate Benzyl 1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azabicycl o[4.1.0]heptane-3- carboxylate (160 mg, 318 μmol) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 um); mobile phase:[0.7% NH3 water-ethanol]; B%: 50%-50%, 15 min) to give benzyl (1S)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azab icyclo[4.1.0]heptane-3- carboxylate (44.0 mg, 0.087 mmol, 27%) as a yellow solid and benzyl (1R)-1-[4-(3-chloro-2- fluoro- anilino)quinazolin-6-yl]-3-azabicyclo[4.1.0]heptane-3-carbox ylate (48.0 mg, 0.095 mmol, 30%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 7.84 - 7.81 (m, 1H), 7.79 - 7.73 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.41 - 7.30 (m, 6H), 5.16 - 5.09 (m, 2H), 4.26 - 4.11 (m, 1H), 3.90 - 3.53 (m, 2H), 2.23 - 2.12 (m, 1H), 1.85 - 1.75 (m, 1H), 1.53 (s, 1H), 1.26 - 1.12 (m, 2H), 0.81 - 0.76 (s, 1H); m/z ES+ [M+H] ⁺ 503.0. ¹ H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 7.84 - 7.81 (m, 1H), 7.79 - 7.73 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.41 - 7.30 (m, 6H), 5.16 - 5.09 (m, 2H), 4.26 - 4.11 (m, 1H), 3.90 - 3.53 (m, 2H), 2.23 - 2.12 (m, 1H), 1.85 - 1.75 (m, 1H), 1.53 (s, 1H), 1.26 - 1.12 (m, 2H), 0.81 - 0.76 (s, 1H); m/z ES+ [M+H] ⁺ 503.0. Step 3.6-[(1S)-3-azabicyclo[4.1.0]heptan-1-yl]-N-(3-chloro-2-fluo ro-phenyl) quinazolin- 4-amine A solution of benzyl (1S)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azab icyclo [4.1.0]heptane-3-carboxylate (38.0 mg, 75.6 μmol) in trifluoroacetic acid (0.3 mL) was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 6-[(1S)-3- azabicyclo[4.1.0]heptan-1-yl]-N-(3-chloro-2-fluoro-phenyl) quinazolin-4-amine (27.9 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 369.0. Step 4. 1-[(1S)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[4.1.0]heptan-3-yl] prop-2-en-1-one To a solution of 6-[(1S)-3-azabicyclo[4.1.0]heptan-1-yl]-N-(3-chloro-2-fluoro -phenyl) quinazolin-4-amine(27.9 mg, 75.6 μmol) in tetrahydrofuran (1 mL) and water (0.25 mL) was added sodium bicarbonate (25.4 mg, 302 μmol) and prop-2-enoylchloride (6.16 mg, 68.0 μmol ) at 0 °C, the mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by addition methanol (0.6 mL). The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150x40 mm,10 um; mobile phase:[water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-60%, 8 min) to give 1-[(1S)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-a zabicyclo[4.1.0]heptan-3- yl]prop-2-en-1-one (14.3 mg, 0.034 mmol, 45%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 - 9.95 (m, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.91 - 7.83 (m, 1H), 7.80 - 7.75 (m, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.35 - 7.28 (m, 1H), 6.83 (td, J = 18.0, 9.6 Hz, 1H), 6.16 (d, J = 16.0 Hz, 1H), 5.75 - 5.65 (m, 1H), 4.57 (d, J = 14.0 Hz, 1H), 4.33 (d, J = 14.0 Hz, 1H), 3.95 (s, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 3.65 (d, J = 12.4 Hz, 1H), 3.02 (s, 1H), 2.19 (s, 1H), 1.83 (s, 1H), 1.56 (s, 1H), 1.23 (d, J = 5.2 Hz, 1H), 0.78 - 0.66 (m, 1H); m/z ES+ [M+H] ⁺ 423.0. Example 68. Preparation of 1-[(1R)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo [4.1.0]heptan-3-yl] prop-2-en-1-one (Compound 163) Step 1. 6-[(1R)-3-azabicyclo[4.1.0]heptan-1-yl]-N-(3-chloro-2-fluoro -phenyl) quinazolin-4-amine A solution of benzyl (1R)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azab icyclo [4.1.0]heptane-3-carboxylate (42 mg, 83.5 μmol) in trifluoroacetic acid (0.3 mL) was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 6-[(1R)-3- azabicyclo[4.1.0]heptan-1-yl]-N-(3-chloro-2-fluoro-phenyl) quinazolin-4-amine (30.8 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 369.0. Step 2. 1-[(1R)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[4.1.0]heptan-3-yl] prop-2-en-1-one To a solution of 6-[(1R)-3-azabicyclo[4.1.0]heptan-1-yl]-N-(3-chloro-2-fluoro -phenyl) quinazolin-4-amine (30.8 mg, 83.5 μmol) in tetrahydrofuran (1 mL) and water (0.25 mL) was added sodium bicarbonate (28.1 mg, 334 μmol) and prop-2-enoyl chloride (6.80 mg, 75.2 μmol) at 0 °C, the mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by methanol (0.6 mL). The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150x40 mm, 10 um; mobile phase:[water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-60%, 8 min) to give 1- [(1R)-1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-aza bicyclo[4.1.0]heptan-3-yl]prop-2- en-1-one (16.6 mg, 0.039 mmol, 47%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 - 9.94 (m, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.93 - 7.83 (m, 1H), 7.81 - 7.73 (m, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.36 - 7.28 (m, 1 H), 6.92 - 6.73 (m, 1 H), 6.16 (d, J = 16.4 Hz, 1H), 5.76 - 5.66 (m, 1H), 4.57 (d, J = 12.4 Hz, 1H), 4.33 (d, J = 12.4 Hz, 1H), 3.96 (s, 1H), 3.88 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 12.8 Hz, 1H), 3.65 (d, J = 13.6 Hz, 1H), 3.03 (s, 1H), 2.20 (d, J = 12.4 Hz, 1H), 1.82 (s, 1 H), 1.56 (s, 1H), 1.23 (d, J = 5.2 Hz, 1H), 0.78 - 0.66 (m, 1H); m/z ES+ [M+H] ⁺ 423.0. Example 69. Preparation of 1-(3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl) tetrahydropyrimidin-1(2H)-yl) prop-2-en-1-one (Compound 193) Step 1. tert-Butyl N-[3-(3-cyano-4-nitro-anilino)propyl]carbamate A mixture of 5-fluoro-2-nitro-benzonitrile (1.50 g, 9.03 mmol), tert-butyl N-(3- aminopropyl)carbamate (2.36 g, 13.6 mmol) and diisopropylethylamine (2.33 g, 18.1 mmol) in N- methylpyrrolidone (20 mL) was heated at 100 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried and concentrated under vacuum to give tert-butyl N-[3-(3-cyano-4-nitro- anilino)propyl]carbamate (2.8 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 321.3. Step 2. tert-Butyl (3-((4-amino-3-cyanophenyl)amino)propyl) carbamate To a solution of tert-butyl N-[3-(3-cyano-4-nitro-anilino)propyl]carbamate (2.5 g, 7.80 mmol) in ethyl acetate (50 mL) was added platinum on carbon (761 mg, 117 μmol, 3 wt. % loading) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with H ₂ 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 5 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (3-((4-amino-3- cyanophenyl)amino)propyl) carbamate (2.5 g, crude) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.88 - 6.79 (m, 1H), 6.76 - 6.71 (m, 1H), 6.67 - 6.62 (m, 1H), 6.46 (d, J = 2.8 Hz, 1H), 5.15 - 5.02 (m, 3H), 2.98 (q, J = 6.4 Hz, 2H), 2.89 (q, J = 6.8Hz, 2H), 1.64 - 1.55 (m, 2H), 1.37 (s, 9H); m/z ES+ [M+H] ⁺ 291.4. Step 3. tert-Butyl (3-((3-cyano-4- (((dimethylamino)methylene)amino)phenyl)amino)propyl)carbama te To a solution of tert-butyl N-[3-(4-amino-3-cyano-anilino)propyl]carbamate (2.5 g, 8.61 mmol) in toluene (25 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (2.05 g, 17.2 mmol) and acetic anhydride (87.9 mg, 861 μmol, 80.6 μL). The mixture was stirred at 100 °C for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give tert- butyl (3-((3-cyano-4-(((dimethylamino)methylene)amino)phenyl)amino )propyl)carbamate (3.5 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 346.4. Step 4. tert-Butyl (3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)amino)propyl)carbamate To a solution of tert-butyl N-[3-[3-cyano-4-[(E)-dimethylaminomethyleneamino] anilino]propyl]carbamate (800 mg, 2.32 mmol) in acetic acid (5 mL) and toluene (5 mL) was added 3-chloro-2-fluoro-aniline (506 mg, 3.47 mmol), it was stirred at 110 °C for 5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/ethyl acetate=5/1 to 0/1) to give tert-butyl (3-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)amino )propyl)carbamate (350 mg, 0.79 mmol, 30%) as a yellow oil. m/z ES+ [M+H] ⁺ 443.0. Step 5. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)tetrahydropyrimidine-1(2H)-carboxylate To a mixture of tert-butyl N-[3-[[4-(3-chloro-2-fluoro-anilino)quinazolin-6- yl]amino]propyl] carbamate (350 mg, 785 μmol) in water (3 mL) was added formaldehyde (3 mL) in one portion at 20 °C under nitrogen atmosphere. The mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was concentrated under vacuum to give tert-butyl 3-(4-((3- chloro-2-fluorophenyl)amino)quinazolin-6-yl)tetrahydropyrimi dine-1(2H)-carboxylate (400 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 458.3. Step 6. N-(3-chloro-2-fluorophenyl)-6-(tetrahydropyrimidin-1(2H)-yl) quinazolin-4- amine To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl] hexahydropyrimidine-1-carboxylate (150 mg, 328 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL), it was stirred at 25 °C for 3 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-(3-chloro-2-fluorophenyl)-6- (tetrahydropyrimidin-1(2H)-yl)quinazolin-4-amine (130 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 358.1. Step 7. 1-(3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)tetr ahydropyrimidin- 1(2H)-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-hexahydropyrimidin-1-yl-quina zolin-4- amine (130 mg, 276 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (116 mg, 1.38 mmol) and prop-2-enoyl chloride (24.9 mg, 276 μmol), it was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 15%-45%, 10 min) and further purified by prep- HPLC (column: Waters Xbridge 150x25 mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 30%-60%, 10 min) to give 1-(3-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)tetrahydropyrimidin-1(2H) -yl)prop-2-en-1-one (22.8 mg, 0.055 mmol, 20%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 - 9.48 (m, 1H), 8.28 (s, 1H), 7.78 - 7.59 (m, 3H), 7.46 (s, 2H), 7.33 - 7.23 (m, 1H), 6.97 - 6.63 (m, 1H), 6.18 - 5.95 (m, 1H), 5.76 - 5.62 (m, 1H), 5.23 - 5.08 (m, 2H), 3.66 (d, J = 4.4 Hz, 4H), 1.74 (s, 2H); m/z ES+ [M+H] ⁺ 412.2. Example 70. Preparation of (S)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6 - yl)piperidin-1-yl)prop-2-en-1-one (Compound 231) Step 1. 6-Bromo-N-(3-chloro-2,4-difluorophenyl)quinazolin-4-amine To a solution of 6-bromo-4-chloro-quinazoline (2 g, 8.23 mmol) in acetonitrile (20 mL) was added 3-chloro-2,4-difluoro-aniline (1.61 g, 9.88 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was filtered and the solid was collected to give 6-bromo-N-(3-chloro-2,4- difluorophenyl)quinazolin-4-amine (3 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 372.0 Step 2. tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)pip eridine- 1-carboxylate To a 40 mL vial equipped with a stir bar was added 6-bromo-N-(3-chloro-2,4-difluoro- phenyl)quinazolin-4-amine (0.75 g, 2.02 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (695 mg, 2.63 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (22.7 mg, 20.2 μmol), NiCl ₂ .dtbbpy (4.03 mg, 10.1 μmol), tris(trimethylsilyl)silane (503 mg, 2.02 mmol), sodium carbonate (429 mg, 4.05 mmol) in dimethoxyethane (20 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150 x 25 mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 38% - 80%, 14 min) and re-purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 52%-82%, 9 min) to give tert-butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)pip eridine-1- carboxylate (500 mg, 1.05 mmol, 50%) as a yellow solid. m/z ES+ [M+H] ⁺ 475.4. Step 3. (S)-tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6- yl)piperidine-1-carboxylate tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)pip eridine-1- carboxylate (500 mg, 1.05 mmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mmx30 mm, 5 um); mobile phase: [0.1% NH3 water ethanol]; B%: 40%-40%, 2.5 min; 35 min) to give (S)-tert-butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)pip eridine-1- carboxylate (0.14 g, 0.29 mmol, 14%) as a yellow oil and (R)-tert-butyl 3-(4-((3-chloro-2,4- difluorophenyl)amino)quinazolin-6-yl)piperidine-1-carboxylat e (0.14 g, 0.29 mmol, 14%) as a yellow oil. m/z ES+ [M+H] ⁺ 475.4. Step 4. (S)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)quinaz olin-4-amine To a solution of tert-butyl (3S)-3-[4-(3-chloro-2,4-difluoro-anilino)quinazolin-6- yl]piperidine-1-carboxylate (0.14 g, 295 μmol) in ethyl acetate (1.5 mL) was added HCl/ethyl acetate (4 M, 1.5 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give compound (S)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)quinaz olin-4- amine (0.13 g, crude, HCl) as a yellow oil. m/z ES+ [M+H] ⁺ 375.3. Step 5. (S)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6 -yl)piperidin-1- yl)prop-2-en-1-one To a solution of (S)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)quinaz olin-4- amine (110 mg, 268 μmol, HCl) in tetrahydrofuran (1.2 mL) and water (1.2 mL) was added sodium bicarbonate (89.9 mg, 1.07 mmol) and prop-2-enoyl chloride (14.5 mg, 160 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50mm, 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 22%-42%, 10 min) to give compound (S)- 1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl) piperidin-1-yl)prop-2-en-1-one (17.8 mg, 0.041 mmol, 16%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.48 (s, 1H), 8.35 (s, 1H), 7.86 - 7.77 (m, 2H), 7.59 - 7.57 (m, 1H), 7.43 - 7.39 (m, 1H), 6.92 - 6.86 (m, 1H), 6.13 (d, J = 16.4 Hz, 1H), 5.69 (t, J = 12.0 Hz, 1H), 4.66 - 4.55 (m, 1H), 4.22 - 4.16 (m, 1H), 3.21 - 3.08 (m, 1H), 2.89 - 2.65 (m, 2H), 2.08 - 2.05 (m, 1H), 1.88 - 1.86 (m, 2H), 1.55 - 1.53 (m, 1H); m/z ES+ [M+H] ⁺ 429.4. Example 71. Preparation of (R)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6 - yl)piperidin-1-yl)prop-2-en-1-one (Compound 232) Step 1. (R)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)quinaz olin-4-amine To a solution of tert-butyl (3R)-3-[4-(3-chloro-2,4-difluoro-anilino)quinazolin-6- yl]piperidine-1-carboxylate (140 mg, 295 μmol) in ethyl acetate (1.5 mL) was added HCl/ethyl acetate (4 M, 1.5 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give (R)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)quinaz olin-4-amine (0.12 g, crude, HCl) as a yellow oil. m/z ES+ [M+1] ⁺ 375.3. Step 2. (R)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6 -yl)piperidin-1- yl)prop-2-en-1-one To a solution of (R)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)quinaz olin-4- amine (120 mg, 293 μmol, HCl) in tetrahydrofuran (1.3 mL) and water (1.3 mL) was added sodium bicarbonate (108 mg, 1.27 mmol) and prop-2-enoyl chloride (17.4 mg, 193 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150x50 mmx3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 22%-42%, 10 min) to give (R)-1-(3-(4-((3- chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)piperidin-1- yl)prop-2-en-1-onem/z (11.4 mg, 0.027 mmol, 7.9%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.48 (s, 1H), 8.35 (s, 1H), 7.87 - 7.77 (m, 2H), 7.58 - 7.57 (m, 1H), 7.43 - 7.39 (m, 1H), 6.92 - 6.86 (m, 1H), 6.15 - 6.11 (m, 1H), 5.69 (t, J = 11.2 Hz, 1H), 4.65 - 4.55 (m, 1H), 4.22 - 4.16 (m, 1H), 3.16 - 3.08 (m, 1H), 2.88 - 2.80 (m, 2H), 2.08 - 2.04 (m, 1H), 1.88 - 1.84 (m, 2H), 1.55 - 1.50 (m, 1H); m/z ES+ [M+H] ⁺ 429.4. Example 72. Preparation of (S)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl) amino)quinazolin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 126) Step 1. tert-Butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)piperidine-1-carboxylate To a solution of tert-butyl 3-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl) piperidine-1-carboxylate (890 mg, 2.50 mmol), 3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7 - yloxy)aniline (0.60 g, 2.50 mmol) in toluene (5 mL) was added acetic acid (5.25 g, 87.4 mmol) and the mixture was stirred at 110 °C for 3 h. The mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-((4- ([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino )quinazolin-6-yl)piperidine-1- carboxylate (1.1 g, 1.99 mmol, 50%) as a yellow solid. m/z ES+ [M+H] ⁺ 552.2. Step 2. (S)-tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)- 3- methylphenyl)amino)quinazolin-6-yl)piperidine-1-carboxylate tert-Butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphe nyl)amino) quinazolin-6-yl)piperidine-1-carboxylate(1.10 g, 2.00 mmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mmx30 mm, 10 um); mobile phase: [acetonitrile/ethanol (0.1% NH ₃ water)]; B%: 45%-45%, 4.5. 180 min) to give (S)-tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)pipe ridine-1-carboxylate (0.4 g, 0.72 mmol, 50%) as a yellow solid. Step 3. N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl] -6-[(3S)-3- piperidyl]quinazolin-4-amine A solution of tert-butyl (3S)-3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino] quinazolin-6-yl]piperidine-1-carboxylate (0.35 g, 634 μmol) in HCl/ethyl acetate (4 M, 6 mL) was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuo to give N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl] -6-[(3S)-3- piperidyl]quinazolin-4-amine (0.3 g, 0.66 mmol, HCl) as a yellow solid. m/z ES+ [M+H] ⁺ 452.2. Step 4. 1-[(3S)-3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]quinazolin-6-yl]-1-piperidyl]prop-2-en-1-one To a solution of N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl] -6-[(3S)-3- piperidyl]quinazolin-4-amine (277 mg, 614 μmol HCl), sodium bicarbonate (154 mg, 1.84 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added prop-2-enoyl chloride (55.6 mg, 614 μmol) at 0 °C. Then the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 25%-55%, 9 min) to give 1-[(3S)-3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yl oxy)anilino]quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one (0.16 g, 0.32 mmol, 48%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.83 (s, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 7.86 - 7.80 (m, 3H), 7.78 - 7.76 (m, 1H), 7.24 - 7.22 (m, 1H), 7.04 (dd, J = 7.6, 2.8 Hz, 1H), 6.91 - 6.87 (m, 1H), 6.81 - 6.80 (m, 1H), 6.14 (d, J = 16.8 Hz, 1H), 5.69 (t, J = 10.8 Hz, 1H), 4.65 - 4.56 (m, 1H), 4.23 - 4.17 (m, 1H), 3.17 - 2.66 (m, 3H), 2.21 (s, 3H), 2.08 - 2.05 (m, 1H), 1.92 - 1.85 (m, 2H), 1.57 - 1.51 (m, 1H); m/z ES+ [M+H] ⁺ 506.3. Example 73. Preparation of (S)-1-(3-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)quinazol in- 6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 237) Step 1. N-(6-Bromoquinazolin-4-yl)-7-fluorobenzo[d]isothiazol-6-amin e A solution of 6-bromo-4-chloro-quinazoline (1.00 g, 4.11 mmol) and 7-fluoro-1,2- benzothiazol-6-amine (0.76 g, 4.52 mmol) in acetonitrile (20 mL) was stirred at 60 °C for 1 hour. On completion, the suspension was filtered and the filter cake was washed with acetonitrile (10 mL), concentrated to give N-(6-bromoquinazolin-4-yl)-7-fluorobenzo[d]isothiazol-6-amin e (1.50 g, 4.00 mmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 375.1. Step 2. tert-butyl 3-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)quinazolin-6- yl)piperidine-1-carboxylate To an 40 mL vial equipped with a stir bar was added N-(6-bromoquinazolin-4-yl)-7- fluoro-1,2-benzothiazol-6-amine (0.80 g, 2.13 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (0.73 g, 2.77 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (24.0 mg, 21.3 μmol), NiCl2.dtbbpy (4.2 mg, 10.1 μmol), tris(trimethylsilyl)silane (0.53 g, 2.13 mmol), sodium carbonate (0.45 g, 4.26 mmol) in dimethoxyethane (15 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hours under nitrogen. On completion, the solution was concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ ethyl acetate = 1/0 to 0/1) and prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 39%-69%, 10 min) to give tert-butyl 3-(4-((7-fluorobenzo[d]isothiazol-6- yl)amino)quinazolin-6-yl)piperidine-1-carboxylate (0.2 g, 0.42 mmol, 19%) as a white solid. m/z ES+ [M+H] ⁺ 480.3. Step 3. (S)-tert-butyl 3-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)quinazolin-6- yl)piperidine-1-carboxylate tert-Butyl 3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazolin-6-yl] piperidine-1- carboxylate (0.20 g, 417 μmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mmx30 mm, 10 um); mobile phase: [0.1% NH ₃ water ethanol]; B%: 50%-50%, 2.2. 40 min) to give (S)-tert-butyl 3-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)quinazolin-6-yl )piperidine-1- carboxylate (90.0 mg, 0.19 mmol, 90%, >99% ee) as a white solid and (R)-tert-butyl 3-(4-((7- fluorobenzo[d]isothiazol-6-yl)amino)quinazolin-6-yl)piperidi ne-1-carboxylate (90.0 mg, 0.19 mmol, 90%, >99% ee) as a white solid. Step 4. (S)-7-fluoro-N-(6-(piperidin-3-yl)quinazolin-4-yl)benzo[d]is othiazol-6-amine To a solution tert-butyl (3S)-3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazolin- 6- yl]piperidine-1-carboxylate (90.0 mg, 188 μmol) in dichloromethane (2 mL) was added HCl/dioxane (4 M, 0.4 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the solution was concentrated to give (S)-7-fluoro-N-(6-(piperidin-3-yl)quinazolin-4- yl)benzo[d]isothiazol-6-amine (70 mg, crude, HCl salt) as a yellow solid. m/z ES+ [M+H] ⁺ 380.2. Step 5. (S)-1-(3-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)quinazol in-6-yl)piperidin-1- yl)prop-2-en-1-one To a solution of (S)-7-fluoro-N-(6-(piperidin-3-yl)quinazolin-4-yl)benzo[d]is othiazol-6- amine (70.0 mg, 168 μmol, HCl salt) and sodium bicarbonate (113 mg, 1.35 mmol) in tetrahydrofuran (2 mL) and water (0.6 mL) was added a solution of prop-2-enoyl chloride (12.0 mg, 135 μmol) in tetrahydrofuran (0.2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.3 hour. On completion, the solution was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm x 10um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 16% - 46%, 10 min) to give (S)-1-(3-(4-((7- fluorobenzo[d]isothiazol-6-yl)amino)quinazolin-6-yl)piperidi n-1-yl)prop-2-en-1-one (29.0 mg, 0.067 mmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (d, J = 4.0 Hz, 1H), 8.55 - 8.51 (m, 1H), 8.37 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.95 - 7.93 (m, 1H), 7.86 - 7.84 (m, 2H), 6.87 (dd, J = 10.8, 16.4 Hz, 1H), 6.28 - 6.23 (m, 1H), 5.81 - 5.76 (m, 1H), 4.81 - 4.64 (m, 1H), 4.34 - 4.24 (m, 1H), 3.45 - 3.23 (m, 1H), 3.04 - 2.80 (m, 2H), 2.24 - 2.21 (m, 1H), 2.06 - 1.98 (m, 2H), 1.75 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 434.4. Example 74. Preparation of 1-(3-(4-((2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2-en -1-one (Compound 273) Step 1. tert-Butyl 3-[4-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy-anilino]quinazoli n-6- yl]piperidine-1-carboxylate A mixture of 2-fluoro-4-(1-methylpyrazol-3-yl)oxy-aniline (50 mg, 241 μmol), tert-butyl 3-[3-cyano-4-(dimethylaminomethyleneamino)phenyl]piperidine- 1-carboxylate (86.0 mg, 241 μmol) in acetic acid (1 mL) and toluene (1 mL) was stirred at 110 °C for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC (1% NH ₃ •water condition) to give tert-butyl 3-[4-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy- anilino]quinazolin-6-yl]piperidine-1-carboxylate (140 mg, 221 μmol, 92%) as yellow soild. m/z ES+ [M+H] ⁺ 519.2. Step 2. N-(2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe ridin-3- yl)quinazolin-4-amine A mixture of tert-butyl 3-[4-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy-anilino]quinazoli n-6- yl]piperidine-1-carboxylate (140 mg, 270 μmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (2 mL) was stirred at 25 °C for 30 min. On completion, The reaction mixture was concentrated under reduced pressure to give N-(2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)-6-(piperidin-3-yl)quinazolin-4-amine (300 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 419.2. Step 3. 1-[3-[4-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy-anilino]quinaz olin-6-yl]-1- piperidyl]prop-2-en-1-one To a solution of N-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-(3- piperidyl)quinazolin-4-amine (50 mg, 120 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (23.6 mg, 282 μmol) at 0 °C, then prop-2-enoyl chloride (10.8 mg, 120 μmol) was added and the mixture was stirred at 0 °C for 30 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 20%-53%, 9 min) and further purified by prep-HPLC (column: Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 11%-41%, 10 min) to give compound 1-[3- [4-[2-fluoro-4-(1-methylpyrazol-3-yl)oxy-anilino]quinazolin- 6-yl]-1-piperidyl]prop-2-en-1-one (15.56 mg, 32.7 μmol, 27%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 8.49 - 8.39 (m, 1H), 8.36 (s, 1H), 7.89 - 7.78 (m, 1H), 7.78 - 7.67 (m, 2H), 7.47 (t, J = 8.8 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.99 - 6.94 (m, 1H), 6.94 - 6.84 (m, 1H), 6.13 (d, J = 17.2 Hz, 1H), 5.95 (d, J = 2.0 Hz, 1H), 5.77 - 5.59 (m, 1H), 4.72 - 4.50 (m, 1H), 4.28 - 4.09 (m, 1H), 3.77 (s, 3H), 3.28 - 3.08 (m, 1H), 2.88 - 2.65 (m, 2H), 2.12 - 2.01 (m, 1H), 1.96 - 1.78 (m, 2H), 1.62 - 1.41 (m, 1H); m/z ES+ [M+H] ⁺ 473.4. Example 75. Preparation of 1-[3-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazolin-6-y l]- 1-piperidyl] prop-2-en-1-one (Compound 285) Step 1. 6-Bromo-N-[3-chloro-4-(2-pyridylmethoxy)phenyl]quinazolin-4- amine A mixture of 6-bromo-4-chloro-quinazoline (1.94 g, 7.97 mmol) and 3-chloro-4-(2- pyridylmethoxy) aniline (2.24 g, 9.56 mmol) in acetonitrile (40.0 mL) was stirred at 60 °C for 2 h. On completion, the mixture was filtered and the filter cake was collected. The crude product was triturated with acetonitrile (20.0 mL) and dichloromethane (20 mL) at 25 ^o C for 5 mins to give 6- bromo-N-[3-chloro-4-(2-pyridylmethoxy)phenyl]quinazolin-4-am ine (3.40 g, 7.73 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.76 (s, 1H), 9.28 (d, J = 4.0 Hz, 1H), 8.95 (s, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8.26 - 8.21 (m, 1H), 8.01 - 7.92 (m, 3H), 7.72 - 7.61 (m, 2H), 7.49 - 7.44 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H). Step 2. tert-Butyl 3-[4-[3-chloro-4-(2-pyridylmethoxy)aniline]quinazolin-6-yl] piperidine-1-carboxylate To a 15.0 mL vial equipped with a stir bar was added 6-bromo-N-[3-chloro-4-(2- pyridylmethoxy)phenyl]quinazolin-4-amine (2.21 g, 5.00 mmol), tert-butyl 3-bromopiperidine-1- carboxylate (1.72 g, 6.50 mmol ), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (56.1 mg, 50.0 μmol), NiCl ₂ .dtbbpy (9.95 mg, 25.0 μmol), tris(trimethylsilyl)silane (1.24 g, 5.00 mmol, 1.54 mL), sodium carbonate (1.06 g, 10.0 mmol) in dimethoxyethane (8.00 mL). The vial was sealed, stirred and irradiated with a 10 W [455 nm] blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 3 hours under nitrogen. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , pure ethyl acetate) to give tert-butyl 3-[4-[3-chloro-4-(2-pyridylmethoxy)aniline]quinazolin-6-yl] piperidine-1-carboxylate (400 mg, 0.73 mmol, 14%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.79 (s, 1H), 8.63 - 8.57 (m, 3H), 8.55 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.79 - 7.77 (m, 1H), 7.76 - 7.73 (m, 2H), 7.38 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H), 5.30 (s, 2H), 4.05 (s, 2H), 2.87 - 2.73 (m, 3H), 1.83 - 1.74 (m, 2H), 1.54 - 1.48 (m, 1H), 1.42 (s, 9H). Step 3. N-[3-chloro-4-(2-pyridylmethoxy) phenyl]-6-(3-piperidyl) quinazolin-4-amine To a solution of tert-butyl 3-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazolin-6- yl]piperidine-1-carboxylate (200 mg, 366 μmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (6.16 g, 54.0 mmol, 4.00 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-[3-chloro-4-(2-pyridylmethoxy) phenyl]-6- (3-piperidyl) quinazolin-4-amine (200 mg, 97%, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 446.2. Step 4. 1-[3-[4-[3-chloro-4-(2-pyridylmethoxy) anilino]quinazolin-6-yl]-1-piperidyl] prop-2-en-1-one To a mixture of N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6-(3-piperidyl)quina zolin-4- amine (180 mg, 321 μmol, trifluoroacetic acid) and sodium bicarbonate (135 mg, 1.61 mmol) in tetrahydrofuran (3.0 mL) and water (3.0 mL) was added prop-2-enoyl chloride (29.1 mg, 321 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was filtered and concentrated to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150x25 mmx 10 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 32%-62%, 11.5 min) to give 1-[3-[4-[3-chloro-4-(2- pyridylmethoxy)anilino]quinazolin-6-yl]-1-piperidyl]prop-2-e n-1-one (78.4 mg, 0.16 mmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 - 9.72 (m, 1H), 8.63 - 8.59 (m, 1H), 8.57 (s, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.91 - 7.72 (m, 4H), 7.60 (d, J = 7.6 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H), 6.90 (dd, J = 10.4, 16.8 Hz, 1H), 6.16 - 6.12 (m, 1H), 5.76 - 5.64 (m, 1H), 5.31 (s, 2H), 4.69 - 4.52 (m, 1H), 4.30 - 4.12 (m, 1H), 3.30 - 3.08 (m, 2H), 2.88 - 2.81 (m, 1H), 2.11 - 2.00 (m, 1H), 1.94 - 1.83 (m, 2H), 1.63 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 500.3. Example 76. Preparation of 1-[3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinazolin- 6- yl]-1-piperidyl]prop-2-en-1-one (Compound 294) Step 1. 2-[(2-chloro-4-nitro-phenoxy)methyl]pyrazine To a solution of 2-chloro-1-fluoro-4-nitro-benzene (3.00 g, 17.1 mmol) in N,N- dimethylformamide (30 mL) was added pyrazin-2-ylmethanol (1.88 g, 17.1 mmol) and potassium carbonate (3.54 g, 25.6 mmol). The mixture was stirred at 60 °C for 2 hours. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-[(2-chloro-4-nitro-phenoxy)methyl]pyrazine (3.6 g, 13.6 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (d, J = 4.0 Hz, 1H), 8.98 - 8.90 (m, 2H), 8.61 (d, J = 2.8 Hz, 1H), 8.54 - 8.47 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 5.80 (s, 2H). Step 2.3-chloro-4-(pyrazin-2-ylmethoxy)aniline To a solution of 2-[(2-chloro-4-nitro-phenoxy)methyl]pyrazine (500 mg, 1.88 mmol) in methanol (10 mL) was added platinum on carbon (250 mg, 3 wt. % loading) in one portion at 25 °C under H ₂ . The mixture was stirred at 25 °C under H ₂ (15 psi) for 1 hour. On completion, the mixture was filtered and concentrated to give 3-chloro-4-(pyrazin-2-ylmethoxy)aniline (400 mg, 1.69 mmol, 90%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 8.69 - 8.55 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 4.0 Hz, 1H), 6.52 - 6.39 (m, 1H), 5.19 - 5.12 (m, 2H), 4.99 (s, 2H); m/z ES+ [M+H] ⁺ 236.0. Step 3.6-bromo-N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]quinazol in-4-amine To a solution of 3-chloro-4-(pyrazin-2-ylmethoxy)aniline (250 mg, 1.06 mmol) in acetonitrile (15 mL) was added 6-bromo-4-chloro-quinazoline (258 mg, 1.06 mmol), the mixture was stirred at 60 °C for 12 hours. On completion, the crude product was triturated with acetonitrile (10 mL) at 25 °C for 5 min to give 6-bromo-N-[3-chloro-4-(pyrazin-2- ylmethoxy)phenyl]quinazolin-4-amine (400 mg, 0.90 mmol, 85%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.21 (s, 1H), 9.70 (d, J = 4.0 Hz, 1H), 9.43 - 9.27 (m, 2H), 9.17 - 9.06 (m, 2H), 8.71 - 8.62 (m, 1H), 8.40 - 8.33 (m, 2H), 8.17 - 8.10 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 5.86 (s, 2H); m/z ES+ [M+H] ⁺ 444.0. Step 4. tert-butyl 3-(4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)quinazol in-6- yl)piperidine-1-carboxylate To an 15 mL vial equipped with a stir bar was added 6-bromo-N-[3-chloro-4-(pyrazin-2- ylmethoxy)phenyl]quinazolin-4-amine (354 mg, 0.8 mmol), tert-butyl 3-bromopiperidine-1- carboxylate (273 mg, 1.04 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (8.98 mg, 8.00 μmol), NiCl ₂ .dtbbpy (1.59 mg, 4.00 μmol), tris(trimethylsilyl)silane (198 mg, 800 μmol), sodium carbonate (169 mg, 1.60 mmol) in dimethoxyethane (8 mL). The vial was sealed, stirred and irradiated with a 10 W [455 nm] blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 3 hr under nitrogen. The mixture was filtered and concentrated to give a residue. The crude product was purified by reversed-phase (0.1% FA condition) to give tert-butyl 3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinazolin-6-y l]piperidine-1- carboxylate (175 mg, 0.32 mmol, 39%) as a white solid. m/z ES+ [M+H]+ 547.4. Step 5. N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-6-(3-piperidyl)qu inazolin-4-amine To a solution of tert-butyl 3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinazolin-6- yl]piperidine-1-carboxylate (160 mg, 292 μmol) in dichloromethane (4.0 mL) was added HCl/dioxane (4 M, 731 μL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated to give N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-6-(3- piperidyl)quinazolin-4-amine (130 mg, crude, HCl salt) as a yellow solid. m/z ES+ [M+H] ⁺ 447.2. Step 6. 1-[3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinazolin- 6-yl]-1-piperidyl] prop-2-en-1-one To a mixture of N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-6-(3-piperidyl)qu inazolin- 4-amine (130 mg, 290 μmol) and sodium bicarbonate (122 mg, 1.45 mmol) in tetrahydrofuran (2.5 mL) and water (2.5 mL) was added prop-2-enoyl chloride (26.3 mg, 290 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was filtered and concentrated to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150x25 mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 12%-42%, 11.5 min) to give 1-[3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinazolin- 6-yl]- 1-piperidyl] prop-2-en-1-one (71.1 mg, 0.14 mmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 8.87 (d, J = 1.2 Hz, 1H), 8.72 - 8.69 (m, 1H), 8.67 - 8.66 (m, 1H), 8.57 (s, 1H), 8.37 (d, J = 1.2 Hz, 1H), 8.03 (s, 1H), 7.86 - 7.74 (m, 3H), 7.36 (d, J = 8.8 Hz, 1H), 6.94 - 6.84 (m, 1H), 6.15 - 6.11 (m, 1H), 5.73 - 5.64 (m, 1H), 5.39 (s, 2H), 4.68 - 4.54 (m, 1H), 4.18 - 4.17 (m, 1H), 3.16 - 3.10 (m, 1H), 2.93 - 2.78 (m, 2H), 1.93 - 1.85 (m, 3H), 1.62 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 501.4. Example 77. Preparation of 1-[3-[4-[3-chloro-4-[(6-fluoro-2- pyridyl)methoxy]anilino]quinazolin-6-yl]-1-piperidyl]prop-2- en-1-one (Compound 291) Step 1. 2-(Chloromethyl)-6-fluoro-pyridine To a solution of 2-fluoro-6-methyl-pyridine (1.00 g, 9.00 mmol) in acetonitrile (10 mL) was added NCS (1.80 g, 13.5 mmol), (E)-2,2'-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (29.5 mg, 179 μmol) and acetic acid (42.0 mg, 699 μmol). The mixture was stirred at 85 °C for 15 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate=10/1 to 1/1) to give 2-(chloromethyl)-6-fluoro-pyridine (798 mg, 5.50 mmol, 52%) as a yellow oil. NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (q, J = 7.2 Hz, 1H), 7.51 (dd, J = 2.4, 7.6 Hz, 1H), 7.17 (dd, J = 2.8, 8.4 Hz, 1H), 4.75 (s, 2H). Step 2.2-[(2-Chloro-4-nitro-phenoxy)methyl]-6-fluoro-pyridine To a solution of 2-chloro-4-nitro-phenol (800 mg, 4.61 mmol) and 2-(chloromethyl)-6- fluoro-pyridine (704 mg, 4.84 mmol) in acetonitrile (8 mL) was added potassium carbonate (764 mg, 5.53 mmol) and NaI (690 mg, 4.61 mmol). The mixture was stirred at 60 °C for 2 hours. On completion, the reaction mixture was quenched by addition water 5 mL at 25 °C and extracted with ethyl acetate 9 mL (3 mL x 3). The combined organic layers were washed with brine (3 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate=10/1 to 1/1) to give 2-[(2-chloro-4-nitro-phenoxy)methyl]-6-fluoro-pyridine (660 mg, 2.34 mmol, 40%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (d, J = 2.8 Hz, 1H), 8.28 - 8.21 (m, 1H), 8.14 - 8.06 (m, 1H), 7.53 (dd, J = 2.4, 7.6 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.23 - 7.12 (m, 1H), 5.44 (s, 2H). Step 3.3-Chloro-4-[(6-fluoro-2-pyridyl)methoxy]aniline A mixture of 2-[(2-chloro-4-nitro-phenoxy)methyl]-6-fluoro-pyridine (560 mg, 1.98 mmol), platinum on carbon (250 mg, 3 wt. % loading) in methanol (5 mL) and ethyl acetate (2 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 2 hours under H ₂ atmosphere (15 Psi). On completion, the mixture was filtered and the filtrate was concentrated to give 3-chloro-4-[(6-fluoro-2-pyridyl)methoxy]aniline (471 mg, 1.87 mmol, 75%) as a light yellow solid. m/z ES+ [M+H] ⁺ 253.0 Step 4. 6-Bromo-N-[3-chloro-4-[(6-fluoro-2-pyridyl)methoxy]phenyl]qu inazolin-4- amine To a solution of 3-chloro-4-[(6-fluoro-2-pyridyl)methoxy]aniline (471 mg, 1.86 mmol) and 6-bromo-4-chloro-quinazoline (544 mg, 2.24 mmol) in acetonitrile (5 mL).was stirred at 60 °C for 2 hours. On completion, the mixture was filtered and the solid was collected to give 6- bromo-N-[3-chloro-4-[(6-fluoro-2-pyridyl)methoxy]phenyl]quin azolin-4-amine (468 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.55 (s, 1H), 9.18 - 9.11 (m, 1H), 8.99 - 8.93 (m, 1H), 8.25 (dd, J = 1.6, 8.8 Hz, 1H), 8.10 (q, J = 8.0 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.68 (dd, J = 2.4, 9.2 Hz, 1H), 7.55 (dd, J = 2.0, 7.2 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 2.0, 8.0 Hz, 1H), 5.32 (s, 2H); m/z ES+ [M+H] ⁺ 459.0. Step 5. tert-Butyl 3-[4-[3-chloro-4-[(6-fluoro-2-pyridyl) methoxy]anilino]quinazolin-6- yl]piperidine-1-carboxylate To an 15 mL vial equipped with a stir bar was added 6-bromo-N-[3-chloro-4-[(6-fluoro- 2-pyridyl)methoxy]phenyl]quinazolin-4-amine (100 mg, 217 μmol), tert-butyl 3- bromopiperidine-1-carboxylate (74.7 mg, 282 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (2.44 mg, 2.18 μmol), NiCl ₂ .dtbbpy (432 ug, 1.09 μmol), tris(trimethylsilyl)silane (54.0 mg, 217 μmol), sodium carbonate (46.1 mg, 435 μmol) in dimethoxyethane (3 mL). The vial was sealed, stirred and irradiated with a 10 W [455 nm] blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 14 hours under nitrogen. On completion, the reaction mixture was quenched by addition water 5 mL and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , dichloromethane: methanol = 20:1) to give tert-butyl 3-[4-[3-chloro-4-[(6-fluoro-2-pyridyl) methoxy]anilino]quinazolin-6-yl]piperidine-1-carboxylate (347 mg, 0.62 mmol, 87%) as a light yellow solid. m/z ES+ [M+H] ⁺ 564.0. Step 6. N-[3-Chloro-4-[(6-fluoro-2-pyridyl)methoxy]phenyl]-6-(3-pipe ridyl) quinazolin- 4-amine To a solution of tert-butyl 3-[4-[3-chloro-4-[(6-fluoro-2- pyridyl)methoxy]anilino]quinazolin-6-yl]piperidine-1-carboxy late (300 mg, 531 μmol) in dichloromethane (15 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol). The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated to give N-[3-chloro-4- [(6-fluoro-2-pyridyl)methoxy]phenyl]-6-(3-piperidyl)quinazol in-4-amine (172 mg, 0.37 mmol, 35%, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 464.0. Step 7. 1-[3-[4-[3-Chloro-4-[(6-fluoro-2-pyridyl)methoxy]anilino] quinazolin-6-yl]-1- piperidyl]prop-2-en-1-one To a solution of N-[3-chloro-4-[(6-fluoro-2-pyridyl)methoxy]phenyl]-6-(3-pipe ridyl) quinazolin-4-amine(172 mg, 370 μmol) and prop-2-enoyl chloride (16.7 mg, 185 μmol) in tetrahydrofuran (3 mL) and water (3 mL) was added sodium bicarbonate (31.1 mg, 370 μmol). The mixture was stirred at 0 °C for 15 min. On completion, the residue was purified by prep-HPLC (Neu:column: Phenomenex luna C18 150 x 25 mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 19%-49%, 11.5 min) to give 1-[3-[4-[3-chloro-4-[(6-fluoro-2- pyridyl)methoxy]anilino]quinazolin-6-yl]-1-piperidyl]prop-2- en-1-one (32.3 mg, 0.062 mmol, 16%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.90 - 9.77 (m, 1H), 8.59 (s, 1H), 8.39 (s, 1H), 8.18 - 7.99 (m, 2H), 7.85 (m, 1H), 7.79 - 7.70 (m, 2H), 7.55 (dd, J = 2.0, 7.2 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.18 (dd, J = 2.0, 8.0 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.14 (d, J = 16.8 Hz, 1H), 5.74 - 5.64 (m, 1H), 5.28 (s, 2H), 4.67 - 4.55 (m, 1H), 4.24 - 4.13 (m, 1H), 3.20 - 3.08 (m, 1H), 2.91 - 2.69 (m, 2H), 2.11 - 1.80 (m, 3H), 1.64 - 1.43 (m, 1H); m/z ES+ [M+H] ⁺ 518.0. Example 78. Preparation of 1-(3-(4-((5-phenoxypyrimidin-2-yl)amino)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one (Compound 300) Step 1.2-Chloro-5-phenoxy-pyrimidine To a solution of 2-chloropyrimidin-5-ol (20 g, 153 mmol) and phenylboronic acid (37.3 g, 306 mmol) in dichloromethane (300 mL) was added copper acetate (33.4 g, 184 mmol), 4Å molecular sieves (153 mmol) and triethylamine (77.5 g, 766 mmol) at 25 °C, the mixture was stirred at 25 °C for 12 hours under oxygen atmosphere. The reaction mixture was quenched by ammonium hydroxide 500 mL at 25 °C, and then extracted with dichloromethane (750 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (0.1% trifluoroacetic acid conditions) to give 2-chloro-5-phenoxy-pyrimidine (7 g, 33.8 mmol, 22%) as a brown solid. m/z ES+ [M+H] ⁺ 207.4 Step 2. 5-Phenoxypyrimidin-2-amine A solution of 2-chloro-5-phenoxy-pyrimidine (7 g, 33.8 mmol) in ammonium hydroxide (50 mL, 35%) and tetrahydrofuran (5 mL) was stirred at 130 °C for 6 hours in autoclave. The reaction mixture was quenched by addition water 100 mL at 25 °C, and then extracted with ethyl acetate (600 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-phenoxypyrimidin-2- amine (6 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 2H), 7.47 - 7.36 (m, 2H), 7.34 - 7.30 (m, 1H), 7.08 - 7.04 (m,2 H), 6.95 - 6.68 (m, 2H). Step 3. tert-Butyl 3-[4-[(5-phenoxypyrimidin-2-yl)amino]quinazolin-6-yl]piperid ine-1- carboxylate To a solution of tert-butyl 3-(4-chloroquinazolin-6-yl)piperidine-1-carboxylate (400 mg, 1.15 mmol) and 5-phenoxypyrimidin-2-amine (215 mg, 1.15 mmol) in dimethyl sulfoxide (5 mL) was added potassium tert-butoxide (1 M in THF, 3.45 mL). The mixture was stirred at 80 °C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.1% FA conditions) to give tert-butyl 3-[4-[(5- phenoxypyrimidin-2-yl)amino]quinazolin-6-yl]piperidine-1-car boxylate (450 mg, 902 μmol, 79%) as a white solid. m/z ES+ [M+H] ⁺ 499.3. Step 4. N-(5-phenoxypyrimidin-2-yl)-6-(3-piperidyl)quinazolin-4-amin e To a solution of tert-butyl 3-[4-[(5-phenoxypyrimidin-2-yl)amino]quinazolin-6- yl]piperidine-1-carboxylate (60 mg, 120 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.4 mmol, 0.4 mL), the mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give N-(5-phenoxypyrimidin-2-yl)-6-(3- piperidyl)quinazolin-4-amine (61.0 mg, trifluoroacetic acid) as a white solid. m/z ES+ [M+H] ⁺ 399.3. Step 5. 1-[3-[4-[(5-phenoxypyrimidin-2-yl)amino]quinazolin-6-yl]-1-p iperidyl]prop-2- en-1-one To a solution of N-(5-phenoxypyrimidin-2-yl)-6-(3-piperidyl)quinazolin-4-amin e (60 mg, 117 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.2 mL) was added potassium carbonate (48.5 mg, 351 μmol) at 0 °C, then prop-2-enoyl chloride (10.6 mg, 117 μmol) was added. The mixture was stirred at 0 °C for 0.2 hour. The mixture reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral:column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 27%- 60%, 9 min) to give 1-[3-[4-[(5-phenoxypyrimidin-2-yl)amino]quinazolin-6-yl]-1-p iperidyl]prop- 2-en-1-one (16.2 mg, 35.3 μmol, 30%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 8.41 (s, 1H), 7.94 - 7.68 (m, 2H), 7.51 - 7.37 (m, 2H), 7.28 - 7.11 (m, 3H), 6.88 - 6.91 m, 1H), 6.19 - 6.03 (m, 1H), 5.79 - 5.57 (m, 1H), 4.68 - 4.48 (m, 1H), 4.17 ( s, 1H), 3.20 - 3.05 (m, 1H), 2.95 - 2.75 (m, 2H), 2.05-2.20 ( d, J = 10.8 Hz, 1H), 1.94 - 1.75 (m, 2H), 1.66 - 1.43 (m, 1H); m/z ES+ [M+H] ⁺ 453.5. Example 79. Preparation of 1-[3-[4-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)anilino]quinazolin-6-yl]-1-piperidyl]prop-2-en-1-o ne (Compound 320) Step 1. 6-Bromo-N-(3-chloro-4-((tetrahydrofuran-3-yl)methoxy)phenyl) quinazolin-4- amine To a solution of 6-bromo-4-chloro-quinazoline (200 mg, 821 μmol) in acetonitrile (5.0 mL) was added 3-chloro-4-(tetrahydrofuran-3-ylmethoxy)aniline (200 mg, 878 μmol). The mixture was stirred at 80 °C for 2 hours. On completion, the mixture was filtered and concentrated to give 6-bromo-N-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]qu inazolin-4-amine (400 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.54 (s, 1H), 9.18 (d, J = 1.6 Hz, 1H), 8.94 (s, 1H), 8.22 (dd, J = 2.0, 8.8 Hz, 1H), 7.99 - 7.83 (m, 2H), 7.66 (dd, J = 2.4, 8.8 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.12 - 3.99 (m, 2H), 3.84 - 3.76 (m, 2H), 3.71 - 3.65 (m, 1H), 3.58 (dd, J = 5.6, 8.4 Hz, 1H), 2.75 - 2.65 (m, 1H), 2.06 - 1.98 (m, 1H), 1.79 - 1.63 (m, 1H). Step 2. tert-Butyl 3-[4-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)anilino]quinaz olin-6- yl]piperidine-1-carboxylate To a 15 mL vial equipped with a stir bar was added 6-bromo-N-[3-chloro-4- (tetrahydrofuran-3-ylmethoxy)phenyl]quinazolin-4-amine (300 mg, 690 μmol), tert-butyl 3- bromopiperidine-1-carboxylate (236 mg, 897 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (7.74 mg, 6.90 μmol), NiCl ₂ .dtbbpy (1.37 mg, 3.45 μmol), tris(trimethylsilyl)silane (171 mg, 690 μmol), sodium carbonate (146 mg, 1.38 mmol) and dimethoxyethane (2.0 mL). The vial was sealed and irradiated with a 10 W [455 nm] blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 16 hours under nitrogen. On completion, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-[3-chloro-4- (tetrahydrofuran-3-ylmethoxy)anilino]quinazolin-6-yl]piperid ine-1-carboxylate (110 mg, 0.20 mmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.72 (s, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.86 - 7.61 (m, 3H), 7.23 (d, J = 9.2 Hz, 1H), 4.13 - 3.93 (m, 4H), 3.87 - 3.74 (m, 2H), 3.68 (q, J = 7.6 Hz, 1H), 3.59 (dd, J = 5.2, 8.6 Hz, 1H), 2.85 - 2.65 (m, 3H), 2.57 (d, J = 3.6 Hz, 1H), 2.11 - 1.96 (m, 2H), 1.85 - 1.65 (m, 3H), 1.59 - 1.47 (m, 1H), 1.42 (s, 9H). Step 3. N-(3-Chloro-4-((tetrahydrofuran-3-yl)methoxy)phenyl)-6-(pipe ridin-3- yl)quinazolin-4-amine To a solution of tert-butyl 3-[4-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)anilino]quinazolin-6-yl]piperidine-1-carboxylate (90.0 mg, 166 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give N-[3- chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-(3-piperidyl )quinazolin-4-amine (70 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 439.2. Step 4. 1-(3-(4-((3-Chloro-4-((tetrahydrofuran-3-yl)methoxy)phenyl)a mino)quinazolin- 6-yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-(3- piperidyl)quinazolin-4-amine (70.0 mg, 159 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (40.1 mg, 478 μmol) and water (0.5 mL) at 0 °C. Then prop-2-enoyl chloride (14.4 mg, 159 μmol) was added and the mixture was stirred at 25 °C for 0.5 hour. On completion, the residue was purified by Prep-HPLC (column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (FA)-ACN]; B%: 15%-45%,11.5 min) to give 1-[3-[4-[3-chloro-4-(tetrahydrofuran- 3-ylmethoxy)anilino]quinazolin-6-yl]-1-piperidyl]prop-2-en-1 -one (50 mg, 0.10 mmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.82 (d, J = 13.6 Hz, 1H), 8.58 (s, 1H), 8.38 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.23 (d, J = 9.2 Hz, 1H), 6.89 (dd, J = 10.4, 16.4 Hz, 1H), 6.13 (d, J = 16.4 Hz, 1H), 5.69 (t, J = 11.6 Hz, 1H), 4.68 - 4.50 (m, 1H), 4.21 - 4.13 (m, 1H), 4.09 - 4.03 (m, 1H), 4.02 - 3.96 (m, 1H), 3.85 - 3.76 (m, 2H), 3.73 - 3.65 (m, 1H), 3.59 (dd, J = 5.6, 8.4 Hz, 1H), 3.19 - 3.06 (m, 1H), 2.67 (s, 3H), 2.12 - 1.98 (m, 2H), 1.94 - 1.82 (m, 2H), 1.79 - 1.66 (m, 1H), 1.58 - 1.46 (m, 1H); m/z ES+ [M+H] ⁺ 493.2. Example 80. Preparation of 1-[3-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy- anilino]quinazolin-6-yl]-1-piperidyl]prop-2-en-1-one (Compound 321) Step 1. 6-Bromo-N-(3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl) quinazolin-4- amine To a solution of 6-bromo-4-chloro-quinazoline (500 mg, 2.05 mmol) in acetonitrile (5 mL) was added 3-chloro-4-(1-methylpyrazol-3-yl)oxy-aniline (551 mg, 2.46 mmol). The mixture was stirred at 80 °C for 2 hours. On completion, the mixture was filtered and concentrated in vacuo to give 6-bromo-N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]quina zolin-4-amine (1.1 g, crude) as a light yellow solid. m/z ES+ [M+H] ⁺ 432.0. Step 2. tert-Butyl 3-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)quinazolin-6-yl)piperidine-1-carboxylate To a 15 mL vial equipped with a stir bar was added 6-bromo-N-[3-chloro-4-(1- methylpyrazol-3-yl)oxy-phenyl]quinazolin-4-amine (350 mg, 813 μmol), tert-butyl 3- bromopiperidine-1-carboxylate (279 mg, 1.06 mmol), tris(trimethylsilyl)silane (202 mg, 813 μmol, 251 μL), NiCl ₂ .dtbbpy (1.62 mg, 4.06 μmol), sodium carbonate (172 mg, 1.63 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (9.12 mg, 8.13 μmol) and dimethoxyethane (3 mL). The vial was sealed and irradiated with a 10 W [455 nm] blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 4 hours under nitrogen. On completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-[3-chloro-4-(1- methylpyrazol-3-yl)oxy-anilino]quinazolin-6-yl]piperidine-1- carboxylate (170 mg, 0.32 mmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.13 - 8.06 (m, 1H), 7.81 - 7.72 (m, 3H), 7.60 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 5.79 (d, J = 2.4 Hz, 1H), 4.08 (s, 2H), 3.70 (s, 3H), 2.83 - 2.74 (m, 2H), 1.98 (d, J = 10.4 Hz, 1H), 1.76 (d, J = 10.8 Hz, 2H), 1.56 - 1.46 (m, 1H), 1.41 - 1.40 (m, 1H), 1.39 (s, 9H); m/z ES+ [M+H] ⁺ 535.3. Step 3. N-(3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe ridin-3- yl)quinazolin-4-amine To a solution of tert-butyl 3-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy- anilino]quinazolin-6-yl]piperidine-1-carboxylate (160 mg, 299 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-4-(1-methylpyrazol-3- yl)oxy-phenyl]-6-(3-piperidyl)quinazolin-4-amine (170 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 435.2. Step 4. 1-(3-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)a mino)quinazolin- 6-yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-(3- piperidyl)quinazolin-4-amine (130 mg, 299 μmol) in tetrahydrofuran (0.4 mL) and water (0.3 mL) was added sodium bicarbonate (25.1 mg, 299 μmol) at 0 °C over 5 minutes and then prop-2-enoyl chloride (27.0 mg, 299 μmol) in tetrahydrofuran (0.4 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 5 minutes. On completion, the residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 12%-42%, 10 min) to give 1-[3-[4-[3-chloro-4-(1-methylpyrazol- 3-yl)oxy-anilino]quinazolin-6-yl]-1-piperidyl]prop-2-en-1-on e (71.5 mg, 0.15 mmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (d, J = 7.6 Hz, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.91 - 7.82 (m, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 10.4, 16.4 Hz, 1H), 6.14 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 2.4 Hz, 1H), 5.74 - 5.64 (m, 1H), 4.69 - 4.53 (m, 1H), 4.26 - 4.12 (m, 1H), 3.73 (s, 3H), 3.22 - 3.07 (m, 1H), 2.93 - 2.69 (m, 2H), 2.07 (br. d, J = 11.6 Hz, 1H), 1.96 - 1.82 (m, 2H), 1.64 - 1.47 (m, 1H); m/z ES+ [M+H] ⁺ 489.2. Example 81. Preparation of 1-(3-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)quinazolin-6-yl)piperidin-1-yl )prop-2-en-1-one (Compound 349) Step 1. 6-Bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)quinazolin-4-a mine To a solution of 6-bromo-4-chloro-quinazoline (208 mg, 852 μmol) in acetonitrile (3 mL) was added 3-chloro-4-(difluoromethoxy)aniline (150 mg, 775 μmol). The mixture was stirred at 60 °C for 2 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate=10:1 to 1:1 and dichloromethane/methanol = 20:1 to 10:1) to give 6-bromo-N-[3-chloro-4- (difluoromethoxy)phenyl]quinazol In-4-amine (300 mg, 0.75 mmol, 96%) as a white solid. m/z ES+ [M+H] ⁺ 402.0. Step 2. tert-Butyl 3-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)quinazolin-6 - yl)piperidine-1-carboxylate To a 15 mL vial equipped with a stir bar was added 6-bromo-N-[3-chloro-4- (difluoromethoxy)phenyl]quinazolin-4-amine (300 mg, 749 μmol), tert-butyl 3-bromopiperidine- 1-carboxylate (257 mg, 974 μmol), tris(trimethylsilyl)silane (186 mg, 749 μmol, 231 μL) NiCl2.dtbbpy (1.49 mg, 3.74 μmol), sodium carbonate (159 mg, 1.50 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (8.40 mg, 7.49 μmol) and dimethoxyethane (5 mL). The vial was sealed and irradiated with a 10 W [455 nm] blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 14 hours under nitrogen. On completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 10:1 to 10:3) to give tert-butyl 3-[4-[3-chloro-4-(difluoromethoxy)anilino]quinazolin-6-yl]pi peridine-1- carboxylate (130 mg, 0.26 mmol, 34%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.69 (s, 1H), 8.44 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.98 - 7.81 (m, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.34 - 7.11 (m, 1H), 4.88 - 4.81 (m, 2H), 4.78 - 4.71 (m, 2H), 3.64 - 3.54 (m, 1H), 2.93 - 2.83 (m, 2H), 1.85 (d, J = 11.2 Hz, 2H), 1.48 (s, 9H); m/z ES+ [M+H] ⁺ 505.3. Step 3. N-(3-chloro-4-(difluoromethoxy)phenyl)-6-(piperidin-3-yl)qui nazolin-4-amine To a solution of tert-butyl 3-[4-[3-chloro-4-(difluoromethoxy)anilino]quinazolin-6- yl]piperidi ne-1-carboxylate (100 mg, 198 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-4-(difluoromethoxy)phenyl]-6-(3- piperidyl)quinazolin-4-amine (100 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 405.2. Step 4. 1-(3-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)quinazoli n-6-yl)piperidin- 1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-6-(3-piperidyl)quinaz olin-4- amine (100 mg, 247 μmol) in tetrahydrofuran (0.3 mL) and water (0.3 mL) was added sodium bicarbonate (104 mg, 1.24 mmol) at 0 °C over 5 minutes and then prop-2-enoyl chloride (20.1 mg, 222 μmol) in tetrahydrofuran (0.3 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 5 minutes. On completion, the residue was purified by prep- HPLC (column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 27%-57%, 10 min) to give 1-[3-[4-[3-chloro-4- (difluoromethoxy)anilino]quinazolin-6-yl]-1-piperidyl]prop-2 -en-1-one (10 mg, 0.022 mmol, 9%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.95 - 9.84 (m, 1H), 8.63 (s, 1H), 8.40 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.92 - 7.84 (m, 2H), 7.82 - 7.78 (m, 1H), 7.46 - 7.41 (m, 1H), 7.28 - 7.04 (m, 1H), 6.89 (dd, J = 10.4, 16.4 Hz, 1H), 6.14 (d, J = 16.8 Hz, 1H), 5.75 - 5.64 (m, 1H), 4.68 - 4.53 (m, 1H), 4.26 - 4.13 (m, 1H), 3.20 - 3.10 (m, 1H), 2.93 - 2.78 (m, 2H), 2.06 (d, J = 11.6 Hz, 1H), 1.96 - 1.85 (m, 2H), 1.61 - 1.49 (m, 1H); m/z ES+ [M+H] ⁺ 459.1. Example 82. Preparation of (S)-1-(3-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2 -en-1-one (Compound 360) Step 1. (S)-tert-Butyl 3-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazol in- 6-yl)piperidine-1-carboxylate & (R)-tert-butyl 3-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidine-1-carboxyl ate tert-Butyl 3-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazolin-6-yl] piperidine-1- carboxylate (450 mg, 824 μmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250mmx30mm, 10 um); mobile phase: [0.1% NH3 water IPA]; B%: 40%-40%, 3.4. 180 min) to give tert-butyl (3S)-3-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazolin-6 -yl]piperidine-1- carboxylate (220 mg, 0.40 mmol, 48%) as a yellow solid and tert-butyl (3R)-3-[4-[3-chloro-4-(2- pyridylmethoxy)anilino]quinazolin-6-yl]piperidine-1-carboxyl ate (215 mg, 0.39 mmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 8.64 - 8.55 (m, 2H), 8.35 (s, 1H), 8.01 (d, J = 4.0 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.82 - 7.78 (m, 1H), 7.75 - 7.71 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.30 (s, 2H), 4.05 (br. d, J = 12.0 Hz, 2H), 2.97 - 2.72 (m, 3H), 2.05 - 1.97 (m, 1H), 1.78 (br. d, J = 12.0 Hz, 2H), 1.57 - 1.49 (m, 1H), 1.42 (s, 9H); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (br. s, 1H), 8.66 - 8.54 (m, 2H), 8.38 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.84 - 7.80 (m, 1H), 7.76 - 7.69 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.31 (s, 2H), 4.16 - 3.99 (m, 2H), 3.32 (br. s, 2H), 2.85 - 2.74 (m, 2H), 2.01 (br. d, J = 12.0 Hz, 1H), 1.83 - 1.73 (m, 2H), 1.42 (s, 9H). Step 2. (S)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-(piperidin- 3-yl)quinazolin-4- amine To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazolin-6 - yl]piperidine-1-carboxylate (220 mg, 402 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (2.31 g, 20.2 mmol, 1.5 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated to give N-[3-chloro-4-(2-pyridylmethoxy) phenyl]-6- [(3S)-3-piperidyl] quinazolin-4-amine (225 mg, 0.51 mmol, 99%, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 446.1. Step 3. (S)-1-(3-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)q uinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one To a mixture of N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6-[(3S)-3- piperidyl]quinazolin-4-amine (225 mg, 401 μmol, trifluoroacetic acid) and sodium bicarbonate (168 mg, 2.01 mmol) in tetrahydrofuran (3.0 mL) and water (3.0 mL) was added prop-2-enoyl chloride (36.3 mg, 401 μmol, 32.7 μL) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hour. On completion, the crude product was purified by Prep-HPLC (column: Phenomenex luna C18 150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 32%-62%, 11.5 min) to give 1-[(3S)-3-[4-[3-chloro-4-(2-pyridylmethoxy) anilino]quinazolin-6-yl]-1-piperidyl] prop-2-en-1-one (87.1 mg, 0.17 mmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.64 - 8.58 (m, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 8.01 (s, 1H), 7.92 - 7.79 (m, 2H), 7.78 - 7.69 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.97 - 6.80 (m, 1H), 6.13 (d, J = 16.0 Hz, 1H), 5.78 - 5.60 (m, 1H), 5.30 (s, 2H), 4.71 - 4.51 (m, 1H), 4.30 - 4.08 (m, 1H), 3.20 - 3.06 (m, 1H), 2.92 - 2.77 (m, 2H), 2.05 (d, J = 12.0 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.59 - 1.47 (m, 1H); m/z ES+ [M+H] ⁺ 500.2. Example 83. Preparation of (R)-1-(3-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2 -en-1-one (Compound 361) Step 1. (R)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-(piperidin- 3-yl)quinazolin-4- amine To a solution of tert-butyl (3R)-3-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazolin- 6-yl]piperidine-1-carboxylate (210 mg, 384 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (2.31 g, 20.2 mmol, 1.5 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated to give N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6- [(3R)-3-piperidyl] quinazolin-4-amine (215 mg, 0.48 mmol, 99%, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 446.2. Step 2. (R)-1-(3-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)q uinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one To a mixture of N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6-[(3R)-3- piperidyl]quinazolin-4-amine (215 mg, 383 μmol, trifluoroacetic acid) and sodium bicarbonate (161 mg, 1.92 mmol) in tetrahydrofuran (3.0 mL) and water (3.0 mL) was added prop-2-enoyl chloride (34.7 mg, 383 μmol, 31.3 μL) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was filtered and concentrated to give a residue. The crude product was purified by Prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 32%-62%, 11.5 min) to give 1-[(3R)-3-[4-[3-chloro- 4-(2-pyridylmethoxy)anilino] quinazolin-6-yl]-1-piperidyl]prop-2-en-1-one (110 mg, 0.22 mmol, 57%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.63 - 8.54 (m, 2H), 8.37 (s, 1H), 8.01 (s, 1H), 7.92 - 7.80 (m, 2H), 7.77 - 7.70 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.93 - 6.84 (m, 1H), 6.13 (d, J = 16.0 Hz, 1H), 5.76 - 5.63 (m, 1H), 5.30 (s, 2H), 4.70 - 4.52 (m, 1H), 4.27 - 4.11 (m, 1H), 2.92 - 2.77 (m, 2H), 2.73 - 2.65 (m, 1H), 2.05 (d, J = 12.0 Hz, 1H), 1.94 - 1.83 (m, 2H), 1.59 - 1.46 (m, 1H); m/z ES+ [M+H] ⁺ 500.2. Example 84. Preparation of (S)-1-(3-(4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2 -en-1-one (Compound 406) Step 1. (S)-tert-Butyl 3-(4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)quinazol in- 6-yl)piperidine-1-carboxylate & (R)-tert-butyl 3-(4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidine-1-carboxyl ate tert-Butyl 3-(4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)quinazol in-6-yl) piperidine-1-carboxylate (850 mg, 1.56 mmol) was purified by SFC (column: DAICEL CHIRALPAK AS(250mmx30mm,10um); mobile phase: [0.1% NH ₃ H ₂ O-methanol]; B%: 35%- 35%,5;100 min) to give (S)-tert-Butyl 3-(4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidine-1-carboxyl ate (400 mg, 0.73 mmol, 47%) as a yellow solid and (R)-tert-butyl 3-(4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidine-1-carboxyl ate (390 mg, 46%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 8.87 (d, J = 0.8Hz, 1H), 8.72 - 8.69 (m, 1H), 8.66 (d, J = 2.4Hz, 1H), 8.56 (s, 1H), 8.35 (s, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.85 - 7.71 (m, 4H), 7.36 (d, J = 9.2Hz, 1H), 5.39 (s, 2H), 4.16 - 4.05 (m, 2H), 3.26 (d, J = 16.01H), 2.84 - 2.77 (m, 2H), 2.05 - 1.95 (m, 2H), 1.78 (d, J = 11.2Hz, 2H), 1.42 (s, 9H); m/z ES+ [M+H] ⁺ 547.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.87 (d, J = 0.8 Hz, 1H), 8.73 - 8.68 (m, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.36 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.83 - 7.71 (m, 3H), 7.36 (d, J = 9.2 Hz, 1H), 5.39 (s, 2H), 4.17 - 4.03 (m, 2H), 3.30 (s, 1H), 2.89 - 2.74 (m, 2H), 2.06 - 1.93 (m, 2H), 1.79 (d, J = 11.2 Hz, 2H), 1.42 (s, 9H); m/z ES+ [M+H] ⁺ 547.2. Step 2. (S)-N-(3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)-6-(piperidin- 3-yl)quinazolin-4- amine A solution of tert-butyl (3S)-3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinazoli n- 6-yl]piperidine-1-carboxylate (350 mg, 639 μmol) in trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-6-[(3S)-3-piperid yl]quinazolin-4-amine (286 mg, 0.64 mmol, 92%) as a yellow oil. m/z ES+ [M+H] ⁺ 447.1. Step 3. (S)-1-(3-(4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)q uinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-6-[(3S)-3- piperidyl]quinazolin-4-amine (286 mg, 639 μmol) in tetrahydrofuran (3.0 mL) and water (3.0 mL) was added sodium bicarbonate (53.7 mg, 639 μmol) at 0 °C until pH = 8. After that, prop-2-enoyl chloride (57.9 mg, 639 μmol, 52.1 μL) was added. The mixture was stirred at 20 °C for 0.25 hr. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: YMC Triart C18 250x50mmx7um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 30%-60%,10 min) to give 1-[(3S)-3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinaz olin-6-yl]-1-piperidyl]prop-2-en-1- one (120 mg, 0.24 mmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 - 9.60 (m, 1H), 8.87 (s, 1H), 8.68 (dd, J = 1.6, 13.2 Hz, 2H), 8.59 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.90 - 7.71 (m, 3H), 7.36 (d, J = 9.2 Hz, 1H), 6.89 (dd, J = 10.4, 16.8 Hz, 1H), 6.13 (d, J = 16.8 Hz, 1H), 5.76 - 5.63 (m, 1H), 5.39 (s, 2H), 4.70 - 4.48 (m, 1H), 4.18 (dd, J = 4.0, 5.6 Hz, 1H), 3.17 - 2.65 (m, 3H), 2.10 - 1.99 (m, 1H), 1.95 - 1.81 (m, 2H), 1.53 (d, J = 3.6 Hz, 1H); m/z ES+ [M+H] ⁺ 501.5. Example 85. Preparation of (R)-1-(3-(4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2 -en-1-one (Compound 405)

Step 1. (R)-N-(3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)-6-(piperidin- 3-yl)quinazolin-4- amine A solution of tert-butyl (3R)-3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinazoli n- 6-yl]piperidine-1-carboxylate (340 mg, 622 μmol) in trifluoroacetic acid (1.00 mL) and dichloromethane (4.00 mL) was stirred at 20 °C for 1 hour. On completion, the reaction mixture was concentrated to give N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-6-[(3R)-3- piperidyl]quinazolin-4-amine (278 mg, 0.62 mmol, 90%) as a yellow oil. m/z ES+ [M+H] ⁺ 447.1. Step 2. (R)-1-(3-(4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)q uinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-6-[(3R)-3- piperidyl]quinazolin-4-amine (278 mg, 622 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (52.2 mg, 622 μmol) at 0 °C until pH = 8. After that, prop-2- enoyl chloride (56.3 mg, 622 μmol, 50.7 μL) was added. The mixture was stirred at 20 °C for 0.25 hour. On completion, the reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: YMC Triart C18250x50mm, 7um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 30%-60%, 10 min) to give 1-[(3R)-3-[4-[3-chloro-4-(pyrazin-2-ylmethoxy)anilino]quinaz olin-6-yl]-1- piperidyl]prop-2-en-1-one (119 mg, 0.24 mmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 - 9.76 (m, 1H), 8.88 (d, J = 1.2 Hz, 1H), 8.79 - 8.64 (m, 2H), 8.59 (s, 1H), 8.39 (s, 1H), 8.02 (s, 1H), 7.92 - 7.72 (m, 3H), 7.37 (d, J = 9.2 Hz, 1H), 6.89 (dd, J = 10.4, 16.8 Hz, 1H), 6.14 (d, J = 16.8 Hz, 1H), 5.79 - 5.62 (m, 1H), 5.40 (s, 2H), 4.69 - 4.53 (m, 1H), 4.29 - 4.12 (m, 1H), 3.18 - 2.78 (m, 3H), 2.06 (d, J = 11.6 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.65 - 1.44 (m, 1H); m/z ES+ [M+H] ⁺ 501.5. Example 86. Preparation of (S)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one (Compound 79) Step 1. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)piperid ine-1- carboxylate To a solution of tert-butyl 3-[3-cyano-4- (dimethylaminomethyleneamino)phenyl]piperidine-1-carboxylate (1.00 g, 2.81 mmol) and 3- chloro-2-fluoro-aniline (0.61 g, 4.21 mmol) in toluene (10 mL) was added acetic acid (10 mL). The mixture was stirred at 110 °C for 3 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 1:1) to give tert-butyl 3-[4-(3-chloro-2- fluoro-anilino)quinazolin-6-yl]piperidine-1-carboxylate (540 mg, 1.18 mmol, 41%) as a white solid. m/z ES+ [M+H] ⁺ 457.1. Step 2. (S)-tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)piperid ine- 1-carboxylate tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]piperidine-1 -carboxylate (540 mg, 1.18 mmol) was purified by SFC (column: DAICELCHIRALPAK IC (250mmx30mm,10um); mobile phase: [0.1% NH3 water ethanol]; B%: 45%-45%, 2.2.50 min) to give (S)-tert-butyl 3-(4- ((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)piperidine-1 -carboxylate (200 mg, 0.44 mmol, 37%) as a yellow solid. Step 3. (S)-N-(3-chloro-2-fluorophenyl)-6-(piperidin-3-yl)quinazolin -4-amine To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6- yl]piperidine-1-carboxylate (200 mg, 0.44 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.2 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro- phenyl)-6-[(3S)-3-piperidyl] quinazolin-4-amine (200 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 357.2. Step 4. (S)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl) piperidin-1- yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-3-piperidyl]quinazolin- 4-amine (200 mg, 0.56 mmol) and sodium bicarbonate (0.14 g, 1.68 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added acryloyl chloride (30 mg, 0.34 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 26%-56%, 8min) to give (S)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl) piperidin-1-yl)prop-2-en-1- one (54.4 mg, 0.13 mmol, 23%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 7.91 - 7.71 (m, 2H), 7.59 - 7.41 (m, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.89 ( J = 16.4, 10.4 Hz, 1H), 6.13 (d, J = 16.8 Hz, 1H), 5.75 - 5.61 (m, 1H), 4.71 - 4.50 (m, 1H), 4.26 - 4.09 (m, 1H), 3.25 - 2.65 (m, 3H), 2.09 - 2.04 (m, 1H), 1.94 - 1.79 (m, 2H), 1.59 - 1.47 (m, 1H); m/z ES+ [M+H] ⁺ 411.1. Example 87. Preparation of 1-(3-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one (Compound 343)

Step 1. tert-Butyl 3-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperidine-1-carboxylate A mixture of tert-butyl3-[3-cyano-4-(dimethylaminomethyleneamino)phenyl]p iperidine- 1-carboxylate (121 mg, 340 μmol) and 4-chloro-5-phenoxy-pyridin-2-amine (50 mg, 227 μmol) in toluene (1 mL) and acetic acid (1 mL) was degassed and purged with nitrogen for 3 times, then the mixture was stirred at 110 °C for 2 hrs under nitrogen atmosphere. On completion, the solution was concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150x50mm, 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B% :70%-100%, 10 min) to give tert-butyl 3-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6-yl) piperidine-1- carboxylate (30 mg, 0.056 mmol, 23%) as a yellow solid. m/z ES+ [M+H] ⁺ 532.2. Step 2. N-(4-Chloro-5-phenoxypyridin-2-yl)-6-(piperidin-3-yl)quinazo lin-4-amine A mixture of tert-butyl 3-[4-[(4-chloro-5-phenoxy-2-pyridyl)amino]quinazolin-6- yl]piperidine-1-carboxylate (20 mg, 37.6 μmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (1 mL) was stirred at 15 °C for 30 min. On completion, the mixture was concentrated to give N-(4-chloro-5-phenoxy-2-pyridyl)-6-(3-piperidyl)quinazolin-4 -amine (20 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 431.9. Step 3. 1-(3-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)quinazolin-6- yl)piperidin-1- yl)prop-2-en-1-one To a solution of N-(4-chloro-5-phenoxy-2-pyridyl)-6-(3-piperidyl)quinazolin-4 -amine (16 mg, 37.0 μmol) and sodium bicarbonate (9.34 mg, 111 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added prop-2-enoyl chloride (3.35 mg, 37.0 μmol) at 0 °C. The mixture solution was stirred at 0 °C for 0.3 hour. On completion, the solution was concentrated. The residue was purified by prep-HPLC (column: UniSil 3-100 C18 UItra (150x25mmx3um); mobile phase:[water (0.225% FA)-acetonitrile]; B%: 38%-68%, 10 min) to give 1-(3-(4-((4-chloro-5- phenoxypyridin-2-yl)amino)quinazolin-6-yl)piperidin-1-yl)pro p-2-en-1-one (12 mg, 0.025 mmol, 67%) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 - 8.68 (m, 2H), 8.75 - 8.15 (m, 1H), 8.17 (s, 1H), 7.92 - 7.76 (m, 2H), 7.41 - 7.32 (m, 2H), 7.18 - 7.10 (m, 1H), 7.02 - 7.65 (m, 2H), 6.88 - 6.81 (m, 1H), 6.27 - 6.20 (m, 1H), 5.79 - 5.73 (m, 1H), 4.86 - 4.67 (m, 1H), 4.26 - 4.18 (m, 1H), 3.49 - 3.38 (m, 2H), 3.05 - 2.95 (m, 1H), 2.20 - 2.16 (m, 1H), 2.02 - 1.90 (m, 2H), 1.75 - 1.60 (m, 1H); m/z ES+ [M+H] ⁺ 486.1. Example 88. Preparation of (R)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one (Compound 34) Step 1. 6-Bromo-4-(3,4-dichloro-2-fluorophenoxy)quinazoline A solution of 6-bromo-4-chloro-quinazoline (672.7 mg, 2.76 mmol), 3,4-dichloro-2- fluoro-phenol (500 mg, 2.76 mmol) and potassium carbonate (763.6 mg, 5.53 mmol) in acetonitrile (5 mL) was stirred at 60 °C for 2 hrs. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was recrystallized in dimethyl sulfoxide (15 mL) and then filtered. The filter cake was collected to give 6-bromo-4-(3,4-dichloro-2-fluoro- phenoxy)quinazoline (670 mg, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 2.0, 8.8 Hz, 1H), 7.97 - 7.90 (m, 1H), 7.40 (dd, J = 2.0, 9.2 Hz, 1H), 7.23 (dd, J = 7.6, 8.8 Hz, 1H). Step 2. tert-Butyl 3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)piperidin e-1- carboxylate To a 8 mL vial equipped with a stir bar was added 6-bromo-4-(3,4-dichloro-2-fluoro- phenoxy)quinazoline (200 mg, 515 μmol), tert-butyl 3-bromopiperidine-1-carboxylate (177 mg, 670 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (5.78 mg, 5.15 μmol), NiCl ₂ ·dtbbpy (1.03 mg, 2.58 μmol), tris(trimethylsilyl)silane (128 mg, 515 μmol, 159.02 μL), sodium carbonate (109 mg, 1.03 mmol) and dimethoxyethane (1.5 mL). The vial was degassed and purged with N ₂ for 3 times. Then the reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hrs. On completion, the reaction mixture was diluted with water (5 mL), and then extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 3:1) to give tert-butyl 3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)piperidin e -1- carboxylate (93 mg, 0.19 mmol, 34%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 1.6, 8.8 Hz, 1H), 7.40 (dd, J = 2.0, 8.8 Hz, 1H), 7.24 (dd, J = 7.6, 8.8 Hz, 1H), 4.46 - 4.08 (m, 2H), 3.00 - 2.76 (m, 3H), 2.17 (m, 1H), 1.88 - 1.67 (m, 3H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 492.2. Step 3. (R)-tert-butyl 3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)piperidin e-1- carboxylate and (S)-tert-butyl 3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)piperidin e-1- carboxylate tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-phenoxy)quinazolin-6-yl]piperidi ne-1-carboxylate (93 mg, 189 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um); mobile phase: [0.1% NH3 water IPA]; B%: 55%-55%,4 min;20 min) to give tert-butyl (R)-3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)piper idine-1- carboxylate (40 mg, 0.081 mmol, 42%) as a yellow oil and tert-butyl (S)-3-(4-(3,4-dichloro-2- fluorophenoxy)quinazolin-6-yl)piperidine-1-carboxylate (50 mg, 0.10 mmol, 50%) as a yellow oil. Step 4. (R)-4-(3,4-dichloro-2-fluorophenoxy)-6-(piperidin-3-yl)quina zoline To a solution of tert-butyl (R)-3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)piperidine-1-carboxylate (40 mg, 81.2 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL). The reaction mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give (R)-4-(3,4-dichloro-2- fluorophenoxy)-6-(piperidin-3-yl)quinazoline (40 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 392.2. Step 5. (R)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)pi peridin-1-yl)prop- 2-en-1-one To a solution of (R)-4-(3,4-dichloro-2-fluorophenoxy)-6-(piperidin-3-yl)quina zoline (40 mg, 79.0 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.2 mL) was added sodium bicarbonate (19.9 mg, 237 μmol) at 0 °C. Then prop-2-enoyl chloride (6.44 mg, 71.1 μmol, 5.80 μL) was added. The reaction was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 0/1) and further purified by prep-HPLC (column: Phenomenex Synergi C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 51%-81%, 10 min) to give (R)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)pi peridin-1-yl)prop-2- en-1-one (13.24 mg, 25.71 μmol, 32%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (m, 1H), 8.40 - 8.13 (m, 2H), 8.09 - 7.89 (m, 1H), 7.43 (m, 1H), 7.27 - 7.20 (m, 1H), 6.75 - 6.55 (m, 1H), 6.33 (m, 1H), 5.74 (m, 1H), 4.99 - 4.73 (m, 1H), 4.28 - 3.95 (m, 1H), 3.39 - 3.12 (m, 1H), 3.09 - 2.97 (m, 1H), 2.92 - 2.80 (m, 1H), 2.28 - 2.22 (m, 1H), 2.00 - 1.87 (m, 2H), 1.76 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 446.1. Example 89. Preparation of (S)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one (Compound 35) Step 1. (S)-4-(3,4-dichloro-2-fluorophenoxy)-6-(piperidin-3-yl)quina zoline To a solution of tert-butyl (S)-3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)piperidine-1-carboxylate (50 mg, 102 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1.92 g, 16.9 mmol, 1.25 mL). The reaction mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give (S)-4-(3,4-dichloro- 2-fluorophenoxy)-6-(piperidin-3-yl)quinazoline (50 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 392.2. Step 2. (S)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)pi peridin-1-yl)prop-2- en-1-one To a solution of 4-(3,4-dichloro-2-fluoro-phenoxy)-6-[(3S)-3-piperidyl]quinaz oline (50 mg, 127 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.2 mL) was added sodium bicarbonate (32.1 mg, 382 μmol) at 0 °C. Then prop-2-enoyl chloride (10.4 mg, 115 μmol, 9.35 μL) was added. The reaction was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 0/1) and further purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 51%- 81%,10 min) to give (S)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)pi peridin-1- yl)prop-2-en-1-one (13 mg, 29.2 μmol, 19.5%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.80 (s, 1H), 8.30 - 8.11 (m, 2H), 8.00 - 7.82 (m, 1H), 7.42 (dd, J = 1.6, 8.8 Hz, 1H), 7.27 - 7.21 (m, 1H), 6.73 - 6.55 (m, 1H), 6.33 (m, 1H), 5.74 (m, 1H), 4.99 - 4.72 (m, 1H), 4.26 - 4.02 (m, 1H), 3.36 - 3.13 (m, 1H), 3.08 - 2.95 (m, 1H), 2.90 - 2.70 (m, 1H), 2.27 - 2.22 (m, 1H), 1.99 - 1.87 (m, 2H), 1.77 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 446.1. Example 90. Preparation of 1-(3-(4-((4-(imidazo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2-en- 1-one (Compound 358)

Step 1. 4-(2-Methyl-4-nitrophenoxy)picolinonitrile To a solution of 2-methyl-4-nitrophenol (1.22 g, 7.94 mmol) in N,N-dimethylformamide (10 mL) was added potassium hydroxide (810 mg, 14.4 mmol). The mixture was stirred at 25 °C for 0.5 hr. Then 4-chloropicolinonitrile (1 g, 7.22 mmol) was added in the mixture and stirred at 100 °C for 12 hr. The mixture was poured into water (200 mL) then extracted with ethyl acetate (200 mL x 2). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 5/1) to give 4- (2-methyl-4-nitrophenoxy)picolinonitrile (0.32 g, 1.25 mmol, 17%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.66 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.18 (dd, J = 2.8, 9.2 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 2.4, 5.6 Hz, 1H), 2.27 (s, 3H). Step 2. (4-(2-Methyl-4-nitrophenoxy)pyridin-2-yl)methanamine To a solution of 4-(2-methyl-4-nitro-phenoxy)pyridine-2-carbonitrile (0.6 g, 2.35 mmol) in tetrahydrofuran (3 mL) was added borane-methyl sulfide complex (10 M in THF, 1.18 mL) at 0 °C. The mixture was stirred at 50 °C for 1 h. The mixture was carefully quenched by methanol (15 mL) and then concentrated in vacuo to give (4-(2-methyl-4-nitrophenoxy)pyridin-2- yl)methanamine (0.6 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 260.2. Step 3. N-((4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)methyl)formamide A solution of [4-(2-methyl-4-nitro-phenoxy)-2-pyridyl]methanamine (0.6 g, 2.31 mmol) in formic acid (6 mL) was stirred at 100 °C for 2 hr. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give N-((4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)methyl)formamide (0.2 g, 0.70 mmol, 30%) as a yellow oil. m/z ES+ [M+H] ⁺ 288.1. Step 4. 7-(2-Methyl-4-nitrophenoxy)imidazo[1,5-a]pyridine To a solution of N-[[4-(2-methyl-4-nitro-phenoxy)-2-pyridyl]methyl]formamide (0.2 g, 696 μmol) in dichloroethane (2 mL) was added a mixture of phosphorus oxychloride (214 mg, 1.39 mmol) in dichloroethane (2 mL). The mixture was stirred at 85 °C for 12 hr. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in dichloromethane (20 mL) and then quenched by sat. sodium bicarbonate solution (20 mL). The organic phase was concentraed in vacuo to give 7-(2-methyl-4-nitrophenoxy)imidazo[1,5-a]pyridine (180 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 270.0. Step 5. 4-(Imidazo[1,5-a]pyridin-7-yloxy)-3-methylaniline To a solution of 7-(2-methyl-4-nitro-phenoxy)imidazo[1,5-a]pyridine (0.18 g, 669 μmol) in methanol (1.5 mL) was added platinum on carbon (180 mg, 690 μmol, 3 wt. % loading). The mixture was stirred at 25 °C for 12 hr under H ₂ at 15 psi. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 22%- 52%, 10 min) and then purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 15%-45%, 8min) to give 4-(imidazo[1,5-a]pyridin-7-yloxy)-3-methylaniline (90 mg, 0.38 mmol, 56%) as a yellow oil. m/z ES+ [M+H] ⁺ 240.1. Step 6. tert-Butyl 3-(4-((4-(imidazo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)piperidine-1-carboxylate A mixture of tert-butyl 3-[3-cyano-4-[(E)- dimethylaminomethyleneamino]phenyl]piperidine-1-carboxylate (20 mg, 56.1 μmol) and 4- imidazo[1,5-a]pyridin-7-yloxy-3-methyl-aniline (8.05 mg, 33.7 μmol) in toluene (0.5 mL) and acetic acid (0.5 mL) was stirred at 110 °C for 3 hrs. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 46%-76%, 8min) to give tert-butyl 7-amino-8-cyano-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxy late (45 mg, 0.082 mmol, 73%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.50 (s, 1H), 8.31 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.21 (s, 1H), 7.88 - 7.81 (m, 1H), 7.80 - 7.73 (m, 2H), 7.70 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 2.4, 8.8 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 1.6, 8.4 Hz, 1H), 7.15 - 7.09 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 2.4, 7.6 Hz, 1H), 6.61 (s, 1H), 4.31 - 4.12 (m, 2H), 4.06 (d, J = 12.8 Hz, 2H), 3.08 (br. d, J = 18.4 Hz, 5H), 2.98 - 2.80 (m, 4H), 2.72 - 2.56 (m, 1H), 2.27 (s, 3H), 1.48 - 1.43 (m, 8H). Step 7. N-(4-(imidazo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-(pipe ridin-3- yl)quinazolin-4-amine To a solution of tert-butyl 3-[4-(4-imidazo[1,5-a]pyridin-7-yloxy-3-methyl- anilino)quinazolin-6-yl]piperidine-1-carboxylate (35 mg, 63.6 μmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (60.0 μL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to give N-(4-(imidazo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6- (piperidin-3-yl)quinazolin-4-amine (40 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 451.1. Step 8. 1-(3-(4-((4-(imidazo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)a mino)quinazolin- 6-yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(4-imidazo[1,5-a]pyridin-7-yloxy-3-methyl-phenyl)-6-(3- piperidyl)quinazolin-4-amine (35 mg, 62 μmol, trifluoroacetic acid) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (20.8 mg, 248 μmol) and prop-2-enoyl chloride (2.81 mg, 31 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC [column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 24%-54%, 8min] to give 1-(3-(4-((4-(imidazo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2-en- 1-one (2.1 mg, 4.17 μmol, 6.3%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.59 - 8.54 (m, 1H), 8.38 (s, 1H), 8.34 - 8.25 (m, 2H), 7.92 (t, J = 7.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J = 9.6 Hz, 1H), 7.14 (d, J = 10.8 Hz, 2H), 6.92 - 6.77 (m, 1H), 6.73 - 6.67 (m, 1H), 6.63 (s, 1H), 6.24 (d, J = 17.2 Hz, 1H), 5.83 - 5.71 (m, 1H), 4.81 - 4.66 (m, 1H), 4.36 - 4.15 (m, 1H), 3.11 - 2.92 (m, 2H), 2.28 (s, 3H), 2.23 - 2.15 (m, 1H), 2.03 - 1.90 (m, 2H), 1.77 - 1.63 (m, 1H), 1.33 - 1.27 (m, 1H); m/z ES+ [M+H] ⁺ 505.1. Example 91. Preparation of 1-(3-(4-((3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2 -en-1-one (Compound 391) Step 1. tert-Butyl 3-(4-((3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)phenyl)amino)quinazolin-6-yl)piperidine-1-carboxyl ate A mixture of tert-butyl 3-(4-chloroquinazolin-6-yl)piperidine-1-carboxylate (150 mg, 431 μmol) and 3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)aniline (99.9 mg, 431 μmol) in acetonitrile (2 mL) was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/ethyl acetate = 0:1) to give tert-butyl 3-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]quinazolin-6-yl]piperidine-1-carboxylate (70 mg, 129 μmol, 30%) as a white solid. m/z ES+ [M+H] ⁺ 543.1. Step 2. N-(3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl)-6-(piperi din-3- yl)quinazolin-4-amine To a mixture of tert-butyl 3-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]quinazoli n-6-yl]piperidine-1-carboxylate (60.0 mg, 110 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The rection mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(oxeta n-3-ylmethoxy)phenyl]-6-(3-piperidyl)quinazolin-4-amine (45 mg, 102 μmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 443.2. Step 3. 1-(3-(4-((3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl)ami no)quinazolin-6- yl)piperidin-1-yl)prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-(3- piperidyl)quinaz olin-4-amine (45.0 mg, 101 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (8.54 mg, 101 μmol) at 0 °C until pH = 7~8. Then prop-2-enoyl chloride (9.20 mg, 101 μmol) was added, the reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 22%-52%,8min) to give 1-[3-[4-[3-chloro- 2-fluoro-4-(oxetan-3-ylmethoxy)anilino]quinazolin-6-yl]-1-pi peridyl]prop-2-en-1-one (9.7 mg, 19.5 μmol, 18%) as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.89 (s, 1H), 8.27 - 8.49 (m, 2H), 7.79 - 7.89 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.81 - 6.96 (m, 1H), 6.13 (d, J = 16.4 Hz, 1H), 5.69 (t, J = 12.0 Hz, 1H), 4.74 (m, 2H), 4.53 - 4.69 (m, 1H), 4.49 (t, J = 6.0 Hz, 2H), 4.37 (d, J = 6.4 Hz, 2H), 4.11 - 4.24 (m, 1H), 3.41 - 3.52 (m, 1H), 3.05 - 3.28 (m, 1H), 2.81 (d, J = 8.4 Hz, 2H), 2.00 - 2.10 (m, 1H), 1.80 - 1.97 (m, 2H), 1.43 - 1.63 (m, 1H); m/z ES+ [M+H] ⁺ 497.1. Example 92. Preparation of (S)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 89)

Step 1. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimi din-6- yl)-5,6-dihydropyridine-1(2H)-carboxylate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimi din-4- amine (1.00 g, 2.91 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (945 mg, 3.06 mmol) in dioxane (12 mL) and water (2 mL) was added potassium carbonate (1.21 g, 8.73 mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (238 mg, 291 μmol). The mixture was stirred at 100 °C for 2 hrs under nitrogen. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=5/1 to 0/1) to afford tert-butyl 5-[4-(3,4- dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]-3,6-d ihydro-2H-pyridine-1-carboxylate (1.4 g, 2.86 mmol, 98%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H), 9.20 –9.12 (m, 1H), 8.63 (s, 1H), 8.42 –8.39 (m, 1H), 7.69 –7.59 (m, 2H), 7.10 –7.05 (m, 1H), 4.46 (s, 2H), 3.57 –3.50 (m, 2H), 2.40 –2.35 (m, 2H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 490. Step 2. tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimi din-6- yl)piperidine-1-carboxylate To a solution of tert-butyl 5-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.30 g, 2.65 mmol) and magnesium oxide (855 mg, 21.2 mmol) in tetrahydrofuran (15 mL) was added palladium on activated carbon (130 mg, 10 wt. % loading) under nitrogen. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under hydrogen gas atmosphere (15 psi) at 25 °C for 12 hrs. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash (C18, 0.1% FA, acetonitrile-water, 0~100%) to afford tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl]piperidine-1- carboxylate (1.2 g, 2.44 mmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 492.3. Step 3. (S)-tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimi din- 6-yl)piperidine-1-carboxylate tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl]piperidine-1- carboxylate (750 mg, 1.52 mmol) was purified by SFC (column: DAICEL CHIRALCEL OJ- H(250mmx30mm,5um); mobile phase: [0.1% NH3 water MEOH]; B%: 35%-35%,3.2 min;40 min) to afford (S)-tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimi din-6- yl)piperidine-1-carboxylate (320 mg, 0.65 mmol, 42%) as a white solid. Step 4. (S)-N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido [3,4-d]pyrimidin-4- amine To a solution of (S)-tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)piperidine-1-carboxylate (320 mg, 650 μmol) in dichloromethane (5 mL) was added HCl/ethyl acetate (4 M, 1 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to afford (S)-N-(3,4-dichloro-2- fluorophenyl)-6-(piperidin-3-yl)pyrido[3,4-d]pyrimidin-4-ami ne (275 mg, crude, HCl salt) as a yellow solid. m/z ES+ [M+H] ⁺ 392.0. Step 5. (S)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d ]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3R)-3-piperidyl]pyrido[ 3,4- d]pyrimidin-4-amine (275 mg, 701 μmol, HCl) in tetrahydrofuran (5 mL) and water (5 mL) was added sodium bicarbonate (118 mg, 1.40 mmol) and prop-2-enoyl chloride (66.6 mg, 736 μmol) at 0 °C. The mixture was stirred at 0 °C for 15 min. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 42%-72%, 7min) to afford (S)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d ]pyrimidin-6-yl)piperidin-1- yl)prop-2-en-1-one (156 mg, 0,35 mmol, 50%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 - 9.98 (m, 1H), 9.17 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.24 (s, 1H), 7.61 (s, 2H), 6.96 - 6.79 (m, 1H), 6.13 (dd, J = 8.8, 16.8 Hz, 1H), 5.70 (t, J = 9.2 Hz, 1H), 4.90 - 4.42 (m, 1H), 4.38 - 4.12 (m, 1H), 3.12 (t, J = 13.2 Hz, 1H), 3.04 - 2.90 (m, 1H), 2.90 - 2.71 (m, 1H), 2.17 (d, J = 12.0 Hz, 1H), 2.03 - 1.81 (m, 2H), 1.65 - 1.48 (m, 1H); m/z ES+ [M+H] ⁺ 446.2. Example 93. Preparation of (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 134) Step 1. tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6-yl)- 5,6-dihydropyridine-1(2H)-carboxylate A mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine (12.0 g, 38.8 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H- pyridine-1-carboxylate (14.4 g, 46.6 mmol), Pd(dppf)Cl ₂ (2.84 g, 3.88 mmol) and potassium carbonate (16.1 g, 116 mmol) in dioxane (150 mL) and water (15 mL) was degassed and purged with nitrogen gas (3x). Then the mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (400 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/ethyl acetate=2:1 to 1:1) to afford tert-butyl 5-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -3,6-dihydro-2H-pyridine-1- carboxylate (17 g, 37.4 mmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 456.1. Step 2. tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6- yl)piperidine-1-carboxylate To a solution of tert-butyl 5-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] - 3,6-dihydro-2H-pyridine-1-carboxylate (10.0 g, 21.9 mmol) in tetrahydrofuran (100 mL) was added palladium on activated carbon (5 g, 10% loading) and magnesium oxide (7.07 g, 175 mmol) under nitrogen. The suspension was degassed under vacuum and purged with H2 several times. Then the mixture was stirred under hydrogen gas atmosphere (15 psi) at 25 °C for 12 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash (C18, 330, acetonitrile-0.1% FA, 0~100) to afford tert- butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] piperidine-1-carboxylate (5.0 g, 10.94 mmol, 49%) as a brown oil. m/z ES+ [M+H] ⁺ 458.2. Step 3. (R)-tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6- yl)piperidine-1-carboxylate & (S)-tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)piperidine-1-carboxylate tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] piperidine-1- carboxylate (5.00 g, 10.94 mmol) was separated by SFC (column: DAICEL CHIRALCEL OJ (250mmx50mm,10um); mobile phase: [Neu-methanol]; B%: 30%-30%,2.6.150min) to give tert- butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6-yl]piperidine-1-carboxylate (2.0 g, 4.38 mmol, 40%) as a brown oil and tert-butyl (3S)-3-[4-(3-chloro-2-fluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]piperidine-1-carboxylate (2.7 g, 5.91 mmol, 53%) as a brown oil. Step 4. (R)-N-(3-chloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido[3,4 -d]pyrimidin-4- amine To a solution of tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6-yl] piperidine-1-carboxylate (130 mg, 284 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (32.4 mg, 284 μmol, 21.0 μL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2- fluoro-phenyl)-6-[(3R)-3- piperidyl]pyrido[3,4-d]pyrimidin-4-amine (101 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 358.0. Step 5. (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyr imidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-3-piperidyl]pyrido[3,4- d]pyrimidin-4-amine (101 mg, 282 μmol, trifluoroacetic acid) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (190 mg, 2.26 mmol) in water (0.3 mL). Then a solution of prop-2-enoyl chloride (23.0 mg, 254 μmol, 20.7 μL) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 36%-66%, 10 min) to give 1-[(3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in-6-yl]-1-piperidyl]prop-2-en- 1-one (52 mg, 0.13 mmol, 44%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 - 10.01 (m, 1H), 9.17 (s, 1H), 8.60 (s, 1H), 8.25 (s, 1H), 7.53 (t, J = 6.8 Hz, 2H), 7.38 - 7.22 (m, 1H), 7.03 - 6.70 (m, 1H), 6.12 (dd, J = 8.4, 16.8 Hz, 1H), 5.69 (t, J = 8.8 Hz, 1H), 4.89 - 4.07 (m, 2H), 3.11 (t, J = 12.8 Hz, 1H), 3.05 - 2.89 (m, 1H), 2.88 - 2.70 (m, 1H), 2.17 (d, J = 12.4 Hz, 1H), 2.03 - 1.78 (m, 2H), 1.66 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 412.3. Example 94. Preparation of (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 135) Step 1. (S)-N-(3-chloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido[3,4 -d]pyrimidin-4- amine To a solution of tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6-yl] piperidine-1-carboxylate (2.70 g, 5.90 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (7.70 g, 67.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2- fluoro-phenyl)-6-[(3R)-3- piperidyl]pyrido[3,4-d]pyrimidin-4-amine (2.78 g, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 358.1. Step 2. (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyr imidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-3-piperidyl]pyrido[3,4- d]pyrimidin-4-amine (2.78 g, 5.89 mmol, trifluoroacetic acid) in tetrahydrofuran (30 mL) and water (15 mL) was added sodium bicarbonate (2.47 g, 29.5 mmol) and prop-2-enoyl chloride (533 mg, 5.89 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was triturated with water (50 mL) and (petroleum ether/ethyl acetate = 1/1, 30 mL), which was further filtered. The solid was concentrated under vacuum to give 1-[(3S)-3-[4-(3-chloro-2- fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]-1-piperidyl]prop -2-en-1-one (1.52 g, 3.69 mmol, 62%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.33 (s, 1H), 9.20 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 7.56 (s, 2H), 7.41 - 7.26 (m, 1H), 7.00 - 6.75 (m, 1H), 6.25 - 6.03 (m, 1H), 5.80 - 5.58 (m, 1H), 4.99 - 4.42 (m, 1H), 4.39 - 4.06 (m, 1H), 3.45 - 3.35 (m 1H), 3.12 (t, J = 12.8 Hz, 1H), 3.05 - 2.90 (m, 1H), 2.88 - 2.71 (m, 1H), 2.23 - 2.13 (m, 1H), 1.98 - 1.85 (m, 2H), 1.64 - 1.49 (m, 1H); m/z ES+ [M+H]+ 412.0. Example 95. Preparation of (S)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 147)

Step 1. 6-Chloro-N-(3-chloro-2,4-difluorophenyl)pyrido[3,4-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (1.00 g, 5.00 mmol) in acetonitrile (20 mL) was added 3-chloro-2,4-difluoro-aniline (981 mg, 6.00 mmol) in acetonitrile (20 mL). The mixture was stirred at 60 °C for 2 hrs. On completion, the mixture was filtered and the filter cake was washed with acetonitrile (10 mL x 2) and petroleum ether (20 mL x 2), then concentrated in vacuo to give 6-chloro-N-(3-chloro-2,4-difluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine (1.60 g, 4.91 mmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.88 (s, 1H), 8.78 (s, 1H), 7.60 -7.56 (m, 1H), 7.48-7.46 (m, 1H); m/z ES+ [M+H] ⁺ 326.9. Step 2. tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d]pyrimi din-6- yl)-5,6-dihydropyridine-1(2H)-carboxylate A mixture of 6-chloro-N-(3-chloro-2,4-difluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine (1.50 g, 4.59 mmol), potassium carbonate (1.90 g, 13.8 mmol), Pd(dppf)Cl ₂ (335.53 mg, 458.55 μmol), and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate (1.70 g, 5.50 mmol) in degassed dioxane (16 mL) and water (4 mL) was heated at 100 °C for 2 h under nitrogen. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/ethyl acetate=1/0 to 1/1) to give tert-butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d]pyrimi din-6-yl)- 5,6-dihydropyridine-1(2H)-carboxylate (1.6 g, 3.38 mmol, 74%) as a yellow solid. m/z ES+ [M+H] ⁺ 474.1. Step 3. tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d]pyrimi din-6- yl)piperidine-1-carboxylate To a solution of tert-butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d] pyrimidin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (900 mg, 1.90 mmol) in tetrahydrofuran (10 mL) was added palladium on activated carbon (250 mg, 10% loading) and magnesium oxide (270 mg, 6.70 mmol). The mixture was stirred at 0 °C for 12 hrs under H ₂ (15 psi). On completion, the solution was filtered and the filtrate was concentrated in vacuum. The crude product was purified by prep-HPLC (Neutral condition; column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 49%-79%,9min) to give tert-butyl 3-(4-((3- chloro-2,4-difluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl) piperidine-1-carboxylate (400 mg, 0.84 mmol, 44%) as a yellow solid. m/z ES+ [M+H] ⁺ 476.1. Step 4. (S)-tert-butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d]pyrimi din- 6-yl)piperidine-1-carboxylate tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d]pyrimi din-6- yl)piperidine-1-carboxylate (370 mg, 777 μmol) was separated by SFC (condition:column: DAICEL CHIRALCEL OJ(250mmx30mm,10um); mobile phase: [0.1% NH ₃ water methanol]; B%: 20%-20%, 3.3 min; 40 min) to give (S)-tert-butyl 3-(4-((3-chloro-2,4- difluorophenyl)amino)pyrido[3,4-d] pyrimidin-6-yl)piperidine-1-carboxylate (160 mg, 0.34 mmol, 43%) as a yellow solid. Step 5. (S)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)pyrido [3,4-d]pyrimidin-4- amine The mixture of (S)-tert-butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d] pyrimidin-6-yl)piperidine-1-carboxylate (140 mg, 294 μmol) in hydrochloric acid/ethyl acetate (4 M, 2 mL) was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give (S)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)pyrido [3,4-d]pyrimidin-4- amine (122 mg, crude, HCl salt) as a yellow oil. m/z ES+ [M+H] ⁺ 376.2. Step 6. (S)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,4-d ]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of (S)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)pyrido [3,4- d]pyrimidin -4-amine (122 mg, 325 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (81.8 mg, 974 μmol). Then prop-2-enoyl chloride (29.4 mg, 325 μmol, 26.5 μL) was added and the mixture was stirred at 0 °C for 20 min. Then prop-2-enoyl chloride (29.4 mg, 325 μmol, 26.5 μL) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (FA condition; column: Unisil 3-100 C18 Ultra 150x50mm, 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 40%-60%, 10 min) to give (S)-1-(3-(4-((3-chloro-2,4- difluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1 -yl)prop-2-en-1-one (44 mg, 0.10 mmol, 32%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.84 - 10.00 (m, 1H), 9.16 (s, 1H), 8.57 (s, 1H), 8.25 (s, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 8.2 Hz, 1H), 6.94 - 6.81 (m, 1H), 6.19 - 6.07 (m, 1H), 5.69 (t, J = 9.2 Hz, 1H), 4.89 - 4.42 (m, 1H), 4.38 - 4.12 (m, 1H), 3.11 (t, J = 13.2 Hz, 1H), 3.02 - 2.91 (m, 1H), 2.88 - 2.71 (m, 1H), 2.23 - 2.11 (m, 1H), 1.99 - 1.82 (m, 2H), 1.65 - 1.48 (m, 1H); m/z ES+ [M+H] ⁺ 430.3. Example 96. Preparation of 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)tetrahydropyrimidin-1(2H)-yl)prop-2-en-1-on e (Compound 280) Step 1. tert-Butyl (3-((4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidi n-6- yl)amino)propyl)carbamate A mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine (1.29 g, 4.17 mmol), tert-butyl N-(3-aminopropyl)carbamate (1.45 g, 8.35 mmol), tBuXPhos Pd G3 (331 mg, 417 μmol) and sodium tert-butoxide (802 mg, 8.35 mmol) in dioxane (20 mL) was stirred at 90 °C for 16 hrs under nitrogen. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 20/1 to 0/1) to give tert-butyl N-[3-[[4-(3-chloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]amino]propyl]carbamate (1.7 g, 3.81 mmol, 91%) as a yellow solid. m/z ES+ [M+1] ⁺ 447.4. Step 2. tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6- yl)tetrahydropyrimidine-1(2H)-carboxylate A mixture of tert-butyl N-[3-[[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl] amino]propyl]carbamate (300 mg, 671 μmol) and paraformaldehyde (3.27 g, 40.3 mmol) in tetrahydrofuran (3 mL) was stirred at 70 °C for 3 hrs. Upon completion, the mixture was concentrated in vacuo to give tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6-yl] hexahydropyrimidine-1-carboxylate (0.3 g, crude) as a brown solid. m/z ES+ [M+1] ⁺ 459.2. Step 3. N-(3-chloro-2-fluorophenyl)-6-(tetrahydropyrimidin-1(2H)-yl) pyrido[3,4- d]pyrimidin-4-amine A solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] hexahydropyrimidine-1-carboxylate (270 mg, 588 μmol) in HCl/ethyl acetate (4 M, 27.0 mL) was stirred at 25 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give N-(3- chloro-2-fluoro-phenyl)-6-hexahydropyrimidin-1-yl-pyrido[3,4 -d]pyrimidin-4-amine (0.2 g, crude) as a yellow solid. m/z ES+ [M+1] ⁺ 359.1. Step 4. 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimid in-6- yl)tetrahydropyrimidin-1(2H)-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-hexahydropyrimidin-1-yl-pyrid o[3,4-d] pyrimidin-4-amine (200 mg, 557 μmol) and sodium bicarbonate (140 mg, 1.67 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added prop-2-enoyl chloride (50.4 mg, 557 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 31%-61%,9min) to give 1-[3-[4-(3- chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]hexahydr opyrimidin-1-yl]prop-2-en-1-one (35 mg, 0.085 mmol, 13%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 - 9.43 (m, 1H), 8.86 (s, 1H), 8.31 (d, J = 4.8 Hz, 1H), 7.65 - 7.39 (m, 3H), 7.34 - 7.25 (m, 1H), 7.04 - 6.77 (m, 1H), 6.08 (dd, J = 1.6, 16.8 Hz, 1H), 5.70 (dd, J = 2.0, 10.4 Hz, 1H), 5.48 (s, 2H), 3.85 - 3.74 (m, 4H), 1.81 (s, 2H); m/z ES+ [M+1] ⁺ 413.4. Example 97. Preparation of 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)tetrahydropyrimidin-1(2H)-yl)prop-2-en-1-on e (Compound 281) Step 1. tert-Butyl (3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyri midin-6- yl)amino)propyl)carbamate A solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine (1.70 g, 4.95 mmol), tert-butyl N-(3-aminopropyl)carbamate (1.72 g, 9.90 mmol), tBuXPhos Pd G3 (393 mg, 494 μmol) and sodium tert-butoxide (951 mg, 9.90 mmol) in dioxane (20 mL) was stirred at 90 °C for 16 hrs under nitrogen. Upon completion, the reaction mixture was diluted by water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried by sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 20/1 to 0/1) to give tert-butyl N-[3-[[4- (3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl]amino]propyl]carbamate (1.7 g, 3.54 mmol, 71%) as a yellow solid. m/z ES+ [M+1] ⁺ 481.4. Step 2. tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimi din-6- yl)tetrahydropyrimidine-1(2H)-carboxylate The mixture of tert-butyl N-[3-[[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in- 6-yl] amino]propyl]carbamate (323 mg, 671 μmol) and paraformaldehyde (3.27 g, 40.3 mmol) in tetrahydrofuran (3 mL) was stirred at 70 °C for 3 hrs. Upon completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% NH ₃ •water conditions) to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]hexahydropyrimidine-1-carboxylate (0.2 g, 0.41 mmol, 41%) as a brown solid. m/z ES+ [M+1] ⁺ 493.2. Step 3. N-(3,4-dichloro-2-fluorophenyl)-6-(tetrahydropyrimidin-1(2H) -yl)pyrido[3,4- d]pyrimidin-4-amine A solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl] hexahydropyrimidine-1-carboxylate (0.2 g, 405 μmol) in HCl/ethyl acetate (4 M, 18.6 mL) was stirred at 25 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give N- (3,4-dichloro-2-fluoro-phenyl)-6-hexahydropyrimidin-1-yl-pyr ido[3,4-d] pyrimidin-4-amine (0.15 g, crude) as a yellow solid. m/z ES+ [M+1] ⁺ 393.1. Step 4. 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyr imidin-6- yl)tetrahydropyrimidin-1(2H)-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-hexahydropyrimidin-1-yl- pyrido[3,4-d] pyrimidin-4-amine (0.15 g, 381 μmol) and sodium bicarbonate (96.1 mg, 1.14 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added prop-2-enoyl chloride (34.5 mg, 381 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 38%-68%, 9 min) to give 1-[3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidi n-6-yl]hexahydropyrimidin- 1-yl]prop-2-en-1-one (15 mg, 0.034 mmol, 8.8%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.01 - 9.50 (m, 1H), 9.06 - 8.75 (m, 1H), 8.54 - 8.23 (m, 1H), 7.78 - 7.46 (m, 3H), 7.02 - 6.79 (m, 1H), 6.08 (dd, J = 1.6, 16.8 Hz, 1H), 5.69 (dd, J = 1.6, 10.4 Hz, 1H), 5.48 (s, 2H), 3.85 - 3.73 (m, 4H), 1.81 (s, 2H); m/z ES+ [M+1] ⁺ 447.1. Example 98. Preparation of 1-(3-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin -1-yl)prop-2-en-1-one (Compound 317)

Step 1. 6-Chloro-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrido[3, 4-d]pyrimidin-4- amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (700 mg, 3.50 mmol) and 3-chloro- 4 -(2-pyridylmethoxy)aniline (985 mg, 4.20 mmol) in acetonitrile (10 mL) was added cesium carbonate (570 mg, 1.75 mmol). The mixture was stirred at 40 °C for 12 hours. On completion, the reaction mixture was filtered. The filter cake was dried in vacuo to give 6-chloro-N-[3-chloro- 4-(2-pyridylmethoxy)phenyl]pyrido[3,4-d] pyrimidin-4-amine (1.3 g, 3.27 mmol, 74%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.03 (s, 1H), 8.95 (s, 1H), 8.74 (s, 1H), 8.67 - 8.58 (m, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.00 - 7.89 (m, 1H), 7.87 - 7.77 (m, 1H), 7.66 - 7.56 (m, 1H), 7.46 - 7.38 (m, 1H), 7.35 - 7.26 (m, 1H), 5.43 - 5.19 (m, 2H); m/z ES+ [M+H] ⁺ 398.2. Step 2. tert-Butyl 3-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)pyrido[3 ,4- d]pyrimidin-6-yl)piperidine-1-carboxylate A mixture of 6-chloro-N-[3-chloro-4-(2-pyridylmethoxy)phenyl]pyrido[3,4-d ]pyrimidin- 4-amine (600 mg, 1.51 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (795 mg, 3.01 mmol), dichloronickel;1,2-dimethoxyethane (33.1 mg, 150 μmol), zinc powder (297 mg, 4.55 mmol) and pyridine-2-carboxamidine (36.5 mg, 301 μmol) in N,N-dimethylacetamide (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 60 °C for 12 hours under nitrogen atmosphere. On completion, the mixture was concentrated. The residue was purified by column chromatography (dichloromethane: methanol = 5:1) and then re-purified by reversed- phase HPLC (0.1% FA condition). The resulting product was triturated with methyl tert-butyl ether/methanol (11 m L, 10/1) to give tert-butyl 3-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin e-1-carboxylate (40 mg, 0.073 mmol, 4.9%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 9.14 (s, 1H), 8.69 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.29 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.90 (m, J = 1.8Hz, 1H), 7.74 (m, J = 2.4, 8.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.38 (m, 7.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 5.32 (s, 2H), 4.10 - 4.00 (m, 1H), 2.99 - 2.83 (m, 2H), 2.83 - 2.75 (m, 1H), 2.17 - 2.06 (m, 1H), 1.93 - 1.76 (m, 2H), 1.63 - 1.49 (m, 1H), 1.47 - 1.35 (m, 9H), 1.30 - 1.21 (m, 1H); m/z ES+ [M+H] ⁺ 547.0. Step 3. N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-(piperidin-3-yl )pyrido[3,4- d]pyrimidin-4-amine The mixture of tert-butyl 3-[4-[3-chloro-4-(2-pyridylmethoxy)anilino]pyrido[3,4- d]pyrimidin-6-yl] piperidine-1-carboxylate (30.0 mg, 54.8 μmol) in trifluoroacetic acid (0.4 mL) and dichloromethane (2.0 mL) was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6-(3- piperidyl)pyrido[3,4-d]pyrimidin-4-amine (24 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 447.1. Step 4. 1-(3-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)pyrid o[3,4- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6-(3-piperidyl)pyrid o[3,4- d]pyrimidin-4-amine (24.0 mg, 45.6 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (11.5 mg, 136 μmol) to adjust pH = 7. Then prop-2-enoyl chloride (4.13 mg, 45.6 μmol) was added. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150x25mm 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 27%-57%,11min]; B%: 34%-64%,11min) to give 1-(3-(4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin -1-yl)prop-2-en-1-one (10 mg, 0.02 mmol, 44%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 9.14 (s, 1H), 8.68 (s, 1H), 8.60 (d, J = 4.4 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.87 (m, J = 1.6, 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 5.2, 7.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 10.4, 16.8 Hz, 1H), 6.16 - 5.60 (m, 2H), 5.31 (s, 2H), 4.80 - 4.10 (m, 2H), 3.02 - 2.94 (m, 3H), 2.19 (d, J = 12.8 Hz, 1H), 2.07 - 1.87 (m, 2H), 1.71 - 1.54 (m, 1H); m/z ES+ [M+H] ⁺ 501. Example 99. Preparation of 1-(3-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1- yl)prop-2-en-1-one (Compound 346) Step 1. tert-Butyl 3-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-5,6-dihydropyridine -1(2H)- carboxylate To a solution of 6-chloropyrido[3,4-d]pyrimidin-4-ol (450 mg, 2.48 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1-carboxylate (996 mg, 3.22 mmol) in dioxane (21 mL) and water (7 mL) was added Pd(dppf)Cl ₂ (181 mg, 248 μmol) and cesium carbonate (2.42 g, 7.43 mmol). The mixture was degassed and purged with nitrogen gas (3x), and then stirred at 100 °C for 2 hours under nitrogen atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 2:1 to 0:1) to give tert-butyl 5-(4-hydroxypyrido[3,4-d]pyrimidin- 6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (970 mg, 2.96 mmol, 95%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.58 (s, 1H), 9.01 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 6.96 (s, 1H), 4.37 (s, 2H), 3.50 (t, J = 5.2 Hz, 2H), 2.33 (d, J = 3.2 Hz, 2H), 1.44 (s, 9H); m/z ES+ [M+H] ⁺ 329.1. Step 2. tert-Butyl 3-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)piperidine-1-carboxy late To a suspension of palladium on activated carbon (400 mg, 10% loading) in tetrahydrofuran (30 mL) was added tert-butyl 5-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (1.13 g, 3.44 mmol) and magnesium oxide (139 mg, 3.44 mmol). The mixture was stirred at 25 °C for 16 hours under H ₂ (15 psi). On completion, the mixture was filtered and concentrated to give tert-butyl 3-(4-hydroxypyrido[3,4-d]pyrimidin-6- yl)piperidine-1-carboxylate (938 mg, 2.84 mmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 9.03 - 8.98 (m, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 4.14 - 3.89 (m, 2H), 3.60 (t, J = 6.0 Hz, 1H), 2.97 - 2.79 (m, 2H), 1.85 - 1.66 (m, 4H), 1.40 (s, 9H); m/z ES+ [M+H] ⁺ 331.1. Step 3. tert-Butyl 3-(4-chloropyrido[3,4-d]pyrimidin-6-yl)piperidine-1-carboxyl ate A mixture of tert-butyl 3-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)piperidine-1- carboxylate (526 mg, 1.59 mmol), phosphorus oxychloride (317 mg, 2.07 mmol, 192 μL) and diisopropylethylamine (1.03 g, 7.96 mmol, 1.39 mL) in toluene (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 110 °C for 4 hours under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl 3-(4-chloropyrido[3,4-d]pyrimidin-6-yl)piperidine-1-carboxyl ate (550 mg, 1.43 mmol, 81%) as a yellow solid. m/z ES+ [M+H-56] ⁺ 293.1. Step 4. tert-Butyl 3-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidine-1 -carboxylate The mixture of tert-butyl 3-(4-chloropyrido[3,4-d]pyrimidin-6-yl)piperidine-1- carboxylate (550 mg, 1.58 mmol) and 3-chloro-4-(1-methylpyrazol-3-yl)oxy-aniline (353 mg, 1.58 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours. On completion, the mixture was concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-anilino]pyrido[3, 4-d]pyrimidin-6- yl]piperidine-1-carboxylate (210 mg, 0.39 mmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 9.15 (s, 1H), 8.73 - 8.70 (m, 1H), 8.30 (s, 1H), 8.17 - 8.12 (m, 1H), 7.80 - 7.74 (m, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.28 - 7.23 (m, 1H), 5.86 - 5.81 (m, 1H), 4.34 - 3.99 (m, 2H), 3.73 (s, 3H), 2.99 - 2.70 (m, 3H), 1.92 - 1.77 (m, 2H), 1.45 (s, 2H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 536.2. Step 5. N-(3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-6-(pipe ridin-3- yl)pyrido[3,4-d]pyrimidin-4-amine To a solution of tert-butyl 3-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,4-d]pyrimidin-6-yl]piperidine-1-carboxylate (190 mg, 354 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol, 2.0 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated to give N-[3-chloro- 4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-(3-piperidyl)pyrido[3, 4-d]pyrimidin-4-amine (150 mg, 0.34 mmol, 87%) as a yellow solid. m/z ES+ [M+H] ⁺ 436.2. Step 6. 1-(3-(4-((3-chloro-4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)a mino)pyrido[3,4- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-(3- piperidyl)pyrido[3,4-d]pyrimidin-4-amine (150 mg, 344 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (28.9 mg, 344 μmol) at 0 °C until pH = 8. After that, prop-2-enoyl chloride (31.1 mg, 344 μmol, 28.1 μL) was added. The mixture was stirred at 0 °C for 0.25 hour. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 28%-58%,10 min) to give 1-[3-[4-[3-chloro-4-(1-methylpyrazol- 3-yl)oxy-anilino]pyrido[3,4-d]pyrimidin-6-yl]-1-piperidyl]pr op-2-en-1-one (61 mg, 0.12 mmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.16 (s, 1H), 8.72 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.87 (td, J = 10.4, 16.8 Hz, 1H), 6.12 (dd, J = 7.2, 16.8 Hz, 1H), 5.84 (d, J = 2.0 Hz, 1H), 5.69 (t, J = 9.2 Hz, 1H), 4.83 - 4.46 (m, 1H), 4.37 - 4.12 (m, 1H), 3.73 (s, 3H), 3.44 - 3.37 (m, 0.5H), 3.11 (t, J = 13.2 Hz, 0.5H), 3.02 - 2.70 (m, 2H), 2.15 (d, J = 12.0 Hz, 1H), 1.99 - 1.83 (m, 2H), 1.56 (d, J = 12.0 Hz, 1H); m/z ES+ [M+H] ⁺ 490.3. Example 100. Preparation of 1-(4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one (Compound 51)

Step 1. tert-Butyl 4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(4- phenoxyphenyl)pyrido[3,2-d] pyrimidin-4-amine (120 mg, 344 μmol), tert-butyl 4- bromopiperidine-1-carboxylate (118 mg, 447 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (3.86 mg, 3.44 μmol), NiCl ₂ .dtbbpy (684 ug, 1.72 μmol), tris(trimethylsilyl)silane (85.6 mg, 344 μmol), sodium carbonate (72.9 mg, 688 μmol) in dimethoxyethane (6 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 h under nitrogen. The reaction mixture was then concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 5/1 to 2/1) to give tert-butyl 4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pip eridine-1- carboxylate (40 mg, 0.08 mmol, 23%) as a yellow oil. Step 2. N-(4-phenoxyphenyl)-6-(piperidin-4-yl)pyrido[3,2-d]pyrimidin -4-amine To a solution of tert-butyl 4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperidine-1- carboxylate (30 mg, 60.3 μmol) in dichloromethane (0.1 mL) was added trifluoroacetic acid (0.01 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give N-(4-phenoxyphenyl)-6-(piperidin-4-yl)pyrido[3,2- d]pyrimidin-4-amine (30 mg, 97%, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 398.2. Step 3. 1-(4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) piperidin-1- yl)prop-2-en-1-one To a solution of N-(4-phenoxyphenyl)-6-(4-piperidyl)pyrido[3,2-d]pyrimidin-4- amine (30 mg, 58.6 μmol, trifluoroacetic acid) in tetrahydrofuran (0.15 mL) was added sodium bicarbonate (14.8 mg, 176 μmol, 6.84 μL) in water (0.3 mL). Then prop-2-enoyl chloride (5.31 mg, 58.7 μmol) in tetrahydrofuran (0.15 mL) was added. The mixture was stirred at 0 °C for 0.1 h. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 33%-63%, 10 min) to give 1-(4-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) piperidin-1-yl)prop- 2-en-1-one (6.6 mg, 0.015 mmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.88 - 7.81 (m, 3H), 7.40 - 7.30 (m, 2H), 7.13 - 7.08 (m, 1H), 7.07 - 6.99 (m, 4H), 6.84 (dd, J = 10.8, 16.8 Hz, 1H), 6.22 (dd, J = 2.0, 16.8 Hz, 1H), 5.76 (dd, J = 2.0, 10.8 Hz, 1H), 4.77 (br. d, J = 13.2 Hz, 1H), 4.31 (br. d, J = 13.2 Hz, 1H), 3.40 - 3.32 (m, 1H), 3.30 - 3.26 (m, 1H), 3.01 - 2.83 (m, 1H), 2.13 (br. d, J = 13.2 Hz, 2H), 2.03 - 1.90 (m, 2H); m/z ES+ [M+H] ⁺ 452.1. Example 101. Preparation of 1-(3-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one (Compound 63) Step 1. tert-Butyl 3-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(4- phenoxyphenyl)pyrido[3,2-d] pyrimidin-4-amine (120 mg, 344 μmol), tert-butyl 3- bromopiperidine-1-carboxylate (118 mg, 447 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (3.86 mg, 3.44 μmol), NiCl ₂ .dtbbpy (685 ug, 1.72 μmol), tris(trimethylsilyl)silane (85.6 mg, 344 μmol), sodium carbonate (72.9 mg, 688 μmol) in dimethoxyethane (6 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 h under nitrogen. The reaction mixture was then concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 5/1 to 2/1) to give tert-butyl 3-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pip eridine-1- carboxylate (120 mg, 0.24 mmol, 56%) as a yellow oil. m/z ES+ [M+H] ⁺ 498.2. Step 2. N-(4-phenoxyphenyl)-6-(piperidin-3-yl)pyrido[3,2-d]pyrimidin -4-amine To a solution of tert-butyl 3-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperidine-1- carboxylate (110 mg, 221 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give N-(4-phenoxyphenyl)-6-(piperidin-3-yl)pyrido[3,2-d]pyrimidin -4- amine (113 mg, 221 μmol, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H]+ 398.4. Step 3. 1-(3-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) piperidin-1- yl)prop-2-en-1-one To a solution of N-(4-phenoxyphenyl)-6-(3-piperidyl)pyrido[3,2-d]pyrimidin-4- amine (113 mg, 221 μmol, trifluoroacetic acid) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (55.7 mg, 663 μmol) in water (1 mL). Then prop-2-enoyl chloride (20.0 mg, 221 μmol) in tetrahydrofuran (0.5 mL) was added. The mixture was stirred at 0 °C for 0.25 h. The reaction mixture was diluted with water 3 mL and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 36%-66%, 11 min) to give 1-(3-(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) piperidin-1-yl)prop-2-en-1- one (38.5 mg, 0.085 mmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (br. d, J = 2.4 Hz, 1H), 8.61 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.04 (br. d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 8.0 Hz, 2H), 7.15 - 7.06 (m, 3H), 7.06 - 7.01 (m, 2H), 6.76 (dd, J = 10.8, 16.8 Hz, 1H), 6.08 - 6.00 (m, 1H), 5.59 (dd, J = 2.4, 10.8 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.02 - 3.92 (m, 1H), 3.45 - 3.27 (m, 1H), 3.25 - 3.17 (m, 1H), 2.93 (br. d, J = 1.6 Hz, 1H), 2.23 - 2.02 (m, 2H), 1.81 - 1.64 (m, 1H), 1.63 - 1.51 (m, 1H); m/z ES+ [M+H] ⁺ 452.1. Example 102. Preparation of 1-(1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[4.1.0]heptan-3-yl)prop-2-en-1 -one (Compound 54)

Step 1. 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of N'-(6-chloro-2-cyano-3-pyridyl)-N,N-dimethyl-formamidine (2.00 g, 9.59 mmol) in toluene (10 mL) and acetic acid (10 mL) was added 3,4-dichloro-2-fluoro-aniline (1.55 g, 8.63 mmol) at 20 °C. The mixture was stirred at 110 °C for 12 hours. The mixture was quenched by sat. sodium bicarbonate solution to adjust pH = 7 and then extracted with ethyl acetate (20 mL x 3). The organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give 6-chloro-N- (3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (1.30 g, 3.79 mmol, 39%) as a white solid. NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 8.64 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 7.60 (dd, J = 1.6, 8.8 Hz, 1H). Step 2. Benzyl 1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)- 3-azabicyclo[4.1.0]heptane-3-carboxylate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (204 mg, 593 μmol) and benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[4.1.0]heptane-3- carboxylate, potassium salt (200 mg, 593 μmol) in toluene (5.0 mL) and water (1.0 mL) was added cesium carbonate (579 mg, 1.78 mmol) and catacxium (R) A PD G3 (43.2 mg, 59.3 μmol) at 20 °C. The mixture was stirred at 110 °C for 12 hours under nitrogen. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO ₂ , petroleum etherr/ethyl acetate = 10/1 to 1/1) to give benzyl 1- [4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-3-azabicyclo[4.1.0]hept ane-3-carboxylate (200 mg, 0.37 mmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 - 9.70 (m, 1H), 8.61 (s, 1H), 8.20 - 7.94 (m, 2H), 7.77 - 7.54 (m, 2H), 7.41 - 7.27 (m, 5H), 5.11 (br. s, 2H), 4.58 (br. d, J = 13.6 Hz, 1H), 4.45 (br. d, J = 12.8 Hz, 1H), 4.26 (br. d, J = 13.6 Hz, 1H), 3.94 (br. d, J = 13.6 Hz, 1H), 3.59 (br. s, 1H), 3.25 - 2.98 (m, 1H), 2.28 - 2.06 (m, 1H), 1.94 - 1.53 (m, 3H), 1.09 - 0.92 (m, 1H). Step 3. 6-(3-Azabicyclo[4.1.0]heptan-1-yl)-N-(3,4-dichloro-2-fluorop henyl)pyrido[3,2- d]pyrimidin-4-amin A solution of benzyl 1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]-3- azabicyclo[4.1.0]heptane-3-carboxylate (200 mg, 371 μmol) in trifluoroacetic acid (2.0 mL) was stirred at 60 °C for 2 hour. The mixture was concentrated under vacuum to give 6-(3- azabicyclo[4.1.0]heptan-1-yl)-N-(3,4-dichloro-2-fluoro-pheny l)pyrido[3,2-d]pyrimidin-4-amine (150 mg, crude) as a brown oil. Step 4. 1-(1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-3- azabicyclo[4.1.0]heptan-3-yl)prop-2-en-1-one To a solution of 6-(3-azabicyclo[4.1.0]heptan-1-yl)-N-(3,4-dichloro-2-fluoro- phenyl)pyrido [3,2-d]pyrimidin-4-amine (150 mg, 371 μmol) in tetrahydrofuran (2.0 mL) and water (0.5 mL) was added sodium bicarbonate (125 mg, 1.48 mmol) and prop-2-enoyl chloride (26.8 mg, 297 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was added methanol (1.0 mL) and filtered. The filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30mm, 3um; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 45%-70%, 6min) to give 1-[1-[4-(3,4-dichloro-2- fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-3-azabicyclo[4.1 .0]heptan-3-yl]prop-2-en-1-one (13.6 mg, 0.030 mmol, 8%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 - 9.79 (m, 1H), 8.65 - 8.56 (m, 1H), 8.21 - 8.11 (m, 1H), 8.03 (t, J = 8.4 Hz, 1H), 7.79 - 7.70 (m, 1H), 7.63 (br. d, J = 8.4 Hz, 1H), 7.02 (dd, J = 10.4, 16.4 Hz, 1H), 6.77 (dd, J = 10.4, 16.4 Hz, 1H), 6.21 - 6.08 (m, 1H), 5.69 (br. d, J = 10.0 Hz, 1H), 4.66 (d, J = 13.6 Hz, 1H), 4.35 (br. d, J = 14.0 Hz, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.88 - 3.67 (m, 1H), 3.40 (s, 1H), 3.05 (s, 1H), 2.21 (br. s, 1H), 1.96 (br. s, 1H), 1.85 - 1.66 (m, 2H), 1.50 (s, 1H), 1.07 - 0.91 (m, 1H); m/z ES+ [M+H] ⁺ 458.0. Example 103. Preparation of (R)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 70)

Step 1. 6-Chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (1 g, 5.00 mmol) in tetrahydrofuran (10 mL) was added 3,4-dichloro-2-fluoro-aniline (990 mg, 5.50 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo and then triturated with petroleum ether/ethyl acetate = 3/1 at 25 °C for 60 min to give 6-chloro-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (1.7 g, 4.97 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 343.0. Step 2. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(3,4-dichloro-2-fluoro- phenyl)pyrido [3,2-d]pyrimidin-4-amine (85 mg, 247 μmol), tert-butyl 3-bromopiperidine-1- carboxylate (84.9 mg, 321.62 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (2.78 mg, 2.47 μmol), NiCl ₂ .dtbbpy (492 ug, 1.24 μmol), tris(trimethylsilyl)silane (61.5 mg, 247 μmol), sodium carbonate (52.4 mg, 495 μmol) in dimethoxyethane (11 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 5/1 to 2/1) to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]piperidine- 1-carboxylate (50 mg, 0.10 mmol, 38%) as a yellow solid. m/z ES+ [M+H] ⁺ 492.2. Step 3. tert-Butyl (R)-3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]py rimidin- 6-yl)piperidine-1-carboxylate tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]piperidine-1- carboxylate (50 mg, 0.10 mmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250mmx30mm,10um); mobile phase: [0.1% NH3 water MEOH]; B%: 60%-60%,3.8min;30min) to give (R)-tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperidine-1-carboxylate (40 mg, 0.081 mmol, 42%) as a white solid. Step 4. (R)-N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido [3,2-d]pyrimidin-4- amine To a solution of (R)-tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl) piperidine-1-carboxylate (30 mg, 60.9 μmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.03 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vocuo to give (R)-N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3- yl)pyrido[3,2-d]pyrimidin-4-amine (30 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H]+ 392.0. Step 5. (R)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a suspension of (R)-N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido [3,2- d]pyrimidin-4- amine (30 mg, 59.3 μmol, trifluoroacetic acid) and sodium bicarbonate (14.9 mg, 178 μmol) in water (0.3 mL) was added prop-2-enoyl chloride (5.90 mg, 65.2 μmol) in tetrahydrofuran (0.3 mL). The mixture was stirred at 0 °C for 0.25 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 48%- 78%,11min) to give (R)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one (12.4 mg, 0.028 mmol, 47%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.68 - 8.60 (m, 1H), 8.42 - 8.25 (m, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.96 - 7.88 (m, 1H), 7.45 (dd, J = 2.0, 8.8 Hz, 1H), 6.92 - 6.77 (m, 1H), 6.19 (d, J = 16.8 Hz, 1H), 5.77 - 5.70 (m, 1H), 4.56 - 4.52 (m, 1H), 4.43 - 4.39 (m, 0.5H), 4.09 - 4.05 (m, 0.5H), 3.77 - 3.52 (m, 1H), 3.46 - 3.37 (m, 0.5H), 3.25 - 3.15 (m, 1H), 3.05 - 2.96 (m, 0.5H), 2.33 - 2.22 (m, 1H), 2.17 - 1.86 (m, 2H), 1.78 - 1.64 (m, 1H); m/z ES+ [M+H] ⁺ 446.3. Example 104. Preparation of 1-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[4.1.0]heptan-3-yl)prop-2-en-1 -one (Compound 77)

Step 1. 6-Chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine A solution of 3-chloro-2-fluoro-aniline (596 mg, 4.10 mmol) and N'-(6-chloro-2–cyano - 3-pyridyl)-N,N-dimethyl-formamidine (950 mg, 4.55 mmol) in toluene (5.0 mL) and acetic acid (5.0 mL) was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 2/1 to 1/1) to give 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (760 mg, 2.47 mmol, 54%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H), 8.61 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.31 - 7.26 (m, 1H). Step 2. Benzyl 1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-3- azabicyclo[4.1.0]heptane-3-carboxylate A mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (165 mg, 533 μmol), benzyl 1-(trifluoro-l4-boraneyl)-3-azabicyclo[4.1.0]heptane-3-carbo xylate, potassium salt (200 mg, 593 μmol), cesium carbonate (579 mg, 1.78 mmol), catacxium(R) A PD G3 (43.2 mg, 59.3 μmol) in toluene (5.0 mL) and water (1.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. The reaction mixture was quenched by water (10 mL) at 20 °C, and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to give benzyl-1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n-6-yl]-3- azabicyclo[4.1.0]heptane-3-carboxylate (185 mg, 0.37 mmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 - 9.71 (m, 1H), 8.60 (s, 1H), 8.16 - 7.94 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.38 - 7.30 (m, 6H), 5.11 (br. s, 2H), 3.93 (br. d, J = 13.2 Hz, 1H), 3.59 (br. s, 1H), 3.22 - 3.02 (m, 1H), 1.98 - 1.49 (m, 4H), 1.36 - 1.08 (m, 1H), 1.03 (br. s, 1H). Step 3. 6-(3-Azabicyclo[4.1.0]heptan-1-yl)-N-(3-chloro-2-fluoropheny l)pyrido[3,2- d]pyrimidin-4-amine A solution of benzyl 1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -3- azabicyclo [4.1.0]heptane-3-carboxylate (185 mg, 367 μmol) in trifluoroacetic acid (2.0 mL) was stirred at 60 °C for 2 h. The mixture was blow-dried with nitrogen to give 6-(3- azabicyclo[4.1.0]heptan-1-yl)-N-(3-chloro-2-fluoro-phenyl)py rido[3,2-d]pyrimidin-4-amine (135 mg, crude, TFA salt) as a brown oil. Step 4. 1-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-3- azabicyclo[4.1.0]heptan-3-yl)prop-2-en-1-one To a solution of 6-(3-azabicyclo[4.1.0]heptan-1-yl)-N-(3-chloro-2-fluoro- phenyl)pyrido[3,2-d] pyrimidin-4-amine (130 mg, 351 μmol) in tetrahydrofuran (0.80 mL) and water (0.20 mL) was added sodium bicarbonate (118 mg, 1.41 mmol) and prop-2-enoyl chloride (25.4 mg, 281 μmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by methanol (0.50 mL). The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150x40mmx10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 40%-60%, 8 min) to give 1-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]-3- azabicyclo[4.1.0]heptan-3-yl]prop-2-en-1-one (28.3 mg, 0.067 mmol, 19%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 - 9.78 (m, 1H), 8.58 (s, 1H), 8.17 - 8.12 (m, 1H), 7.96 (t, J = 7.2 Hz, 1H), 7.73 (t, J = 9.2 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.06 - 6.97 (m, 0.5H), 6.77 (dd, J = 10.4, 16.8 Hz, 0.5H), 6.18 - 6.06 (m, 1H), 5.69 (dd, J = 2.4, 10.0 Hz, 1H), 4.68 (dd, J = 3.2, 13.6 Hz, 1H), 4.35 (d, J = 14.0 Hz, 0.5H), 4.11 (d, J = 13.6 Hz, 0.5H), 3.87 - 3.70 (m, 1H), 3.07 - 2.97 (m, 0.5H), 2.26 - 2.12 (m, 1H), 1.98 - 1.90 (m, 0.5H), 1.86 - 1.68 (m, 2.5H), 1.52 - 1.45 (m, 0.5H), 1.02 - 0.93 (m, 1H); m/z ES+ [M+H] ⁺ 424.0. Example 105. Preparation of (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 115)

Step 1. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(3-chloro-2-fluoro - phenyl)pyrido[3,2-d]pyrimidin-4-amine (300 mg, 970 μmol), tert-butyl 3-bromopiperidine-1- carboxylate (333 mg, 1.26 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (10.9 mg, 9.70 μmol,), NiCl ₂ .dtbbpy (1.93 mg, 4.85 μmol), tris(trimethylsilyl)silane (241.3 mg, 970 μmol, 299 μL) and sodium carbonate (206 mg, 1.94 mmol) in dimethoxyethane (5.0 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hrs under nitrogen. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]piperidine-1-carboxylate (270 mg, 0.59 mmol, 61%) as a yellow solid. m/z ES+ [M+H] ⁺ 458.1. Step 2. tert-Butyl (R)-3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperidine-1-carboxylate tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] piperidine-1- carboxylate (270 mg, 590 μmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250mmx30mm,10um); mobile phase:[0.1% NH3 water MEOH]; B%: 60%-60%,4.0.40min) to give tert-butyl (R)-3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperidine- 1-carboxylate (137 mg, 0.30 mmol, 51%) as a yellow solid. m/z ES+ [M+H] ⁺ 458.1. Step 3. (R)-N-(3-chloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido[3,2 -d]pyrimidin-4- amine To a solution of tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin- 6-yl] piperidine-1-carboxylate (97.0 mg, 212 μmol) in dichloromethane (0.9 mL) was added trifluoroacetic acid (327 mg, 2.87 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give (R)-N-(3-chloro-2- fluorophenyl)-6-(piperidin-3-yl)pyrido[3,2-d]pyrimidin-4-ami ne (75.0 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 358.0. Step 4. (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of (R)-N-(3-chloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido[3,2 - d]pyrimidin-4-amine (75.0 mg, 210 μmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (141 mg) in water (0.3 mL). Then a solution of prop-2-enoyl chloride (17.1 mg, 189 μmol) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150x50mm, 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 45%-65%, 10 min) to give (R)-1-(3-(4- ((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) piperidin-1-yl)prop-2-en-1-one (30.8 mg, 0.075 mmol, 36%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (br. d, J = 9.2 Hz, 1H), 8.61 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.05 - 7.86 (m, 2H), 7.54 - 7.41 (m, 1H), 7.38 - 7.24 (m, 1H), 6.89 (dt, J = 10.4, 17.6 Hz, 1H), 6.09 (br. d, J = 16.4 Hz, 1H), 5.72 - 5.57 (m, 1H), 4.54 - 4.39 (m, 1H), 4.37 - 3.97 (m, 1H), 3.76 - 3.58 (m, 1H), 3.28 - 2.80 (m, 2H), 2.14 (br. d, J = 11.6 Hz, 1H), 2.07 - 1.71 (m, 2H), 1.64 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 412.3. Example 106. Preparation of (R)-1-(3-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 117)

Step 1. 6-Chloro-N-(6-phenoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-a mine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.35 g, 1.75 mmol) in acetonitrile (5 mL) was added 6-phenoxypyridin-3-amine (358 mg, 1.92 mmol). The mixture was stirred at 25 °C for 2 h. On completion, the reaction was filtered and the filtered cake was washed with acetonitrile (5 mL x 2). The crude product was purified by column chromatography:(petroleum ether: ethyl acetate from 10:1 to 0:1) to afford 6-chloro-N-(6-phenoxy-3-pyridyl)pyrido[3,2- d]pyrimidin-4-amine (0.5 g, 1.43 mmol, 74%) as a yellow solid. m/z ES+ [M+H] ⁺ 350.0. Step 2. tert-Butyl 3-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)piperidine-1-carboxylate To a solution of 6-chloro-N-(6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimidin-4-ami ne (0.3 g, 858 μmol) and tert-butyl 3-bromopiperidine-1-carboxylate (340 mg, 1.29 mmol) in dimethylacetamide (6 mL) was added NiCl2.glyme (18.8 mg, 85.8 μmol), zinc powder (168 mg, 2.57 mmol) and pyridine-2-carboxamidine;hydrochloride (27 mg, 172 μmol). The mixture was degassed and purged with nitrogen for 3 times and then stirred at 60 °C for 24 h. On completion, the reaction was concentrated in vacuum. The crude product was purified by column chromatography: (petroleum ether: ethyl acetate from 10:1 to 1:1) to afford tert-butyl 3-[4-[(6- phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]piperidi ne-1-carboxylate (0.15 g, 0.30 mmol, 32%) as a yellow solid. m/z ES+ [M+H] ⁺ 499.2. Step 3. tert-Butyl (R)-3-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidi n-6- yl)piperidine-1-carboxylate tert-Butyl 3-[4-[(6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl ]piperidine-1- carboxylate (0.15 g, 301 μmol) was separated by SFC ("Column: Chiralpak AD-350×4.6mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for MeOH+ACN(0.05%DEA); Gradient elution: 40% MeOH +ACN(0.05% DEA) in CO2; Flow rate: 3mL/min;Detector: PDA; Column Temp: 35C;Back Pressure: 100Bar) to afford tert-butyl (R)-3-(4-((6-phenoxypyridin-3-yl) amino)pyrido[3,2-d]pyrimidin-6-yl)piperidine-1-carboxylate (50 mg, 0.10 mmol, 33%) as a yellow solid and tert-butyl (S)-3-[4-[(6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin- 6-yl] piperidine-1-carboxylate (55 mg, 0.11 mmol, 36%) as a yellow solid. Step 4. (R)-N-(6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyrido[3,2-d ]pyrimidin-4-amine A solution of tert-butyl (3R)-3-[4-[(6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin - 6-yl]piperidine-1-carboxylate (50 mg, 100 μmol) in dichloromethane (0.2 mL) and HCl/ethyl acetate (4 M, 2.0 mL) was stirred at 20 °C for 0.5 h. On completion, the reaction was concentrated in vacuum to afford (R)-N-(6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyrido[3,2-d ]pyrimidin-4- amine (40 mg, crude, HCl salt) as a yellow solid. Step 5. (R)-1-(3-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrim idin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(6-phenoxy-3-pyridyl)-6-[(3R)-3-piperidyl]pyrido[3,2-d]pyr imidin-4- amine (40 mg, 100 μmol) in tetrahydrofuran (1.5 mL) was added sodium bicarbonate (42.2 mg, 502 μmol) and prop-2-enoyl chloride (10.9 mg, 120 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the reaction was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 31%-61%, 10 min) to afford (R)-1-(3-(4-((6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-e n-1-one (12 mg, 0.026 mmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 - 9.76 (m, 1H), 8.85 - 8.79 (m, 1H), 8.68 - 8.61 (m, 1H), 8.48 (br dd, J = 2.8, 8.8 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.26 - 7.12 (m, 3H), 7.09 (d, J = 8.8 Hz, 1H), 6.78 (dd, J = 10.8, 16.8 Hz, 1H), 6.05 (dd, J = 2.4, 16.8 Hz, 1H), 5.61 (dd, J = 2.4, 10.8 Hz, 1H), 4.19 - 4.09 (m, 1H), 4.04 - 3.95 (m, 1H), 3.45 - 3.30 (m, 1H), 3.28 - 3.20 (m, 1H), 3.12 - 3.06 (m, 1H), 2.97 - 2.94 (m, 1H), 2.24 - 2.16 (m, 1H), 2.14 - 2.04 (m, 1H), 1.81 - 1.67 (m, 1H), 1.66 - 1.55 (m, 1H); m/z ES+ [M+H] ⁺ 453.4. Example 107. Preparation of (S)-1-(3-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 118) Step 1. (S)-N-(6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyrido[3,2-d ]pyrimidin-4-amine A solution of tert-butyl (S)-3-[4-[(6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin- 6- yl] piperidine-1-carboxylate (50 mg, 100 μmol) in dichloromethane (0.2 mL) and HCl/ethyl acetate (4 M, 2.0 mL) was stirred at 20 °C for 0.5 h. On completion, the reaction was concentrated in vacuum to afford (S)-N-(6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyrido[3,2-d ]pyrimidin-4- amine (40 mg, crude, HCl salt) as a yellow solid. Step 2. (S)-1-(3-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrim idin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(6-phenoxy-3-pyridyl)-6-[(3S)-3-piperidyl]pyrido[3,2-d]pyr imidin-4- amine (40 mg, 100 μmol) in tetrahydrofuran (1.5 mL) was added sodium bicarbonate (42.2 mg, 502 μmol) and prop-2-enoyl chloride (10.9 mg, 120 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the reaction was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 31%-61%, 10 min) to afford (S)-1-(3-(4-((6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-e n-1-one (9 mg, 0.020 mmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 - 9.92 (m, 1H), 8.84 - 8.65 (m, 1H), 8.64 - 8.59 (m, 1H), 8.54 - 8.37 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.49 - 7.39 (m, 2H), 7.24 - 7.19 (m, 1H), 7.18 - 7.11 (m, 3H), 6.97 - 6.78 (m, 1H), 6.15 - 6.03 (m, 1H), 5.68 - 5.59 (m, 1H), 4.43 - 4.00 (m, 2H), 3.87 - 3.73 (m, 1H), 3.55 - 3.47 (m, 1H), 3.19 - 2.88 (m, 1H), 2.21 - 1.92 (m, 2H), 1.88 - 1.50 (m, 2H); m/z ES+ [M+H] ⁺ 453.4. Example 108. Preparation of (R)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 128) Step 1. 6-Chloro-N-(3-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (380 mg, 1.90 mmol) in acetonitrile (5.0 mL) was added 3-chloro-2,4-difluoro-aniline (466 mg, 2.85 mmol). The mixture was stirred at 60 °C for 12 hrs. On completion, the reaction mixture was filtered. The filtered cake was washed with petroleum ether (30 mL) and then concentrated under reduced pressure to give 6-chloro-N- (3-chloro-2,4-difluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (595 mg, 1.83 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 - 10.69 (m, 1H), 8.80 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.67 (dt, J = 6.0, 8.8 Hz, 1H), 7.45 (dt, J = 2.0, 9.2 Hz, 1H); m/z ES+ [M+H] ⁺ 326.9. Step 2. tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(3-chloro-2,4-difluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (530 mg, 1.62 mmol), tert-butyl 3-bromopiperidine-1- carboxylate (556 mg, 2.11 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (18.2 mg, 16.2 μmol), NiCl ₂ .dtbbpy (3.22 mg, 8.10 μmol), tris(trimethylsilyl)silane (403 mg, 1.62 mmol, 500 μL) and sodium carbonate (343 mg, 3.24 mmol) in dimethoxyethane (10.0 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hrs under nitrogen. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give tert-butyl 3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]piperidine-1-carboxylate (230 mg, 0.48 mmol, 30%) as a yellow solid. m/z ES+ [M+H] ⁺ 476.1. Step 3. tert-Butyl (R)-3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]py rimidin- 6-yl)piperidine-1-carboxylate tert-Butyl 3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]piperidine-1- carboxylate (230 mg, 483 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um); mobile phase:[0.1% NH ₃ water IPA]; B%: 40%-40%, 3.5 min; 60 min) to give tert-butyl (R)-3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimid in-6- yl]piperidine- 1-carboxylate (87.0 mg, 0.18 mmol, 38%) as a yellow solid and tert-butyl (S)-3-[4- (3-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]p iperidine -1-carboxylate (76.0 mg, 0.16 mmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (br. s, 1H), 8.58 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.99 - 7.82 (m, 2H), 7.43 (br. t, J = 8.8 Hz, 1H), 4.21 - 3.84 (m, 2H), 3.43 - 3.35 (m, 1H), 3.13 - 3.02 (m, 1H), 3.00 - 2.81 (m, 1H), 2.08 (br. d, J = 11.2 Hz, 1H), 1.92 - 1.70 (m, 2H), 1.57 - 1.48 (m, 1H), 1.39 (s, 9H); m/z ES+ [M+H] ⁺ 476.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (br. s, 1H), 8.57 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.01 - 7.79 (m, 2H), 7.43 (t, J = 8.8 Hz, 1H), 4.20 - 3.87 (m, 2H), 3.43 - 3.34 (m, 1H), 3.07 (br. t, J = 10.4 Hz, 1H), 3.01 - 2.77 (m, 1H), 2.13 - 2.02 (m, 1H), 1.93 - 1.82 (m, 1H), 1.74 (br. d, J = 2.8 Hz, 1H), 1.52 (br. d, J = 12.0 Hz, 1H), 1.39 (s, 9H); m/z ES+ [M+H] ⁺ 476.1. Step 4. (R)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)pyrido [3,2-d]pyrimidin-4- amine To a solution of tert-butyl (3R)-3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl] piperidine-1-carboxylate (87.0 mg, 183 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (20.8 mg, 183 μmol, 13.5 μL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-(3-chloro-2,4-difluoro-phenyl)-6-[(3R)-3-piperidyl]pyrido[ 3,2-d]pyrimidin-4-amine (68 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 376.0. Step 5. (R)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2,4-difluoro-phenyl)-6-[(3R)-3-piperidyl]pyrido[ 3,2- d]pyrimidin-4- amine (68.0 mg, 181 μmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (122 mg, 1.45 mmol) in water (0.2 mL). Then a solution of prop-2-enoyl chloride (16.4 mg, 181 μmol) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 44%-77%, 11 min) to give (R)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (32.0 mg, 0.074 mmol, 41%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 - 9.77 (m, 1H), 8.57 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.97 - 7.81 (m, 2H), 7.43 (t, J = 9.2 Hz, 1H), 6.89 (ddd, J = 10.4, 16.8, 19.6 Hz, 1H), 5.74 - 5.54 (m, 1H), 4.52 - 4.39 (m, 1H), 4.36 - 3.97 (m, 1H), 3.78 - 3.44 (m, 1H), 3.26 - 2.74 (m, 2H), 2.20 - 2.08 (m, 1H), 2.05 - 1.72 (m, 2H), 1.63 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 430.3. Example 109. Preparation of (S)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 129) Step 1. (S)-N-(3-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)pyrido [3,2-d]pyrimidin-4- amine To a solution of tert-butyl (3S)-3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl] piperidine-1-carboxylate (76.0 mg, 160 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (18.2 mg, 160 μmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N- (3-chloro-2,4-difluoro-phenyl)-6-[(3S)-3-piperidyl]pyrido[3, 2-d]pyrimidin-4-amine (60.0 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 376.0. Step 2. (S)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2,4-difluoro-phenyl)-6-[(3S)-3-piperidyl]pyrido[ 3,2- d]pyrimidin- 4-amine (60.0 mg, 160 μmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (107 mg, 1.28 mmol) in water (0.2 mL). Then a solution of prop-2-enoyl chloride (13.0 mg, 144 μmol) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 44%-77%,11min) to give (S)-1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (31 mg, 0.072 mmol, 45%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (br. s, 1H), 8.57 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.00 - 7.77 (m, 2H), 7.43 (br. t, J = 8.8 Hz, 1H), 6.99 - 6.76 (m, 1H), 6.09 (br dd, J = 5.2, 16.4 Hz, 1H), 5.65 (br. t, J = 11.2 Hz, 1H), 4.53 - 4.38 (m, 1H), 4.36 - 3.96 (m, 1H), 3.74 - 3.46 (m, 1H), 3.28 - 2.76 (m, 2H), 2.12 (br. s, 1H), 2.06 - 1.68 (m, 2H), 1.54 (br. d, J = 9.2 Hz, 1H); m/z ES+ [M+H] ⁺ 430.3. Example 110. Preparation of (R)-1-(3-(4-((5-chloro-6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-e n-1-one (Compound 132) Step 1. tert-Butyl 3-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyr imidin- 6-yl)piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(5-chloro-6-phenoxy-3- pyridyl)pyrido[3,2-d]pyrimidin-4-amine (220 mg, 572 μmol), tert-butyl 3-bromopiperidine-1- carboxylate (196 mg, 744 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (6.42 mg, 5.73 μmol), NiCl ₂ .dtbbpy (227 mg, 572 μmol), tris(trimethylsilyl)silane (142 mg, 572 μmol), sodium carbonate (60.6 mg, 572 μmol) in dimethoxyethane (5 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. On completion, the mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , dichloromethane: methanol = 40:1) to give compound tert-butyl 3-[4-[(5-chloro- 6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]piperi dine-1-carboxylate (150 mg, 0.28 mmol, 49%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.89 - 9.60 (m, 1H), 8.88 - 8.69 (m, 3H), 8.15 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.25 - 7.16 (m, 3H), 4.45 - 4.09 (m, 1H), 3.91 - 3.66 (m, 1H), 3.58 - 3.36 (m, 2H), 3.28 - 3.09 (m, 1H), 2.24 - 2.09 (m, 2H), 1.42 (s, 9H), 1.26 (s, 1H), 0.93 - 0.78 (m, 1H); m/z ES+ [M+H] ⁺ 533.1. Step 2. tert-Butyl (R)-3-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidine-1-carboxylate tert-Butyl 3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrim idin-6- yl]piperidine-1- carboxylate (120 mg, 225 μmol) was separated by SFC (column: Phenomenex- Cellulose-2 (250mmx30mm,10um); mobile phase: [0.1% NH ₃ water-methano]; B%: 50%-50%, 5.0 min; 60 min). to give compound tert-butyl (R)-3-(4-((5-chloro-6-phenoxypyridin-3- yl)amino)pyrido[3,2-d] pyrimidin-6-yl)piperidine-1-carboxylate (50.0 mg, 0.094 mmol, 41%) and tert-butyl (S)-3-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d ]pyrimidin-6- yl)piperidine-1-carboxylate (50.0 mg, 0.094 mmol, 40%) as white solids. Step 3. (R)-N-(5-chloro-6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyr ido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl (3R)-3-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin- 6-yl]piperidine-1-carboxylate (45.0 mg, 84.4 μmol) in ethyl acetate (0.5 mL) was added HCl/ethyl acetate (4 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was concentrated under reduced pressure to give compound (R)-N-(5-chloro-6- phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyrido[3,2-d]pyrimidi n-4-amine (50.0 mg, crude, HCl salt) as a red solid. m/z ES+ [M+H] ⁺ 433.1. Step 4. (R)-1-(3-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3, 2-d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of (R)-N-(5-chloro-6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyr ido [3,2- d]pyrimidin-4-amine (40.0 mg, 92.4 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (23.3 mg, 277 μμmol), then prop-2-enoyl chloride (10.0 mg, 110 μmol) was added. The resulting mixture was stirred at 0 °C for 0.5 hr. On completion, the residue was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 44%-74%,8min) to give compound (R)-1-(3-(4-((5-chloro-6- phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperi din-1-yl)prop-2-en-1-one (10.4 mg, 0.021 mmol, 22%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 - 9.85 (m, 1H), 8.82 (d, J = 14.8 Hz, 1H), 8.73 - 8.59 (m, 2H), 8.18 (d, J = 8.8 Hz, 1H), 7.99 - 7.87 (m, 1H), 7.49 - 7.39 (m, 2H), 7.29 - 7.20 (m, 1H), 7.19 - 7.10 (m, 2H), 6.98 - 6.77 (m, 1H), 6.15 - 6.00 (m, 1H), 5.72 - 5.57 (m, 1H), 4.44 - 3.96 (m, 2H), 3.85 - 3.69 (m, 1H), 3.57 - 3.45 (m, 1H), 3.28 - 3.21 (m, 1H), 3.19 - 2.85 (m, 1H), 2.16 - 2.10 (m, 1H), 2.00 - 1.77 (m, 1H), 1.54 (s, 1H); m/z ES+ [M+H] ⁺ 487.3. Example 111. Preparation of (S)-1-(3-(4-((5-chloro-6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-e n-1-one (Compound 133) Step 1. (S)-N-(5-chloro-6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)pyr ido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl (S)-3-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidine-1-carboxylate (50.0 mg, 93.8 μmol) in ethyl acetate (0.5 mL) was added HCl/ethyl acetate (4 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was concentrated under reduced pressure to give compound (S)-1-(3-(4-((5-chloro-6- phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperi din-1-yl)prop-2-en-1-one (50.0 mg, crude, HCl salt) as a red solid. m/z ES+ [M+H] ⁺ 433.1. Step 2. (S)-1-(3-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3, 2-d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(5-chloro-6-phenoxy-3-pyridyl)-6-[(3S)-3-piperidyl]pyrido[ 3,2- d]pyrimidin- 4-amine (40 mg, 92.4 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (23.2 mg, 277 μmol) and water (0.5 mL), then prop-2-enoyl chloride (10.0 mg, 110 μmol) was added. The resulting mixture was stirred at 0 °C for 0.5 hr. On completion, the residue was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 44%-74%,8min) to give compound (S)-1-(3-(4-((5-chloro-6- phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperi din-1-yl)prop-2-en-1-one (7.3 mg, 0.015 mmol, 16%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 - 9.79 (m, 1H), 8.81 ( d, J = 14.0 Hz, 1H), 8.72 - 8.58 (m, 2H), 8.18 (d, J = 8.8 Hz, 1H), 7.99 - 7.86 (m, 1H), 7.50 - 7.38 (m, 2H), 7.28 - 7.19 (m, 1H), 7.19 - 7.10 (m, 2H), 6.99 - 6.76 (m, 1H), 6.18 - 5.99 (m, 1H), 5.76 - 5.53 (m, 1H), 4.44 - 3.96 (m, 2H), 3.85 - 3.69 (m, 1H), 3.58 - 3.44 (m, 1H), 3.27 - 3.18 (m, 1H), 3.18 - 2.84 (m, 1H), 2.15 - 2.10 (m, 1H), 2.00 - 1.78 (m, 1H), 1.54 (d, J = 4.4 Hz, 1H); m/z ES+ [M+H] ⁺ 487.3. Example 112. Preparation of 1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-y l)prop-2-en-1-one (Compound 161) Step 1. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-chloro pyrido[3,2- d]pyrimidin-4-amine A solution of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline (1.2 g, 4.24 mmol) and 4,6- dichloropyrido[3,2-d]pyrimidine (848.79 mg, 4.24 mmol) in acetonitrile (20 mL) was stirred at 25 °C for 12 hr. On completion, the mixture was filtered and the filter cake was concentrated. The crude product was purified by column chromatography (Petroleum ether/Ethyl acetate = 5/1~0/1) to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-chloro pyrido[3,2-d]pyrimidin-4- amine (1.1 g, 2.82 mmol, 67%) as a yellow solid. m/z ES+ [M+H] ⁺ 390.2. Step 2. tert-Butyl 5-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-3,6-dihydrop yridine-1(2H)-carboxylate To a solution of 6-chloro-N-[4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl] pyrido[3,2- d] pyrimidin-4-amine (240 mg, 615 μmol) in dioxane (5 mL) and water (1 mL) was added tert- butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1-carboxylate (228 mg, 738 μmol), potassium carbonate (255 mg, 1.85 mmol) and Pd(dppf)Cl ₂ (45.0 mg, 61.6 μmol). The mixture was stirred at 100 °C for 2 h under nitrogen. On completion, the mixture was quenched by water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/ethyl acetate = 1/1~0/1) to give tert-butyl-5-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)an ilino]pyrido[3,2-d]pyrimidin-6- yl]-3,6-dihydro-2H-pyridine-1-carboxylate (150 mg, 0.28 mmol, 45%) as a yellow solid. m/z ES+ [M+H] ⁺ 537.2. Step 3. tert-Butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidine-1- carboxylate To a solution of tert-butyl 5-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d] pyrimidin-6-yl]-3,6-dihydro-2Hpyridine-1-carboxylate (150 mg, 279 μmol) in tetrahydrofuran (5 mL) was added palladium on activated carbon (15 mg, 10% loading) and magnesium oxide (90.1 mg, 2.24 mmol). The mixture was stirred at 25 °C for 8 h under hydrogen (15 psi). On completion, the mixture was filtered and the filtrate was concentrated to give tert-butyl 3-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]pyrid o[3,2-d]pyrimidin-6- yl]piperidine-1-carboxylate (150 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 539.2. Step 4. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-(piper idin-3-yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 3-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d] pyrimidin-6-yl]piperidine-1-carboxylate (130 mg, 241 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.4 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N- (4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-(piperid in-3-yl)pyrido[3,2-d]pyrimidin-4- amine (130 mg, crude, TFA salt) as a white solid. Step 5. 1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)am ino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl)-6-(piper idin-3- yl)pyrido[3,2-d]pyrimidin-4-amine (130 mg, 235 μmol, trifluoroacetic acid) in tetrahydrofuran (2 mL) was added prop-2-enoyl chloride (23.4 mg, 258 μmol) and sodium bicarbonate (79.0 mg, 941 μmol) in water (2 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Shim-pack C18 150x25, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 24%-44%,10 min) to give 1-[3-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1-piperidyl]prop- 2-en-1-one (27.5 mg, 0.056 mmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.15 (s, 1H), 9.94 - 9.89 (m, 1H), 8.99 - 8.93 (m, 1H), 8.69 - 8.64 (m, 1H), 8.41 (s, 1H), 8.29 (br. d, J = 8.8 Hz, 1H), 8.22 - 8.11 (m, 2H), 7.98 - 7.90 (m, 1H), 7.33 (br. d, J = 8.8 Hz, 2H), 7.08 - 6.99 (m, 2H), 6.97 - 6.79 (m, 1H), 6.10 (dd, J = 2.4, 16.8 Hz, 1H), 5.68 - 5.59 (m, 1H), 4.38 - 4.20 (m, 1H), 4.00 - 3.53 (m, 3H), 3.08 - 2.90 (m, 1H), 2.26 - 2.08 (m, 2H), 2.06 - 1.80 (m, 1H), 1.60 - 1.47 (m, 2H); m/z ES+ [M+H] ⁺ 493.4. Example 113. Preparation of (R)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-y l)prop-2-en-1-one (Compound 182)

Step 1. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl) -6- chloropyrido[3,2-d]pyrimidin-4-amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 600 μmol) and 3-methyl-4- ([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline (144 mg, 600 μmol) in acetonitrile (3 mL) was stirred at 60 °C for 2 hours. On completion, the reaction mixture was filtered and the solid was concentrated under reduced pressure to give compound N-(4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)-3-methylphenyl)-6-chloropyrido[3,2-d]pyrimidin-4-amin e (230 mg, 0.57 mmol, 93%) as a yellow solid. m/z ES+ [M+H] ⁺ 404.2. Step 2. tert-Butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidine-1- carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-[3-methyl-4- ([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]pyrido[3,2-d]p yrimidin-4-amine (230 mg, 570 μmol), tert-butyl 3-bromopiperidine-1-carboxylate (301 mg, 1.14 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (6.39 mg, 5.70 μmol), NiCl ₂ .dtbbpy (1.13 mg, 2.85 μmol), tris(trimethylsilyl)silane (142 mg, 570 μmol), sodium carbonate (122 mg, 1.14 mmol) in dimethoxyethane (5 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. On completion, the mixture was directly purified by prep-HPLC (0.1% FA conditions) to give tert- butyl 3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anil ino]pyrido[3,2-d]pyrimidin-6- yl]piperidine-1-carboxylate (0.12 g, 0.22 mmol, 37%) as a yellow oil. m/z ES+ [M+H] ⁺ 553.4. Step 3. tert-Butyl (R)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidine-1- carboxylate tert-Butyl 3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anil ino]pyrido[3,2- d]pyrimidin-6-yl]piperidine-1-carboxylate (0.12 g, 217 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um); mobile phase: [0.1% NH ₃ water IPA]; B%: 55%-55%; 35 min) to give compound tert-butyl (R)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pipe ridine-1-carboxylate (35 mg, 0.063 mmol, 29%) as a yellow solid and tert-butyl (S)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pipe ridine-1-carboxylate (35 mg, 0.063 mmol, 29%) as a yellow solid. m/z ES+ [M+H] ⁺ 553.4. Step 4. (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphe nyl)-6-(piperidin-3- yl)pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl (R)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino) pyrido[3,2-d]pyrimidin-6-yl)piperidine-1-carboxylate (30 mg, 54.3 μmol) in dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to give compound (R)- N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl) -6-(piperidin-3-yl)pyrido[3,2- d]pyrimidin-4-amine (25 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 453.3. Step 5. (R)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-y l)prop-2-en-1-one To a mixture of (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphe nyl)-6- (piperidin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (25 mg, 55.3 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (13.9 mg, 166 μmol) in one portion at 20 °C. Then prop-2-enoyl chloride (5.00 mg, 55.3 μmol) was added, and the mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 24%-54%, 10 min) to give (R)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-me thylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (7.5 mg, 0.015 mmol, 27%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 - 9.85 (m, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.77 - 8.57 (m, 1H), 8.39 (s, 1H), 8.23 - 8.10 (m, 2H), 8.03 (br. s, 1H), 7.97 - 7.87 (m, 1H), 7.26 (br. d, J = 6.8 Hz, 1H), 7.04 (dd, J = 2.4, 7.2 Hz, 1H), 6.96 - 6.82 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.12 (br. d, J = 16.4 Hz, 1H), 5.71 - 5.51 (m, 1H), 4.40 - 4.15 (m, 1H), 3.88 - 3.70 (m, 1H), 3.56 (td, J = 6.4, 12.8 Hz, 1H), 3.24 - 3.11 (m, 1H), 3.16 (br. s, 1H), 3.03 - 2.92 (m, 0.4H), 2.22 (s, 3H), 2.21 - 2.18 (m, 1.5H), 2.17 - 2.07 (m, 1H), 2.00 - 1.82 (m, 1H), 1.57 - 1.51 (m, 1.5H), 1.33 - 1.19 (m, 1.4H), 0.86 - 0.84 (m, 1H); m/z ES+ [M+H] ⁺ 507.3. Example 114. Preparation of (S)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-y l)prop-2-en-1-one (Compound 183) Step 1. (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphe nyl)-6-(piperidin-3- yl)pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl (3S)-3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido [3,2-d]pyrimidin-6-yl]piperidine-1-carboxylate (30.0 mg, 54.3 μmol) in dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25 C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to give compound (S)- N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl) -6-(piperidin-3-yl)pyrido[3,2- d]pyrimidin-4-amine (25 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 453.3. Step 2. (S)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-y l)prop-2-en-1-one To a mixture of (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphe nyl)-6- (piperidin-3- yl)pyrido[3,2-d]pyrimidin-4-amine (25.0 mg, 55.3 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (13.9 mg, 166 μmol) in one portion at 20 °C. Then prop-2-enoyl chloride (5.00 mg, 55.3 μmol) was added and the mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 25%-55%, 10 min) to give (S)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-me thylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (14.7 mg, 0.029 mmol, 53%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 - 9.84 (m, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 8.25 - 8.12 (m, 2H), 8.03 (br. s, 1H), 7.94 (br. d, J = 8.4 Hz, 1H), 7.26 (br. d, J = 8.4 Hz, 1H), 7.04 (dd, J = 2.4, 7.4 Hz, 1H), 6.96 - 6.82 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.11 (br. d, J = 16.9 Hz, 1H), 5.70 - 5.58 (m, 1H), 4.40 - 3.96 (m, 2H), 3.89 - 3.71 (m, 1H), 3.56 (br dd, J = 6.0 12.8 Hz, 0.6H), 3.22 - 3.12 (m, 1H), 3.04 - 2.94 (m, 0.4H), 2.22 (s, 3H), 2.19 - 2.08 (m, 1.5H), 2.00 - 1.82 (m, 1H), 1.60 - 1.50 (m, 1.5H); m/z ES+ [M+H] ⁺ 507.3. Example 115. Preparation of 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)tetrahydropyrimidin-1(2H)-yl)prop-2-en-1-on e (Compound 206) Step 1. tert-Butyl (3-((4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6- yl)amino)propyl)carbamate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (120 mg, 388 μmol) and tert-butyl N-(3-aminopropyl)carbamate (149 mg, 854 μmol) in N- methylpyrrolidone (3 mL) was added diisopropylethylamine (151 mg, 1.16 mmol). The mixture was stirred at 120 °C for 6 hours. On completion, the mixture was concentrated under vacuum to give tert-butyl (3-((4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6- yl)amino)propyl)carbamate (321 mg, crude) as a black oil. ¹ H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 2.0 Hz, 1H), 8.49 - 8.40 (m, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.60 (t, J = 5.2 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.85 (t, J = 5.2 Hz, 1H), 3.59 - 3.43 (m, 2H), 3.19 - 3.16 (m, 1H), 3.15 - 2.95 (m, 2H), 2.82 - 2.74 (m, 1H), 1.81 - 1.71 (m, 2H), 1.40 - 1.32 (m, 9H); m/z ES+ [M+H] ⁺ 447.0. Step 2. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)tetrahydropyrimidine-1(2H)-carboxylate To a mixture of tert-butyl N-[3-[[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]amino]propyl]carbamate (220 mg, 492 μmol) in water (2 mL) and methanol (2.0 mL) was added paraformaldehyde (16.8 mg, 492 μmol) in one portion at 20 °C. The mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo and then extracted with ethyl acetate (5 mL x 2). The organic layers were dried over sodium sulfate and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (ISCO®; 0.32 g SepaFlash® Silica Flash Column, eluent of 0~50% ethyl acetate/Petroleum ether gradient @ 6 mL/min) to give tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)tetrahydropyrimidine-1(2H)-carboxylate (57.0 mg, 0.12 mmol, 25%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 - 9.29 (m, 1H), 8.46 - 8.44 (m, 1H), 8.16 - 8.10 (m, 1H), 8.05 - 8.00 (m, 1H), 7.70 - 7.65 (m, 1H), 7.44 - 7.38 (m, 1H), 7.33 - 7.27 (m, 1H), 5.34 - 5.23 (m, 2H), 4.05 - 3.93 (m, 2H), 3.64 - 3.53 (m, 2H), 1.73 - 1.60 (m, 2H), 1.36 - 1.30 (m, 10H). Step 3. N-(3-chloro-2-fluorophenyl)-6-(tetrahydropyrimidin-1(2H)-yl) pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]hexahydropyrimidine-1-carboxylate (40.0 mg, 87.2 μmol) in dichloromethane (13.2 g, 155 mmol, 10 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.0 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated to give N-(3-chloro-2-fluoro- phenyl)-6-hexahydropyrimidin-1-yl-pyrido[3,2-d] pyrimidin-4-amine (96.0 mg, 0.27 mmol, 90%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.11 - 10.03 (m, 1H), 8.79 - 8.69 (m, 2H), 8.57 - 8.52 (m, 1H), 8.17 - 8.08 (m, 1H), 7.85 - 7.74 (m, 2H), 7.60 - 7.51 (m, 1H), 7.40 - 7.31 (m, 1H), 5.36 - 5.26 (m, 2H), 4.06 - 3.97 (m, 2H), 3.32 - 3.27 (m, 2H), 1.90 - 1.80 (m, 2H); m/z ES+ [M+H] ⁺ 358.9. Step 4. 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6- yl)tetrahydropyrimidin-1(2H)-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-hexahydropyrimidin-1-yl-pyrid o[3,2- d]pyrimidin-4- amine (80.0 mg, 223 μmol) in tetrahydrofuran (3 mL) was added sodium bicarbonate (93.7 mg, 1.11 mmol) in water (3 mL) at 0 °C. Then prop-2-enoyl chloride (20.2 mg, 223 μmol, 18.2 μL) in tetrahydrofuran (3.0 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 5 min. On completion, the mixture was concentrated to give a residue. The crude product was purified by prep-HPLC (column: Waters xbridge 150x25mm, 10um; mobile phase: [water (10 mM, NH ₄ HCO ₃ ).-acetonitrile]; B%: 34%-64%, 11 min) to give 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6- yl)tetrahydropyrimidin-1(2H)-yl)prop-2-en-1-on (4.8 mg, 0.012 mmol, 5%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 8.49 - 8.30 (m, 1H), 8.20 – 7.98 (m, 2H), 7.76 – 7.60 (m, 1H), 7.58 - 7.40 (m, 1H), 7.38 - 7.23 (m, 1.5H), 6.80 – 6.72 (m, 0.5H), 6.20 - 6.03 (m, 1H), 5.76 - 5.55 (m, 2H), 5.50 - 5.40 (m, 1H), 4.13 - 3.65 (m, 4H), 1.76 - 1.60 (m, 2H); m/z ES+ [M+H] ⁺ 413.1. Example 116. Preparation of 1-(3-(4-((5-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 218) Step 1. 6-Chloro-N-(5-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 1 mmol) in acetonitrile (5 mL) was added 5-chloro-2,4-difluoro-aniline (163 mg, 1 mmol). The mixture was stirred at 20 °C for 2 hrs. On completion, the mixture was filtered and the filter cake was collected to give 6-chloro- N-(5-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (300 mg, 0.92 mmol, 92%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.77 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.99 (br. t, J = 7.6 Hz, 1H), 7.75 (br. t, J = 9.6 Hz, 1H); m/z ES+ [M+H] ⁺ 327.1. Step 2. tert-Butyl 3-(4-((5-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)piperidine-1-carboxylate To an 30 mL vial equipped with a stir bar was added 6-chloro-N-(5-chloro-2,4-difluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 611 μmol), tert-butyl 3-bromopiperidine-1- carboxylate (210 mg, 795 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (6.86 mg, 6.11 μmol), NiCl ₂ .dtbbpy (1.22 mg, 3.06 μmol), tris(trimethylsilyl)silane (152 mg, 611 μmol) and sodium carbonate (130 mg, 1.22 mmol) in dimethoxyethane (6 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. On completion, the mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate = 10:1 to 1:1) to give tert-butyl 3-(4-((5-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)piperidine-1- carboxylate (210 mg, 0.44 mmol, 65%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.68 - 9.28 (m, 1H), 8.84 (s, 1H), 8.29 - 8.21 (m, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.4, 10.4 Hz, 1H), 4.29 (d, J = 12.4 Hz, 1H), 2.01 - 1.87 (m, 2H), 1.86 - 1.77 (m, 2H), 1.76 - 1.57 (m, 4H), 1.47 (s, 9H); m/z ES+ [M+H] ⁺ 476.3. Step 3. N-(5-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)pyrido[3,2 -d]pyrimidin-4- amine A solution of tert-butyl 3-[4-(5-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl] piperidine-1-carboxylate (200 mg, 420 μmol) in dichloromethane (2 mL) and HCl/dioxane (2 mL) was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuum to give N- (5-chloro-2,4-difluorophenyl)-6-(piperidin-3-yl)pyrido[3,2-d ]pyrimidin-4-amine (155 mg, 0.41 mmol, 98%, HCl salt) as a yellow solid. m/z ES+ [M+H] ⁺ 376.1. Step 4. 1-(3-(4-((5-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(5-chloro-2,4-difluoro-phenyl)-6-(3-piperidyl)pyrido[3,2-d ] pyrimidin-4-amine (155 mg, 412 μmol) in tetrahydrofuran (4 mL) and water (1 mL) was added sodium bicarbonate (104 mg, 1.24 mmol) at 0 °C. Then prop-2-enoyl chloride (33.6 mg, 371 μmol) was added dropwise to the mixture. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum. The residue was diluted with N,N-dimethylformamide (2 mL) and filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 37%-67%, 10 min) to give 1- (3-(4-((5-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrim idin-6-yl)piperidin-1-yl)prop-2- en-1-one (42.9 mg, 0.10 mmol, 24%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 - 9.86 (m, 1H), 8.65 - 8.62 (m, 1H), 8.29 - 8.20 (m, 2H), 7.98 - 7.93 (m, 1H), 7.77 - 7.72 (m, 1H), 6.95 - 6.84 (m, 1H), 6.10 (d, J = 16.4 Hz, 1H), 5.70 - 5.63 (m, 1H), 4.72 - 4.43 (m, 1H), 4.34 - 4.02 (m, 1H), 3.78 - 3.44 (m, 1H), 3.26 - 2.78 (m, 2H), 2.16 - 2.14 (m, 1H), 2.07 - 1.75 (m, 2H), 1.57 - 1.53 (m, 1H); m/z ES+ [M+H] ⁺ 430.3. Example 117. Preparation of 1-(3-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 220) Step 1. 6-Chloro-N-(5-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 750 μmol) in acetonitrile (1.0 mL) was added 5-chloro-2-fluoro-aniline (120 mg, 825 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give 6- chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4- amine (170 mg, 0.55 mmol, 73%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.69 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.06 - 8.00 (m, 2H), 7.46 - 7.34 (m, 2H). Step 2. tert-Butyl 3-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)piperidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(5-chloro-2-fluoro-phenyl) pyrido[3,2-d]pyrimidin-4-amine (150 mg, 485 μmol), tert-butyl 3-bromopiperidine-1-carboxylate (167 mg, 631 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (5.44 mg, 4.85 μmol), NiCl ₂ .dtbbpy (966 ug, 2.43 μmol), tris(trimethylsilyl)silane (121 mg, 485 μmol), sodium carbonate (103 mg, 970 μmol) in dimethoxyethane (2.0 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate=1/0 to 5/1) to give tert-butyl 3-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)piperidine-1-carboxylate (130 mg, 0.28 mmol, 47%) as an orange oil. m/z ES+ [M+H] ⁺ 458.3. Step 3. N-(5-chloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido[3,2-d]p yrimidin-4-amine To a solution of tert-butyl 3-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]piperidine-1- carboxylate (95.0 mg, 207 μmol) in dichloromethane (1 mL) was added HCl/ethyl acetate (4 M, 51.9 μL). The mixture was stirred at 25 °C for 20 min. On completion, the reaction mixture was concentrated in vacuo to give N-(5-chloro-2-fluorophenyl)-6-(piperidin-3- yl)pyrido[3,2-d]pyrimidin-4-amine (82 mg, crude, HCl salt) as a yellow oil. m/z ES+ [M+H] ⁺ 358.2. Step 4. 1-(3-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)piperidin- 1-yl)prop-2-en-1-one To a solution of N-(5-chloro-2-fluorophenyl)-6-(piperidin-3-yl)pyrido[3,2-d]p yrimidin-4- amine (82.0 mg, 229 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (57.8 mg, 687.51 μmol). Then prop-2-enoyl chloride (20.7 mg, 229 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition;column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 49%-79%, 10 min) to give 1-(3-(4-((5-chloro-2-fluorophenyl) amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1 -one (23.2 mg, 0.056 mmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 - 9.76 (m, 1H), 8.69 (s, 1H), 8.29 (d, J = 6.4 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.97 - 7.95 (m, 1H), 7.45 (t, J = 9.6 Hz, 1H), 7.36 (s, 1H), 6.94 - 6.84 (m, 1H), 6.10 (d, J = 16.8 Hz, 1H), 5.70 - 5.63 (m, 1H), 4.54 - 4.43 (m, 1H), 4.36 - 4.03 (m, 1H), 3.67 - 2.80 (m, 3H), 2.16 - 2.03 (m, 1H), 2.00 - 1.77 (m, 2H), 1.57 - 1.54 (m, 1H); m/z ES+ [M+H] ⁺ 412.3. Example 118. Preparation of (R)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en- 1-one (Compound 38)

Step 1. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxypyrido[3, 2- d]pyrimidin-6-yl)piperidine-1-carboxylate A mixture of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)-7-methoxy-pyrido[3 ,2- d]pyrimidin-4-amine (500 mg, 1.34 mmol), tert-butyl 3-bromopiperidine-1-carboxylate (707 mg, 2.68 mmol), NiCl ₂ .glyme (58.8 mg, 267 μmol), pyridine-2-carboxamidine;hydrochloride (84.3 mg, 535 μmol) and Zn powder (875 mg, 13.3 mmol) in N,N-dimethylacetamide (15 mL) was degassed and purged with nitrogen gas (3x) and then the mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. On completion, the mixture was filtered through celite and then washed with ethyl acetate (50 mL). The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were dried over sodium sulfate and then concentrated. The residue was purified by reverse-phase HPLC (FA: mobile phase: [water (0.5% FA) - acetonitrile]; B%: 90%-100%,10 min) to give tert-butyl 3-(4-((3,4-dichloro-2- fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)pip eridine-1-carboxylate (300 mg, 0.57 mmol, 42%) as a white solid. m/z ES+ [M+H] ⁺ 522.2. Step 2. tert-Butyl (R)-3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxypyrid o[3,2- d]pyrimidin-6-yl)piperidine-1-carboxylate The compound tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)-7-methoxy-pyrido[3,2- d]pyrimidin-6-yl]piperidine-1-carboxylate (300 mg, 574 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250mm x 30 mm, 10 um); mobile phase: [0.1% NH ₃ water IPA]; B%: 50% - 50%, 4; 90 min) to give tert-butyl (R)-3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d]pyrimidin-6-yl)piperidine-1-carboxylate (160 mg, 0.31 mmol, 52%) as a white solid and tert-butyl (S)-3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxypyrid o[3,2- d]pyrimidin-6-yl)piperidine-1-carboxylate (120 mg, 0.23 mmol, 40%) as a white solid. Step 3. (R)-N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-3 -yl)pyrido[3,2- d]pyrimidin-4-amine A solution of tert-butyl (R)-3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d] pyrimidin-6-yl)piperidine-1-carboxylate (80 mg, 153 μmol) in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) was stirred at 25 °C for 0.1 h. On completion, the mixture was concentrated to give (R)-N-(3,4-dichloro-2-fluorophenyl)-7- methoxy-6-(piperidin-3-yl)pyrido[3,2-d] pyrimidin-4-amine (70 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 422.2. Step 4. (R)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxypy rido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one To a solution of (R)-N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-3 - yl)pyrido[3,2-d] pyrimidin-4-amine (70 mg, 166 μmol) and sodium bicarbonate (69.6 mg, 829 μmol) in tetrahydrofuran (1 mL) and water (0.3 mL) was added a solution of prop-2-enoyl chloride (15 mg, 166 μmol) in tetrahydrofuran (0.5 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the reaction was concentrated under vacuum. The residue was purified by Prep-HPLC (FA: column: Phenomenex luna C ₁₈ 150 x 25 mm x 10 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 50% - 80%, 10 min) to give (R)-1-(3-(4-((3,4-dichloro-2- fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)pip eridin-1-yl)prop-2-en-1-one (19.4 mg, 0.041 mmol, 24%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (d, J =10.4 Hz, 1H), 8.57 (s, 1H), 8.05 (t, J =8.0 Hz, 1H), 7.61 - 7.59 (m, 2H), 6.90 - 6.82 (m, 1H), 6.10 - 6.06 (m, 1H), 5.68 - 5.64 (m, 1H), 4.50 - 4.47 (m, 1H), 4.24 - 4.02 (m, 4H), 3.61 - 2.75 (m, 2H), 2.06 - 1.83 (m, 3H), 1.78 - 1.23 (m, 2H); m/z ES+ [M+H] ⁺ 476.2. Example 119. Preparation of (S)-1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en- 1-one (Compound 39) Step 1. (S)-N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-3 -yl)pyrido[3,2- d]pyrimidin-4-amine A solution of tert-butyl (S)-3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d] pyrimidin-6-yl)piperidine-1-carboxylate (60 mg, 115 μmol) in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) was stirred at 25 °C for 0.1 h. On completion, the reaction was concentrated to give (S)-N-(3,4-dichloro-2-fluorophenyl)-7- methoxy-6-(piperidin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (50 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 422.2. Step 2. (S)-1-(3-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3, 2-d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of (S)-N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-3 - yl)pyrido[3,2-d] pyrimidin-4-amine (50 mg, 118 μmol) and sodium bicarbonate (49.7 mg, 592 μmol) in tetrahydrofuran (1 mL) and water (0.3 mL) was added a solution of prop-2-enoyl chloride (10.7 mg, 118 μmol) in tetrahydrofuran (0.5 mL) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. On completion, the mixture was concentrated under vacuum. The residue was purified by Prep-HPLC (FA: column: Phenomenex luna C ₁₈ 150 x 25 mm x 10 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 50% - 80%, 10 min) to give (S)-1-(3-(4-((5-chloro-6- phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperi din-1-yl)prop-2-en-1-one (31.8 mg, 0.067 mmol, 56%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 8.57 (s, 1H), 8.03 (t, J =8.4 Hz, 1H), 7.62 - 7.59 (m, 2H), 6.87 - 6.82 (m, 1H), 6.09 (dd, J =2.0, 8.8 Hz, 1H), 5.67 - 5.64 (m, 1H), 4.49 (t, J =11.6 Hz, 1H), 4.25 - 3.55 (m, 5H), 3.21 - 2.75 (m, 1H), 2.07 - 1.91 (m, 3H), 1.87 - 1.50 (m, 2H); m/z ES+ [M+H] ⁺ 476.2. Example 120. Preparation of 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1 -one (Compound 65) Step 1. 6-Bromo-N-(3,4-dichloro-2-fluorophenyl)-7-fluoropyrido[3,2-d ]pyrimidin-4- amine To a solution of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (0.42 g, 1.60 mmol) in acetonitrile (3 mL) was added 3,4-dichloro-2-fluoro-aniline (288 mg, 1.60 mmol). The mixture was stirred at 25 °C for 10 min. On completion, the reaction was quenched by water (10 mL) and then filtered. The filter caker was dried under reduced pressure to give 6-bromo-N-(3,4-dichloro- 2-fluoro-phenyl)-7-fluoro-pyrido[3,2-d]pyrimidin-4-amine (0.40 g, 0.99 mmol, 62%) as a gray solid. Step 2. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-fluoropyrido[3,2 - d]pyrimidin-6-yl)piperidine-1-carboxylate A mixture of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)-7-fluoro-pyrido[3,2 - d]pyrimidin-4-amine (180 mg, 444 μmol), tert-butyl 3-bromopiperidine-1-carboxylate (152 mg, 576 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (5.0 mg, 4.44 μmol), NiCl ₂ .dtbbpy (0.9 mg, 2.2 μmol), sodium carbonate (93.9 mg, 888 μmol) and tris(trimethylsilyl)silane (110 mg, 444 μmol) in dimethoxyethane (6 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 6 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mm, 3um; mobile phase: [water (0.2% FA)-acetonitrile]; B%: 60%-99%, 8 min) to give tert- butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-fluoropyrido[3,2 -d]pyrimidin-6-yl)piperidine- 1-carboxylate (42.0 mg, 0.082 mmol, 19%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (br. s, 1H), 8.80 (s, 1H), 8.79 - 8.69 (m, 1H), 7.83 (d, J = 10.0 Hz, 1H), 7.38 (dd, J = 2.0, 9.0 Hz, 1H), 4.32 (br. d, J = 11.6 Hz, 1H), 4.21 - 3.77 (m, 1H), 3.51 - 3.15 (m, 3H), 2.95 (br. s, 1H), 2.18 (br. d, J = 10.8 Hz, 1H), 2.01 - 1.82 (m, 2H), 1.47 (s, 9H), 1.38 - 1.23 (m, 1H), 0.24 - 0.06 (m, 4H); m/z ES+ [M+H] ⁺ 510.1. Step 3. N-(3,4-dichloro-2-fluorophenyl)-7-fluoro-6-(piperidin-3-yl)p yrido[3,2- d]pyrimidin-4-amine A solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2-d] pyrimidin-6-yl]piperidine-1-carboxylate (37.0 mg, 72.5 μmol) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give N-(3,4-dichloro-2-fluorophenyl)-7-fluoro-6-(piperidin-3- yl)pyrido[3,2-d] pyrimidin-4-amine (38.0 mg, crude, trifluoroacetic acid) as a yellow solid. m/z ES+ [M+H] ⁺ 410.2. Step 4. 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-fluoropyrido[ 3,2-d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-7-fluoro-6-(3-piperidyl)pyr ido[3,2- d]pyrimidin- 4-amine (38.0 mg, 72.5 μmol, trifluoroacetic acid) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (6.09 mg, 72.5 μmol) and prop-2-enoyl chloride (6.56 mg, 72.5 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mm, 3um; mobile phase: [water (0.2% FA)-acetonitrile]; B%: 50%-90%, 8 min) to give 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-fluoropyrido[ 3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (9.6 mg, 0.021 mmol, 29%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (d, J = 8.0 Hz, 1H), 8.61 (s, 1H), 8.18 - 8.06 (m, 1H), 7.89 (t, J = 8.8 Hz, 1H), 7.63 (dd, J = 2.4, 8.8 Hz, 1H), 6.88 – 6.82 (m, 1H), 6.12 - 6.09 (m, 1H), 5.66 (t, J = 8.4 Hz, 1H), 4.48 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 4.04 (d, J = 13.2 Hz, 1H), 3.69 (t, J = 12.0 Hz, 1H), 3.53 – 3.48 (m, 1H), 3.27 - 3.20 (m, 1H), 2.77 (t, J = 12.0 Hz, 1H), 2.18 - 1.72 (m, 3H), 1.77 – 1.57 (m, 1H); m/z ES+ [M+H] ⁺ 464.0. Example 121. Preparation of 1-(3-(4-((3-chloro-2-fluorophenyl)amino)-7-fluoropyrido[3,2- d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 140) Step 1. 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-fluoropyrido[3,2-d]pyr imidin-4-amine To a solution of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (0.26 g, 991 μmol) in acetonitrile (8 mL) was added 3-chloro-2-fluoro-aniline (216 mg, 1.49 mmol). The mixture was stirred at 25 °C for 16 h. On completion, the reaction was filtered and the filter cake was washed with acetonitrile (2 mL x 2) to afford 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[3,2- d]pyrimidin-4-amine (0.28 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 372.9. Step 2. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7-fluoropyrido[3,2- d]pyrimidin-6-yl)piperidine-1-carboxylate To a solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[3,2-d]p yrimidin- 4-amine (0.16 g, 431 μmol) and tert-butyl 3-bromopiperidine-1-carboxylate (171 mg, 646 μmol) in dimethoxyethane (3 mL) was added NiCl ₂ .glyme (9.46 mg, 43 μmol), tris(trimethylsilyl)silane (107 mg, 431 μmol), sodium carbonate (91.3 mg, 861 μmol) and pyridine-2- carboxamidine;hydrochloride (13.6 mg, 86.1 μmol). The mixture was degassed and purged with nitrogen for 3 times and then stirred at 20 °C for 16 h. On completion, the reaction was concentrated in vacuum to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate from 100:1 to 10:1) to afford tert-butyl 3-(4-((3-chloro-2- fluorophenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl) piperidine-1-carboxylate (60 mg, 0.13 mmol, 26%) as a yellow solid. m/z ES+ [M+H] ⁺ 476.2. Step 3. N-(3-chloro-2-fluorophenyl)-7-fluoro-6-(piperidin-3-yl)pyrid o[3,2-d]pyrimidin- 4-amine To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl] piperidine-1-carboxylate (50 mg, 105 μmol) in dichloromethane (1.5 mL) was added HCl/ethyl acetate (4 M, 0.5 mL). The mixture was stirred at 20 °C for 1 h. On completion, the reaction was concentrated in vacuo to afford N-(3-chloro-2-fluorophenyl)-7-fluoro-6- (piperidin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (40 mg, crude, HCl salt) as a yellow solid. m/z ES+ [M+H] ⁺ 376.3. Step 4. 1-(3-(4-((3-chloro-2-fluorophenyl)amino)-7-fluoropyrido[3,2- d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-7-fluoro-6-(3-piperidyl)pyrido[ 3,2- d]pyrimidin-4- amine (40 mg, 106 μmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was added sodium bicarbonate (44.7 mg, 532 μmol) and prop-2-enoyl chloride (10.6 mg, 117 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the reaction was concentrated in vacuum to give a residue, which was purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to afford 1-(3-(4-((3-chloro-2-fluorophenyl)amino)-7-fluoropyrido[3,2- d]pyrimidin-6- yl)piperidin-1-yl)prop-2-en-1-one (15 mg, 0.035 mmol, 32%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (br. d, J = 6.0 Hz, 1H), 8.60 (s, 1H), 8.11 (br. d, J = 10.8 Hz, 1H), 7.84 (br. t, J = 7.2 Hz, 1H), 7.52 (br. t, J = 7.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.94 - 6.78 (m, 1H), 6.16 - 6.04 (m, 1H), 5.72 - 5.60 (m, 1H), 4.58 - 4.44 (m, 1H), 4.34 - 4.01 (m, 1H), 3.77 - 3.45 (m, 1H), 3.33 - 3.23 (m, 2H), 2.16 - 2.03 (m, 2H), 1.98 - 1.74 (m, 1H), 1.66 - 1.48 (m, 1H); m/z ES+ [M+H] ⁺ 430.3. Example 122. Preparation of 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- fluoroquinazolin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 125) Step 1. 6-Bromo-7-fluoroquinazolin-4-ol To a solution of 2-amino-5-bromo-4-fluoro-benzoic acid (2.00 g, 8.55 mmol) in acetic acid (5.0 mL) was added formimidamide acetate (1.78 g, 17.1 mmol). The mixture was stirred at 125 °C for 20 hours. On completion, the mixture was poured into 10 mL water and filtered. The filter cake was washed with methyl tert-butyl ether (5 mL) and then dried under vacuum to afford 6-bromo-7-fluoro-quinazolin-4-ol (1.60 g, 6.58 mmol, 77%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.51 (br. s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.66 (d, J = 10.0 Hz, 1H); m/z ES+ [M+H] ⁺ 242.9. Step 2. 6-Bromo-4-chloro-7-fluoroquinazoline To a solution of 6-bromo-7-fluoro-quinazolin-4-ol (1.50 g, 6.17 mmol) in thionyl chloride (49.2 g, 414 mmol, 30 mL) was added N,N-dimethylformamide (90.2 mg, 1.23 mmol) at 0 °C. The mixture was stirred at 80 °C for 5 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted in sat. sodium bicarbonate solution (15 mL) and then filtered. The filter cake was dried under vacuum to give 6-bromo-4-chloro-7-fluoro-quinazoline (1.00 g, 3.80 mmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.67 (d, J = 10.0 Hz, 1H); m/z ES+ [M+H] ⁺ 262.7. Step 3. 6-Bromo-N-(3,4-dichloro-2-fluorophenyl)-7-fluoroquinazolin-4 -amine A solution of 6-bromo-4-chloro-7-fluoro-quinazoline (1 g, 3.82 mmol), 3,4-dichloro-2- fluoro-aniline (1.03 g, 5.74 mmol) and trifluoroacetic acid (43.6 mg, 382 μmol) in acetonitrile (10 mL) was stirred at 25 °C for 14 h. On completion, the reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (dichloromethane/methanol = 10/1) and further purified by reversed-phase HPLC (FA: 100% acetonitrile) to give 6-bromo-N-(3,4- dichloro-2-fluorophenyl)-7-fluoroquinazolin-4-amine (1.3 g, 3.20 mmol, 80%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 8.96 - 8.94 (m, 1H), 8.57 (s, 1H), 7.82 - 7.74 (m, 1H), 7.60 (s, 2H); m/z ES+ [M+H] ⁺ 406.0. Step 4. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-fluoroquinazolin -6- yl)piperidine-1-carboxylate To an 40 mL vial equipped with a stir bar was added 6-bromo-N-(3,4-dichloro-2-fluoro- phenyl)-7-fluoro-quinazolin-4-amine (600 mg, 1.48 mmol), tert-butyl 3-bromopiperidine-1- carboxylate (508 mg, 1.93 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (16.6 mg, 14.8 μmol), NiCl ₂ .dtbbpy (2.95 mg, 7.41 μmol), tris(trimethylsilyl)silane (368 mg, 1.48 mmol), sodium carbonate (314 mg, 2.96 mmol) in dimethoxyethane (20 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hr under nitrogen. On completion, the reaction mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (FA:column: Phenomenex luna C ₁₈ 150 x 40 mm x 15 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 60% - 90%, 10 min) to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)-7-fluoro-quinazolin-6-y l]piperidine-1- carboxylate (110 mg, 0.22 mmol, 14%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (s, 1H), 8.50 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 7.62 - 7.57 (m, 3H), 4.19 - 4.04 (m, 2H), 3.02 - 2.80 (m, 3H), 2.05 - 1.80 (m, 3H), 1.57 - 1.53 (m, 1H), 1.41 - 1.37 (m, 9H); m/z ES+ [M+H] ⁺ 509.2. Step 5. N-(3,4-dichloro-2-fluorophenyl)-7-fluoro-6-(piperidin-3-yl)q uinazolin-4-amine A solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)-7-fluoro-quinazolin-6- yl]piperidine-1- carboxylate (100 mg, 196 μmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (5 mL) was stirred at 25 °C for 0.2 h. On completion, the mixture was concentrated under vacuum to give N-(3,4-dichloro-2-fluoro-phenyl)-7-fluoro-6-(3- piperidyl)quinazolin-4-amine (100 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 409.2. Step 6. 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-fluoroquinazo lin-6-yl)piperidin- 1-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-7-fluoro-6-(3-piperidyl)qui nazolin-4- amine (100 mg, 244 μmol) and sodium bicarbonate (61.5 mg, 733 μmol) in tetrahydrofuran (1 mL) and water (0.2 mL) was added prop-2-enoyl chloride (22.1 mg, 244 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the reaction was concentrated to give a residue. The residue was purified by Prep-HPLC (FA:column: Phenomenex luna C ₁₈ 150 x 25 mm x 10 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 39% - 69%, 10 min) to give 1-[3-[4-(3,4- dichloro-2-fluoro-anilino)-7-fluoro-quinazolin-6-yl]-1-piper idyl]prop-2-en-1-one (34.8 mg, 0.075 mmol, 30%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 8.48 - 8.40 (m, 2H), 7.61 - 7.55(m, 3H), 6.91 - 6.81 (m, 1H), 6.15 - 6.10 (m, 1H), 5.71 - 5.68 (m, 1H), 4.71 - 4.60 (m, 1H), 4.26 - 4.18 (m, 1H), 3.19 - 3.00 (m, 2H), 2.76 - 2.66 (m, 1H), 2.08 - 1.86 (m, 3H), 1.56 - 1.52(m, 1H); m/z ES+ [M+H] ⁺ 463.3. Example 123. Preparation of (S)-1-(3-(7-methoxy-4-((6-phenoxypyridin-3- yl)amino)quinazolin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 166)

Step 1. 6-Bromo-7-methoxy-N-(6-phenoxypyridin-3-yl)quinazolin-4-amin e To a solution of 6-bromo-4-chloro-7-methoxy-quinazoline (450 mg, 1.65 mmol) in acetonitrile (6 mL) was added 6-phenoxypyridin-3-amine (337 mg, 1.81 mmol). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was filtered and the filter cake was collected to give 6-bromo-7-methoxy-N-(6-phenoxy-3-pyridyl)quinazolin-4-amine (600 mg, 1.42 mmol, 86%) as a yellow solid. m/z ES+ [M+H] ⁺ 424.9. Step 2. tert-Butyl 3-(7-methoxy-4-((6-phenoxypyridin-3-yl)amino)quinazolin-6- yl)piperidine-1-carboxylate To a solution of 6-bromo-7-methoxy-N-(6-phenoxy-3-pyridyl)quinazolin-4-amine (300 mg, 708 μmol) in dimethoxyethane (10 mL) was added tert-butyl 3-bromopiperidine-1- carboxylate (205 mg, 779 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (7.95 mg, 7.09 μmol), NiCl ₂ .dtbbpy (1.41 mg, 3.54 μmol), tris(trimethylsilyl)silane (176 mg, 708 μmol) and sodium carbonate (150 mg, 1.42 mmol). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 h under nitrogen. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give tert-butyl 3-(7-methoxy-4-((6- phenoxypyridin-3-yl)amino)quinazolin-6-yl)piperidine-1-carbo xylate (160 mg, 0.30 mmol, 43%) as a yellow solid. m/z ES+ [M+H] ⁺ 528.2. Step 3. (S)-tert-Butyl 3-(7-methoxy-4-((6-phenoxypyridin-3-yl)amino)quinazolin-6- yl)piperidine-1-carboxylate tert-Butyl 3-(7-methoxy-4-((6-phenoxypyridin-3-yl)amino)quinazolin-6-yl )piperidine-1- carboxylate (160 mg, 303 μmol) was separated by SFC (column: DAICEL CHIRALPAK IG (250mmx30mm,10um); mobile phase: [0.1% NH ₃ water-methanol]; B%: 55%-55%, 60min) to give (S)-tert-butyl 3-(7-methoxy-4-((6-phenoxypyridin-3-yl)amino)quinazolin-6-yl ) piperidine-1- carboxylate (70 mg, 0.13 mmol, 44%) as a white solid. m/z ES+ [M+H] ⁺ 528.2. Step 4. (S)-7-Methoxy-N-(6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)qu inazolin-4-amine To a solution of (S)-tert-butyl 3-(7-methoxy-4-((6-phenoxypyridin-3- yl)amino)quinazolin-6-yl)piperidine-1-carboxylate (60.0 mg, 113 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give (S)-7-methoxy- N-(6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)quinazolin-4-ami ne (60 mg, crude, trifluoroacetic acid) as a yellow solid. Step 5. (S)-1-(3-(7-methoxy-4-((6-phenoxypyridin-3-yl)amino)quinazol in-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of (S)-7-methoxy-N-(6-phenoxypyridin-3-yl)-6-(piperidin-3-yl)qu inazolin- 4-amine (47.3 mg, 110 μmol, trifluoroacetic acid) in tetrahydrofuran (4 mL) and water (4 mL) was added prop-2-enoyl chloride (13.0 mg, 144 μmol) and sodium bicarbonate (37.2 mg, 443 μmol). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Shim- pack C18150x25x10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 22%-42%,10 min) to give 1-[(3S)-3-[7-methoxy-4-[(6-phenoxy-3-pyridyl)amino]quinazoli n-6-yl]-1-piperidyl]prop- 2-en-1-one (12 mg, 0.025 mmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.83 (d, J = 6.8 Hz, 1H), 8.47 (s, 2H), 8.37 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.25 - 8.18 (m, 1H), 7.47 - 7.40 (m, 2H), 7.24 - 7.18 (m, 2H), 7.17 - 7.12 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.94 - 6.75 (m, 1H), 6.13 (dd, J = 2.4, 16.8 Hz, 1H), 5.71 (dd, J = 2.8, 7.2 Hz, 1H), 4.70 - 4.54 (m, 1H), 4.26 - 4.14 (m, 1H), 3.97 (d, J = 5.6 Hz, 3H), 3.14 - 3.03 (m, 3H), 2.76 (t, J = 11.6 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.87 (d, J = 12.4 Hz, 1H), 1.61 - 1.48 (m, 1H); m/z ES+ [M+H] ⁺ 482.3. Example 124. Preparation of (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)piperidin-1-yl)prop-2-en-1-one (Compound 186) Step 1. 6-Bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-am ine To a solution of 6-bromo-4-chloro-7-methoxy-quinazoline (400 mg, 1.46 mmol) in acetonitrile (6 mL) was added 3-chloro-2-fluoro-aniline (234 mg, 1.61 mmol). The mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was filtered and the filter cake was collected to give 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-methoxy-quinazolin-4- amine (500 mg, 1.31 mmol, 89%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.96 (s, 1H), 7.69 - 7.60 (m, 1H), 7.57 - 7.48 (m, 2H), 7.37 (dt, J = 1.2, 8.0 Hz, 1H), 6.94 - 6.88 (m, 1H), 6.85 - 6.80 (m, 1H), 6.76 - 6.70 (m, 1H), 4.08 (s, 3H). Step 2. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)piperidine-1-carboxylate To a solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-methoxy-quinazolin-4- amine (500 mg, 1.31 mmol) in dimethoxyethane (10 mL) was added tert-butyl 3-bromopiperidine-1- carboxylate (448 mg, 1.70 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (14.6 mg, 13.0 μmol), NiCl ₂ .dtbbpy (2.60 mg, 6.53 μmol), tris(trimethylsilyl)silane (324 mg, 1.31 mmol) and sodium carbonate (277 mg, 2.61 mmol). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 h under nitrogen. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/ethyl acetate = 3/1 to 1/1) to give tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)piperidine-1- carboxylate (100 mg, 0.21 mmol, 16%) as a yellow solid. m/z ES+ [M+H] ⁺ 487.3. Step 3. (R)-tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)piperidine-1-carboxylate tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)piperidine- 1-carboxylate (100 mg, 205 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um); mobile phase: [0.1% NH3 water MEOH]; B%: 35%-35%,7 min;60 min) to give (R)-tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin- 6-yl)piperidine-1-carboxylate (45 mg, 0.092 mmol, 45%) as a white solid. m/z ES+ [M+H] ⁺ 487.3. Step 4. (R)-N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-3-yl) quinazolin-4- amine To a solution of (R)-tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)piperidine-1-carboxylate (40.0 mg, 82.1 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give (R)-N-(3-chloro- 2-fluorophenyl)-7-methoxy-6-(piperidin-3-yl)quinazolin-4-ami ne (40 mg, crude, trifluoroacetic acid) as a white solid. Step 5. (R)-1-(3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinaz olin-6- yl)piperidin-1-yl)prop-2-en-1-one To a solution of (R)-N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-3- yl)quinazolin-4-amine (40.0 mg, 103 μmol, trifluoroacetic acid) in tetrahydrofuran (4 mL) and water (4 mL) was added prop-2-enoyl chloride (12.1 mg, 134 μmol) and sodium bicarbonate (34.7 mg, 413 μmol). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 37%-67%, 10 min) to give 1-[(3R)-3-[4-(3-chloro-2-fluoro-anilino)-7-methoxy- quinazolin-6-yl]-1-piperidyl]prop-2-en-1-one (13 mg, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (br. s, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.91 - 7.74 (m, 2H), 7.59 - 7.46 (m, 2H), 7.30 (br. t, J = 8.8 Hz, 1H), 6.89 (br dd, J = 10.8, 16.4 Hz, 1H), 6.13 (br. d, J = 17.6 Hz, 1H), 5.69 (br. t, J = 11.6 Hz, 1H), 4.70 - 4.51 (m, 1H), 4.26 - 4.12 (m, 1H), 3.21 - 3.05 (m, 1H), 2.92 - 2.71 (m, 2H), 2.07 (br. d, J = 11.6 Hz, 1H), 1.87 (br. d, J = 6.0 Hz, 2H), 1.62 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 411.1. Example 125. Preparation of N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 27) Step 1. tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)azetidin-3-yl)carbamate To a mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (150 mg, 485 μmol) and tert-butyl N-(azetidin-3-yl)carbamate (203 mg, 970 μmol, HCl salt) in N- methylpyrrolidone (3.0 mL) was added diisopropylethylamine (188 mg, 1.46 mmol). The mixture was heated to 80 °C with stirring for 2 hours. On completion, the mixture was poured into water (5.0 mL) and filtered. The suspension was filtered and the filter cake was washed with water (5 mL x 3), dried in vacuum to give tert-butyl N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl] azetidin-3-yl]carbamate (220 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.44 (s, 1H), 8.34 - 8.26 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 6.4 Hz, 1H), 7.43 - 7.27 (m, 2H), 7.10 (d, J = 9.1 Hz, 1H), 4.54 - 4.29 (m, 3H), 4.00 (dd, J = 4.8, 8.8 Hz, 2H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 445.1. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(3-chloro-2-fluorophenyl)pyrido[3 ,2-d]pyrimidin-4- amine To a mixture of tert-butyl N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl] azetidin-3-yl]carbamate (160 mg, 360 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (924 mg, 8.10 mmol) in one portion at 25 °C under nitrogen. The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give 6-(3-aminoazetidin-1-yl)-N-(3-chloro-2-fluoro-phenyl)pyrido[ 3,2-d]pyrimidin-4-amine (130 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 345.1. Step 3. N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)azetidin- 3-yl)acrylamide To a mixture of 6-(3-aminoazetidin-1-yl)-N-(3-chloro-2-fluoro-phenyl)pyrido[ 3,2- d]pyrimidin-4-amine (120 mg, 348 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (87.7 mg, 1.04 mmol). Then a solution of prop-2-enoyl chloride (31.5 mg, 348 μmol) in tetrahydrofuran (0.3 mL) was added dropwise at 0 °C over 2 min under nitrogen. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was poured into water (6.0 mL). The suspension was filtered and the filter cake was washed with water (2.0 mL x 3), dried in vacuum. The crude product was triturated with DMSO (3.0 mL), and then the suspension was filtered and the filter cake was washed with acetonitrile (3.0 mL), dried in vacuum to give N-[1- [4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]az etidin-3-yl]prop-2- enamide (47 mg, 0.12 mmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 8.46 (s, 1H), 8.36 - 8.26 (m, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.41 - 7.27 (m, 2H), 7.15 (d, J = 9.2 Hz, 1H), 6.32 - 6.10 (m, 2H), 5.67 (dd, J = 2.4, 9.6 Hz, 1H), 4.82 - 4.70 (m, 1H), 4.49 (t, J = 8.4 Hz, 2H), 4.05 (dd, J = 5.2, 8.8 Hz, 2H); m/z ES+ [M+H] ⁺ 399.2. Example 126. Preparation of N-(1-(4-((5-ethynyl-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 119) Step 1. tert-Butyl (1-(4-((5-ethynyl-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6- yl)azetidin-3-yl)carbamate To a solution of tert-butyl N-[1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl]carbamate (120 mg, 357 μmol) in acetonitrile (3 mL) was added 2-fluoro-5-(2- trimethylsilylethynyl)aniline (148 mg, 714 μmol), and then cesium carbonate (115 mg, 355 μmol) was added. The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was quenched by sat. ammonium chloride 5 mL and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=8/1 to 0/1) to give tert-butyl N-[1-[4-(5- ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]azetidi n-3-yl]carbamate (150 mg, 0.34 mmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 435.1. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(5-ethynyl-2-fluorophenyl)pyrido[ 3,2-d]pyrimidin- 4-amine To a solution of tert-butyl N-[1-[4-(5-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]azetidin-3-yl]carbamate (140 mg, 322 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(3-aminoazetidin-1-yl)-N-(5- ethynyl-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (140 mg, crude) as a yellow solid. Step 3. N-(1-(4-((5-ethynyl-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)azetidin- 3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(5-ethynyl-2-fluoro-phenyl)pyrido [3,2- d]pyrimidin-4-amine (140 mg, 312 μmol) in tetrahydrofuran (4 mL) and water (4 mL) was added sodium bicarbonate (104 mg, 1.25 mmol) and prop-2-enoyl chloride (31 mg, 343 μmol). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 21%-51%, 10 min) to give N-[1-[4-(5-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]azetidin-3-yl]prop-2-enamide (14.6 mg, 0.038 mmol, 12%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.88 (d, J = 6.8 Hz, 1H), 8.62 (dd, J = 2.0, 7.6 Hz, 1H), 8.54 - 8.49 (m, 1H), 8.47 - 8.41 (m, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 8.4, 10.8 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.15 (d, J = 9.2 Hz, 1H), 6.28 - 6.10 (m, 2H), 5.66 (dd, J = 2.4, 9.6 Hz, 1H), 4.78 - 4.69 (m, 1H), 4.48 (t, J = 8.4 Hz, 2H), 4.23 (s, 1H), 4.04 (dd, J = 5.6, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 389.2. Example 127. Preparation of N-(1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 121) Step 1. tert-Butyl (1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrim idin-6- yl)azetidin-3-yl)carbamate A solution of tert-butyl N-[1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl]carbamate (100 mg, 297 μmol) and 3,4-dichloro-2-fluoro-aniline (80.4 mg, 446 μmol) in acetonitrile (2 mL) was stirred at 60 °C for 12 h. On completion, the mixture was filtered and the filter cake was concentrated to give compound tert-butyl N-[1-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]carbamate (100 mg, crude) as a yellow solid. NMR (400 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 8.71 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.90 (t, J = 8.4 Hz, 1H), 7.74 - 7.63 (m, 2H), 7.23 (d, J = 9.2 Hz, 1H), 4.51 - 4.39 (m, 4H), 4.11 - 3.98 (m, 3H), 1.41 (s, 9H). Step 2. 6-(3-Aminoazetidin-1-yl)-N-(3,4-dichloro-2-fluorophenyl)pyri do[3,2- d]pyrimidin-4-amine A solution of tert-butyl N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n-6- yl]azetidin-3-yl]carbamate (100 mg, 208 μmol) and trifluoroacetic acid (308 mg, 2.70 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuum to give compound 6-(3-aminoazetidin-1-yl)-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude, trifluoroacetic acid) as a yellow solid. Step 3. N-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(3,4-dichloro-2-fluoro-phenyl)pyr ido[3,2- d]pyrimidin-4-amine (130 mg, 263 μmol) and sodium bicarbonate (110 mg, 1.32 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added prop-2-enoyl chloride (28.6 mg, 316 μmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 40%-70%, 9 min) to give compound N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n-6-yl]azetidin-3-yl]prop-2- enamide (8 mg, 18.5 μmol, 7%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (br. s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.46 (s, 1H), 8.34 (t, J = 8.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 6.31 - 6.10 (m, 2H), 5.66 (dd, J = 2.4, 9.6 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.48 (t, J = 8.4 Hz, 2H), 4.04 (dd, J = 5.2, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 433.1. Example 128. Preparation of N-(1-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)azetidin-3-yl)acrylamide (Compound 158) Step 1. tert-Butyl (1-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)azetidin-3-yl)carbamate To a solution of 6-chloro-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (163 mg, 501 μmol) in N-methylpyrrolidone (2.0 mL) was added tert-butyl N-(azetidin-3-yl)carbamate (129 mg, 751 μmol) and diisopropylethylamine (291 mg, 2.25 mmol, 391 μL). Then the reaction was stirred at 50 °C for 2 hrs. On completion, the reaction was added brine (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 0/1] to give tert-butyl (1-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)azetidin-3-yl)carbamate (180 mg, 390 μmol, 78%) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.42 (s, 1H), 8.52 - 8.41 (m, 2H), 8.13 - 8.03 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.08 (d, J = 9.3 Hz, 1H), 4.52 - 4.37 (m, 3H), 4.05 – 3.95 (m, 2H), 1.40 (s, 9H). Step 2. 6-(3-Aminoazetidin-1-yl)-N-(3,4-dichlorophenyl)pyrido[3,2-d] pyrimidin-4- amine To a solution of tert-butyl N-[1-[4-(3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]carbamate (180 mg, 390 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.0 mL), then the reaction was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated by blowing nitrogen to give 6-(3- aminoazetidin-1-yl)-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrim idin-4-amine (0.14 g, 388 μmol, 99%) as a yellow oil. m/z ES+ [M+H] ⁺ 361.0. Step 4. N-(1-(4-((3,4-Dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)azetidin-3- yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(3,4-dichlorophenyl)pyrido[3,2-d] pyrimidin- 4-amine (140 mg, 388 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (163 mg, 1.94 mmol). Then prop-2-enoyl chloride (42.1 mg, 465 μmol, 37.9 μL) was added and the reaction was stirred at 0 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.2% FA)-ACN]; B%: 40%-60%, 8 min) to give N-[1-[4- (3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3- yl]prop-2-enamide (30.0 mg, 0.072 mmol, 19%, FA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.63 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 8.57 (s, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.03 (dd, J = 2.4, 8.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 6.32 - 6.10 (m, 2H), 5.71 - 5.64 (m, 1H), 4.82 - 4.67 (m, 1H), 4.52 (t, J = 8.4 Hz, 2H), 4.08 (dd, J = 5.3, 9.3 Hz, 2H); m/z ES+ [M+H] ⁺ 415.0. Example 129. Preparation of N-(1-(4-(benzo[d]isothiazol-6-ylamino)pyrido[3,2-d]pyrimidin - 6-yl)azetidin-3-yl)acrylamide (Compound 174)

Step 1. tert-Butyl (1-(4-(benzo[d]isothiazol-6-ylamino)pyrido[3,2-d]pyrimidin-6 - yl)azetidin-3-yl)carbamate To a solution of N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-1,2-benzothiazol-6-a mine (100 mg, 319 μmol) in N-methylpyrrolidone (2 mL) was added diisopropylethylamine (165 mg, 1.27 mmol) and tert-butyl N-(azetidin-3-yl)carbamate (HCl salt, 71.7 mg, 249 μmol). The mixture was stirred at 80 °C for 2 hours. On completion, the mixture was poured into 10 mL water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 10/1 to 1/1] to give tert-butyl N-[1-[4- (1,2-benzothiazol-6-ylamino)pyrido[3,2-d]pyrimidin-6-yl]azet idin-3-yl]carbamate (130 mg, 0.29 mmol, 91%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.89 - 8.80 (m, 2H), 8.35 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.85 - 7.72 (m, 2H), 7.50 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 4.35 - 4.18 (m, 3H), 3.84 (dd, J = 4.0, 8.0 Hz, 2H), 1.22 (s, 9H). Step 2. N-(6-(3-Aminoazetidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)benzo [d]isothiazol-6- amine To a solution of tert-butyl N-[1-[4-(1,2-benzothiazol-6-ylamino)pyrido[3,2-d]pyrimidin- 6-yl] azetidin-3-yl]carbamate (120 mg, 133 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (609 mg, 5.34 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was dried by blowing nitrogen to give N-[6-(3-aminoazetidin-1-yl)pyrido[3,2- d] pyrimidin-4-yl]-1,2-benzothiazol-6-amine (46.5 mg, 0.13 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 350.1. Step 3. N-(1-(4-(Benzo[d]isothiazol-6-ylamino)pyrido[3,2-d]pyrimidin -6-yl)azetidin-3- yl)acrylamide To a solution of N-[6-(3-aminoazetidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl]-1,2- benzothiazol-6-amine (46.5 mg, 133 μmol) in tetrahydrofuran (1 mL) and water (0.20 mL) was added sodium bicarbonate (44.7 mg, 532 μmol). Then prop-2-enoyl chloride (10.8 mg, 120 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 25%-45%, 8min) to give N-[1-[4-(1,2-benzothiazol-6-ylamino)pyrido[3,2-d]pyrimidin-6 -yl]azetidin-3-yl]prop-2- enamide (11.1 mg, 0.027 mmol, 21%) as a yellow solid. ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 10.0 (s, 1H), 9.04 (d, J = 6.8 Hz, 2H), 8.87 (d, J =7.2 Hz, 1H), 8.55 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.05 - 7.95 (m, 2H), 7.15 (d, J = 9.2 Hz, 1H), 6.30 - 6.12 (m, 2H), 5.66 (dd, J = 2.4, 10.0 Hz, 1H), 4.80 – 4.70 (m, 1H), 4.54 (t, J = 8.0 Hz, 2H), 4.09 (dd, J = 5.2, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 404.1. Example 130. Preparation of N-(1-(4-((5-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 228) Step 1. tert-Butyl (1-(4-((5-chloro-2,4-Difluorophenyl)amino)pyrido[3,2-d]pyrim idin-6- yl)azetidin-3-yl)carbamate To a mixture of 6-chloro-N-(5-chloro-2,4-difluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (200 mg, 611 μmol) and tert-butyl N-(azetidin-3-yl)carbamate (HCl salt, 127 mg, 520 μmol) in N-methylpyrrolidone (3.0 mL) was added diisopropylethylamine (395 mg, 3.06 mmol, 532 μL). The reaction mixture was stirred at 100 °C for 1 hr. On completion. The reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1-(4-((5-chloro-2,4- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl)carbamate (280 mg, 0.60 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 463.3. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(5-chloro-2,4-difluorophenyl)pyri do[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl N-[1-[4-(5-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]azetidin-3-yl]carbamate (260 mg, 561 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(3-aminoazetidin-1- yl)-N-(5-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimidin-4- amine (200 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 363.0. Step 3. N-(1-(4-((5-Chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)azetidin-3-yl)acrylamide To a mixture of 6-(3-aminoazetidin-1-yl)-N-(5-chloro-2,4-difluoro-phenyl)pyr ido[3,2-d] pyrimidin-4-amine (200 mg, 551 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (46.3 mg, 551 μmol). Then prop-2-enoyl chloride (59.8 mg, 661 μmol, 53.9 μL) was added, and the reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-60%, 10 min) to give N-(1-(4-((5-chloro-2,4- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl)acrylamide (11.6 mg, 0.028 mmol, 4.5%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 8.85 (d, J = 5.6 Hz, 1H), 8.57 - 8.52 (m, 1H), 8.46 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.73 (t, J = 10.4 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 6.26 - 6.19 (m, 2H), 5.73 - 5.58 (m, 1H), 4.80 - 4.67 (m, 1H), 4.47 (t, J = 8.4 Hz, 2H), 4.05 – 4.02 (m, 2H); m/z ES+ [M+H] ⁺ 417.3. Example 131. Preparation of N-(1-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 219)

Step 1. tert-Butyl (1-(4-((5-chloro-2-Fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)azetidin-3-yl)carbamate To a solution of 6-chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (150 mg, 485 μmol) and tert-butyl N-(azetidin-3-yl)carbamate (HCl salt, 101 mg, 485 μmol) in N- methylpyrrolidone (1 mL) was added diisopropylethylamine (313 mg, 2.43 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was quenched by water 10 mL, and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine 20 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert- butyl N-[1-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]carbamate (170 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 445.4. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(5-chloro-2-fluorophenyl)pyrido[3 ,2-d]pyrimidin-4- amine To a solution of tert-butyl N-[1-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]carbamate (150 mg, 337 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give 6-(3-aminoazetidin-1-yl)-N-(5-chloro- 2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 345.3. Step 3. N-(1-(4-((5-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)azetidin- 3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(5-chloro-2-fluorophenyl)pyrido[3 ,2- d]pyrimidin-4-amine (100 mg, 290 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (24.3 mg, 290 μmol). Then prop-2-enoyl chloride (26.2 mg, 290 μmol) was added. The mixture was stirred at 0 °C for 15 min. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-ACN]; B%: 22%-52%, 10 min) to give N- [1-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl ]azetidin-3-yl]prop-2-enamide (5.9 mg, 0.015 mmol, 4%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1 H), 8.87 (d, J = 6.4 Hz, 1 H), 8.65 - 8.63 (m, 1 H), 8.53 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.41 (t, J = 8.8 Hz, 1 H), 7.22 - 7.20 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 6.26 - 6.12 (m, 2 H), 5.66 (dd, J = 9.6, 2.0 Hz, 1 H), 4.78 - 4.71 (m, 1H), 4.48 (t, J = 8.4 Hz, 2 H), 4.06 – 4.02 (m, 2H); m/z ES+ [M+H] ⁺ 399.3. Example 132. Preparation of N-(1-(4-((4-chloro-2,5-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 224) Step 1. N-(1-(4-((4-Chloro-2,5-difluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)azetidin-3-yl)acrylamide To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 1.00 mmol) in acetonitrile (2 mL) was added 4-chloro-2,5-difluoro-aniline (163.53 mg, 1.00 mmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated in vacuo and further triturated with petroleum ether/ethyl acetate (12 mL, 5/1) at 25 ^o C for 30 min to give 6-chloro-N-(4-chloro-2,5- difluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (240 mg, 734 μmol, 73%) as a yellow solid. m/z ES+ [M+H]+327.0. Step 2. tert-Butyl (1-(4-((4-Chloro-2,5-difluorophenyl)amino)pyrido[3,2-d]pyrim idin-6- yl)azetidin-3-yl)carbamate To a solution of 6-chloro-N-(4-chloro-2,5-difluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (120 mg, 367 μmol) in N-methylpyrrolidone (2 mL) was added diisopropylethylamine (237.06 mg, 1.83 mmol, 320 μL) and tert-butyl N-(azetidin-3-yl)carbamate (HCl salt, 84.21 mg, 403 μmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched by water (3 mL). The resulting precipitate was filtered, collected and further concentrated in vacuo to give tert-butyl N-[1-[4-(4-chloro-2,5-difluoro-anilino)pyrido[3,2-d]pyrimidi n-6-yl]azetidin-3- yl]carbamate (150 mg, 324 μmol, 88%) as a yellow solid. m/z ES+ [M+H] ⁺ 462.9. Step 3. 6-(3-Aminoazetidin-1-yl)-N-(4-chloro-2,5-difluorophenyl)pyri do[3,2- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-(4-chloro-2,5-difluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]azetidin-3-yl]carbamate (150 mg, 324 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give 6-(3-aminoazetidin-1-yl)-N-(4-chloro-2,5-difluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (154 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 363.0. Step 4. N-(1-(4-((4-Chloro-2,5-difluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(4-chloro-2,5-difluoro-phenyl)pyr ido[3,2- d]pyrimidin-4-amine (144 mg, 302 μmol, trifluoroacetic acid salt) in water (1 mL) was added sodium bicarbonate (127 mg, 1.51 mmol) and prop-2-enoyl chloride (30.1 mg, 332 μmol) in tetrahydrofuran (1 mL). The mixture was stirred at 0 °C for 0.2 h. The reaction mixture was diluted with water 3 mL and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine 5 mL, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 32%-62%, 7 min) to give N-[1-[4-(4-chloro-2,5- difluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]p rop-2-enamide (9.55 mg, 22.3 μmol, 7.4%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.64 (dd, J = 11.2, 7.2 Hz, 1H), 8.53 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.80 (dd, J = 10.8, 6.8 Hz, 1H), 7.16 (d, J = 9.2 Hz, 1H), 6.27 - 6.20 (m, 1H), 6.16 - 6.11 (m, 1H), 5.66 (dd, J = 9.6, 2.4 Hz, 1H), 4.75 - 4.73 (m, 1H), 4.48 (t, J = 8.4 Hz, 2H), 4.06 - 4.02 (m, 2H); m/z ES+ [M+H] ⁺ 417.3. Example 133. Preparation of N-(1-(4-((4,5-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 244)

Step 1. 6-Chloro-N-(4,5-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4-amine To a solution of 4,5-dichloro-2-fluoro-aniline (200 mg, 1.11 mmol) in acetonitrile (5 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (270 mg, 1.35 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtered. The solid was collected and washed with ethyl acetate (10 mL) to give compound 6-chloro-N-(4,5-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (300 mg, 0.87 mmol, 76%) as a yellow solid. m/z ES+ [M+H] ⁺ 343.0. Step 2. tert-Butyl (1-(4-((4,5-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrim idin-6- yl)azetidin-3-yl)carbamate To a solution of 6-chloro-N-(4,5-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (150 mg, 436 μmol) in N-methylpyrrolidone (3 mL) was added diisopropylethylamine (169 mg, 1.31 mmol) and tert-butyl N-(azetidin-3-yl)carbamate (HCl salt, 95.6 mg, 458 μmol). The mixture was stirred at 100 °C for 2 hrs. On completion, the reaction mixture was diluted with water 5 mL. The resulting precipitate was filtered, collected and further dried under vacuo to give compound tert-butyl N-[1-[4-(4,5-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n-6- yl]azetidin-3-yl]carbamate (200 mg, 0.42 mmol, 78%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.15 (s, 1H), 9.13 (s, 1H), 8.67 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 10.4 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 4.78 - 4.63 (m, 1H), 4.52 (d, J = 8.0 Hz, 2H), 4.09 - 4.01 (m, 2H), 1.48 (s, 9H). Step 3. 6-(3-Aminoazetidin-1-yl)-N-(4,5-dichloro-2-fluorophenyl)pyri do[3,2- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-(4,5-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]azetidin-3-yl]carbamate (200 mg, 417 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.36 mL). The mixture was stirred at 25 °C for 20 min. On completion, the reaction mixture was concentrated under vacuo to give compound 6-(3-aminoazetidin-1-yl)-N- (4,5-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (300 mg, crude) as a red oil. m/z ES+ [M+H] ⁺ 378.9. Step 4. N-(1-(4-((4,5-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(4,5-dichloro-2-fluoro-phenyl)pyr ido[3,2- d]pyrimidin-4-amine (150 mg, 395 μmol) in water (1 mL) and tetrahydrofuran (1 mL) was added sodium bicarbonate (99.7 mg, 1.19 mmol) and prop-2-enoyl chloride (27.0 mg, 298 μmol). The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , dichloromethane: methanol = 10:1) and prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%,7min) to give compound N-[1-[4-(4,5- dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]azetid in-3-yl]prop-2-enamide (8.39 mg, 0.019 mmol, 4.7%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.52 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 10.8 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.27 - 6.12 (m, 2H), 5.67 - 5.64 (m, 1H), 4.73 (d, J = 4.0 Hz, 1H), 4.47 (d, J = 8.0 Hz, 2H), 4.05 - 4.02 (m, 2H); m/z ES+ [M+H] ⁺ 433.3. Example 134. Preparation of N-(1-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 341) Step 1. tert-Butyl (1-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)azetidin-3-yl)carbamate To a solution of N-(3-bromo-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]pyrimidin- 4-amine (400 mg, 1.13 mmol) in N-methylpyrrolidone (8.0 mL) was added diisopropylethylamine (438 mg, 3.39 mmol, 0.6 mL). And then tert-butyl N-(azetidin-3-yl)carbamate (389 mg, 2.26 mmol) was added. The mixture was stirred at 100 °C for 2 hours. On completion, the mixture was poured into water (10 mL) and the suspension was filtered. The filter cake was washed with water (0.5 mL x 2), dried under vacuum to give tert-butyl N-[1-[4-(3-bromo-2-fluoro -anilino)pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]carbamate (523 mg, 1.07 mmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 491.1. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(3-bromo-2-fluorophenyl)pyrido[3, 2-d]pyrimidin-4- amine A solution of tert-butyl N-[1-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]carbamate (470 mg, 960 μmol) in trifluoroacetic acid (1.0 mL) and dichloromethane (5.0 mL) was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(3-aminoazetidin-1-yl)-N-(3-bromo-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (350 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 389.3. Step 3. N-(1-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)azetidin- 3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(3-bromo-2-fluoro-phenyl)pyrido[3 ,2- d]pyrimidin-4-amine (350 mg, 899 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (226 mg, 2.70 mmol). And then prop-2-enoyl chloride (97.6 mg, 1.08 mmol) was added. The mixture was stirred at 0 °C for 15 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition: column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-ACN]; B%: 21%-51%, 10 min) to give N-(1-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (136 mg, 0.31 mmol, 33%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 8.46 (s, 1H), 8.41 - 8.30 (m, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.55 - 7.44 (m, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 6.31 - 6.08 (m, 2H), 5.67 (dd, J = 2.4, 9.6 Hz, 1H), 4.79 - 4.70 (m, 1H), 4.49 (t, J = 8.4 Hz, 2H), 4.05 (dd, J = 5.2, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 445.3. Example 135. Preparation of 1-(6-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl) - 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 85) Step 1. tert-Butyl 6-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-1, 6- diazaspiro[3.3]heptane-1-carboxylate To a mixture of 6-bromo-N-(3,4-dichloro-2-fluorophenyl)quinazolin-4-amine (200 mg, 517 μmol), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (251 mg, 517 μmol), (5- diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosp hane (29.9 mg, 51.7 μmol) and sodium tert-butoxide (149 mg, 1.55 mmol) in dioxane (5 mL) was added palladium acetate (11.6 mg, 51.7 μmol) at 20 °C under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 hr. On completion, the mixture was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/0 to 0/1) to give tert-butyl 6-[4-(3,4-dichloro- 2-fluoro-anilino)quinazolin-6-yl]-1,6-diazaspiro[3.3]heptane -1-carboxylate (60.0 mg, 0.12 mmol, 23%) as a brown solid. m/z ES+ [M+H] ⁺ 504.1. Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan -6-yl)quinazolin-4- amine To a mixture of tert-butyl 6-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (40.0 mg, 79.3 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (452 mg, 3.97 mmol) at 20 °C under nitrogen atmosphere. The mixture was stirred at 40 °C for 3 hr. On completion, the mixture was concentrated in vacuum to give 6-(1,6 - diazaspiro[3.3]heptan-6-yl)-N-(3,4-dichloro-2-fluoro-phenyl) quinazolin-4-amine (30.0 mg, 0.074 mmol, 94%) as a brown oil. m/z ES+ [M+H] ⁺ 404.0. Step 3. 1-(6-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6-yl) -1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3,4-dichloro-2-fluoro- phenyl)quinazolin-4-amine (30.0 mg, 74.2 μmol) and sodium bicarbonate (18.7 mg, 223 μmol) in water (2 mL) was dropwise added acryloyl chloride (6.38 mg, 70.5 μmol) in tetrahydrofuran (2 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was added water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 10 min) to give 1-[6-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl] prop-2-en-1-one (8.00 mg, 0.018 mmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.73 - 9.66 (m, 1H), 8.40 - 8.30 (m, 1H), 7.72 - 7.65 (m, 1H), 7.63 - 7.55 (m, 2H), 7.28 - 7.14 (m, 2H), 6.33 - 6.25 (m, 1H), 6.13 - 6.06 (m, 1H), 5.77 - 5.65 (m, 1H), 4.62 - 4.56 (m, 1H), 4.41 - 4.22 (m, 1H), 4.18 - 4.10 (m, 3H), 3.84 -3.77 (m, 1H), 2.66 - 2.59 (m, 2H); m/z ES+ [M+H] ⁺ 458.1. Example 136. Preparation of 1-(6-(4-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 86) Step 1. 6-Chloro-N-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,2-d]pyr imidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 750 μmol) and 6- (trifluoromethyl)pyridin-3-amine (183 mg, 1.12 mmol) in acetonitrile (3.0 mL) was stirred at 40 °C for 2 h. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was concentrated in vacuum to give 6-chloro-N-[6-(trifluoromethyl)-3-pyridyl]pyrido[3,2- d]pyrimidin-4-amine (180 mg, 0.55 mmol, 74%) as a white solid. m/z ES+ [M+H] ⁺ 326.0. Step 2. tert-Butyl 6-(4-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrido[3,2-d]py rimidin- 6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[6-(trifluoromethyl)-3-pyridyl]pyrido[3,2-d]pyrim idin-4- amine (170 mg, 522 μmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added diisopropylethylamine (203 mg, 1.57 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1- carboxylate (207 mg, 1.04 mmol). The mixture was stirred at 80 °C for 1.5 hr. On completion, the reaction mixture was diluted with water (20 mL) and filtered, the filter cake was concentrated in vacuum to give tert-butyl 6-[4-[[6-(trifluoromethyl)-3-pyridyl]amino]pyrido[3,2-d]pyri midin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (260 mg, 0.53 mmol, 92 %) as a yellow solid. m/z ES+ [M+H] ⁺ 488.3. Step 3. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-(6-(trifluoromethyl)pyr idin-3- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-(4-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (210 mg, 431 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (2.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(1,6-diazaspiro[3.3]heptan-6- yl)-N-[6-(trifluoromethyl)-3-pyridyl]pyrido [3,2-d]pyrimidin-4-amine (216 mg, 0.56 mmol, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 388.2. Step 4. 1-(6-(4-((6-(Trifluoromethyl)pyridin-3-yl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[6-(trifluoromethyl)-3- pyridyl]pyrido [3,2-d]pyrimidin-4-amine (216 mg, 558 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (141 mg, 1.67 mmol). The mixture was added prop- 2-enoyl chloride (50.5 mg, 558 μmol) at 0 °C and then stirred at 0 °C for 30 min. On completion, the reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 28%-48%, 10 min) to give 1-[6-[4-[[6-(trifluoromethyl)-3-pyridyl]amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (81.2 mg, 0.18 mmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 - 9.69 (m, 1H), 9.33 - 9.27 (m, 1H), 8.87 - 8.83 (m, 1H), 8.61 - 8.52 (m, 1H), 8.07 - 7.91 (m, 2H), 7.25 - 7.12 (m, 1H), 6.66 - 6.06 (m, 2H), 5.79 - 5.68 (m, 1H), 4.87 (d, J = 9.6 Hz, 1.5H), 4.64 - 4.51 (m, 1H), 4.34 (d, J = 9.6 Hz, 1.5H), 4.17 (t, J = 7.2 Hz, 1.5H), 3.84 (t, J = 7.2 Hz, 0.5H), 2.65 - 2.54 (m, 2H); m/z ES+ [M+H] ⁺ 442.1. Example 137. Preparation of 1-(6-(4-((6-(2,2,2-trifluoroethoxy)pyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]hep tan-1-yl)prop-2-en-1-one (Compound 87) Step 1. 6-Chloro-N-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyrido[3,2 -d]pyrimidin-4- amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 499 μmol) in acetonitrile (3 mL) was added 6-(2,2,2-trifluoroethoxy)pyridin-3-amine (96.0 mg, 499 μmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was filtered to give 6-chloro-N- [6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrido[3,2-d]pyrimidin- 4-amine (145 mg, 0.41 mmol, 81%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.75 - 8.71 (m, 1H), 8.65 (d, J = 2.8 Hz, 1H), 8.33 - 8.26 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 5.02 (q, J = 9.2 Hz, 2H). Step 2. tert-Butyl 6-(4-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)pyrido[3, 2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrido[3,2-d ]pyrimidin- 4-amine (100 mg, 281 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (89.1 mg, 309 μmol) in 1-methylpyrrolidin-2-one (1 mL) was added diisopropylethylamine (109 mg, 843 μmol). The mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was quenched with saturated ammonium chloride (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were washed with brine (10 mL x 3) and dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to give tert-butyl 6-[4- [[6-(2,2,2-trifluoroethoxy)-3-pyridyl]amino]pyrido[3,2-d]pyr imidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (135 mg, 0.21 mmol, 92%) as a yellow solid. Step 3. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-(6-(2,2,2-trifluoroetho xy)pyridin-3- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[[6-(2,2,2-trifluoroethoxy)-3-pyridyl]amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (130 mg, 251 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated under reduced pressure to give 6- (1,6-diazaspiro[3.3]heptan-6-yl)-N-[6-(2,2,2-trifluoroethoxy )-3-pyridyl]pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 0.24 mmol, crude) as a yellow solid. Step 4. 1-(6-(4-((6-(2,2,2-Trifluoroethoxy)pyridin-3-yl)amino)pyrido [3,2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[6-(2,2,2-trifluoroetho xy)-3- pyridyl]pyrido[3,2-d]pyrimidin-4-amine (100 mg, 239 μmol) in tetrahydrofuran (4 mL) and water (4 mL) was added sodium bicarbonate (80.5 mg, 958 μmol) and prop-2-enoyl chloride (23.8 mg, 263 μmol). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 x 30 mm x 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 30%-60%, 8 min) to give 1-[6-[4-[[6-(2,2,2-trifluoroethoxy)-3- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3. 3]heptan-1-yl]prop-2-en-1-one (55.8 mg, 0.13 mmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 - 9.30 (m, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.43 - 8.32 (m, 2H), 7.99 - 7.89 (m, 1H), 7.18 - 7.02 (m, 2H), 6.35 - 6.25 (m, 1H), 6.16 - 6.08 (m, 1H), 5.78 - 5.66 (m, 1H), 5.00 (q, J = 9.2 Hz, 2H), 4.83 (d, J = 9.6 Hz, 1.5H), 4.57 - 4.47 (m, 1H), 4.29 (d, J = 9.6 Hz, 1.5H), 4.16 (t, J = 7.6 Hz, 1.5H), 3.82 (t, J = 7.6 Hz, 0.5H), 2.64 - 2.53 (m, 2H); m/z ES+ [M+H] ⁺ 472.1. Example 138. Preparation of 1-(6-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 96)

Step 1. tert-Butyl 6-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6- diazaspiro[3.3]heptane-1-carboxylate To a mixture of 6-chloro-N-(6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimidin-4-ami ne (200 mg, 572 μmol), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (247 mg, 858 μmol, oxalic acid) and diisopropylethylamine (369.51 mg, 2.86 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 100 °C for 12 hr. On completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 2/1) to give tert-butyl 6-[4-[(6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl ]-1,6- diazaspiro[3.3]heptane-1-carboxylate (170 mg, 332 μmol, 58%) as a white solid. m/z ES+ [M+H] ⁺ 512.3. Step 2. N-(6-Phenoxypyridin-3-yl)-6-(1,6-diazaspiro[3.3]heptan-6-yl) pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (135 mg, 264 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuum to give N-(6-phenoxypyridin-3-yl)- 6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-a mine (135 mg, 0.38 mmol, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 412.3. Step 3. 1-(6-(4-((6-Phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(6-phenoxypyridin-3-yl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (135 mg, 257 μmol, trifluoroacetic acid salt) and sodium bicarbonate (108 mg, 1.28 mmol) in water (2 mL) was added prop-2-enoyl chloride (25.6 mg, 283 μmol) in tetrahydrofuran (2 mL). The mixture was stirred at 0 °C for 0.1 hr. On completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm, 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 19%-49%, 11 min) to give 1-(6-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (44 mg, 88 μmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 - 9.29 (m, 1H), 8.66 (d, J = 2.8 Hz, 1H), 8.47 - 8.37 (m, 2H), 8.01 - 7.86 (m, 1H), 7.45 - 7.37 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.16 - 7.06 (m, 4H), 6.66 - 6.04 (m, 2H), 5.78 - 5.64 (m, 1H), 4.82 (d, J = 9.2 Hz, 1.5H), 4.58 - 4.45 (m, 1H), 4.29 (d, J = 10.0 Hz, 1.5H), 4.15 (t, J = 8.0 Hz, 1.5H), 3.87 - 3.75 (m, 0.5H), 2.67 - 2.53 (m, 2H); m/z ES+ [M+H] ⁺ 466.2. Example 139. Preparation of 1-(6-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 97) Step 1. 6-Chloro-N-(2-(trifluoromethyl)pyridin-4-yl)pyrido[3,2-d]pyr imidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 600 μmol) in acetonitrile (1.0 mL) was added 2-(trifluoromethyl)pyridin-4-amine (146 mg, 900 μmol) and cesium carbonate (391 mg, 1.20 mmol). The mixture was stirred at 60 °C for 1.5 hr. On completion, the reaction mixture was diluted with water (20 mL) and filtered, the filter cake was dried in vacuum to give 6-chloro-N-[2-(trifluoromethyl)-4-pyridyl]pyrido[3,2-d]pyrim idin-4-amine (150 mg, 438 μmol, 73%) as a yellow solid. m/z ES+ [M+H] ⁺ 325.9. Step 2. tert-Butyl 6-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrido[3,2-d]py rimidin- 6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[2-(trifluoromethyl)-4-pyridyl]pyrido[3,2-d]pyrim idin-4- amine (100 mg, 307 μmol) in 1-methylpyrrolidin-2-one (1.0 mL) was added diisopropylethylamine (119 mg, 921 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1- carboxylate (89.6 mg, 184 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (20 mL) and filtered, the filter cake was concentrated in vacuum to give tert-butyl 6-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrido[3,2-d]py rimidin-6- yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (260 mg, 0.53 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 488.2. Step 3. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-(2-(trifluoromethyl)pyr idin-4- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (260 mg, 533 μmol) in trifluoroacetic acid (0.4 mL) and dichloromethane (2.0 mL) was stirred at 25 °C for 1.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(1,6-diazaspiro[3.3]heptan-6- yl)-N-[2-(trifluoromethyl)-4-pyridyl]pyrido[3,2-d]pyrimidin- 4-amine (260 mg, crude, trifluoroacetic acid salt) as an orange oil. m/z ES+ [M+H] ⁺ 388.1. Step 4. 1-(6-(4-((2-(Trifluoromethyl)pyridin-4-yl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[2-(trifluoromethyl)-4- pyridyl]pyrido[3,2-d]pyrimidin-4-amine (260 mg, 671 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (169 mg, 2.01 mmol). The mixture was added prop- 2-enoyl chloride (60.8 mg, 671 μmol) and stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 38%-68%, 10 min) to give 1-[6-[4-[[2-(trifluoromethyl)-4-pyridyl]amino]pyrido[3,2-d]p yrimidin- 6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (33.5 mg,75.96 μmol, 11%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 - 9.83 (m, 1H), 8.69 - 8.63 (m, 3H), 8.50 - 8.45 (m, 1H), 8.08 - 7.98 (m, 1H), 7.27 - 7.15 (m, 1H), 6.37 - 6.25 (m, 1H), 6.17 - 6.07 (m, 1H), 5.73 - 5.68 (m, 1H), 4.88 (d, J = 9.6 Hz, 1.5H), 4.64 - 4.52 (m, 1H), 4.35 (d, J = 9.6 Hz, 1.5H), 4.17 (t, J = 7.6 Hz, 1.5H), 3.83 (t, J = 7.6 Hz, 0.5H), 2.61 (t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 442.3. Example 140. Preparation of N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)-N-methylacrylamide (Compound 100) Step 1. tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)azetidin-3-yl)(methyl)carbamate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 323 μmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added diisopropylethylamine (125 mg, 970 μmol) and tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate (108 mg, 485 μmol, HCl salt). The mixture was stirred at 100 °C for 3 hr. On completion, the mixture was poured into water (2.0 mL) and the suspension was filtered. The filter cake was washed with ethyl acetate (5 mL x 3), dried in vacuum to give tert-butyl N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]-N-methyl-carbamate (130 mg, 0.28 mmol, 88%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.47 (s, 1H), 8.42 - 8.32 (m, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.44 - 7.27 (m, 2H), 7.14 (d, J = 9.2 Hz, 1H), 4.39 (t, J = 8.8 Hz, 2H), 4.23 (dd, J = 6.0, 9.2 Hz, 2H), 3.31 (s, 1H), 2.92 (s, 3H), 1.42 (s, 9H). Step 2. N-(3-chloro-2-fluorophenyl)-6-(3-(methylamino)azetidin-1-yl) pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)(methyl)carbamate (100 mg, 218 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuum to give N-(3-chloro-2-fluoro- phenyl)-6-[3-(methylamino)azetidin-1-yl]pyrido[3,2-d]pyrimid in -4-amine (80 mg, 0.22 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 359.2. Step 3. N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)azetidin- 3-yl)-N-methylacrylamide To a mixture of N-(3-chloro-2-fluorophenyl)-6-(3-(methylamino)azetidin-1- yl)pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 223 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (65.6 mg, 780 μmol). Then prop-2-enoyl chloride (20.1 mg, 223 μmol) in tetrahydrofuran (0.2 mL) was dropwise added at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuum. The residue was purified by Prep-HPLC [column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -ACN]; B%: 33%-63%, 10 min] to give N-(1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl )-N-methylacrylamide (22.38 mg, 54.3 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.47 (s, 1H), 8.39 - 8.30 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.43 - 7.24 (m, 2H), 7.14 (d, J = 9.2 Hz, 1H), 6.93 - 6.73 (m, 1H), 6.26 - 6.05 (m, 1H), 5.75 (d, J = 10.0 Hz, 1H), 5.42 - 5.25 (m, 1H), 4.52 - 4.38 (m, 2H), 4.35 - 4.18 (m, 2H), 3.17 - 3.06 (m, 3H); m/z ES+ [M+H] ⁺ 413.2. Example 141. Preparation of 1-(2-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazaspiro[3.4]octan-5-yl)prop-2-en-1- one (Compound 102) Step 1. tert-Butyl 2-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 2,5-diazaspiro[3.4]octane-5-carboxylate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 323 μmol) in 1-methylpyrrolidin-2-one (1.0 mL) was added diisopropylethylamine (125 mg, 970 μmol) and tert-butyl 2,5-diazaspiro[3.4]octane-5-carboxylate (133 mg, 259 μmol). The mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was concentrated in vacuum to give tert-butyl 2-[4-(3- chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-dia zaspiro[3.4]octane-5-carboxylate (200 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 485.2. Step 2. N-(3-Chloro-2-fluorophenyl)-6-(2,5-diazaspiro[3.4]octan-2-yl )pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 2-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 2,5-diazaspiro[3.4]octane-5-carboxylate (200 mg, 412 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuum to give N-(3-chloro-2-fluoro-phenyl)-6-(2,5-diazaspiro[3.4]octan-2- yl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 385.0. Step 3. 1-(2-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-2,5- diazaspiro[3.4]octan-5-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-(2,5-diazaspiro[3.4]octan-2- yl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 520 μmol) in water (1.0 mL) and tetrahydrofuran (1.0 mL) was added sodium bicarbonate (131 mg, 1.56 mmol). The mixture was added prop-2-enoyl chloride (47.0 mg, 520 μmol) at 0 °C and stirred for 0.5 hr. On completion, the reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-66%, 10 min) to give 1-[2-[4-(3-chloro-2-fluoro-anilino) pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazaspiro[3.4]octan-5- yl]prop-2-en-1-one (25.4 mg, 57.99 mmol, 11%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.40 (s, 1H), 8.52 (s, 1H), 8.39 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.40 - 7.28 (m, 2H), 7.14 (d, J = 9.2 Hz, 1H), 6.63 (dd, J = 10.4, 16.8 Hz, 1H), 6.12 (dd, J = 2.0, 16.8 Hz, 1H), 5.72 - 5.66 (m, 1H), 4.85 (d, J = 8.0 Hz, 2H), 4.05 (d, J = 8.0 Hz, 2H), 3.64 (t, J = 6.8 Hz, 2H), 2.32 (t, J = 6.8 Hz, 2H), 1.93 - 1.82 (m, 2H); m/z ES+ [M+H] ⁺ 439.2. Example 142. Preparation of 1-(2-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,6-diazaspiro[3.4]octan-6-yl)prop-2-en-1- one (Compound 104)

Step 1. tert-Butyl 2-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 2,6-diazaspiro[3.4]octane-6-carboxylate To a mixture of tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (98.2 mg, 463 μmol) and 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (130 mg, 421 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (217 mg, 1.68 mmol) at 20 °C. The mixture was stirred at 100 °C for 3 hr. On completion, the solution was poured into water (10 mL). The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl 2-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin- 6-yl]-2,7-diazaspiro[3.4]octane-7-carboxylate (180 mg, 0.37 mmol, 78%) as a yellow solid. m/z ES+ [M+H] ⁺ 485.1. Step 2. N-(3-chloro-2-fluorophenyl)-6-(2,6-diazaspiro[3.4]octan-2-yl )pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 2-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 2,7-diazaspiro[3.4]octane-7-carboxylate (180 mg, 371 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1.27 g, 11.1 mmol) at 20 °C. The mixture was stirred at 40 °C for 3 hr. On completion, the mixture was concentrated in vacuum to give N-(3-chloro-2-fluoro-phenyl)-6- (2,7-diazaspiro[3.4]octan-2-yl)pyrido[3,2-d]pyrimidin-4-amin e (130 mg, 0.34 mmol, 69%) as a yellow solid. m/z ES+ [M+H] ⁺ 385.0. Step 3. 1-(2-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-2,6- diazaspiro[3.4]octan-6-yl)prop-2-en-1-one To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-(2,7-diazaspiro[3.4]octan-2- yl)pyrido[3,2-d]pyrimidin-4-amine (130 mg, 338 μmol) and sodium bicarbonate (85.1 mg, 1.01 mmol) in water (2 mL) was dropwise added prop-2-enoyl chloride (29.1 mg, 321 μmol) in tetrahydrofuran (2 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was added water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 35%-68%, 10 min) to give 1-[2-[4- (3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,7- diazaspiro[3.4]octan-7-yl]prop-2- en-1-one (65.0 mg, 0.15 mmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.46 (s, 1H), 8.43 - 8.36 (m, 1H), 7.96 (dd, J = 1.2, 9.2 Hz, 1H), 7.37 - 7.25 (m, 2H), 7.10 (dd, J = 5.2, 8.8 Hz, 1H), 6.65 - 6.52 (m, 1H), 6.18 - 6.12 (m, 1H), 5.72 - 5.60 (m, 1H), 4.18 - 4.09 (m, 4H), 3.85 (s, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 6.8 Hz, 1H), 2.26 (t, J = 6.8 Hz, 1H), 2.16 (t, J = 6.8 Hz, 1H); m/z ES+ [M+H] ⁺ 439.1. Example 143. Preparation of 1-(6-(4-((5-Chloro-6-methoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 111) Step 1. 6-Chloro-N-(5-chloro-6-methoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 499 μmol) in acetonitrile (3 mL) was added 5-chloro-6-methoxy-pyridin-3-amine (79.2 mg, 499 μmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was filtered to give 6-chloro-N-(5- chloro-6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (145 mg, 0.44 mmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 322.0. Step 2. tert-Butyl 6-(4-((5-chloro-6-methoxypyridin-3-yl)amino)pyrido[3,2-d]pyr imidin- 6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(5-chloro-6-methoxypyridin-3-yl)pyrido[3,2-d]pyri midin-4- amine (120 mg, 372 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (118 mg, 409 μmol, oxalic acid salt) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (144 mg, 1.12 mmol). The mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was quenched with saturated ammonium chloride (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 5/1 to 0/1) to give tert-butyl 6-(4-((5- chloro-6-methoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptane- 1-carboxylate (80 mg, 0.17 mmol, 44%) as a yellow solid. m/z ES+ [M+H] ⁺ 484.1. Step 3. N-(5-Chloro-6-methoxypyridin-3-yl)-6-(1,6-diazaspiro[3.3]hep tan-6- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-(4-((5-chloro-6-methoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (75 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(5-chloro-6- methoxypyridin-3-yl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrid o[3,2-d]pyrimidin-4-amine (77 mg, 0.20 mmol, crude) as a yellow solid. Step 4. 1-(6-(4-((5-chloro-6-methoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(5-chloro-6-methoxypyridin-3-yl)-6-(1,6-diazaspiro[3.3]hep tan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (77 mg, 154 μmol) in tetrahydrofuran (4 mL) and water (4 mL) was added sodium bicarbonate (51.9 mg, 618 μmol) and prop-2-enoyl chloride (15.4 mg, 170 μmol). The mixture was stirred at 25°C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 31%-61%, 9 min) to get 1-(6-(4-((5-chloro-6-methoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (42.86 mg, 98.1 μmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 - 9.33 (m, 1H), 8.67 (s, 1H), 8.59 - 8.52 (m, 1H), 8.47 - 8.40 (m, 1H), 8.00 - 7.88 (m, 1H), 7.19 - 7.06 (m, 1H), 6.58 (dd, J = 10.0, 16.4 Hz, 1H), 6.35 - 6.23 (m, 1H), 6.16 - 6.07 (m, 1H), 5.78 - 5.66 (m, 1H), 4.83 (d, J = 9.2 Hz, 1H), 4.58 - 4.47 (m, 1H), 4.29 (d, J = 9.6 Hz, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.82 (t, J = 7.2 Hz, 1H), 2.64 - 2.52 (m, 2H) ; m/z ES+ [M+H] ⁺ 438.2. Example 144. Preparation of N-(1-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 112) Step 1. tert-Butyl (1-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6 - yl)azetidin-3-yl)carbamate To a solution of tert-butyl (1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl)carbamate (100 mg, 297 μmol) and 6-phenoxypyridin-3-amine (83.1 mg, 446 μmol) in acetonitrile (2 mL) was stirred at 25 °C for 12 hr. On completion, the mixture was filtered and the filter cake was concentrated to give tert-butyl (1-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)carbamate (140 mg, 0.29 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 486.2. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(6-phenoxypyridin-3-yl)pyrido[3,2 -d]pyrimidin-4- amine A solution of tert-butyl (1-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6 - yl)azetidin-3-yl)carbamate (130 mg, 267 μmol) and trifluoroacetic acid (400 mg, 3.51 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum to give 6-(3-aminoazetidin-1-yl)-N-(6-phenoxypyridin-3-yl)pyrido[3,2 - d]pyrimidin-4-amine (130 mg, crude, trifluoroacetic acid salt) as a yellow solid. Step 3. N-(1-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)azetidin-3- yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(6-phenoxypyridin-3-yl)pyrido[3,2 - d]pyrimidin-4-amine (130 mg, 260 μmol, trifluoroacetic acid salt) and sodium bicarbonate (109 mg, 1.30 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added prop-2-enoyl chloride (28.2 mg, 312 μmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 10 min) to give N-(1-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)azetidin-3-yl)acrylamide (32 mg, 72.7 μmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.65 (d, J = 2.8 Hz, 1H), 8.43 - 8.34 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.23 - 7.16 (m, 1H), 7.15 - 7.07 (m, 4H), 6.27 - 6.09 (m, 2H), 5.71 - 5.63 (m, 1H), 4.78 - 4.68 (m, 1H), 4.49 (t, J = 8.4 Hz, 2H), 4.05 (dd, J = 5.2, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 440.4. Example 145. Preparation of N-(1-(4-((6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 113) Step 1. tert-Butyl 2-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 2,6-diazaspiro[3.5]nonane-6-carboxylate A solution of 6-chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine (0.08 g, 258 μmol), tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (84.2 mg, 155 μmol), diisopropylethylamine (100 mg, 776 μmol) in 1-methylpyrrolidin-2-one (3.0 mL) was stirred at 100 °C for 16 hr. On completion, the mixture was diluted with water (15 ml) and filtered. The crude product was purified by re-crystallization from water (15 mL) at 25 ^o C to give tert-butyl 2- (4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-2,6-diazaspiro[3.5]nonane-6- carboxylate (0.15 g, 0.30 mmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 499.1. Step 2. N-(3-Chloro-2-fluorophenyl)-6-(2,6-diazaspiro[3.5]nonan-2-yl )pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 2-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (0.12 g, 240 μmol) in trifluoroacetic acid (924 mg, 8.10 mmol) and dichloromethane (1.0 mL) was stirred at 25 °C for 2 hr. On completion the mixture was concentrated in vacuum to give N-(3-chloro-2-fluorophenyl)-6-(2,6-diazaspiro[3.5]nonan-2- yl)pyrido[3,2-d]pyrimidin-4-amine (0.09 g, 0.23 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 399.2. Step 3. 1-(2-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-2,6- diazaspiro[3.5]nonan-6-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluorophenyl)-6-(2,6-diazaspiro[3.5]nonan-2- yl)pyrido[3,2-d]pyrimidin-4-amine (0.11 g, 275 μmol) and sodium bicarbonate (69.5 mg, 827 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added prop-2-enoyl chloride (24.9 mg, 275 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 41%-74%, 9 min) to give 1-(2-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-2,6- diazaspiro[3.5]nonan-6-yl)prop-2-en-1-one (0.029 g, 64.2 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.44 (s, 1H), 8.31 (t, J = 7.6 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.39 - 7.26 (m, 2H), 7.11 (d, J = 9.2 Hz, 1H), 7.03 - 6.81 (m, 1H), 6.23 - 6.08 (m, 1H), 5.71 (dd, J = 2.0, 10.4 Hz, 1H), 3.93 - 3.77 (m, 6H), 3.53 (d, J = 1.6 Hz, 2H), 1.90 (s, 2H), 1.56 (d, J = 4.0 Hz, 2H); m/z ES+ [M+H] ⁺ 453.2. Example 146. Preparation of N-(1-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 136)

Step 1. tert-Butyl (1-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin-6 - yl)azetidin-3-yl)carbamate To a solution of tert-butyl (1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl)carbamate (100 mg, 297 μmol) in tetrahydrofuran (1 mL) was added 5-phenoxypyridin-2-amine (83.1 mg, 446 μmol) and potassium tert-butoxide (66.8 mg, 595 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to give tert-butyl (1-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)carbamate (60 mg, 0.12 mmol, 41%) as a yellow solid. m/z ES+ [M+H] ⁺ 486.1. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(5-phenoxypyridin-2-yl)pyrido[3,2 -d]pyrimidin-4- amine To a solution of tert-butyl (1-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin- 6-yl)azetidin-3-yl)carbamate (50 mg, 102 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(3-aminoazetidin-1-yl)-N-(5- phenoxy-2-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (50 mg, 0.13 mmol, crude) as a yellow solid. Step 3. N-(1-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)azetidin-3- yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(5-phenoxy-2-pyridyl)pyrido[3,2- d]pyrimidin-4-amine (50 mg, 100 μmol) in tetrahydrofuran (4 mL) and water (4 mL) was added sodium bicarbonate (33.6 mg, 400 μmol) and prop-2-enoyl chloride (9.97 mg, 110 μmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 32%-65%, 9 min) to give N-(1-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)azetidin-3-yl)acrylamide (18.0 mg, 40.9 μmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.69 (d, J = 9.2 Hz, 1H), 8.55 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.68 (dd, J = 2.8, 9.2 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.19 - 7.11 (m, 2H), 7.09 - 7.00 (m, 2H), 6.29 - 6.10 (m, 2H), 5.66 (dd, J = 2.4, 9.6 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.50 (t, J = 8.4 Hz, 2H), 4.06 (dd, J = 5.2, 8.8 Hz, 2H); m/z ES+ [M+H] ⁺ 440.4. Example 147. Preparation of 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]hepta n-1-yl)prop-2-en-1-one (Compound 141) Step 1. tert-Butyl 6-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate A solution of 6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxypyrido[3,2-d]py rimidin-4- amine (0.2 g, 521 μmol), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (113 mg, 573 μmol) and diisopropylethylamine (202 mg, 1.56 mmol) in 1-methylpyrrolidin-2-one (5 mL) was stirred at 80 °C for 2 hr. Upon completion, the mixture was quenched by water (30 mL) and the mixture was stirred at 25 °C for 0.5 hr. Then the mixture was filtered and the filtered cake was concentrated in vacuum to give tert-butyl 6-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (0.26 g, crude) as a yellow solid. Step 2. N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-(1,6-diazaspiro[3.3] heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (0.13 g, 259 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (400 mg, 3.51 mmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give N-(3- chloro-2-fluorophenyl)-7-methoxy-6-(1,6-diazaspiro[3.3]hepta n-6-yl)pyrido[3,2-d]pyrimidin-4- amine (0.10 g, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 401.1. Step 3. 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2 -d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(1,6-diazaspiro[3.3] heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (0.1 g, 249 μmol) and sodium bicarbonate (62.8 mg, 748 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added prop-2-enoyl chloride (22.5 mg, 249 μmol). The mixture was stirred at 0 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Shim-pack C18150x25, 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 29%-51%, 11 min) to give 1-(6-(4-((3- chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin -6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (25 mg, 55.1 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.16 - 8.98 (m, 1H), 8.47 - 8.31 (m, 2H), 7.40 - 7.20 (m, 3H), 6.34 - 6.24 (m, 1H), 6.15 - 6.08 (m, 1H), 5.80 - 5.65 (m, 1H), 4.94 (d, J = 9.6 Hz, 2H), 4.69 - 4.53 (m, 1H), 4.45 - 4.25 (m, 1H), 4.13 (t, J = 7.2 Hz, 1H), 3.99 - 3.89 (m, 3H), 3.80 (t, J = 7.6 Hz, 1H), 2.60 (t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 455.2. Example 148. Preparation of 1-(6-(4-((6-(Cyclopropylmethoxy)pyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]hep tan-1-yl)prop-2-en-1-one (Compound 148)

Step 1. 6-Chloro-N-(6-(cyclopropylmethoxy)pyridin-3-yl)pyrido[3,2-d] pyrimidin-4- amine To a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 750 μmol) and 6- (cyclopropylmethoxy)pyridin-3-amine (209 mg, 1.27 mmol) in acetonitrile (2 mL) was stirred at 25 °C for 16 hr. On completion, the reaction mixture was filtered and the filter cake was dried to give 6-chloro-N-(6-(cyclopropylmethoxy)pyridin-3-yl)pyrido[3,2-d] pyrimidin-4-amine (0.2 g, 0.61 mmol, 81%) as a yellow solid. m/z ES+ [M+H] ⁺ 328.2. Step 2. tert-Butyl 6-(4-((6-(cyclopropylmethoxy)pyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a mixture of 6-chloro-N-(6-(cyclopropylmethoxy)pyridin-3-yl)pyrido[3,2- d]pyrimidin-4-amine (100 mg, 305 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (96.8 mg, 336 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (158 mg, 1.22 mmol). The mixture was stirred 100 °C for 2 hr. On completion, the reaction mixture was quenched by addition water (15 mL) and filtered. The filter cake was dried to give tert-butyl 6-[4- [[6-(cyclopropylmethoxy)-3-pyridyl]amino]pyrido[3,2-d]pyrimi din-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (0.15 g, 0.31 mmol, 85%) as a yellow solid. m/z ES+ [M+H] ⁺ 490.4. Step 3. N-(6-(cyclopropylmethoxy)pyridin-3-yl)-6-(1,6-diazaspiro[3.3 ]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl 6-[4-[[6-(cyclopropylmethoxy)-3-pyridyl]amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (0.15 g, 306 μmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(6- (cyclopropylmethoxy)pyridin-3-yl)-6-(1,6-diazaspiro[3.3]hept an-6-yl)pyrido[3,2-d]pyrimidin-4- amine (0.1 g, 0.26 mmol, 71%) as a yellow solid. m/z ES+ [M+H] ⁺ 390.3. Step 4. 1-(6-(4-((6-(Cyclopropylmethoxy)pyridin-3-yl)amino)pyrido[3, 2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of N-(6-(cyclopropylmethoxy)pyridin-3-yl)-6-(1,6-diazaspiro[3.3 ]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (0.1 g, 257 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (64.7 mg, 770 μmol) in one portion at 20 °C. The mixture was added prop-2-enoyl chloride (23.2 mg, 257 μmol) and stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 16%-46%, 10 min) to give 1-(6-(4-((6- (cyclopropylmethoxy)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (3.19 mg, 7.20 μmol, 2.8%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 - 8.51 (m, 1H), 8.60 - 8.45 (m, 1H), 8.38 - 8.30 (m, 1H), 8.16 (dd, J = 2.8, 8.8 Hz, 1H), 7.93 - 7.79 (m, 1H), 7.14 - 6.99 (m, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.76 - 6.20 (m, 2H), 5.80 - 5.70 (m, 1H), 4.94 (d, J = 10.0 Hz, 1H), 4.67 - 4.52 (m, 1.5 H), 4.33 (d, J = 10.0 Hz, 1.5H), 4.23 (t, J = 7.6 Hz, 1.5 H), 4.11 (d, J = 7.2 Hz, 2H), 3.97 (t, J = 7.6 Hz, 0.5H), 2.71 - 2.60 (m, 2H), 1.35 - 1.21 (m, 1H), 0.65 - 0.51 (m, 2H), 0.39 - 0.29 (m, 2H); m/z ES+ [M+H] ⁺ 444.4. Example 149. Preparation of 1-(6-(4-((5-Ethynyl-2-fluoropyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 149) Step 1. 6-Chloro-N-(5-ethynyl-2-fluoropyridin-3-yl)pyrido[3,2-d]pyri midin-4-amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.15 g, 749 μmol) and 5-ethynyl-2- fluoro-pyridin-3-amine (102 mg, 749 μmol) in acetonitrile (2.0 mL) was stirred at 25 °C for 2 hr. Upon completion, the mixture was quenched by addition water (10 mL) and stirred at 25 ^o C for 10 min. The mixture was filtered and the filtrate was concentrated in vacuo to give 6-chloro-N-(5- ethynyl-2-fluoropyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (0.2 g, 0.67 mmol, 88%) as a brown solid. m/z ES+ [M+H] ⁺ 300.0. Step 2. tert-Butyl 6-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)pyrido[3,2-d]pyr imidin- 6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate A solution of 6-chloro-N-(5-ethynyl-2-fluoropyridin-3-yl)pyrido[3,2-d]pyri midin-4- amine, tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (132 mg, 667 μmol) and diisopropylethylamine (258 mg, 2.00 mmol) in 1-methylpyrrolidin-2-one (4 mL) was stirred at 100 °C for 2 hr. Upon completion, the mixture was quenched by addition water (10 ml) and stirred at 25 ^o C for 30 min. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 6-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)pyrido[3,2-d]pyr imidin-6-yl)-1,6- diazaspiro[3.3]heptane-1-carboxylate (0.15 g, 0.33 mmol, 48%) as a brown solid. Step 3. N-(5-ethynyl-2-fluoropyridin-3-yl)-6-(1,6-diazaspiro[3.3]hep tan-6-yl)pyrido[3,2- d]pyrimidin-4-amine A solution of tert-butyl 6-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (0.12 g, 260 μmol) in dichloromethane (3.0 mL) and trifluoroacetic acid (8.89 mg, 78.0 μmol) was stirred at 25 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give 6-(1,6- diazaspiro[3.3]heptan-6-yl)-N-(5-ethynyl-2- fluoro-3-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (0.09 g, crude, TFA salt) as a yellow solid. Step 4. 1-(6-(4-((5-Ethynyl-2-fluoropyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(5-ethynyl-2-fluoropyridin-3-yl)-6-(1,6-diazaspiro[3.3]hep tan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (0.09 g, 249 μmol) and sodium bicarbonate (62.7 mg, 747 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added prop-2-enoyl chloride (22.5 mg, 249 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo. The residue was triturated with methanol (5.0 mL) at 25 ^o C for 30 min and then filtered. The filter cake was further purified by prep-HPLC (column: Shim-pack C18150x25, 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 31%-51%, 10 min) to give 1-(6-(4-((5- ethynyl-2-fluoropyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1- yl)prop-2-en-1-one (8.0 mg, 19.3 μmol, 7.7%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 - 9.13 (m, 1H), 9.12 - 8.95 (m, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 8.13 - 8.06 (m, 1H), 8.06 - 7.98 (m, 1H), 7.24 - 7.15 (m, 1H), 6.39 - 6.24 (m, 1H), 6.17 - 6.07 (m, 1H), 5.79 - 5.65 (m, 1H), 4.80 (d, J = 9.6 Hz, 2H), 4.50 (s, 2H), 4.31 (d, J = 9.6 Hz, 1H), 4.16 (t, J = 7.2 Hz, 2H), 2.65 - 2.55 (m, 2H); m/z ES+ [M+H] ⁺ 416.3. Example 150. Preparation of N-(1-(4-((3-chloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 153) Step 1. tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)carbamate A solution of 6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxypyrido[3,2-d]py rimidin-4- amine (0.2 g, 521 μmol), tert-butyl azetidin-3-ylcarbamate hydrochloride (127 mg, 521 μmol) and diisopropylethylamine (269 mg, 2.09 mmol) in 1-methylpyrrolidin-2-one (5.0 mL) was stirred at 80 °C for 2 hr. Upon completion, the mixture was quenched by addition water (30 mL) and stirred at 25 °C for 30 min. The mixture was filtered and the filter cake was dried in vacuo to give tert- butyl (1-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2-d ]pyrimidin-6-yl)azetidin-3- yl)carbamate (0.24 g, crude) as a yellow solid. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(3-chloro-2-fluorophenyl)-7-metho xypyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)carbamate (0.12 g, 252 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (295 mg, 2.59 mmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give 6-(3-aminoazetidin-1-yl)-N-(3-chloro- 2-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine (0.09 g, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 375.1. Step 3. N-(1-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2 -d]pyrimidin-6- yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(3-chloro-2-fluorophenyl)-7- methoxypyrido[3,2-d]pyrimidin-4-amine (0.09 g, 240 μmol) and sodium bicarbonate (60.5 mg, 720 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added prop-2-enoyl chloride (21.7 mg, 240 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 42%-72%, 10 min) to give N-[1-[4-(3-chloro-2- fluoro-anilino)-7-methoxy-pyrido[3,2-d]pyrimidin-6-yl]azetid in-3- yl]prop-2-enamide (11.0 mg, 25.7 μmol, 10%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.83 (d, J = 6.4 Hz, 1H), 8.42 (s, 1H), 8.35 - 8.27 (m, 1H), 7.34 - 7.24 (m, 3H), 6.30 - 6.08 (m, 2H), 5.65 (dd, J = 2.4, 9.6 Hz, 1H), 4.71 - 4.61 (m, 1H), 4.55 (t, J = 8.4 Hz, 2H), 4.14 (dd, J = 5.2, 9.6 Hz, 2H), 3.94 (s, 3H); m/z ES+ [M+H] ⁺ 429.2. Example 151. Preparation of 1-(6-(4-((7-Fluorobenzo[d]isothiazol-6-yl)amino)pyrido[3,2- mpound 154) Step 1. tert-Butyl 6-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)pyrido[3,2-d]py rimidin- 6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a mixture of N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-7-fluoro-1,2-benzoth iazol-6- amine (0.05 g, 151 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate;oxalic acid (73.3 mg, 151 μmol) in N-methyl-2-pyrrolidone (1 mL) was added N,N-diisopropylethylamine (77.9 mg, 603 μmol) in one portion at 25 °C under nitrogen atmosphere. The mixture was stirred at 50 °C for 0.5 hr. On completion, the mixture was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with brine (3 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert- butyl 6-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)pyrido[3,2-d]py rimidin-6-yl)-1,6- diazaspiro[3.3]heptane-1-carboxylate (50 mg, 101 μmol, 67%) as a yellow solid. m/z ES+ [M+H] ⁺ 494.1. Step 2. N-(6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin- 4-yl)-7- fluorobenzo[d]isothiazol-6-amine To a mixture of tert-butyl 6-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (50.0 mg, 142 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in reduced pressure to give N-(6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin- 4-yl)-7- fluorobenzo[d]isothiazol-6-amine (0.07 g, crude, TFA salt) as a brown oil. m/z ES+ [M+H] ⁺ 393.9. Step 3. 1-(6-(4-((7-Fluorobenzo[d]isothiazol-6-yl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of N-(6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin- 4-yl)-7- fluorobenzo[d]isothiazol-6-amine (70.0 mg, 178 μmol) and sodium bicarbonate (16.7 mg, 198 μmol, 7.71 μL) in tetrahydrofuran (1 mL) and water (0.2 mL) was added prop-2-enoyl chloride (16.2 mg, 178 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was quenched by methanol (0.5 mL) and filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C1875x30mm, 3 um; mobile phase: [water (0.2% FA)-acetonitrile]; B%: 15%- 45%, 8 min) to give 1-(6-(4-((7-fluorobenzo[d]isothiazol-6-yl)amino)pyrido[3,2-d ]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (8 mg, 17 μmol, 10%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 9.43 (s, 1H), 9.19 - 9.13 (m, 1H), 8.67 (dd, J = 7.2, 8.8 Hz, 1H), 8.58 - 8.53 (m, 1H), 8.50 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 6.36 - 6.24 (m, 1H), 6.16 - 6.08 (m, 1H), 5.77 - 5.67 (m, 1H), 4.82 (d, J = 9.6 Hz, 2H), 4.59 - 4.48 (m, 1H), 4.31 (d, J = 9.6 Hz, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.82 (br. t, J = 7.2 Hz, 1H), 2.63 - 2.54 (m, 2H); m/z ES+ [M+H] ⁺ 448.1. Example 152. Preparation of 1-(6-(4-((3-chloro-5-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 155) Step 1. 6-chloro-N-(3-chloro-5-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 500 μmol) in acetonitrile (2.0 mL) was added 3-chloro-5-fluoro-aniline (109 mg, 750 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the filter cake was washed with acetonitrile (2 mL x 3), dried in vacuum to give 6-chloro-N-(3-chloro-5-fluoro-phenyl) pyrido[3,2-d]pyrimidin-4-amine (120 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.55 (s, 1H), 8.85 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.17 - 8.11 (m, 1H), 8.05 - 8.02 (m, 1H), 7.21 (td, J = 2.0, 8.4 Hz, 1H), 6.45 - 6.42 (m, 1H). Step 2. tert-Butyl 6-(4-((3-chloro-5-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3-chloro-5-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (120 mg, 388 μmol) in N-methyl-2-pyrrolidone (2.0 mL) was added N,N-diisopropylethylamine (100 mg, 776 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (113 mg, 233 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl 6-[4-(3-chloro-5-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -1,6- diazaspiro[3.3]heptane-1-carboxylate (100 mg, 310 μmol, 80%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 8.54 (s, 1H), 8.19 - 8.07 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.20 - 7.06 (m, 2H), 4.77 - 4.49 (m, 2H), 4.41 - 4.28 (m, 2H), 3.87 - 3.68 (m, 2H), 2.78 (d, J = 5.6 Hz, 2H), 1.18 (t, J = 7.2 Hz, 9H); m/z ES+ [M+H] ⁺ 472.9. Step 3. N-(3-Chloro-5-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(3-chloro-5-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,6-diazaspiro[3.3]heptane-1-carboxylate (80.0 mg, 170 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.80 mL) in one portion at 25 °C under nitrogen. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-5-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (63 mg, 153 μmol, 90%, TFA salt) as yellow solid. m/z ES+ [M+H] ⁺ 371.0. Step 4. 1-(6-(4-((3-Chloro-5-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-5-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (63.0 mg, 170 μmol) in tetrahydrofuran (0.50 mL) and water (0.50 mL) was added sodium bicarbonate (49.9 mg, 595 μmol) at 0 °C. Then prop-2-enoyl chloride (15.4 mg, 170 μmol) in tetrahydrofuran (0.10 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC [column: Waters xbridge 150x25mm 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 40%-70%, 11.5 min] to give 1-[6-[4- (3-chloro-5-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2- en-1-one (4.04 mg, 8.5 μmol, 5%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 - 9.37 (m, 1H), 8.63 - 8.50 (m, 1H), 8.17 - 7.87 (m, 3H), 7.26 - 7.01 (m, 2H), 6.65 - 6.04 (m, 2H), 5.78 - 5.60 (m, 1H), 4.86 (d, J = 9.6 Hz, 1.5H), 4.64 - 4.47 (m, 1H), 4.39 - 4.12 (m, 3H), 3.83 (t, J = 7.2 Hz, 0.5H), 2.65 - 2.54 (m, 2H); m/z ES+ [M+H] ⁺ 425.1. Example 153. Preparation of 1-(6-(4-((3,4-Dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 156)

Step 1. tert-Butyl 6-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -1,6- diazaspiro[3.3]heptane-1-carboxylate A mixture of 6-chloro-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (150 mg, 460 μmol), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (179 mg, 368 μmol) and N,N- diisopropylethylamine (178 mg, 1.63 mmol) in N-methyl-2-pyrrolidone (3.0 mL) was heated to 80 °C with stirring for 12 hr. On completion, the mixture was poured into water (10 mL) and filtered. The solid was collected to give tert-butyl 6-[4-(3,4-dichloroanilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (236 mg, 368 μmol, 80%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.53 - 8.47 (m, 2H), 8.14 - 8.06 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.17 - 7.08 (m, 1H), 4.77 - 4.51 (m, 2H), 4.43 - 4.21 (m, 2H), 3.91 - 3.67 (m, 2H), 2.56 - 2.52 (m, 2H), 1.50 - 1.05 (m, 9H). Step 2. N-(3,4-dichlorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyr ido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (186 mg, 381 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.85 g, 16.2 mmol). The reaction was stirred at 25 °C for 30 min. On completion, the mixture was concentrated to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3,4- dichlorophenyl) pyrido[3,2-d]pyrimidin-4-amine (365 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 386.9. Step 3. 1-(6-(4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3,4-dichlorophenyl)pyr ido[3,2- d]pyrimidin-4-amine (315 mg, 813 μmol, trifluoroacetic acid) and sodium bicarbonate (239 mg, 2.8 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added prop-2-enoyl chloride (73.6 mg, 813 μmol) at 0 °C. The reaction was stirred at 0 °C for 10 min. On completion, the mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 35%- 65%, 11.5 min) to give 1-[6-[4-(3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1, 6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (28 mg, 60 μmol, 8%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 - 9.42 (m, 1H), 8.56 - 8.46 (m, 2H), 8.11 - 7.92 (m, 2H), 7.69 - 7.60 (m, 1H), 7.21 - 7.09 (m, 1H), 6.65 - 5.63 (m, 3H), 4.90 - 4.79 (m, 1H), 4.61 - 4.47 (m, 1H), 4.36 - 4.27 (m, 2H), 4.22 - 4.11 (m, 1H), 3.89 - 3.77 (m, 1H), 2.64 - 2.56 (m, 2H); m/z ES+ [M+H] ⁺ 441.0. Example 154. Preparation of 1-(6-(4-((1-Phenyl-1H-indazol-5-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 157) Step 1. tert-Butyl 6-(4-((1-phenyl-1H-indazol-5-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(1-phenylindazol-5-yl)pyrido[3,2-d]pyrimidin-4-am ine (90 mg, 241 μmol) in N-methyl-2-pyrrolidone (1 mL) was added N,N-diisopropylethylamine (156 mg, 1.21 mmol, 210 μL) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (104 mg, 362 μmol, oxalic acid). The mixture was stirred at 100 °C for 2 h. The reaction mixture was added water (3 mL) and then filtered. The filter cake was concentrated in vacuo to give tert-butyl 6-[4-[(1- phenylindazol-5-yl)amino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-di azaspiro[3.3]heptane-1- carboxylate (100 mg, 0.19 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 535.4. Step 2. N-(1-Phenyl-1H-indazol-5-yl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl6-[4-[(1-phenylindazol-5-yl)amino]pyrido[3,2-d]pyr imidin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (100 mg, 187 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(1-phenylindazol- 5-yl)pyrido[3,2-d]pyrimidin-4-amine (110 mg, crude, trifluoroacetic acid) as a white solid. m/z ES+ [M+H] ⁺ 435.2. Step 3. 1-(6-(4-((1-Phenyl-1H-indazol-5-yl)amino)pyrido[3,2-d]pyrimi din-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(1-phenylindazol-5-yl)p yrido[3,2- d]pyrimidin-4-amine (110 mg, 200 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) was added sodium bicarbonate (84.2 mg, 1.00 mmol) in water (1 mL). Then prop-2-enoyl chloride (20.0 mg, 221 μmol) in tetrahydrofuran (1 mL) was added. The mixture was stirred at 0 °C for 0.2 h. The reaction mixture was diluted with water 3 mL and extracted with ethyl acaetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 20%-50%,10 min) to give 1-[6-[4-[(1-phenylindazol-5-yl)amino]pyrido[3,2-d]pyrimidin- 6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (40.3 mg, 82.6 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 - 9.37 (m, 1H), 8.70 (s, 1H), 8.52 - 8.44 (m, 1H), 8.41 (s, 1H), 8.01 - 7.86 (m, 3H), 7.81 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 8.0 Hz, 2H), 7.46 - 7.37 (m, 1H), 7.20 - 7.04 (m, 1H), 6.66 - 6.07 (m, 2H), 5.70 (dd, J = 2.0, 10.4 Hz, 1H), 4.85 (br. d, J = 9.6 Hz, 1H), 4.63 - 4.48 (m, 1H), 4.32 (d, J = 9.2 Hz, 2H), 4.16 (br. t, J = 7.2 Hz, 1H), 3.82 (br. t, J = 7.6 Hz, 1H), 2.65 - 2.53 (m, 2H); m/z ES+ [M+H] ⁺ 489.4. Example 155. Preparation of 1-(6-(4-((3-chloro-4-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 159)

Step 1. 6-Chloro-N-(3-chloro-4-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 599 μmol) and 3-chloro-4- fluoro-aniline (104 mg, 719 μmol) in acetonitrile (2 mL) was stirred at 40 °C for 2 hr. On completion, the mixture was filtered and the solid was collected to give 6-chloro-N-(3-chloro-4- fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 8.86 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.24 (dd, J = 2.4, 6.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.93 (m, 1H), 7.51 (t, J = 9.2 Hz, 1H). Step 2. tert-Butyl 6-(4-((3-chloro-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate A mixture of 6-chloro-N-(3-chloro-4-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (150 mg, 485 μmol), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (139 mg, 485 μmol) and N,N- diisopropylethylamine (188 mg, 1.46 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was stirred at 80 °C for 12 hr. On completion, the mixture was poured into water (10 mL) and filtered. The solid was collected to give 6-[4-(3-chloro-4-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -1,6- diazaspiro[3.3]heptane-1-carboxylate (150 mg, 320 μmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.47 (s, 1H), 8.38 (dd, J = 2.4, 6.8 Hz, 1H), 8.07 - 8.00 (m, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.49 - 7.40 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 4.75 - 4.53 (m, 2H), 4.43 - 4.24 (m, 2H), 3.89 - 3.70 (m, 2H), 2.23 - 2.12 (m, 1H), 1.96 - 1.85 (m, 1H), 1.43 - 1.11 (m, 9H). Step 3. N-(3-chloro-4-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(3-chloro-4-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,6- diazaspiro[3.3]heptane-1-carboxylate (120 mg, 254 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.85 g, 16.2 mmol). The reaction was stirred at 25 °C for 30 min. On completion, the mixture was concentrated to give N-(3-chloro-4-fluoro-phenyl)-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, crude, trifluoroacetic acid) as yellow oil. m/z ES+ [M+H] ⁺ 371.0. Step 4. 1-(6-(4-((3-chloro-4-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of N-(3-chloro-4-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, 247 μmol, trifluoroacetic acid) and sodium bicarbonate (41.5 mg, 495 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2- enoyl chloride (26.8 mg, 297 μmol) at 0 °C. The reaction was stirred at 0 °C for 10 min. On completion, the mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [water (0.05% ammonia hydroxide v/v)- acetonitrile]; B%: 35%-65%, 11.5 min) to give 1-[6-[4-(3-chloro-4-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (19.2 mg, 84 μmol, 17%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 - 9.37 (m, 1H), 8.55 - 8.44 (m, 1H), 8.37 (dd, J = 2.8, 6.8 Hz, 1H), 8.03 - 7.91 (m, 2H), 7.52 - 7.40 (m, 1H), 7.24 - 7.07 (m, 1H), 6.64 - 5.61 (m, 3H), 4.90 - 4.45 (m, 3H), 4.39 - 4.11 (m, 3H), 3.83 (t, J = 7.6 Hz, 1H), 2.65 - 2.54 (m, 2H); m/z ES+ [M+H] ⁺ 425.2. Example 156. Preparation of 1-(6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 50) Step 1. tert-Butyl 6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (300 mg, 970 μmol) in N-methyl-2-pyrrolidone (8.0 mL) was added N,N-diisopropylethylamine (376 mg, 2.91 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (283 mg, 582 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was poured into water (10 mL) and filtered. The filter cake was washed with water (5 mL x 3), dried in vacuum to give tert- butyl 6-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -1,6-diazaspiro[3.3]heptane-1- carboxylate (450 mg, 670 μmol, 70%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.52 - 8.30 (m, 2H), 8.09 - 7.91 (m, 1H), 7.40 - 7.07 (m, 3H), 4.74 - 4.48 (m, 2H), 4.41 - 4.20 (m, 2H), 3.93 - 3.65 (m, 2H), 2.53 (s, 2H), 1.41 - 1.17 (m, 9H); m/z ES+ [M+H] ⁺ 471.2. Step 2. N-(3-chloro-2-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,6-diazaspiro[3.3]heptane-1-carboxylate (450 mg, 956 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL) in one portion at 25 °C under nitrogen. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3- chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)py rido[3,2-d]pyrimidin-4-amine (355 mg, crude) as yellow solid. m/z ES+ [M+H] ⁺ 371.0. Step 4. 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido [3,2-d]pyrimidin-4-amine (354 mg, 955 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (281 mg, 3.34 mmol) at 0 °C. Then acryloyl chloride (86.4 mg, 955 μmol) in tetrahydrofuran (0.5 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC [column: Waters xbridge 150x25mm 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 35%-65%, 10 min] to give 1-[6-[4-(3-chloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (143 mg, 334 μmol, 35%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 - 9.15 (m, 1H), 8.55 - 8.24 (m, 2H), 8.07 - 7.88 (m, 1H), 7.44 - 7.08 (m, 3H), 6.65 - 6.07 (m, 2H), 5.82 - 5.64 (m, 1H), 4.83 - 4.26 (m, 4H), 4.20 - 3.76 (m, 2H), 2.65 - 2.55 (m, 2H); m/z ES+ [M+H] ⁺ 371.0. Example 157. Preparation of 1-(6-(4-((5-Chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 168) Step 1. tert-Butyl 6-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]pyr imidin- 6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(5-chloro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimi din-4- amine (100 mg, 260 μmol) in N-methyl-2-pyrrolidone (1 mL) was added N,N- diisopropylethylamine (100 mg, 780 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1- carboxylate (101 mg, 208 μmol). The mixture was stirred at 80 °C for 2 hr. On completion, the residue was diluted with water (25 mL) and filtered. The filter cake was collected to give tert-butyl 6-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrim idin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (200 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.40 - 8.28 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.26 - 7.20 (m, 1H), 7.19 - 7.14 (m, 2H), 6.88 (d, J = 9.2 Hz, 1H), 4.93 - 4.82 (m, 1H), 4.66 (d, J = 7.6 Hz, 1H), 4.32 - 4.19 (m, 2H), 3.95 - 3.84 (m, 2H), 2.59 - 2.51 (m, 2H), 1.76 (s, 9H). Step 2. N-(5-chloro-6-phenoxypyridin-3-yl)-6-(1,6-diazaspiro[3.3]hep tan-6- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (100 mg, 183 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was concentrated under reduced pressure to give N-(5-chloro-6-phenoxy-3-pyridyl)-6-(1,6-diazaspiro[3.3]hepta n-6-yl)pyrido[3,2- d]pyrimidin-4-amine (200 mg, crude) as a red solid. Step 3. 1-(6-(4-((5-Chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(5-chloro-6-phenoxy-3-pyridyl)-6-(1,6-diazaspiro[3.3]hepta n-6- yl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 357 μmol) in tetrahydrofuran (2 mL) and water (1 mL) was added sodium bicarbonate (90.0 mg, 1.07 mmol) and prop-2-enoyl chloride (19.4 mg, 214 μmol). The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 36%-66%, 8min) to give 1-[6-[4-[(5-chloro-6-phenoxy-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3. 3]heptan-1-yl]prop-2-en-1-one (63.7 mg, 120 μmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 - 9.41 (m, 1H), 8.80 - 8.71 (m, 1H), 8.69 - 8.62 (m, 1H), 8.50 - 8.43 (m, 1H), 8.01 - 7.90 (m, 1H), 7.48 - 7.38 (m, 2H), 7.26 - 7.06 (m, 4H), 6.63 - 6.05 (m, 2H), 5.78 - 5.63 (m, 1H), 4.83 (d, J = 9.6 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.30 (d, J = 9.6 Hz, 2H), 4.19 - 4.10 (m, 2H), 3.86 - 3.78 (m, 1H), 2.64 - 2.53 (m, 2H); m/z ES+ [M+H] ⁺ 500.3. Example 158. Preparation of 1-(6-(4-((4-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 181) Step 1. 6-chloro-N-(4-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 749 μmol) in acetonitrile (5.0 mL) was added 4-chloro-2-fluoro-aniline (130 mg, 899 μmol), the mixture was stirred at 25 °C for 2 hr. On completed, the mixture was filtered and the solid was collected to give 6-chloro-N-(4- chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (190 mg, 524 μmol, 74%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.87 (s, 1H), 8.34 (d, J = 8.8Hz, 1H), 8.22 (d, J = 1.6Hz, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.39 (t, J = 1.6 Hz, 1H), 6.59 - 6.51 (m, 1H); m/z ES+ [M+H] ⁺ 309.0. Step 2. tert-Butyl 6-(4-((4-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(4-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (130 mg, 420 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (122 mg, 252 μmol) in N-methyl-2-pyrrolidone (3.0 mL) was added N,N-diisopropylethylamine (108 mg, 841 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was poured into water (10 mL) and filtered. The filter cake was collected to give tert-butyl 6-[4-(4-chloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspir [3.3]heptane-1-carboxylate (100 mg, 190 μmol, 50%) as yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 8.79 (s, 1H), 8.54 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.15 (m, 2H), 6.80 (m, 1H), 3.81 (m, 2H), 3.25 (m, 2H), 2.50 (s, 2H), 2.23 - 2.12 (m, 2H), 1.25 (d, 9H); m/z ES+ [M+H] ⁺ 471. Step 3. N-(4-Chloro-2-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(4-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,6-diazaspiro[3.3]heptane-1-carboxylate (80.0 mg, 169 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated to give N-(4-chloro-2-fluoro-phenyl)-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 120 μmol, 80%) as a yellow solid. m/z ES+ [M+H] ⁺ 371.0. Step 4. 1-(6-(4-((4-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(4-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, 188 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (111 mg, 1.32 mmol), then prop-2-enoyl chloride (17.0 mg, 188 μmol) was added to above mixture. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated. The residue was purified by prep-HPLC (column:waters xbridge 150x250mm,10 um, mobile phase: [water (0.225% FA)-acetonitrile]; B%: 26%-56%, 11 min) to give 1-[6-[4-(4-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (4.99 mg, 11 μmol, 6%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (s, 1H), 8.85 (t, J = 8.8 Hz, 1H), 8.64 (s, 1H), 8.15 - 8.02 (m, 1H), 7.26 - 7.19 (m, 2H), 6.98 - 6.88 (m, 1H), 6.60 - 6.0 (m, 2H), 5.74 (d, J = 1.2, 10.4 Hz, 1H), 5.08 (d, J = 8.8 Hz, 2H), 4.30 (d, J = 8.8 Hz, 4H), 2.74 - 2.59 (m, 2H); m/z ES+ [M+H] ⁺ 424. Example 159. Preparation of 1-(6-(4-((3,5-Dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 169) Step 1. 6-Chloro-N-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 749 μmol) in acetonitrile (3.0 mL) was added 3,5-dichloroaniline (146 mg, 899 μmol). The mixture was stirred at 40 °C for 4 hr. On completed, the mixture was filtered and the solid was collected to give 6-chloro-N-(4- chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (190 mg, 556 μmol, 74%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.87 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 1.6 Hz, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.39 (t, J = 1.6 Hz, 1H), 6.59 - 6.51 (m, 1H); m/z ES+ [M+H] ⁺ 324.0. Step 2. tert-Butyl 6-(4-((3,5-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (130 mg, 399 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (155 mg, 319 μmol) in N- methyl-2-pyrrolidone (3.0 mL) was added N,N-diisopropylethylamine (103 mg, 798 μmol, 200 μL). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was poured into water (10 mL) and filtered to give tert-butyl 6-[4-(3,5-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (100 mg, 160 μmol, 43%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.55 (s, 1H), 8.29 (s, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.28 (s, 1H), 7.13 (m, 1H), 4.80 - 4.50 (m, 2H), 4.42 - 4.23 (m, 2H), 3.91 - 3.64 (m, 2H), 2.70 (s, 2H), 2.23 - 2.12 (m, 2H), 1.91 (m, J = 7.6 Hz, 2H), 1.40 (d, 3H), 1.15 (d, 6H); m/z ES+ [M+H] ⁺ 487.0. Step 3. N-(3,5-Dichlorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyr ido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(3,5-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro [3.3]heptane-1-carboxylate (80 mg, 164 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (15.4 g, 135 mmol).The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3,5- dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amine (60 mg, crude) as yellow solid. m/z ES+ [M+H] ⁺ 387.0. Step 4. 1-(6-(4-((3,5-Dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(4-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, 188 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (111 mg, 1.32 mmol), then prop-2-enoyl chloride (17.1 mg, 189 μmol) was added. The reaction was stirred at 0 °C for 10 min. On completion, the mixture was concentrated. The residue was purified by prep-HPLC (The residue was purified by prep- HPLC (column:waters xbridge 150x250mm,10um,mobile phase:[water (0.225% FA)- acetonitrile]; B%: 26%-56%, 11 min) to give 1-[6-[4-(3,5-dichloroanilino)pyrido[3,2-d]pyrimidin- 6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (16.4 mg, 37 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11 ( s, 1H), 8.68 (s, 1H), 8.35 (d, J = 2.8, 6.0 Hz, 1H), 7.88 (d, J = 1.2 Hz, 2H), 7.23 - 7.17 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 6.19 (m, J = 10.4, Hz, 1H), 5.76 (d, J = 10.4 Hz, 1H), 5.10 (m, J = 8.8 Hz, 2H), 4.52 - 3.90 (m, 4H), 2.71 (d, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 441.0. Example 160. Preparation of 1-(6-(4-(Benzo[d]isothiazol-6-ylamino)pyrido[3,2-d]pyrimidin - 6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 171)

Step 1. tert-Butyl 6-(4-(benzo[d]isothiazol-6-ylamino)pyrido[3,2-d]pyrimidin-6- yl)-1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-1,2-benzothiazol-6-a mine (78.0 mg, 249 μmol) in N-methyl-2-pyrrolidone (2 mL) was added N,N-diisopropylethylamine (129 mg, 994 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate;oxalic acid (71.7 mg, 249 μmol). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether /ethyl acetate = 10/1 to 1/2) to give tert-butyl 6-[4-(1,2-benzothiazol-6-ylamino)pyrido[3,2-d]pyrimidin-6-yl ]-1,6- diazaspiro[3.3]heptane-1-carboxylate (90.0 mg, 161 μmol, 76%) as a yellow solid. ¹ HNMR (400 MHz, CDCl ₃ ) δ 9.10 - 9.00 (m, 2H), 8.84 (s, 1H), 8.68 (s, 1H), 8.12 - 7.86 (m, 2H), 7.64 (br. s, 1H), 6.89 (d, J=9.2 Hz, 1H), 4.95 - 4.43 (m, 2H), 4.30 (br. s, 2H), 3.91 (br. t, J =7.6 Hz, 2H), 2.57 (t, J =7.6 Hz, 2H), 1.63 (br. s, 9H); m/z ES+ [M+H] ⁺ 476.1. Step N-(6-(1,6-Diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin- 4- yl)benzo[d]isothiazol-6-amine To a solution of tert-butyl 6-[4-(1,2-benzothiazol-6-ylamino)pyrido[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (70.0 mg, 147 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (504 mg, 4.42 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was dried by blowing nitrogen to give N-[6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-yl]-1,2- benzothiazol-6-amine (55.0 mg, 138 μmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 376.0. Step 3. 1-(6-(4-(Benzo[d]isothiazol-6-ylamino)pyrido[3,2-d]pyrimidin -6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-[6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin- 4-yl]-1,2- benzothiazol-6-amine (55.0 mg, 146 μmol) in tetrahydrofuran (1 mL) and water (0.20 mL) was added sodium bicarbonate (49.2 mg, 586 μmol) to adjust pH = 7. Then prop-2-enoyl chloride (11.9 mg, 132 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-50%, 8min) to give 1-[6-[4-(1,2-benzothiazol-6-ylamino)pyrido[3,2-d]pyrimidin-6 -yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (11.0 mg, 20 μmol, 17%) as a yellow solid. ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.65 - 9.52 (m, 1H), 9.05 (d, J = 18.4 Hz, 2H), 8.60 - 8.53 (m, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.04 - 7.94 (m, 2H), 7.22 - 7.10 (m, 1H), 6.35 - 6.24 (m, 1H), 6.16 - 6.08 (m, 1H), 5.77 - 5.65 (m, 1H), 4.86 (br. d, J = 9.6 Hz, 2H), 4.56 (q, J = 10.4 Hz, 1H), 4.33 (d, J = 9.6 Hz, 2H), 4.20 - 4.15 (m, 1H), 2.61 (br. t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 429.1. Example 161. Preparation of N-(1-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 172) Step 1. tert-Butyl (1-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)carbamate To a solution of 6-chloro-N-(5-chloro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimi din-4- amine (150 mg, 390 μmol) in N-methyl-2-pyrrolidone (3 mL) was added N,N- diisopropylethylamine (227 mg, 1.76 mmol) and tert-butyl N-(azetidin-3-yl)carbamate(122 mg, 586 μmol, hydrochloride). The mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to1/1) to give tert-butyl N- [1-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyri midin-6-yl]azetidin-3- yl]carbamate (92 mg, 160 μmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.75 - 8.64 (m, 2H), 8.45 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.66 (br. s, 1H), 7.48 - 7.40 (m, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.17 - 7.07 (m, 3H), 4.48 - 4.39 (m, 3H), 4.02 (br. d, J = 4.0 Hz, 2H), 1.41 (s, 9H). Step 2. 6-(3-Aminoazetidin-1-yl)-N-(5-chloro-6-phenoxypyridin-3-yl)p yrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]carbamate (82.0 mg, 158 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 6-(3-aminoazetidin-1-yl)-N-(5-chloro-6- phenoxy-3-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (66.2 mg, crude) as a yellow oil. Step 3. N-(1-(4-((5-Chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6- yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(5-chloro-6-phenoxy-3-pyridyl)pyr ido[3,2- d]pyrimidin-4-amine (66.2 mg, 158 μmol) in tetrahydrofuran (0.4 mL) and water (0.1 mL) added sodium bicarbonate (53.0 mg, 631 μmol) and prop-2-enoylchloride (12.9 mg, 142 μmol). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80x40mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 25%-55%, 8 min) to give N-[1-[4-[(5-chloro-6-phenoxy- 3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]pr op-2-enamide (10 mg, 18.0 μmol, 14%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.86 (br. d, J = 6.8 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 9.2 Hz, 3H), 6.27 - 6.20 (m, 1H), 6.17 - 6.12 (m, 1H), 5.66 (dd, J = 2.4, 9.6 Hz, 1H), 4.77 - 4.71 (m, 1H), 4.51 (t, J = 8.4 Hz, 2H), 4.07 (br. dd, J = 5.6, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 474.0. Example 162. Preparation of N-(1-(4-((5-fluoro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 173)

Step 1. tert-Butyl (1-(4-((5-fluoro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d]py rimidin- 6-yl)azetidin-3-yl)carbamate To a solution of 6-chloro-N-(5-fluoro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimi din-4- amine (200 mg, 544 μmol) in N-methyl-2-pyrrolidone (5.0 mL) was added N,N- diisopropylethylamine (211 mg, 1.63 mmol) and tert-butyl N-(azetidin-3-yl)carbamate (113 mg, 544 μmol, hydrochloride). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether/ethyl acetate (3/1, 10 mL) to give tert-butyl N-[1-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]carbamate (170 mg, 0.34 mmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.60 (dd, J = 12.0, 2.4 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.45 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.67 (br. d, J = 6.4 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.20 - 7.24 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 9.2 Hz, 1H), 4.37 - 4.52 (m, 3H), 4.02 (br. d, J = 4.0 Hz, 2H), 1.41 (s, 9H). Step 2. 6-(3-Aminoazetidin-1-yl)-N-(5-fluoro-6-phenoxypyridin-3-yl)p yrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]carbamate(150 mg, 298 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (68.0 mg, 596 μmol). The mixture was stirred at 20 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(3- aminoazetidin-1-yl)-N-(5-fluoro-6-phenoxy-3-pyridyl)pyrido[3 ,2-d]pyrimidin-4-amine (120 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 404.1. Step 3. N-(1-(4-((5-fluoro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6- yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(5-fluoro-6-phenoxy-3-pyridyl)pyr ido[3,2- d]pyrimidin-4-amine (100 mg, 248 μmol) in tetrahydrofuran (2.0 mL) was added sodium bicarbonate (20.8 mg, 248 μmol, 9.64 μL) in water (0.5 mL). Then prop-2-enoyl chloride (22.4 mg, 248 μmol, 49.6 μL) was added dropwise. The mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was quenched by methanol (3 mL) and dissolved in N,N- dimethylformamide (3 mL). The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 40%-60%, 8 min) to give N-[1-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]py rimidin- 6-yl]azetidin-3-yl]prop-2-enamide (28.2 mg, 42 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1 H), 8.86 (d, J = 6.8 Hz, 1 H), 8.61 (dd, J = 12.0, 2.4 Hz, 1 H), 8.56 (d, J = 2.4 Hz, 1 H), 8.46 (s, 1 H), 7.95 (d, J = 9.2 Hz, 1 H), 7.39 - 7.47 (m, 2 H), 7.19 - 7.26 (m, 1 H), 7.10 - 7.18 (m, 3 H), 6.20 - 6.30 (m, 1 H), 6.10 - 6.19 (m, 1 H), 5.63 - 5.70 (m, 1 H), 4.68 - 4.79 (m, 1 H), 4.51 (t, J = 8.4 Hz, 2 H), 4.07 (dd, J = 9.2, 5.2 Hz, 2 H); m/z ES+ [M+H] ⁺ 458.1. Example 163. Preparation of 1-(6-(4-((4-chloro-3-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 175) Step 1. 6-Chloro-N-(4-chloro-3-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 749 μmol) in acetonitrile (2.0 mL) was added 4-chloro-3-fluoro-aniline (131 mg, 899 μmol). The mixture was stirred at 25 °C for 2 hr. On completed, the mixture was filtered and the solid was collected to give 6-chloro- N-(4-chloro-3-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-amine (190 mg, 711 μmol, 79%) as a yellow solid. m/z ES+ [M+H] ⁺ 309.0. Step 2. tert-butyl 6-(4-((4-chloro-3-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(4-chloro-3-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (160. mg, 517 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (201 mg, 414 μmol) in N-methyl-2-pyrrolidone (3.0 mL) was added N,N-diisopropylethylamine (133 mg, 1.04 mmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was added water (5.0 mL) and then filtered. The filter cake was collected to give tert-butyl 6-[4-(4-chloro-3-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept ane-1-carboxylate (200 mg, crude) as yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.88 (s, 1H), 7.32 (m, 2H), 6.90 (m, 1H),3.80 (m, 2H), 3.31(m, 4H), 2.55(m, 2H), 1.36 (d, 3H), 1.18 (d, 6H); m/z ES+ [M+H] ⁺ 471. Step 3. N-(4-Chloro-3-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(4-chloro-3-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,6-diazaspiro[3.3]heptane-1-carboxylate (200 mg, 424 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (15.9 g, 139 mmol). On completion, the mixture was concentrated to give N-(4-chloro-3-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4- amine (140 mg, crude) as yellow solid. m/z ES+ [M+H] ⁺ 371. Step 4. 1-(6-(4-((4-Chloro-3-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(4-chloro-3-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (140 mg, 377 μmol) in tetrahydrofuran (2.0 mL) and water (2 mL) was added sodium bicarbonate (317 mg, 3.78 mmol). Then prop-2-enoyl chloride (34.2 mg, 377 μmol) was added. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated. The residue was purified by prep-HPLC (The residue was purified by prep-HPLC (column: Phenomenex Gemini 150x25mm, 10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 25%-55%, 10 min) to give 1-[6-[4-(4-chloro-3-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (52.8 mg, 105 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 - 9.30 (m, 1H), 8.64 - 8.46 (m, 1H), 8.33 (d, J = 12.4 Hz, 1H), 8.04 - 7.79 (m, 2H), 7.58 (t, J = 8.8 Hz, 1H), 7.21 - 7.06 (m, 1H), 6.68 - 6.04 (m, 2H), 5.80 - 5.61 (m, 1H), 4.85 (d, J = 8.8 Hz, 4H), 4.78 - 4.55 (m, 2H), 2.64 - 2.55 (m, 2H); m/z ES+ [M+H] ⁺ 425. Example 164. Preparation of 1-(6-(4-((2,3-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 176) Step 1. tert-Butyl 6-(4-((2,3-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(2,3-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (134 mg, 458 μmol) in N-methyl-2-pyrrolidone (3.0 mL) was added N,N-diisopropylethylamine (178 mg, 1.37 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (134 mg, 275 μmol). The mixture was stirred at 80 °C for 5 hr. On completion, mixture was poured into water (5.0 mL) and the suspension was filtered. The filter cake was washed with water (2 mL x 3), dried in vacuum to give tert-butyl 6-[4-(2,3-difluoroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (200 mg, 361 μmol, 82%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.47 (s, 1H), 8.21 (t, J = 7.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.43 - 7.10 (m, 3H), 4.76 - 4.47 (m, 2H), 4.43 - 4.25 (m, 2H), 3.86 - 3.67 (m, 2H), 2.53 (d, J = 1.6 Hz, 2H); m/z ES+ [M+H] ⁺ 455.4. Step 2. N-(2,3-Difluorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyr ido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(2,3-difluoroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (200 mg, 440 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.60 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give 6-(1,6- diazaspiro[3.3]heptan-6-yl)-N-(2,3-difluorophenyl)pyrido[3,2 -d]pyrimidin-4-amine (156 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 355.0. Step 3. 1-(6-(4-((2,3-Difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(2,3-difluorophenyl)pyr ido[3,2- d]pyrimidin-4-amine (156 mg, 440 μmol) in tetrahydrofuran (0.50 mL) and water (0.50 mL) was added sodium bicarbonate (129 mg, 1.54 mmol) at 0 °C. Then prop-2-enoyl chloride (39.8 mg, 440 μmol) in tetrahydrofuran (0.20 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. On completion, the residue was purified by prep-HPLC (column: Waters xbridge 150x25mm, 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30% - 60%, 21 min) to give 1-[6-[4-(2,3-difluoroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1, 6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (39 mg, 89 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 - 9.22 (m, 1H), 8.48 (s, 1H), 8.30 - 7.85 (m, 2H), 7.35 - 7.08 (m, 3H), 6.66 - 6.02 (m, 2H), 5.83 - 5.65 (m, 1H), 4.80 - 4.23 (m, 4H), 4.16 - 3.82 (m, 2H), 2.56 (s, 2H); m/z ES+ [M+H] ⁺ 409.3. Example 165. Preparation of 1-(6-(4-((2-isopropoxypyrimidin-5-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 184) Step 1. N-(2-isopropoxypyrimidin-5-yl)-1,1-diphenylmethanimine To a solution of 5-bromo-2-isopropoxy-pyrimidine (300 mg, 1.38 mmol) in xylene (2 mL) was added sodium tert-butoxide (199 mg, 2.07 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'- binaphthalene (8.61 mg, 13.82 μmol), tris(dibenzylideneacetone)dipalladium (25.3 mg, 27.6 μmol) and diphenylmethanimine (275 mg, 1.52 mmol). The mixture was stirred at 130 °C for 2 h under nitrogen. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 20/1) to give N-(2- isopropoxypyrimidin-5-yl)-1,1-diphenyl-methanimine (300 mg, 945 μmol, 68%) as a yellow solid. m/z ES+ [M+H] ⁺ 318.4. Step 2. 2-Isopropoxypyrimidin-5-amine To a solution of N-(2-isopropoxypyrimidin-5-yl)-1,1-diphenyl-methanimine (280 mg, 882 μmol) in methanol (3 mL) was added sodium acetate (362 mg, 4.41 mmol) and hydroxylamine;hydrochloride (91.9 mg, 1.32 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to give 2-isopropoxypyrimidin-5-amine (100 mg, 653 μmol, 74%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 8.02 (s, 2H), 5.10 (td, J = 6.0, 12.4 Hz, 1H), 1.33 (d, J = 6.0 Hz, 6H). Step 3. 6-Chloro-N-(2-isopropoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidi n-4-amine To a solution of 2-isopropoxypyrimidin-5-amine (67 mg, 437 μmol) in acetonitrile (1 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (79.5 mg, 398 μmol). The mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated in vacuo to give 6-chloro-N-(2- isopropoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, 379 μmol, 95%) as a yellow solid. m/z ES+ [M+H] ⁺ 317.0. Step 4. tert-Butyl 6-(4-((2-isopropoxypyrimidin-5-yl)amino)pyrido[3,2-d]pyrimid in-6- yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(2-isopropoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidi n-4- amine (90 mg, 284 μmol) in N-methyl-2-pyrrolidone (1 mL) was added N,N- diisopropylethylamine (110 mg, 852 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1- carboxylate (111 mg, 227 μmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was added water (3 mL) and filtered. The filter cake was concentrated in vacuo to give tert-butyl 6-[4-[(2-isopropoxypyrimidin-5-yl)amino]pyrido[3,2-d]pyrimid in-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 479.3. Step 5. N-(2-Isopropoxypyrimidin-5-yl)-6-(1,6-diazaspiro[3.3]heptan- 6-yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[(2-isopropoxypyrimidin-5-yl)amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (100 mg, 209 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give 6-(1,6-diazaspiro[3.3]heptan-6- yl)-N-(2-isopropoxypyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-a mine (102 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 379.3. Step 6. 1-(6-(4-((2-Isopropoxypyrimidin-5-yl)amino)pyrido[3,2-d]pyri midin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(2-isopropoxypyrimidin- 5- yl)pyrido[3,2-d]pyrimidin-4-amine (102 mg, 207 μmol, trifluoroacetic acid) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (87.0 mg, 1.04 mmol) in water (0.1 mL). Then prop-2- enoyl chloride (20.6 mg, 228 μmol) in tetrahydrofuran (0.1 mL) was added. The mixture was stirred at 0 °C for 0.2 h. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 11%-41%, 10 min) to give 1-[6-[4-[(2-isopropoxypyrimidin-5- yl)amino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hep tan-1-yl]prop-2-en-1-one (26.55 mg, 61.4 μmol, 30%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 - 9.34 (m, 1H), 9.06 - 8.99 (m, 2H), 8.40 - 8.36 (m, 1H), 8.01 - 7.87 (m, 1H), 7.21 - 7.03 (m, 1H), 6.64 - 6.06 (m, 2H), 5.79 - 5.64 (m, 1H), 5.19 (td, J = 6.0, 12.4 Hz, 1H), 4.82 (br. d, J = 9.2 Hz, 2H), 4.58 - 4.45 (m, 1H), 4.29 (d, J = 9.6 Hz, 2H), 4.15 (br. t, J = 7.2 Hz, 2H), 3.82 (br. t, J = 7.6 Hz, 1H), 2.65 - 2.53 (m, 2H), 1.33 (d, J = 6.0 Hz, 6H); m/z ES+ [M+H] ⁺ 433.3. Example 166. Preparation of N-(1-(4-((1-phenyl-1H-indazol-5-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 188)

Step 1. tert-Butyl N-[1-[4-[(1-phenylindazol-5-yl)amino]pyrido[3,2-d]pyrimidin- 6- yl]azetidin-3-yl]carbamate To a mixture of 6-chloro-N-(1-phenylindazol-5-yl)pyrido[3,2-d]pyrimidin-4-am ine (150 mg, 402 μmol) and tert-butyl N-(azetidin-3-yl)carbamate (104 mg, 604 μmol) in N-methyl-2- pyrrolidone (2 mL) was added N,N-diisopropylethylamine (208 mg, 1.61 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 10 minutes, then stirred at 80 °C for 2 hr. On completion, the reaction mixture was quenched by addition water (3 mL) at 25 °C, and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[1-[4-[(1-phenylindazol-5-yl)amino]pyrido[3,2-d]pyrimidin- 6-yl]azetidin-3-yl]carbamate (140 mg, 275 μmol, 68%) as a yellow solid. m/z ES+ [M+H] ⁺ 509.2. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(1-phenyl-1H-indazol-5-yl)pyrido[ 3,2-d]pyrimidin- 4-amine To a solution of tert-butyl N-[1-[4-[(1-phenylindazol-5-yl)amino]pyrido[3,2-d]pyrimidin- 6-yl]azetidin-3-yl]carbamate (100 mg, 197 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in reduced pressure to give 6-(3-aminoazetidin-1-yl)-N- (1-phenyl-1H-indazol-5-yl)pyrido[3,2-d]pyrimidin-4-amine (0.08 g, 195 μmol, 99%) as a brown oil. Step 3. N-(1-(4-((1-Phenyl-1H-indazol-5-yl)amino)pyrido[3,2-d]pyrimi din-6-yl)azetidin- 3-yl)acrylamide To a mixture of 6-(3-aminoazetidin-1-yl)-N-(1-phenyl-1H-indazol-5-yl)pyrido[ 3,2- d]pyrimidin-4-amine (0.08 g, 196 μmol) and sodium bicarbonate (65.8 mg, 783 μmol) in tetrahydrofuran (1 mL) and water (0.25 mL) was added prop-2-enoyl chloride (17.7 mg, 196 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was quenched by methanol (0.5 mL) and filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-50%, 8 min) to give N-(1-(4-((1-phenyl-1H-indazol-5-yl)amino)pyrido[3,2-d]pyrimi din-6- yl)azetidin-3-yl)acrylamide(16.6 mg, 31 μmol, 18%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.41 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.65 (d, J = 1.2 Hz, 1H), 8.49 - 8.39 (m, 2H), 7.98 - 7.87 (m, 3H), 7.81 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 8.0 Hz, 2H), 7.44 - 7.36 (m, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.29 - 6.20 (m, 1H), 6.19 - 6.10 (m, 1H), 5.66 (dd, J = 2.4, 10.0 Hz, 1H), 4.82 - 4.69 (m, 1H), 4.52 (t, J = 8.4 Hz, 2H), 4.07 (dd, J = 5.6, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 463.1. Example 167. Preparation of 1-(6-(4-((3,4-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 191) Step 1. 6-Chloro-N-(3,4-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 500 μmol) in acetonitrile (3.0 mL) was added 3,4-difluoroaniline (77.4 mg, 599 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the filter cake was washed with acetonitrile (2 mL x 3), dried in vacuum to give 6-chloro-N-(3,4-difluorophenyl)pyrido[3,2- d]pyrimidin-4-amine (117 mg, crude) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.81 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.15 (m, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.87 - 7.75 (m, 1H), 7.59 - 7.42 (m, 1H). Step 2. tert-Butyl 6-(4-((3,4-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3,4-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (117 mg, 399 μmol) in N-methyl-2-pyrrolidone (3 mL) was added N,N-diisopropylethylamine (155 mg, 1.20 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (155 mg, 319 μmol). The mixture was stirred at 100 °C for 4 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl 6-[4-(3,4-difluoroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (129 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 8.54 (s, 1H), 8.19 - 8.07 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.20 - 7.06 (m, 2H), 4.77 - 4.49 (m, 2H), 4.41 - 4.28 (m, 2H), 3.87 - 3.68 (m, 2H), 2.78 (d, J = 5.6 Hz, 2H), 1.18 (t, J = 7.2 Hz, 9H); m/z ES+ [M+H] ⁺ 455.0. Step 3. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-(3,4-difluorophenyl)pyr ido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(3,4-difluoroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (129 mg, 283 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 3 hr. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3,4-difluorophenyl)pyr ido[3,2-d]pyrimidin-4-amine (100 mg, 279 μmol, 99%) as a yellow oil. m/z ES+ [M+H] ⁺ 355.0. Step 4. 1-(6-(4-((3,4-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3,4-difluorophenyl)pyr ido[3,2- d]pyrimidin-4-amine (100 mg, 282 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (82.9 mg, 987 μmol) at 0 °C. Then prop-2-enoyl chloride (25.5 mg, 282 μmol) in tetrahydrofuran (0.2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with water/methanol = 5/1 to give 1-[6-[4-(3,4- difluoroanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[ 3.3]heptan-1-yl]prop-2-en-1-one (56.0 mg, 127 μmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 - 9.33 (m, 1H), 8.57 - 8.45 (m, 1H), 8.28 (m, 1H), 8.04 - 7.93 (m, 1H), 7.85 - 7.76 (m, 1H), 7.53 - 7.32 (m, 1H), 7.25 - 7.03 (m, 1H), 6.65 - 6.08 (m, 2H), 5.83 - 5.64 (m, 1H), 4.87 - 4.29 (m, 4H), 4.20 - 3.64 (m, 2H), 2.65 - 2.55 (m, 2H); m/z ES+ [M+H] ⁺ 409.4. Example 168. Preparation of 1-[6-[4-(4-Bromo-3-chloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (Compound 234) Step 1. N-(4-Bromo-3-chloro-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]p yrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (85 mg, 424 μmol) in acetonitrile (5 mL) was added 4-bromo-3-chloro-2-fluoro-aniline (104 mg, 467 μmol), the mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was filtered and the filter cake was collected to give N-(4-bromo-3-chloro-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]p yrimidin-4-amine (160 mg, 414 μmol, 97%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 - 10.42 (m, 1H), 8.70 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.74 - 7.66 (m, 2H). Step 2. tert-Butyl 6-[4-(4-bromo-3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimid in-6-yl]- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (65.3 mg, 226 μmol, oxalic acid) and N-(4-bromo-3-chloro-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]p yrimidin-4-amine (80 mg, 206 μmol) in N-methyl pyrrolidone (2 mL) was added diisopropylethylamine (79.9 mg, 618 μmol). The mixture was stirred at 100 °C for 12 h. On completion, the reaction mixture was quenched with sat. ammonium chloride (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to give tert-butyl 6-[4-(4-bromo- 3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-d iazaspiro[3.3]heptane-1-carboxylate (90 mg, 164 μmol, 79%) as a yellow solid. m/z ES+ [M+H] ⁺ 551.2. Step 3. N-(4-bromo-3-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]h eptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(4-bromo-3-chloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (80 mg, 145 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N- (4-bromo-3-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]hep tan-6-yl)pyrido[3,2-d]pyrimidin- 4-amine (65 mg, 144 μmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 450.1. Step 4. 1-[6-[4-(4-Bromo-3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyri midin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of N-(4-bromo-3-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]h eptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (65 mg, 144 μmol) in tetrahydrofuran (4 mL) was added prop- 2-enoyl chloride (14.3 mg, 158 μmol) and sodium bicarbonate (48.5 mg, 578 μmol) in water (4 mL), the mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 49%-79%, 8 min) and further purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 50%-80%, 8 min) to give 1-[6-[4-(4-bromo-3- chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-dia zaspiro[3.3]heptan-1-yl]prop-2-en- 1-one (8.55 mg, 17.0 μmol 11%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 - 9.26 (m, 1H), 8.49 - 8.41 (m, 2H), 8.00 - 7.97 (m, 1H), 7.73 - 7.70 (m, 1H), 7.15 (d, J = 9.2 Hz, 1H), 6.55 - 5.68 (m, 3H), 4.81 - 3.80 (m, 6H), 2.62 - 2.50 (m, 2H); m/z ES+ [M+H] ⁺ 503.3. Example 169. Preparation of 1-[6-[4-(5-Chloro-2-fluoro-4-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (Compound 233)

Step 1. 1-Chloro-4-fluoro-2-methoxy-5-nitro-benzene To a solution of 1-chloro-4-fluoro-2-methoxy-benzene (2 g, 12.4 mmol) in sulfuric acid (20 mL) was added potassium nitrate (1.26 g, 12.4 mmol) at 0 °C, the mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was quenched by sat. sodium bicarbonate (300 mL) at 0 °C and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (900 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-chloro-4-fluoro-2-methoxy-5-nitro-benzene (1.8 g, 8.78 mmol, 70%) as a red solid. m/z ES+ [M+H]+206.2. Step 2. 5-Chloro-2-fluoro-4-methoxy-aniline To a solution of 1-chloro-4-fluoro-2-methoxy-5-nitro-benzene (1.85 g, 9.00 mmol) in ethanol (20 mL) and water (4 mL) was added iron powder (2.51 g, 45.0 mmol) and ammonium chloride (4.81 g, 89.9 mmol), the mixture was stirred at 60 ^o C for 1 h. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph (SiO ₂ , petroleum ether / ethyl acetate =1/0~5/1) to give 5-chloro-2-fluoro-4-methoxy-aniline (1.19 g, 6.80 mmol, 75%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.96 (d, J = 12.8 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 4.88 (s, 2H), 3.72 (s, 3H). Step 3. 6-Chloro-N-(5-chloro-2-fluoro-4-methoxy-phenyl)pyrido[3,2-d] pyrimidin-4- amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (80 mg, 399 μmol) in acetonitrile (5 mL) was added 5-chloro-2-fluoro-4-methoxy-aniline (77.2 mg, 439 μmol), the mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was filtered and the filter cake was collected to give 6-chloro-N-(5-chloro-2-fluoro-4-methoxy-phenyl)pyrido[3,2-d] pyrimidin-4-amine (120 mg, 355 μmol, 88%) as a yellow solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.79 - 10.64 (m, 1H), 8.77 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 12.0 Hz, 1H). Step 4. tert-Butyl 6-[4-(5-chloro-2-fluoro-4-methoxy-anilino)pyrido[3,2-d]pyrim idin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (93.5 mg, 324 μmol, oxalic acid) and 6-chloro-N-(5-chloro-2-fluoro-4-methoxy-phenyl)pyrido[3,2-d] pyrimidin-4- amine (100 mg, 294 μmol) in N-methyl pyrrolidone (0.5 mL) was added diisopropylethylamine (114 mg, 884 μmol), the mixture was stirred at 100 °C for 12 h. On completion, the reaction mixture was quenched with sat. ammonium chloride (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were washed with brine (10 mL x 3), dried with sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give tert-butyl 6-[4-(5- chloro-2-fluoro-4-methoxy-anilino)pyrido[3,2-d]pyrimidin-6-y l]-1,6-diazaspiro[3.3]heptane-1- carboxylate (140 mg, 280 μmol, 94%) as a yellow solid. m/z ES+ [M+H] ⁺ 501.3. Step 5. N-(5-Chloro-2-fluoro-4-methoxy-phenyl)-6-(1,6-diazaspiro[3.3 ]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(5-chloro-2-fluoro-4-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (80 mg, 159 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N- (5-chloro-2-fluoro-4-methoxy-phenyl)-6-(1,6-diazaspiro[3.3]h eptan-6-yl)pyrido[3,2- d]pyrimidin-4-amine (64 mg, 159 μmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 401.2. Step 6. 1-[6-[4-(5-Chloro-2-fluoro-4-methoxy-anilino)pyrido[3,2-d]py rimidin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of N-(5-chloro-2-fluoro-4-methoxy-phenyl)-6-(1,6-diazaspiro[3.3 ]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (60 mg, 149 μmol) in tetrahydrofuran (4 mL) was added prop- 2-enoyl chloride (14.9 mg, 164 μmol) and sodium bicarbonate (50.3 mg, 598 μmol) in water (4 mL), the mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 30%-60%,10 min) to give 1-[6-[4-(5-chloro-2-fluoro-4-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (21.9 mg, 48.2 μmol, 32%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 - 9.03 (m, 1H), 8.42 (s, 1H), 8.38 - 8.26 (m, 1H), 7.99 - 7.93 (m, 1H), 7.30 (d, J = 12.8 Hz, 1H), 7.17 - 7.09 (m, 1H), 6.60 - 6.09 (m, 2H), 5.72 - 5.70 (m, 1H), 4.78 (d, J = 9.6 Hz, 1.5H), 4.53 - 4.46 (m, 1H), 4.28 (d, J = 9.2 Hz, 1.5H), 4.15 (t, J = 7.6 Hz, 1.5H), 3.89 (s, 3H), 3.83 - 3.79 (m, 0.5 H), 2.62 - 2.50 (m, 2H); m/z ES+ [M+H] ⁺ 455.4. Example 170. Preparation of 1-[6-[4-(3-Ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]-1,6-dia-zaspiro[3.3]heptan-1-yl]prop-2-en-1-one (Compound 230) Step 1. tert-Butyl 6-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl ]-1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3-ethynyl-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin -4-amine (100 mg, 335 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (79.6 mg, 402 μmol) in N-methylpyrrolidone (5 mL) was added diisopropylethylamine (130 mg, 1.00 mmol). The mixture was stirred at 100 °C for 16 hr. On completion, the mixture was quenched with brine (10 mL) and extracted with dichloromethane (15 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/1) to give tert-butyl 6-[4-(3- ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-di azaspiro[3.3]heptane-1-carboxylate (100 mg, 217 μmol, 65%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (s, 1H), 8.79 (d, J = 4.0 Hz, 1H), 8.49 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.08 (d, J = 6.4 Hz, 2H), 6.79 (d, J = 8.8 Hz, 1H), 4.62 - 4.49 (m, 1H), 4.23 - 4.09 (m, 2H), 3.83 - 3.73 (m, 2H), 2.45 (t, J = 7.2 Hz, 2H), 2.13 - 2.04 (m, 2H), 1.96 (s, 9H); m/z ES+ [M+H] ⁺ 461.3. Step 2. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-(3-ethynyl-2-fluoro-phe nyl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl ]- 1,6-diazaspiro[3.3]heptane-1-carboxylate (90 mg, 195 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.93 g, 16.9 mmol). The mixture was stirred at 25 °C for 5 hr. On completion, the mixture was concentrated under reduced pressure to give 6-(1,6- diazaspiro[3.3]heptan-6-yl)-N-(3-ethynyl-2-fluoro-phenyl)pyr ido[3,2-d]pyrimidin-4-amine (80 mg, 169 μmol, 86%) as a yellow oil. m/z ES+ [M+H] ⁺ 361.4. Step 3. 1-[6-[4-(3-Ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]-1,6-dia- zaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3-ethynyl-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 169 μmol) in tetrahydrofuran (3.5 mL) and water (3.5 mL) was added sodium bicarbonate (42.5 mg, 506 μmol) to adjust pH = 8. The mixture was added prop-2-enoyl chloride (15.3 mg, 169 μmol) at 0 °C and then stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30 mmx3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 22%-52%, 7 min) to give 1-[6-[4-(3-ethynyl-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (30.3 mg, 73.1 μmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 - 9.24 (m, 1H), 8.57 - 8.33 (m, 2H), 8.08 - 7.90 (m, 1H), 7.35 - 7.26 (m, 2H), 7.19 - 7.12 (m, 1H), 6.58 - 6.10 (m, 2H), 5.76 - 5.59 (m, 1H), 4.81 - 4.51 (m, 3H), 4.31 - 4.14 (m, 3H), 3.86 - 3.78 (m, 1H), 2.65 - 2.57 (m, 2H); m/z ES+ [M+H] ⁺ 415.4. Example 171. Preparation of 1-[6-[4-(3-Bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro [3.3]heptan-1-yl]prop-2-en-1-one (Compound 229)

Step 1. tert-Butyl 6-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyramiddin-6-yl] -1,6- diazaspiro[3.3]heptane-1-carboxylate To a mixture of N-(3-bromo-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]pyrimidin- 4-amine (150 mg, 424 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (84.1 mg, 424 μmol) in N-methylpyrrolidone (3.0 mL) was added diisopropylethylamine (274 mg, 2.12 mmol), the reaction mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2- d]pyramiddin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (210 mg, 408 μmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 517.0. Step 2. N-(3-Bromo-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6 -yl)pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]- 1,6- diazaspiro[3.3]heptane-1-carboxylate (190 mg, 368 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-bromo-2-fluoro- phenyl)-6-(1,6-diazaspiro[3.3]heptan-6 -yl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 361 μmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 417.0. Step 3. 1-[6-[4-(3-Bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-y l]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a mixture of N-(3-bromo-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrid o[3,2-d]pyrimidin-4-amine (150 mg, 361 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (30.3 mg, 361 μmol), and then prop-2-enoyl chloride (39.2 mg, 433 μmol) was added, the reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 35%-65%, 10 min) to give 1-[6-[4-(3-bromo-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (13.5 mg, 28.8 μmol, 7.7%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 - 9.26 (m, 1H), 8.49 - 8.39 (m, 2H), 8.03 - 7.92 (m, 1H), 7.51 - 7.45 (m, 1H), 7.27 - 7.22 (m, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.33 - 6.24 (m, 1H), 6.16 - 6.08 (m, 1H), 5.73 - 5.67 (m, 1H), 4.81 (d, J = 9.6 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.31 (d, J = 9.2 Hz, 2H), 4.18 - 3.80 (m, 2H), 2.63 - 2.56 (m, 2H); m/z ES+ [M+H] ⁺ 469.3. Example 172. Preparation of 1-(6-(4-((3-(Neopentyloxy)phenyl)amino)pyrido[3,2- nd 199) Step 1. 1-(2,2-Dimethylpropoxy)-3-nitro-benzene To a suspension of 3-nitrophenol (1.00 g, 7.19 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.99 g, 14.3 mmol) and 1-bromo-2,2-dimethyl-propane (1.30 g, 8.63 mmol). The mixture was stirred at 50 °C for 3 hr. On completion, the reaction mixture was quenched by water 30 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to give 1-(2,2-dimethylpropoxy)-3-nitro-benzene (965 mg, 4.61 mmol, 64%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (dd, J = 1.6, 8.0 Hz, 1H), 7.63 (t, J = 2.4 Hz, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.35 (dd, J =2.0, 8.4 Hz, 1H), 3.69 (s, 2H), 0.98 (s, 9H). Step 2. 3-(2,2-Dimethylpropoxy)aniline To a solution of 1-(2,2-dimethylpropoxy)-3-nitro-benzene (300 mg, 1.43 mmol) in ethanol (8 mL) was added palladium on activated carbon (50 mg, 10% loading) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 4 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give 3-(2,2-dimethylpropoxy)aniline (185 mg, 1.03 mmol, 67%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.87 (t, J = 7.6 Hz, 1H), 6.27 - 5.97 (m, 3H), 5.00 (s, 2H), 3.55 - 3.45 (m, 2H), 3.42 - 3.35 (m, 1H), 1.08 - 0.90 (m, 9H). Step 3. 6-Chloro-N-[3-(2,2-dimethylpropoxy)phenyl]pyrido[3,2-d]pyrim idin-4-amine To a solution of 3-(2,2-dimethylpropoxy)aniline (161 mg, 899 μmol) in acetonitrile (2.0 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 749 μmol). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was poured into water (5.0 mL) and the suspension was filtered. The filter cake was washed with water (2.0 mL × 3), dried in vacuum to give 6-chloro- N-[3-(2,2-dimethylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-am ine (255 mg, 746 μmol 98%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.80 - 8.60 (m, 1H), 8.33 - 8.19 (m, 1H), 8.05 - 7.92 (m, 1H), 7.74 - 7.58 (m, 2H), 7.40 - 7.20 (m, 1H), 6.74 (dd, J = 1.6, 8.0 Hz, 1H), 3.66 (s, 1H), 3.60 - 3.56 (m, 1H), 1.03 (s, 9H). Step 4. tert-Butyl 6-[4-[3-(2,2-dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[3-(2,2-dimethylpropoxy)phenyl]pyrido[3,2-d]pyrim idin-4- amine (100 mg, 291 μmol) in N-methylpyrrolidone (3 mL) was added diisopropylethylamine (668 mg, 5.17 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (113 mg, 233 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was poured into water (3.0 mL) and the suspension was filtered. The filter cake was washed with acetonitrile (1.0 mL × 3), dried in vacuum to give tert-butyl 6-[4-[3-(2,2-dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]- 1,6-diazaspiro[3.3]heptane-1-carboxylate (140 mg, 277 μmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.98 (s, 1H), 9.28 (s, 1H), 8.74 (d, J = 9.2 Hz, 1H), 8.50 - 8.44 (m, 2H), 8.14 - 8.03 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 5.62 - 4.98 (m, 3H), 4.49 (s, 2H), 4.54 (s, 1H), 4.10 (s, 2H), 2.78 - 2.60 (m, 13H), 2.08 - 1.91 (m, 9H), 1.85 (s, 9H). Step 5. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-[3-(2,2- dimethylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[3-(2,2-dimethylpropoxy)anilino]pyrido[3,2-d] pyrimidin- 6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (140 mg, 277 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (995 mg, 8.73 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(1,6-diazaspiro[3.3]heptan- 6-yl)-N-[3-(2,2-dimethylpropoxy)phenyl]pyrido[3,2-d]pyrimidi n-4-amine (110 mg, 271 μmol, 98%) as a brown oil. m/z ES+ [M+H] ⁺ 405.5. Step 6. 1-[6-[4-[3-(2,2-Dimethylpropoxy)anilino]pyrido[3,2-d]pyrimid in-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[3-(2,2- dimethylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (110 mg, 271 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (22.8 mg, 271 μmol) at 0 °C. Then prop-2-enoyl chloride (24.6 mg, 271 μmol) in tetrahydrofuran (0.2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150x25mm 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 46%-76%, 11.5 min) to give 1-[6-[4-[(4-phenoxycyclohexyl)amino] pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (17.7 mg, 38.5 μmol, 34%) as an off-white solid. ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.31 - 9.09 (m, 1H), 8.56 - 8.42 (m, 1H), 8.04 - 7.88 (m, 1H), 7.72 - 7.59 (m, 2H), 7.37 - 7.07 (m, 2H), 6.78 - 6.56 (m, 1H), 6.37 - 6.22 (m, 1H), 6.19 - 6.04 (m, 1H), 5.83 - 5.50 (m, 1H), 5.05 - 4.24 (m, 4H), 3.83 (t, J = 7.2 Hz, 2H), 3.67 (s, 2H), 2.64 - 2.57 (m, 2H), 1.03 (s, 9H); m/z ES+ [M+H] ⁺ 459.5. Example 173. Preparation of 1-[6-[4-(3-Phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (Compound 195)

Step 1. tert-Butyl 6-[4-(3-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 430 μmol), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (146 mg, 301 μmol) in N-methyl pyrrolidone (3 mL) was added diisopropylethylamine (167 mg, 1.29 mmol). The mixture was stirred at 100 °C for 3 hr. On completion, the reaction mixture was quenched by water (5 mL) and filtered. The filter cake was collected to give tert-butyl 6-[4-(3-phenoxyanilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (200 mg, 392 μmol, 91%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.43 (s, 1H), 7.98 -7.90 (m, 2H), 7.84 - 7.77 (m, 1H), 7.46 - 7.36 (m, 3H), 7.18 - 7.04 (m, 4H), 6.71 (dd, J = 2.0, 8.0 Hz, 1H), 4.75 - 4.48 (m, 2H), 4.37 - 4.26 (m, 2H), 3.86 - 3.69 (m, 2H), 2.21 - 2.15 (m, 1H), 1.95 - 1.86 (m, 1H), 1.45 - 1.10 (m, 9H). Step 2. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-(3-phenoxyphenyl)pyrido [3,2-d] pyrimidin-4-amine To a solution of tert-butyl 6-[4-(3-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro [3.3]heptane-1-carboxylate (200 mg, 392 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3- phenoxyphenyl)pyrido[3,2-d] pyrimidin-4-amine (100 mg, 244 μmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 411.0. Step 3. 1-[6-[4-(3-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3-phenoxyphenyl)pyrido [3,2- d]pyrimidin-4-amine (100 mg, 244 μmol) in tetrahydrofuran (3 mL) was added sodium bicarbonate (102 mg, 1.22 mmol) in water (3 mL) at 0 °C over 5 min. Then prop-2-enoyl chloride (22.1 mg, 244 μmol) in tetrahydrofuran (3 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 5 minutes. On completion, the reaction was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (FA)-ACN]; B%: 23%-53%,10 min) to give 1-[6-[4-(3- phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3 .3]heptan-1-yl]prop-2-en-1-one (32.1 mg, 69.2 μmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 - 9.26 (m, 1H), 8.48 - 8.43 (m, 1H), 8.00 - 7.89 (m, 2H), 7.81 - 7.76(m, 1H), 7.45 - 7.36 (m, 3H), 7.19 - 7.03 (m, 4H), 6.74 - 6.69 (m, 1H), 6.62 - 5.67 (m, 3H), 4.83 (d, J = 10.0 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.30 (d, J = 9.6 Hz, 2H), 4.19 - 3.78 (m, 2H), 2.60 (t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 465.3. Example 174. Preparation of 1-[6-[4-[4-(2,2-Dimethylpropoxy)anilino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (Compound 200) Step 1. 6-Chloro-N-[4-(2,2-dimethylpropoxy )pheny l]pyrido[3,2-d]pyrimidin-4-amine To a solution of 6-chloro-N-[4-(2,2-dimethylpropoxy)phenyl]pyrido[3,2-d]pyrim idin-4- amine (150 mg, 437 μmol) in N-methyl pyrrolidone (4.0 mL) was added diisopropylethylamine (169 mg, 1.31 mmol) and bis(1-tert-butoxycarbonyl-1-aza-6-azoniaspiro[3.3]heptan-6-y l)oxalate (170 mg, 350 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was poured into water (3.0 mL) and filtered. The filter cake was dried in vacuo to give tert-butyl 6-[4- [4-(2,2-dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl] -1,6-diazaspiro[3.3]heptane-1- carboxylate (200 mg, 396 μmol, 95%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.31 (s, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.81 - 7.79 (m, 1H), 7.79 - 7.77 (m, 1H), 7.73 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.92 - 6.91 (m, 1H), , 4.65 - 4.12 (m, 4H), 3.78 - 3.61 (m, 2H), 3.60 - 3.51 (m, 2H), 2.63 (s, 9H), 2.49 - 2.46 (m, 2H), 0.95 (s, 9H). Step 2. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-[4-(2,2- dimethylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[4-(2,2-dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (200 mg, 396 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was poured into water (3.0 mL) and filtered. The filter cake was concentrated in vacuo to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[4-(2,2- dimethylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (160 mg, 395 μmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 405.1. Step 3. 1-[6-[4-[4-(2,2-Dimethylpropoxy)anilino]pyrido[3,2-d]pyrimid in-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[4-(2,2- dimethylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (160 mg, 395 μmol) in tertrahydrofurane (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (116 mg, 1.38 mmol) and prop-2-enoyl chloride (107 mg, 1.19 mmol). The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% ammonium bicarbonate) to give 1-[6-[4-[4-(2,2- dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-dia zaspiro[3.3]heptan-1-yl]prop-2- en-1-one (28.4 mg, 62.0 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (s, 1H), 8.47 - 8.25 (m, 1H), 7.99 - 7.60 (m, 3H), 7.17 - 7.04 (m, 3H), 6.36 – 6.21 (m, 2H), 5.80 - 5.62 (m, 1H), 4.82 (d, J = 9.6 Hz, 1.5H), 4.60-3.75(m, 4.5H), 3.64 (s, 2H), 2.60 (t, J = 7.2 Hz, 2H), 1.02 (s, 9H). m/z ES+ [M+H] ⁺ 459.5. Example 175. Preparation of N-[1-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]prop-2-enamide (Compound 213)

Step 1. tert-Butyl N-[1-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]carbamate To a solution of N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-7-fluoro-1,2-benzoth iazol-6- amine (290 mg, 874 μmol) and tert-butyl N-(azetidin-3-yl)carbamate;hydrochloride (186 mg, 891 μmol) in N-methylpyrrolidone (6 mL) was added diisopropylethylamine (343 mg, 2.65 mmol). The mixture was stirred at 100 °C for 16 hr. On completion, the mixture was quenched with brine (20 mL) and extracted with dichloromethane/methanol 10/1 (25 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 0/1) to give tert-butyl N-[1-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]pyrido[3,2-d] pyrimidin-6- yl]azetidin-3-yl]carbamate (350 mg, 709 μmol, 71.0%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (s, 1H), 8.90 (t, J = 8.0 Hz, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.50 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.31 - 6.18 (m, 1H), 4.44 - 4.34 (m, 2H), 3.44 (t, J = 7.2 Hz, 1H), 2.40 (t, J = 8.0 Hz, 2H), 1.34 (s, 9H); m/z ES+ [M+H] ⁺ 468.3. Step 2. N-[6-(3-Aminoazetidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl]-7-fl uoro-1,2- benzothiazol-6-amine To a solution of tert-butyl N-[1-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]carbamate (330 mg, 706 μmol) in dichloromethane (9 mL) was added trifluoroacetic acid (2.54 g, 22.3 mmol, 1.65 mL). The mixture was stirred at 25 °C for 2 hr. After 2 hr, the mixture was added trifluoroacetic acid (847 mg, 7.43 mmol), then stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give N-[6-(3-aminoazetidin-1- yl)pyrido[3,2-d]pyrimidin-4-yl]-7-fluoro-1,2-benzothiazol-6- amine (300 mg, 621 μmol, 88%) as a yellow oil. m/z ES+ [M+H]+ 368.1. Step 3. N-[1-[4-[(7-Fluoro-1,2-benzothiazol-6-yl)amino]pyrido[3,2-d] pyrimidin-6- yl]azetidin-3-yl]prop-2-enamide To a solution of N-[6-(3-aminoazetidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl]-7-fl uoro-1,2- benzothiazol-6-amine (150 mg, 312 μmol) in tetrahydrofuran (3.5 mL) and water (3 mL) was added sodium bicarbonate (78.5 mg, 935 μmol) to adjust pH = 8. The mixture was added prop-2- enoyl chloride (28.2 mg, 312 μmol) at 0 °C and stirred for 0.5 hr. On completion, the mixture was concentrated under reduced pressure. The crude product was triturated with water (10 mL), then filtered. The filter cake was triturated with ethyl acetate (10 mL) and further triturated with methanol (10 mL) to give N-[1-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]prop-2-enamide (25.8 mg, 61.3 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 9.17 (d, J = 4.0 Hz, 1H), 8.86 (d, J = 6.0 Hz, 1H), 8.56 (t, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 6.27 - 6.13 (m, 2H), 5.66 (d, J = 9.2 Hz, 1H), 4.75-4.74 (m, 1H), 4.49 (t, J = 8.0 Hz, 2H), 4.07 - 4.04 (m, 2H); m/z ES+ [M+H] ⁺ 422.3. Example 176. Preparation of N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyramid in-6-yl]azetidin-3-yl]-N-methyl-prop-2-enamide (Compound 205) Step 1. tert-Butyl N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n-6- yl]azetidin-3-yl]-N-methyl-carbamate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (0.30 g, 873 μmol) and tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate (214 mg, 960 μmol, hydrochloric acid salt) in N-methyl pyrrolidone (2 mL) was added diisopropylethylamine (564 mg, 4.37 mmol). The reaction mixture was stirred at 100°C for 12 hr. The reaction mixture was diluted with water (30 mL) and filtered. The filter cake concentrated under reduce pressure to give tert-butyl N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n-6-yl]azetidin-3-yl]- N-methyl-carbamate (0.4 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 493.1. Step 2. N-(3,4-Dichloro-2-fluoro-phenyl)-6-[3-(methylamino)azetidin- 1-yl]pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]azetidin-3-yl]-N-methyl-carbamate (0.2 g, 405 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The reaction mixture was stirred at 20 °C for 0.5 hr. The mixture was concentrated via blowing nitrogen. The residue was diluted with aq. ammonium hydroxide to adjusted pH = 8 and then filtered. The filter cake was collected to afford N-(3,4- dichloro-2-fluoro-phenyl)-6-[3-(methylamino)azetidin-1-yl]py rido[3,2-d]pyrimidin-4-amine (0.12 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 393.0. Step 3. N-[1-[4-(3,4-Dichloro-2-fluoro-anilino)pyrido[3,2-d]pyramid in-6-yl]azetidin-3- yl]-N-methyl-prop-2-enamide To a mixture of N-(3,4-dichloro-2-fluoro-phenyl)-6-[3-(methylamino)azetidin- 1- yl]pyrido[3,2-d]pyrimidin-4-amine (180 mg, 457 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (38.4 mg, 457 μmol), and then prop-2-enoyl chloride (49.7 mg, 549 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-ACN]; B%: 34%-73%, 14 min) to give N-[1-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,2-d]pyramid in-6-yl]azetidin-3-yl]-N-methyl-prop-2-enamide (35.2 mg, 78.9 μmol, 55%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.47 (s, 1H), 8.38 (t, J = 8.6 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.59 (dd, J = 1.8, 9.0 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.87 - 6.71 (m, 1H), 6.21 - 6.06 (m, 1H), 5.78 - 5.67 (m, 1H), 5.36 - 5.20 (m, 1H), 4.51 - 4.36 (m, 2H), 4.34 - 4.20 (m, 2H), 3.16 (s, 3H); m/z ES+ [M+H] ⁺ 447.3. Example 177. Preparation of N-[1-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-prop-2-enamide (Compound 216)

Step 1. tert-Butyl N-[1-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-carbamate To a mixture of 6-chloro-N-(5-chloro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimi din-4- amine (150 mg, 390 μmol) and tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate (104 mg, 468 μmol) in N-methylpyrrolidone (2.0 mL) was added diisopropylethylamine (252 mg, 1.95 mmol), the reaction mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[1-[4-[(5-chloro-6-phenoxy-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]-N-m ethyl-carbamate (50.0 mg, 93.6 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (d, J = 2.4 Hz, 1H), 8.64 - 8.56 (m, 2H), 8.34 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.18 - 7.14 (m, 2H), 6.88 (d, J = 9.4 Hz, 1H), 4.42 (t, J = 8.8 Hz, 2H), 4.23 (dd, J = 5.8, 9.1 Hz, 2H), 3.00 (s, 3H), 2.02 - 1.99 (m, 1H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 534.4. Step 2. N-(5-chloro-6-phenoxy-3-pyridyl)-6-[3-(methylamino)azetidin- 1-yl]pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl N-[1-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-carbamate (50.0 mg, 93.6 μmol) in dichloromethane (1.00 mL) was added zinc dibromide (42.1 mg, 187 μmol), the reaction mixture was stirred at 30 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(5- chloro-6-phenoxy-3-pyridyl)-6-[3-(methylamino)azetidin-1-yl] pyrido[3,2-d]pyrimidin-4-amine (30.0 mg, 69.1 μmol, 74%) as a yellow solid. m/z ES+ [M+H] ⁺ 434.3. Step 3. N-[1-[4-[(5-chloro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d] pyrimidin-6- yl]azetidin-3-yl]-N-methyl-prop-2-enamide To a mixture of N-(5-chloro-6-phenoxy-3-pyridyl)-6-[3-(methylamino)azetidin- 1- yl]pyrido[3,2-d]pyrimidin-4-amine (30.0 mg, 69.1 μmol) in tetrahydrofuran (0.50 mL) and water (0.5 mL) was added sodium bicarbonate (5.81 mg, 69.1 μmol, 2.69 μL), and then prop-2-enoyl chloride (7.51 mg, 82.9 μmol) was added. The reaction was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150x25mmx 10um; mobile phase: [water (0.225% FA)-ACN]; B%: 32%-65%,11min) and then purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM -ACN]; B%: 35%-65%, 10 min) to give N-[1-[4-[(5-chloro-6-phenoxy-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]-N-m ethyl-prop-2-enamide (3.09 mg, 6.3 μmol, 9.2%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.52 - 9.50 (m, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.45 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.15 - 7.11 (m, 3H), 6.82 - 6.78 (m, 1H), 6.18 - 6.13 (m, 1H), 5.75 - 5.72 (m, 1H), 5.31 - 5.28 (m, 1H), 4.47 - 4.44 (m, 2H), 4.25 - 4.24 (m, 2H), 3.16 - 3.04 (m, 3H); m/z ES+ [M+H] ⁺ 488.4. Example 178. Preparation of N-[1-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]azetidin-3-yl]-N-methyl-prop-2-enamide (Compound 217) Step 1. tert-Butyl N-[1-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]azetidin-3-yl]-N-methyl-carbamate To a solution of 6-chloro-N-(3-ethynyl-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin -4-amine (250 mg, 837 μmol) and tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate (205 mg, 921 μmol) in N-methylpyrrolidone (1 mL) was added diisopropylethylamine (541 mg, 4.18 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 20/1) to give tert-butyl N-[1-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]azetidin- 3-yl]-N-methyl-carbamate (300 mg, 0.67 mmol, 75%) as a yellow solid. m/z ES+ [M+H] ⁺ 449.3. Step 2. N-(3-Ethynyl-2-fluoro-phenyl)-6-[3-(methylamino)azetidin-1-y l]pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]azetidin-3-yl]-N-methyl-carbamate (100 mg, 223 μmol) in dichloromethane (4 mL) was added zinc bromide (502 mg, 2.23 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-ethynyl-2-fluoro-phenyl)- 6-[3-(methylamino)azetidin-1-yl]pyrido[3,2-d]pyrimidin-4-ami ne (77 mg, 170 μmol, 77%) as a yellow solid. m/z ES+ [M+H] ⁺ 349.4. Step 3. N-[1-[4-(3-Ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]azetidin-3-yl]- N-methyl-prop-2-enamide To a solution of N-(3-ethynyl-2-fluoro-phenyl)-6-[3-(methylamino)azetidin-1- yl]pyrido[3,2-d]pyrimidin-4-amine (77 mg, 221 μmol) in tetrahydrofuran (4 mL), water (1 mL) was added sodium bicarbonate (37.1 mg, 442 μmol), followed by prop-2-enoyl chloride (20.0 mg, 221 μmol) at 0 °C. The mixture was stirred at 0~25 °C for 1 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 30%-60%, 10 min) to give N-[1-[4-(3-ethynyl-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl- prop-2-enamide (16.7 mg, 7.04 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.47 - 8.42 (m, 2H), 7.98 (d, J = 9.2 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.15 (d, J = 9.2 Hz, 1H), 6.83 - 6.80 (m, 1H), 6.20 - 6.15 (m, 1H), 5.74 (d, J = 9.6 Hz, 1H), 5.32 - 5.27 (m, 1H), 4.57 (s, 1H), 4.46 - 4.30 (m, 2H), 4.26 - 4.22 (m, 2H), 3.12 (d, J = 45.6 Hz, 3H); m/z ES+ [M+H] ⁺ 403.4. Example 179. Preparation of N-[1-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2-d] pyrimidin-6-yl]azetidin-3-yl]-N-methyl-prop-2-enamide (Compound 223) Step 1. tert-Butyl N-[1-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2-d]py rimidin-6- yl]azetidin-3-yl]-N-methyl-carbamate To a solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[3,2-d]p yrimidin- 4-amine (500 mg, 1.35 mmol) and tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate (501 mg, 2.69 mmol) in dimethyl acetamide (2 mL) was added 1,4-diazabicyclo[2.2.2]octane (543 mg, 4.84 mmol), NiBr ₂ .glyme (20.7 mg, 67.2 μmol) and Ir(ppy) ₂ (dtbbpy)PF ₆ (24.6 mg, 26.9 μmol). The mixture was stirred at 25 °C for 6 hr under bule LEDs under nitrogen. On completion, the mixture was concentrated under vacuum. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl N-[1-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-carbamate (120 mg, 252 μmol, 18%) as yellow solid. m/z ES+ [M+H] ⁺ 477.4. Step 2 N-(3-Chloro-2-fluoro-phenyl)-7-fluoro-6-[3-(methylamino)azet idin-1- yl]pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-carbamate (120 mg, 251 μmol) in dichloromethane (5 mL) was added zinc bromide (566 mg, 2.52 mmol). The mixture was stirred at 25 °C for 6 hr. On completion, the mixture was concentrated in vacuo to give N-(3-chloro-2-fluoro-phenyl)-7-fluoro- 6-[3-(methylamino)azetidin-1-yl]pyrido[3,2-d]pyrimidin-4-ami ne (95 mg, 250 μmol, 99%) as a yellow oil. m/z ES+ [M+H] ⁺ 377.3. Step 3 N-[1-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2-d]py rimidin-6- yl]azetidin-3-yl]-N-methyl-prop-2-enamide To a solution of N-(3-chloro-2-fluoro-phenyl)-7-fluoro-6-[3-(methylamino)azet idin-1- yl]pyrido[3,2-d]pyrimidin-4-amine (95 mg, 252) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (21.1 mg, 252 μmol). Then prop-2-enoyl chloride (22.8 mg, 252 μmol) was added. The mixture was stirred at 0 °C for 15 min. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 40%-70%,10 min) to give N-[1-[4-(3-chloro-2-fluoro- anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl] -N-methyl-prop-2-enamide (25.7 mg, 56.7 μmol, 22%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 - 9.24 (m, 1 H), 8.47 - 8.43 (m, 1 H), 8.15 - 8.11 (m, 1 H), 7.89 - 7.83 (m, 1 H), 7.42 - 7.28 (m, 2 H), 6.82 - 6.75 (m, 1 H), 6.18 - 6.15 (m, 1 H), 5.74 - 5.71 (m, 1 H), 5.29 - 5.27 (m, 1 H), 4.57 - 4.51 (m, 2 H), 4.39 - 4.37 (m, 1 H), 3.19 - 3.07 (m, 3 H); m/z ES+ [M+1] ⁺ 431.3. Example 180. Preparation of 1-[6-[4-(5-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (Compound 227) Step 1. tert-Butyl 6-[4-(5-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyramidin-6 -yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate To a mixture of 6-chloro-N-(5-chloro-2,4-difluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (150 mg, 458 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (90.9 mg, 458 μmol) in N-methylpyrrolidone (3.0 mL) was added diisopropylethylamine (296 mg, 2.29 mmol), the reaction mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-[4-(5-chloro-2,4-difluoro- anilino)pyrido[3,2-d]p yramidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (240 mg, 377 μmol, 77%) as a yellow solid. m/z ES+ [M+H] ⁺ 489.1. Step 2. N-(5-Chloro-2,4-difluoro-phenyl)-6-(1,6-diazaspiro[3.3]hepta n-6-yl)pyrido[3,2- d] pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(5-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (220 mg, 449 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(5-chloro-2,4- difluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3, 2-d] pyrimidin-4-amine (160 mg, 374 μmol, 91%) as a yellow solid. m/z ES+ [M+H] ⁺ 389.1 Step 3. 1-[6-[4-(5-Chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidi n-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a mixture of N-(5-chloro-2,4-difluoro-phenyl)-6-(1,6-diazaspiro[3.3]hepta n-6- yl)pyrido [3,2-d]pyrimidin-4-amine (160 mg, 411 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (34.5 mg, 411 μmol), and then prop-2-enoyl chloride (44.7 mg, 493 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 35%-65%, 10 min) to give 1-[6-[4-(5-chloro-2,4-difluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (17.6 mg, 3.97 μmol 10%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 - 9.15 (m, 1H), 8.66 - 8.56 (m, 1H), 8.49 (s, 1H), 8.03 - 7.94 (m, 1H), 7.77 - 7.70 (m, 1H), 7.20 - 7.12 (m, 1H), 6.59 - 6.26 (m, 1H), 6.13 - 6.09 (m, 1H), 5.73 - 5.68 (m, 1H), 4.79 = 9.2 Hz, 2H), 4.54 - 4.47 (m, 1H), 4.29 (d, J = 9.2 Hz, 2H), 4.17 - 3.77 (m, 2H), 2.60 (t, J = 6.8 Hz, 2H); m/z ES+ [M+H] ⁺ 443.3. Example 181. Preparation of 1-[6-[4-(4-Bromo-3-chloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (Compound 201)

Step 1. 3-[(4-Nitrophenoxy)methyl]tetrahydrofuran To a solution of tetrahydrofuran-3-ylmethanol (542 mg, 5.32 mmol, 512 μL) in tetrahydrofuran (10.0 mL) was added sodium hydride (212 mg, 5.32 mmol, 60% in mineral oil) at 0 °C for 10 min. Then 1-fluoro-4-nitro-benzene (500 mg, 3.54 mmol) was added. The mixture was heated to 70 °C with stirring for 16 hr. On completion, the mixture was poured into 10 mL ice- water and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-[(4- nitrophenoxy)methyl]tetrahydrofuran (500 mg, 2.24 mmol, 63%) as a black oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d. J = 9.4 Hz, 2H), 6.97 (d. J = 9.4 Hz, 2H), 4.07 - 3.92 (m, 4H), 3.86 - 3.72 (m, 2H), 2.85 - 2.74 (m, 1H), 2.21 - 2.14 (m, 1H), 1.81 - 1.76 (m, 1H). Step 2. 4-(Tetrahydrofuran-3-ylmethoxy) aniline To a mixture of 3-[(4-nitrophenoxy) methyl]tetrahydrofuran (400 mg, 1.79 mmol) and aq. ammonium chloride (7.00 M, 2.0 mL) in ethanol (10.0 mL) was added iron powder (500 mg, 8.96 mmol). The mixture was stirred at 70 °C for 16 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 20/1 to 3/1] to give 4-(tetrahydrofuran-3-ylmethoxy) aniline (300 mg, 1.55 mmol, 86%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.70 - 6.64 (m, 2H), 6.60 - 6.53 (m, 2H), 3.87 - 3.59 (m, 6H), 3.50 - 3.23 (m, 2H), 2.63 (td. J = 6.7, 13.2 Hz, 1H), 2.09 - 1.94 (m, 1H), 1.71 - 1.61 (m, 1H). Step 3. 6-chloro-N-[4-(tetrahydrofuran-3-ylmethoxy) phenyl]pyrido[3,2-d]pyrimidin-4- amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (130 mg, 649 μmol) in acetonitrile (3.0 mL) was added 4-(tetrahydrofuran-3-ylmethoxy)aniline (188 mg, 974 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was filtered and the filter cake was washed with acetonitrile (2 mL x 3) and concentrated in vacuo to give 6-chloro-N-[4- (tetrahydrofuran-3-ylmethoxy) phenyl]pyrido[3,2-d]pyrimidin-4-amine (186 mg, 522 μmol, 70%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 8.61 (s, 1H), 8.24 (d. J = 8.6 Hz, 1H), 7.95 (d. J = 8.8 Hz, 1H), 7.82 (d. J = 9.2 Hz, 2H), 7.06 - 6.95 (m, 2H), 4.00 - 3.87 (m, 2H), 3.84 - 3.74 (m, 2H), 3.71 - 3.62 (m, 1H), 3.56 (dd. J = 5.5, 8.6 Hz, 1H), 2.37 - 2.31 (m, 1H), 2.10 - 1.98 (m, 1H), 1.67 (dt. J = 7.5, 13.1 Hz, 1H). Step 4. tert-Butyl 6-[4-[4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d]py rimidin- 6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[4-(tetrahydrofuran-3-ylmethoxy)phenyl]pyrido[3,2 - d]pyrimidin-4-amine (130 mg, 364 μmol) and bis(1-tert-butoxycarbonyl-1-aza-6 azoniaspiro[3.3]heptan-6-yl)oxalate (141 mg, 291 μmol) in N-methyl pyrrolidone (5.0 mL) was added diisopropylethylamine (141 mg, 1.09 mmol, 190 μL). The mixture was stirred at 100 °C for 3 hr. On completion, the reaction mixture was quenched by water (5 mL) and filtered. The filter cake was washed with acetonitrile (2.0 mL x 3) and dried in vacuo to give tert-butyl 6-[4-[4- (tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]-1,6-diazaspiro[3.3]heptane- 1-carboxylate (159 mg, 307 μmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.37 (s, 1H), 7.91 - 7.80 (m, 3H), 7.11 - 6.95 (m, 3H), 4.74 - 4.50 (m, 2H), 4.42 - 4.20 (m, 2H), 4.01 - 3.50 (m, 8H), 2.33 (td. J = 1.7, 3.6 Hz, 1H), 2.11 - 1.95 (m, 2H), 1.67 (dt. J = 6.9, 13.2 Hz, 1H), 1.39 (br. t. J = 6.4 Hz, 4H), 1.28 - 1.21 (m, 1H), 1.14 (s, 5H). Step 5. 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[4-(tetrahydrofuran- 3ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl 6-[4-[4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (159 mg, 306 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL). After addition, the mixture was stirred at 80 °C for 2 hr, the solid was collected to give 6-(1,6- diazaspiro[3.3]heptan-6-yl)-N-[4-(tetrahydrofuran-3ylmethoxy )phenyl]pyrido[3,2-d]pyrimidin-4- amine (100 mg, 238 μmol, 78%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.41 - 9.26 (m, 2H), 8.66 - 8.60 (m, 1H), 7.98 (d. J = 9.4 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.28 - 7.22 (m, 1H), 7.08 - 7.01 (m, 2H), 4.70 - 4.62 (m, 2H), 4.48 (d. J = 12.4 Hz, 2H), 3.99 - 3.77 (m, 8H), 2.76 (br t. J = 8.4 Hz, 2H), 2.71 - 2.65 (m, 2H), 1.73 - 1.63 (m, 1H). Step 6. 1-[6-[4-[4-(Tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d ]pyrimidin-6-yl]- 1,6diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (100 mg, 238 μmol) in tetrahydrofuran (1.0 mL) was added sodium bicarbonate (100 mg, 1.19 mmol) in water (1.00 mL) at 0 °C, and then prop-2-enoyl chloride (32.4 mg, 358 μmol, 29.2 μL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was poured into 10.0 mL water and extracted with dichloromethane (10.0 mL x 3). The combined organic layers were washed with brine and concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 1-[6-[4-[4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2- d]pyrimidin-6-yl]-1,6diazaspiro[3.3]heptan-1-yl]prop-2-en-1- one (50.0 mg, 106 μmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 - 9.03 (m, 1H), 8.42 (s, 1H), 8.38 - 8.26 (m, 1H), 7.99 - 7.93 (m, 1H), 7.30 (d. J = 12.8 Hz, 1H), 7.17 - 7.09 (m, 1H), 6.60 - 6.09 (m, 2H), 5.72 - 5.70 (m, 1H), 4.78 (d. J = 9.6 Hz, 1.5H), 4.53 - 4.46 (m, 1H), 4.28 (d. J = 9.2 Hz, 1.5H), 4.15 (t. J = 7.6 Hz, 1.5 H), 3.89 (s, 3H), 3.83 – 3.79 (m, 0.5 H), 2.62 - 2.50 (m, 2H); m/z ES+ [M+H] ⁺ 455.4. Example 182. Preparation of N-[1-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6- Step 1. tert-Butyl N-[1-[4-(3-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetid in-3- yl]carbamate A mixture of 6-chloro-N-(3-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (300 mg, 860 μmol), tert-butyl N-(azetidin-3-yl)carbamate (215 mg, 1.03 mmol, hydrochloric acid salt) and diisopropylethylamine (555 mg, 4.30 mmol) in N-methyl pyrrolidone (5 mL) was stirred at 100 °C for 2 hr. On completion, the mixture was poured into water (10 mL) and stirred for 10 minutes. Then the mixture was filtered and the filter cake was dried in vacuo to give compound tert-butyl N-[1-[4-(3-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetid in-3-yl]carbamate (385 mg, 795 μmol, 92%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.41 (s, 1H), 7.93 - 7.88 (m, 2H), 7.76 (dd. J = 1.2, 8.0 Hz, 1H), 7.43 - 7.35 (m, 3H), 7.17 - 7.11 (m, 1H), 7.08 - 7.00 (m, 3H), 6.70 (dd. J = 2.0, 8.0 Hz, 1H), 4.49 - 4.37 (m, 3H), 4.00 (dd. J = 4.4, 8.4 Hz, 2H), 2.69 (s, 1H), 1.40 (s, 9H). Step 2. N-(4-bromo-3-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]h eptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl N-[1-[4-(3-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetid in- 3-yl]carbamate (100 mg, 206 μmol) and trifluoroacetic acid (23.5 mg, 206 μmol) in dichloromethane (2.0 mL) was stirred at 20 °C for 2 hr. On completion, the reaction mixture was concentrated to give 6-(3-aminoazetidin-1-yl)-N-(3-phenoxyphenyl)pyrido[3,2-d]pyr imidin-4- amine (95 mg, 204 μmol, 99%) as a brown oil. m/z ES+ [M+H] ⁺ 385.1. Step 3. N-[1-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetid in-3-yl]prop-2- enamide To a mixture of 6-(3-aminoazetidin-1-yl)-N-(3-phenoxyphenyl)pyrido[3,2-d]pyr imidin-4- amine (102 mg, 204 μmol, TFA salt) and sodium bicarbonate (34.4 mg, 409 μmol) in tetrahydrofuran (5.0 mL) and water (1.00 mL) was added prop-2-enoyl chloride (20.4 mg, 225 μmol). The mixture was stirred at 20 °C for 5 min. On completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150x25mm, 10um; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-61%, 12 min) to give N-[1-[4-(4- phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]pro p-2-enamide (13.2 mg, 29.8 μmol, 14%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.87 (d, J = 7.2 Hz, 1H), 8.43 (s, 1H), 7.96 - 7.88 (m, 2H), 7.77 (d. J = 9.2 Hz, 1H), 7.40 (d. J = 8.4 Hz, 3H), 7.20 - 7.08 (m, 2H), 7.05 (d. J = 8.0 Hz, 2H), 6.70 (dd. J = 1.6, 8.4 Hz, 1H), 6.29 - 6.09 (m, 2H), 5.65 (dd. J = 2.4, 10.0 Hz, 1H), 4.79 - 4.68 (m, 1H), 4.52 - 4.47 (m, 2H), 4.05 (dd. J = 5.2, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 439.3. Example 183. Preparation of N-(1-(4-((4-(neopentyloxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl) azetidin-3-yl)acrylamide (Compound 197) Step 1. tert-Butyl N-[1-[4-[4-(2,2- dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]carbamate A solution of 6-chloro-N-[4-(2,2-dimethylpropoxy)phenyl]pyrido[3,2-d]pyrim idin-4- amine (0.3 g, 875 μmol), tert-butyl N-(azetidin-3-yl)carbamate (219 mg, 1.05 mmol, hydrochloric acid), diisopropylethylamine (339 mg, 2.63 mmol) in N-methyl pyrrolidone (3.0 mL) was stirred at 100 °C for 2 hr. Upon completion, the mixture was quenched by water (15 mL) and stirred at 25 °C for 30 min. The mixture was filtered and the filter cake was dried in vacuo to give tert-butyl N-[1-[4-[4-(2,2- dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]azetidin -3-yl]carbamate (0.3 g, 626 μmol, 62%) as a yellow solid. m/z ES+ [M+H] ⁺ 479.5. Step 2. 6-(3-Aminoazetidin-1-yl)-N-[4-(2,2-dimethylpropoxy)phenyl]py rido[3,2-d] pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-[4-(2,2-dimethylpropoxy)anilino]pyrido[3,2- d]pyrimidin -6-yl]azetidin-3-yl]carbamate (0.3 g, 626 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (71.4 mg, 626 μmol). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give 6-(3-aminoazetidin-1-yl)-N-[4-(2,2- dimethylpropoxy)phenyl]pyrido[3,2-d] pyrimidin-4-amine (0.20 g, 529 μmol, 85%) as a yellow solid. m/z ES+ [M+H] ⁺ 379.4. Step 3. N-[1-[4-[4-(2,2-Dimethylpropoxy)anilino]pyrido[3,2-d]pyrimid in-6-yl]azetidin- 3-yl]prop-2-enamide To a solution of 6-(3-aminoazetidin-1-yl)-N-[4-(2,2-dimethylpropoxy)phenyl]py rido[3,2- d] pyrimidin-4-amine (0.2 g, 528 μmol), sodium bicarbonate (133 mg, 1.59 mmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added prop-2-enoyl chloride (47.8 mg, 528 μmol). The mixture was stirred at 0 °C for 0.5 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40%-70%, 10 min) to give N-[1-[4-[4-(2,2- dimethylpropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]azetidin -3-yl]prop-2-enamide (0.06 g, 139 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.85 (d. J = 7.2 Hz, 1H), 8.37 (s, 1H), 7.90 (d. J = 9.2 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.07 (d. J = 9.2 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.28 - 6.19 (m, 1H), 6.17 - 6.11 (m, 1H), 5.69 - 5.62 (m, 1H), 4.80 - 4.68 (m, 1H), 4.49 (t, J = 8.4 Hz, 2H), 4.04 (dd. J = 5.2, 9.2 Hz, 2H), 3.63 (s, 2H), 1.01 (s, 9H); m/z ES+ [M+H] ⁺ 433.3. Example 184. Preparation of 1-[6-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (Compound 235) Step 1. tert-Butyl 6-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (148 mg, 479 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (95.0 mg, 479 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (309 mg, 2.40 mmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was quenched by addition water 50 mL at 25 °C, and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,6-diazaspiro[3.3]heptane-1-carboxylate (150 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 471.4. Step 2. N-(5-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,6-diazaspiro[3.3]heptane-1-carboxylate (130 mg, 276 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give N-(5-chloro-2-fluoro-phenyl)-6-(1,6- diazaspiro[3.3]heptan-6-yl) pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude) as a yellow oil. Step 3. 1-[6-[4-(5-Chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of N-(5-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, 269 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (22.6 mg, 269 μmol) to adjust pH = 7 ~ 8. Then prop-2-enoyl chloride (24.4 mg, 269 μmol) was added. The mixture was stirred at 0 °C for 15 min. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-TLC (dichloromethane: ethyl acetate 1:1) to give 1-[6-[4-(5-chloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (57.1 mg, 127 μmol, 47%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 - 9.10 (m, 1 H), 9.08 - 9.04 (m, 1 H), 8.71 - 8.66 (m, 1 H), 8.02 - 7.91 (m, 1 H), 7.10 - 7.05 (m, 1 H), 7.00 - 6.98 (m, 1 H), 6.90 - 6.88 (m, 1 H), 6.55 - 6.36 (m, 1 H), 6.20 - 6.14 (m, 1 H), 5.76 - 5.70 (m, 1 H), 5.08 - 4.62 (m, 2 H), 4.47 - 4.25 (m, 2 H), 4.23 - 4.01 (m, 2 H), 2.70 - 2.58 (m, 2 H); m/z ES+ [M+H] ⁺ 425.3. Example 185. Preparation of 1-(6-(4-((5-Phenoxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 139)

Step 1. 6-Chloro-N-(5-phenoxypyridin-2-yl)pyrido[3,2-d]pyrimidin-4-a mine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (400 mg, 2.00 mmol) and 5- phenoxypyridin-2-amine (372 mg, 2.00 mmol) in acetonitrile (4.00 mL) was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-chloro-N-(5- phenoxypyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine (330 mg, 0.95 mmol, 47%) as a yellow solid. m/z ES+ [M+H] ⁺ 350.1. Step 2. tert-Butyl 6-(4-((5-phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin-6- yl)-1,6- diazaspiro[3.3]heptane-1-carboxylate To a mixture of 6-chloro-N-(5-phenoxy-2-pyridyl)pyrido[3,2-d]pyrimidin-4-ami ne (200 mg, 571 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (113 mg, 571 μmol) in 1- methylpyrrolidin-2-one (3.0 mL) was added diisopropylethylamine (369 mg, 2.86 mmol), the reaction mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-(4-((5-phenoxypyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]hep tane-1-carboxylate (280 mg, 0.55 mmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 512.5 Step 3. N-(5-Phenoxypyridin-2-yl)-6-(1,6-diazaspiro[3.3]heptan-6-yl) pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-[(5-phenoxy-2-pyridyl)amino]pyrido[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (250 mg, 488 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(5-phenoxypyridin- 2-yl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimid in-4-amine (150 mg, 0.36 mmol 74%) as a yellow solid. m/z ES+ [M+H] ⁺ 412.4. Step 4. 1-(6-(4-((5-Phenoxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin -6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(5-phenoxy-2-pyridyl)py rido[3,2-d] pyrimidin-4-amine (150 mg, 364 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (30.6 mg, 364 μmol), and then prop-2-enoyl chloride (33.0 mg, 364 μmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 25%-55%,10 min) to give 1-(6-(4-((5-phenoxypyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]hep tan-1-yl)prop-2-en-1-one (32.1 mg, 0.069 mmol, 18.8%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 - 9.31 (m, 1H), 8.70 (d, J = 9.2 Hz, 1H), 8.58 - 8.55 (m, 1H), 8.22 - 8.20 (m, 1H), 8.04 - 7.97 (m, 1H), 7.68 (dd, J = 2.8, 9.2 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.16 - 7.13 (m, 2H), 7.06 - 7.04 (m, 2H), 6.55 - 6.24 (m, 1H), 6.14 - 6.09 (m, 1H), 5.75 - 5.68 (m, 1H), 4.81 - 4.51 (m, 2H), 4.33 (d, J = 9.6 Hz, 2H), 4.15 (t, J = 7.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 466.4. Example 186. Preparation of 1-(6-(4-((2-Fluoro-4-phenoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 258) Step 1. 6-Chloro-N-(2-fluoro-4-phenoxyphenyl)pyrido[3,2-d]pyrimidin- 4-amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 999 μmol) and 2-fluoro-4- phenoxy-aniline (203 mg, 999 μmol) in acetonitrile (1.0 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was filtered and the filter cake was concentrated in vacuo to give 6-chloro-N-(2-fluoro-4-phenoxyphenyl)pyrido[3,2-d]pyrimidin- 4-amine (300 mg, 0.82 mmol, 82%) as a yellow solid. m/z ES+ [M+H] ⁺ 367.0. Step 2. tert-Butyl 6-(4-((2-fluoro-4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a mixture of 6-chloro-N-(2-fluoro-4-phenoxy-phenyl)pyrido[3,2-d]pyrimidin -4-amine (280 mg, 763 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (151 mg, 763 μmol) in 1-methylpyrrolidin-2-one (3.0 mL) was added diisopropylethylamine (493 mg, 3.82 mmol), the reaction mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture quenched by water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-(4-((2-fluoro-4-phenoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (380 mg, 0.72 mmol, 94%) as a black-brown solid. m/z ES+ [M+H] ⁺ 529.2. Step 3. N-(2-Fluoro-4-phenoxyphenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(2-fluoro-4-phenoxy-anilino)pyrido[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (350 mg, 662 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1 mL), the reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(2-fluoro-4- phenoxyphenyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2- d]pyrimidin-4-amine (200 mg, 0.47 mmol, 71%) as a yellow solid. m/z ES+ [M+H] ⁺ 429.1. Step 4. 1-(6-(4-((2-Fluoro-4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(2-fluoro-4-phenoxy- phenyl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 466 μmol) in tetrahydrofuran (1.50 mL) and water (1.50 mL) was added sodium bicarbonate (39.2 mg, 466 μmol), and then prop-2-enoyl chloride (42.2 mg, 466 μmol, 38.0 μL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the residue was concentrated in vacuo. The residue was purified by re- crystallization from acetonitrile (10.0 mL) and water (30.0 mL) at 25 ^o C to give 1-(6-(4-((2-fluoro- 4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diaza spiro[3.3]heptan-1-yl)prop-2-en- 1-one (143 mg, 0.29 mmol, 61%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 - 9.10 (m, 1H), 8.42 (s, 1H), 8.33 - 8.16 (m, 1H), 8.00 - 7.94 (m, 1H), 7.45 - 7.41 (m, 2H), 7.20 - 7.16 (m, 1H), 7.10 - 7.07 (m, 3H), 6.95 - 6.93 (m, 1H), 6.32 - 6.26 (m, 1H), 6.14 - 6.09 (m, 1H), 5.76 - 5.68 (m, 1H), 4.78 (d, J = 9.2 Hz, 2H), 4.53 - 4.47 (m, 1H), 4.28 (d, J = 9.6 Hz, 2H), 4.19 - 4.02 (m, 2H), 2.62 - 2.55 (m, 2H); m/z ES+ [M+H] ⁺ 483.4. Example 187. Preparation of N-[1-[4-(3,4-dichloroanilino) pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]-N-methyl-prop-2-enamide (Compound 262) Step 1. tert-Butyl N-[1-[4-(3,4- dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3- yl]-N- methyl-carbamate A solution of 6-chloro-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (0.1 g, 307 μmol), tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate;hydrochloride (136 mg, 614 μmol), diisopropylethylamine (158 mg, 1.23 mmol) in 1-methylpyrrolidin-2-one (5 mL) was stirred at 100 °C for 5 hr. On completion. The mixture was quenched by water (30 mL) and stirred at 25 °C for 0.5 hr. The mixture was filtered and the filter cake was concentrated in vacuo to give tert-butyl N-[1-[4-(3,4- dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]-N -methyl-carbamate (0.15 g, 0.32 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 475.1. Step 2. N-(3,4-dichlorophenyl)-6-[3-(methylamino)azetidin-1-yl]pyrid o[3,2-d]pyrimidin- 4-amine To a solution of tert-butyl N-[1-[4-(3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]-N-methyl-carbamate (0.15 g, 315 μmol) in dichloromethane (5 mL) was added zinc bromide (923 mg, 4.10 mmol). The mixture was stirred at 25 °C for 5 hr. Upon completion, the mixture was quenched by methanol (30 mL) and stirred at 25 °C for 0.5 hr. The mixture was filtered and concentrated in vacuo to give N-(3,4-dichlorophenyl)-6-[3-(methylamino)azetidin-1- yl]pyrido[3,2-d]pyrimidin-4-amine(0.110 g, 0.29 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 375.0. Step 4. N-[1-[4-(3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]aze tidin-3-yl]-N- methyl-prop-2-enamide To a solution of N-(3,4-dichlorophenyl)-6-[3-(methylamino)azetidin-1-yl]pyrid o[3,2-d] pyrimidin-4-amine (0.09 g, 239 μmol), sodium bicarbonate (60.4 mg, 719 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (21.7 mg, 239 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM ammonium bicarbonate)-ACN]; B%: 41%-74%, 10 min) to give N- [1-[4-(3,4-dichloroanilino)pyrido[3,2-d]pyrimidin-6-yl]azeti din-3-yl]-N-methyl-prop-2-enamide (32 mg, 0.075 mmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.58 - 8.42 (m, 2H), 8.06 (dd, J = 2.4, 8.8 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 6.89 - 6.71 (m, 1H), 6.24 - 6.06 (m, 1H), 5.74 (d, J = 9.6 Hz, 1H), 5.39 - 5.17 (m, 1H), 4.46 (d, J = 7.6 Hz, 2H), 4.38 - 4.17 (m, 2H), 3.22 - 2.98 (m, 3H); m/z ES+ [M+H] ⁺ 429.3. Example 188. Preparation of N-[1-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin- 3- yl] prop-2-enamide (Compound 57) Step 1. tert-Butyl N-[1-[4-(3-chloro-2- fluoro-phenoxy)quinazolin-6-yl]azetidin-3- yl]carbamate A solution of 6-bromo-4-(3-chloro-2-fluoro-phenoxy)quinazoline (240 mg, 679 μmol), tert-butyl N-(azetidin-3-yl)carbamate;hydrochloride (170 mg, 815 μmol), tris(dibenzylideneacetone)dipalladium (62.2 mg, 67.8 μmol), (±)-2,2'-bis(diphenylphosphino)- 1,1'-binaphthalene (84.5 mg, 136 μmol) and cesium carbonate (663 mg, 2.04 mmol) in toluene (3.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 70 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give tert-butyl N-[1-[4-(3-chloro-2- fluoro-phenoxy)quinazolin- 6-yl]azetidin-3-yl]carbamate (60 mg, 89.9 μmol, 6%) as a yellow solid. m/z ES+ [M+H] ⁺ 445.2. Step 2. 1-[4-(3-Chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin-3-a mine A solution of tert-butyl N-[1-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin- 3- yl]carbamate (50.0 mg, 112 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 1-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin-3-a mine (50 mg, 108 μmol, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 345.1. Step 3. N-[1-[4-(3-Chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin- 3-yl] prop-2- enamide To a solution of 1-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin-3-a mine (50.0 mg, 145 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (36.6 mg, 435 μmol). The mixture was added prop-2-enoyl chloride (13.1 mg, 145 μmol) stirred at 0 °C for 10 min. Then the reaction was added prop-2-enoyl chloride (13.1 mg, 145 μmol) and stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 38%-68%, 10 min) to give N-[1-[4- (3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin-3-yl] prop-2-enamide (8.09 mg, 19.1 μmol, 13%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (d, J = 7.2 Hz, 1H), 8.48 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.60 (dt, J = 1.6, 7.6 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.42 - 7.33 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.28 - 6.19 (m, 1H), 6.18 - 6.10 (m, 1H), 5.68 - 5.63 (m, 1H), 4.83 - 4.71 (m, 1H), 4.37 (t, J = 8.0 Hz, 2H), 3.87 (dd, J = 5.6, 8.0 Hz, 2H); m/z ES+ [M+H] ⁺ 399.3. Example 189. Preparation of N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl]azetidin-3-yl]-N-methyl-prop-2-enamide (Compound 214) Step 1. N-(3-Chloro-2-fluoro-phenyl)-6-fluoro-pyrido[3,4-d]pyrimidin -4-amine To a solution of 4-chloro-6-fluoro-pyrido[3,4-d]pyrimidine (100 mg, 544 μmol) in acetonitrile (1 mL) was added 3-chloro-2-fluoro-aniline (118 mg, 817 μmol). The mixture was stirred at 30 °C for 2 hr. On completion, the mixture was filtered and the solid was concentrated in vacuo to give N-(3-chloro-2-fluoro-phenyl)-6-fluoro-pyrido[3,4-d]pyrimidin -4-amine (0.1 g, 0.34 mmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.35 (td, J=8.13, 1.25 Hz, 1H) 7.51 - 7.57 (m, 1H) 7.60 (td, J=7.50, 1.50 Hz, 1H) 8.48 (s, 1 H) 8.73 (s, 1H) 9.03 (s, 1H). Step 2. tert-Butyl N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl]azetidin-3-yl]-N-methyl-carbamate To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-fluoro-pyrido[3,4-d]pyrimidin -4-amine (500 mg, 1.71 mmol) and tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate (477 mg, 2.56 mmol) in 1-methylpyrrolidin-2-one (5.0 mL) was added diisopropylethylamine (1.10 g, 8.54 mmol), the reaction mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl]azetidin-3-yl]- N-methyl-carbamate (200 mg, 436 μmol, 26%) as a yellow solid. m/z ES+ [M+H] ⁺ 459.1. Step 3. N-(3-chloro-2-fluoro-phenyl)-6-[3-(methylamino)azetidin-1-yl ]pyrido[3,4- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl] azetidin-3-yl]-N-methyl-carbamate (160 mg, 348 μmol) in dichloromethane (3.0 mL) was added zinc bromide (785 mg, 3.49 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-2-fluoro-phenyl)- 6-[3-(methylamino)azetidin-1-yl]pyrido[3,4-d]pyrimidin-4-ami ne (70 mg, 195 μmol, 56%) as a yellow solid. m/z ES+ [M+H] ⁺ 359.4. Step 4. N-[1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl]azetidin-3-yl]-N- methyl-prop-2-enamide To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-[3-(methylamino)azetidin-1- yl]pyrido[3,4-d] pyrimidin-4-amine (70.0 mg, 195 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (16.3 mg, 195 μmol), and then prop-2-enoyl chloride (17.6 mg, 195 μmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM ammonium bicarbonate)- acetonitrile]; B%: 30%-60%, 10 min) to give N-[1-[4-(3-chloro-2- fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]azetidin-3-yl]-N- methyl-prop-2-enamide (37.71 mg, 91.3 μmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 - 9.80 (s, 1H), 9.05 - 8.60 (s, 1H), 8.45 - 8.20 (m, 1H), 7.75 - 7.40 (s, 2H), 7.35 - 7.23 (t, J = 8.4 Hz, 1H), 7.20 - 7.10 (s, 1H), 6.90 - 6.65 (m, 1H), 6.25 - 6.05 (m, 1H), 5.80 - 5.60 (m, 1H), 5.40 - 5.15 (m, 1H), 4.40 - 4.25 (m, 2H), 4.23 - 4.05 (m, 2H), 3.25 - 3.02 (m, 3H); m/z ES+ [M+H] ⁺ 413.4. Example 190. Preparation of 1-[6-[4-[(5-Ethynyl-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (Compound 278) Step 1. 6-Chloro-N-(5-ethynyl-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrim idin-4-amine To a solution of 5-ethynyl-6-phenoxy-pyridin-3-amine (105 mg, 499 μmol) in acetonitrile (10 mL) was added 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 499 μmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was added water (20 mL) and then filtered. The filter cake was washed with water (5 mL) and petroleum ether (10 mL) and then concentrated under reduced pressure to give 6-chloro-N-(5-ethynyl-6-phenoxy-3- pyridyl)pyrido[3,2-d]pyrimidin-4-amine (175 mg, 468 μmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 8.69 (s, 1H), 8.61 (s, 2H), 8.31 - 8.28 (m, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.27 - 7.21 (m, 1H), 7.19 - 7.15 (m, 2H), 3.94 (s, 1H); m/z ES+ [M+H] ⁺ 374.0. Step 2. tert-Butyl 6-[4-[(5-ethynyl-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyri midin - 6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (58.3 mg, 294 μmol) in 1-methylpyrrolidin-2-one (1 mL) was added 6-chloro-N-(5-ethynyl-6-phenoxy-3- pyridyl)pyrido[3,2-d] pyrimidin-4-amine (100 mg, 267 μmol) and diisopropylethylamine (104 mg, 803 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was added water (10 mL) and filtered. The filter cake was collected, further triturated with ethyl acetate/petroleum ether (1/5, 18 mL) at 25 ^o C for 30 min to give tert-butyl 6-[4-[(5-ethynyl-6- phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin -6-yl]-1,6-diazaspiro[3.3]heptane-1- carboxylate (100 mg, 187 μmol, 70%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.91 - 8.64 (m, 2H), 8.47 - 8.40 (m, 1H), 7.97 - 7.89 (m, 1H), 7.47 - 7.39 (m, 2H), 7.26 - 7.20 (m, 1H), 7.15 (d, J = 7.6 Hz, 2H), 4.73 - 4.62 (m, 1H), 4.59 (s, 1H), 4.38 - 4.24 (m, 2H), 3.81 (s, 1H), 3.73 (t, J = 7.2 Hz, 1H), 2.56 - 2.52 (m, 4H), 1.39 (s, 3H), 1.21 - 1.09 (m, 6H); m/z ES+ [M+H] ⁺ 536.2. Step 3. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-(5-ethynyl-6-phenoxy-3- pyridyl)pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl 6-[4-[(5-ethynyl-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (100 mg, 186 μmol), trifluoroacetic acid (0.5 mL) in dichloromethane (2 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(5- ethynyl-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (90 mg, 207 μmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 436.4. Step 4. 1-[6-[4-[(5-Ethynyl -6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]- 1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(5-ethynyl-6-phenoxy-3- pyridyl)pyrido [3,2-d]pyrimidin-4-amine (80.0 mg, 183 μmol) and sodium bicarbonate (15.4 mg, 183 μmol) in tetrahydrofuran (4 mL) and water (1 mL) was added prop-2-enoyl chloride (14.9 mg, 165 μmol) in tetrahydrofuran (4 mL) at 0 °C, then the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Waters Xbridge 150x25 mmx 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 38%-68%, 8 min) to give 1-[6-[4-[(5-ethynyl -6-phenoxy-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3. 3]heptan-1-yl]prop-2-en-1-one (23.6 mg, 48.2 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.45 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.24 - 7.18 (m, 1H), 7.17 - 7.07 (m, 3H), 6.42 - 6.23 (m, 1H), 6.22 - 6.04 (m, 1H), 5.72 - 5.66 (m, 1H), 4.86 (s, 2H), 4.48 - 4.26 (m, 3H), 4.16 (d, J = 0.8 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 490.2. Example 191. Preparation of 1-[6-[4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one ( Step 1. tert-Butyl 6-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]pyrid o[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate A solution of 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl] pyrido[3,2- d] pyrimidin-4-amine (0.25 g, 659 μmol), tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (130 mg, 659 μmol), diisopropylethylamine (255 mg, 1.98 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 100 °C for 3 hr. On completion, the mixture was quenched by water (20 mL) and stirred at 25 °C for 0.5 h. Then the mixture was filtered and the filter cake was concentrated in vacuo to give tert-butyl 6-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]pyrid o[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (0.35 g, 647 μmol, crude) as a yellow solid. m/z ES+ [M+1] ⁺ 541.2. Step 2. N-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido [3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxyl ate (0.35 g, 646 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (21.5 g, 189 mmol). The mixture was stirred at 25 °C for 3 hr. On completion, the mixture was concentrated in vacuo to give N-[3- chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-(1,6-diazas piro[3.3]heptan-6-yl)pyrido[3,2- d]pyrimidin-4-amine (0.25 g, 567 μmol, crude) as a yellow solid. Step 3. 1-[6-[4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]py rido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-(1,6-d iazaspiro [3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (0.25 g, 567 μmol), sodium bicarbonate (143 mg, 1.70 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (51.3 mg, 567 μmol). The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 47%-77%, 9 min) to give 1-[6-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]py rido[3,2-d]pyrimidin-6-yl]- 1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (0.08 g,162 μmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.25 - 9.06 (m, 1H), 8.36 (s, 1H), 8.05 - 7.84 (m, 2H), 7.19 - 7.00 (m, 2H), 6.38 - 6.23 (m, 1H), 6.17 - 6.04 (m, 1H), 5.81 - 5.63 (m, 1H), 4.78 (d, J = 9.2 Hz, 2H), 4.58 - 4.43 (m, 1H), 4.27 (d, J = 9.2 Hz, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.97 (d, J = 7.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 1H), 2.54 (s, 1H), 1.34 - 1.20 (m, 1H), 0.67 - 0.53 (m, 2H), 0.43 - 0.32 (m, 2H); m/z ES+ [M+1] ⁺ 495.1. Example 192. Preparation of 1-(6-(4-((3-Chloro-2-fluoro-4- isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diaz aspiro[3.3]heptan-1- yl)prop-2-en-1-one (Compound 284) Step 1. 2-Chloro-3-fluoro-1-isopropoxy-4-nitrobenzene To a mixture of 2-chloro-3-fluoro-4-nitro-phenol (300 mg, 1.57 mmol) and 2-iodo propane (1.33 g, 7.83 mmol) in N,N-dimethylformamide (3.0 mL) was added potassium carbonate (649 mg, 4.70 mmol), the reaction mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture quenched by water (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1) to give 2-chloro-3-fluoro-1- isopropoxy-4-nitrobenzene (320 mg, 1.37 mmol, 87%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (dd, J = 8.4, 9.2 Hz, 1H), 6.80 (dd, J = 1.6, 9.6 Hz, 1H), 4.75 (d, J = 6.4, 12.4 Hz, 1H), 1.46 (s, 3H), 1.45 (s, 3H). Step 2. 2-Chloro-3-fluoro-1-isopropoxy-4-nitrobenzene To a mixture of 2-chloro-3-fluoro-1-isopropoxy-4-nitro-benzene (300 mg, 1.28 mmol) in ethanol (2 mL) and water (2 mL) was added iron powder (358 mg, 6.42 mmol) and ammonium chloride (686 mg, 12.8 mmol). The reaction mixture was stirred at 60 °C for 1 hr. On completion, the reaction mixture was filtered and the filtrate was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-2-fluoro-4- isopropoxyaniline (260 mg, 1.28 mmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 204.1. Step 3. 6-Chloro-N-(3-chloro-2-fluoro-4-isopropoxyphenyl)pyrido[3,2- d]pyrimidin-4- amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 999 μmol) and 3-chloro-2- fluoro-4-isopropoxy-aniline (203 mg, 999 μmol) in acetonitrile (3.0 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was filtered and the filter cake was concentrated in vacuo to give 6-chloro-N-(3-chloro-2-fluoro-4-isopropoxyphenyl)pyrido[3,2- d]pyrimidin-4-amine (130 mg, 0.36 mmol, 35%) as a yellow solid. m/z ES+ [M+H] ⁺ 367.3 Step 4. tert-Butyl 6-(4-((3-chloro-2-fluoro-4-isopropoxyphenyl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a mixture of 6-chloro-N-(3-chloro-2-fluoro-4-isopropoxy-phenyl)pyrido[3,2 -d] pyrimidin-4-amine (100 mg, 272 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (70.2 mg, 354 μmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added diisopropylethylamine (175 mg, 1.36 mmol), the reaction mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-(4-((3-chloro-2- fluoro-4-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -1,6-diazaspiro[3.3]heptane-1- carboxylate (220 mg, 0.42 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 529.1. Step 5. N-(3-chloro-2-fluoro-4-isopropoxyphenyl)-6-(1,6-diazaspiro[3 .3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine To a mixture of tert-butyl 6-[4-(3-chloro-2-fluoro-4-isopropoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (200 mg, 378 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-2-fluoro-4-isopropoxyphenyl)-6-(1,6-diazaspiro[3 .3]heptan-6-yl)pyrido[3,2- d]pyrimidin-4-amine (150 mg, 0.35 mmol, 93%) as a yellow solid. m/z ES+ [M+H] ⁺ 429.4 Step 6. 1-(6-(4-((3-Chloro-2-fluoro-4-isopropoxyphenyl)amino)pyrido[ 3,2-d]pyrimidin- 6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a mixture of N-(3-chloro-2-fluoro-4-isopropoxy-phenyl)-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 349 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (29.3 mg, 349 μmol) at 0 °C, and then prop-2-enoyl chloride (31.6 mg, 349 μmol) was added. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 26%-56%, 10 min) to give 1-(6-(4-((3-chloro-2- fluoro-4-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -1,6-diazaspiro[3.3]heptan-1- yl)prop-2-en-1-one (64.9 mg, 0.13 mmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 - 9.06 (m, 1H), 8.37 (s, 1H), 8.09 - 7.82 (m, 2H), 7.22 - 7.03 (m, 2H), 6.63 - 6.24 (m, 1H), 6.15 - 6.05 (m, 1H), 5.76 - 5.66 (m, 1H), 4.80 - 4.71 (m, 2H), 4.49 (d, J = 2.8 Hz, 1H), 4.29 - 4.12 (m, 3H), 2.60 (t, J = 7.4 Hz, 2H), 1.33 (d, J = 6.4 Hz, 6H); m/z ES+ [M+H] ⁺ 483.4. Example 193. Preparation of 1-[6-[4-[3-Chloro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspir o[3.3]heptan -1-yl]prop-2-en- 1-one (Compound 325) Step 1. tert-Butyl 6-[4-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrido [3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (100 mg, 255 μmol) and tert-butyl 1,6- diazaspiro[3.3]heptane-1-carboxylate (74.6 mg, 153 μmol) in 1-methylpyrrolidin-2-one (3.0 mL) was added diisopropylethylamine (66.0 mg, 511 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, the residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=0:1) to give tert-butyl 6-[4-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrido [3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (40 mg, 0.072 mmol, 25%) as a yellow solid. m/z ES+ [M+H] ⁺ 553.2. Step 2. N-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl-6-[4-[3-chloro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspir o[3.3]heptane-1-carboxylate (40.0 mg, 72.3 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (8.25 mg, 72.3 μmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-(1,6-di azaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (30 mg, 0.66 mmol, crude) as yellow oil. m/z ES+ [M+H] ⁺ 453.1. Step 3. 1-[6-[4-[3-Chloro-4-(tetrahydrofuran-3-ylmethoxy)anilino]pyr ido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one To a solution of N-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (30.0 mg, 66.2 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (5.56 mg, 66.2 μmol) and water (0.5 mL). Then prop-2-enoyl chloride (1.60 mg, 17.6 μmol) was added at 0 °C and the mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was purified by prep-HPLC (column: Waters xbridge 150x25mm, 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 29%-59%, 11 min) to give 1-[6-[4-[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)anilino]pyr ido[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (10.0 mg, 19.8 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 - 9.17 (m, 1H), 8.51 - 8.41 (m, 1H), 8.29 - 8.17 (m, 1H), 8.00 - 7.80 (m, 2H), 7.34 - 7.02 (m, 2H), 6.83 - 6.02 (m, 2H), 5.79 - 5.57 (m, 1H), 4.83 (d, J = 9.6 Hz, 1.5H), 4.59 - 4.47 (m, 1H), 4.35 - 4.12 (m, 3H), 4.09 - 4.01 (m, 1H), 4.00 - 3.94 (m, 1H), 3.86 - 3.75 (m, 2.5H), 3.72 - 3.65 (m, 1H), 3.59 (dd, J = 5.5, 8.6 Hz, 1H), 2.76 - 2.65 (m, 1H), 2.63 - 2.54 (m, 2H), 2.10 - 1.97 (m, 1H), 1.77 - 1.65 (m, 1H); m/z ES+ [M+H] ⁺ 507.4. Example 194. Preparation of 1-[6-[4-[3-Chloro-4-(difluoromethoxy)anilino]pyrido[3,2-d] yramid in-6-y]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (Compound 348)

Step 1. tert-Butyl 6-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2-d]pyrim idin -6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(difluoromethoxy)phenyl]pyrido[3,2- d]pyrimidin-4-amine (100 mg, 280 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (61.0 mg, 308 μmol) in 1-methylpyrrolidin-2-one (1.0 mL) was added diisopropylethylamine (180 mg, 1.40 mmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was poured into water (2.0 mL) and the suspension was filtered. The filter cake was washed with water (0.5 mL ^ 3), dried in vacuum to give tert-butyl 6-[4-[3-chloro-4- (difluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-di azaspiro[3.3]heptane-1-carboxylate (105 mg, 0.20 mmol, 67%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.49 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.24 (s, 1H), 7.13 (d, J = 9.2 Hz, 1H), 4.80 - 4.49 (m, 2H), 4.45 - 4.23 (m, 2H), 3.90 - 3.63 (m, 2H), 2.54 (s, 2H), 1.48 - 1.04 (m, 9H); m/z ES+ [M+H] ⁺ 519.1. Step 2. N-[3-chloro-4-(difluoromethoxy)phenyl]-6-(1,6-diazaspiro[3.3 ]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl 6-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (86.0 mg, 165 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 40 min. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4- (difluoromethoxy)phenyl]-6-(1,6-diazaspiro[3.3]heptan-6-yl)p yrido[3,2-d]pyrimidin-4-amine (65.0 mg, 0.16 mmol, crude) as a brown oil. m/z ES+ [M+H] ⁺ 419.1. Step 3. 1-(6-(4-((3-Chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3, 2-d]pyrimidin-6- yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-6-(1,6-diazaspiro[3.3 ]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (65.0 mg, 155 μmol) in tetrahydrofuran (0.25 mL) and water (0.25 mL) was added sodium bicarbonate (39.1 mg, 465 μmol). Then prop-2-enoyl chloride (11.2 mg, 124 μmol) was added to the mixture. The mixture was stirred at 0 °C for 30 minutes. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition, column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 25%-55%,11.5min) to give 1-(6-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1 ,6-diazaspiro[3.3]heptan-1- yl)prop-2-en-1-one (37.7 mg, 0.079 mmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d6) δ 9.49 - 9.39 (m, 1H), 8.54 - 8.48 (m, 1H), 8.42 - 8.37 (m, 1H), 8.08 - 8.00 (m, 1H), 7.99 - 7.92 (m, 1H), 7.45 - 7.36 (m, 1H), 7.27 - 7.16 (m, 1H), 7.15 - 7.03 (m, 1H), 6.42 - 6.22 (m, 1H), 6.18 - 5.64 (m, 2H), 4.85 - 4.32 (m, J = 9.6 Hz, 4H), 4.16 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 473.1. Example 195. Preparation of N-[1-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]prop-2-ena mide (Compound 397) Step 1. tert-Butyl N-[1-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]carbamate To a solution of 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d] pyrimidin-4-amine (140 mg, 369 μmol) in 1-methylpyrrolidin-2-one (1.0 mL) was added diisopropylethylamine (143 mg, 1.11 mmol). Then tert-butyl N-(azetidin-3- yl)carbamate (127 mg, 738 μmol) was added. The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was poured into water (10 mL) and the suspension was filtered. The filter cake was washed with water (0.5 mL x 3), dried in vacuum to give tert-butyl N-[1-[4-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin -6-yl]azetidin-3-yl]carbamate (179 mg, 0.33 mmol, 90%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.34 (s, 1H), 7.96 - 7.85 (m, 2H), 7.65 (d, J = 6.0 Hz, 1H), 7.10 - 7.02 (m, 2H), 4.51 - 4.42 (m, 1H), 4.39 (t, J = 8.0 Hz, 2H), 3.99 (d, J = 7.2 Hz, 4H), 1.41 (s, 9H), 1.38 - 1.35 (m, 1H), 0.62 (dd, J = 1.6, 8.0 Hz, 2H), 0.39 (dd, J = 1.6, 4.8 Hz, 2H). Step 2. 6-(3-Aminoazetidin-1-yl)-N-[3-chloro-4-(cyclopropylmethoxy)- 2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido [3,2-d]pyrimidin-6-yl]azetidin-3-yl]carbamate (120 mg, 233 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 30 minutes. On completion, The reaction mixture was concentrated under reduced pressure to give 6-(3-aminoazetidin-1-yl)-N-[3-chloro-4-(cyclopropylmethoxy)- 2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (95.0 mg, 0.23 mmol, 88%, TFA salt) as a brown oil. m/z ES+ [M+H] ⁺ 415.1. Step 3. -[4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]pyrido [3,2- d]pyrimidin-6-yl]azetidin-3-yl]prop-2-enamide To a solution of 6-(3-aminoazetidin-1-yl)-N-[3-chloro-4-(cyclopropylmethoxy)- 2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (95.0 mg, 228 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (57.7 mg, 686 μmol). And then prop-2-enoyl chloride (20.7 mg, 228 μmol) was added in the mixture. The mixture was stirred at 0 °C for 15 minutes. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition, column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 28%-58%,10 min) to give N-[1-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]py rido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]prop-2-enamide (9.5 mg, 20.3 μmol, 13%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.35 (s, 1H), 7.98 - 7.83 (m, 2H), 7.16 - 7.03 (m, 2H), 6.30 - 6.10 (m, 2H), 5.70 - 5.62 (m, 1H), 4.74 (d, J = 7.2 Hz, 1H), 4.48 (t, J = 8.4 Hz, 2H), 4.03 (dd, J = 5.2, 9.2 Hz, 2H), 3.99 (d, J = 7.2 Hz, 2H), 1.28 (d, J = 7.2 Hz, 1H), 0.65 - 0.58 (m, 2H), 0.38 (d, J = 4.8 Hz, 2H); m/z ES+ [M+H] ⁺ 469.4. Example 196. Preparation of N-[1-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-3-yl]prop-2-enamide (Compound 431) Step 1. tert-Butyl 6-[4-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilino]pyrido [3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (100 mg, 253 μmol) in 1-methylpyrrolidin-2- one (2.0 mL) was added tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (60.2 mg, 303 μmol) and diisopropylethylamine (98.1 mg, 759 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was quenched by water (10.0 mL) and then filtered. The filter cake was collected to give tert-butyl 6-[4-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilino]pyrido [3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (120 mg, 0.22 mmol, 77%) as a yellow solid. m/z ES+ [M+H] ⁺ 557.2. Step 2. N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspir o[3.3]heptane-1-carboxylate (100 mg, 179 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was filtered and concentrated to give N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (80 mg, 0.18 mmol, 97%) as a yellow oil. m/z ES+ [M+H] ⁺ 457.2. Step 3. 1-[6-[4-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilino]pyr ido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one To a solution of N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 175 μmol) in tetrahydrofuran (1.00 mL) was added sodium bicarbonate (44.1 mg, 525 μmol), prop-2-enoyl chloride (15.8 mg, 175 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was purified by Prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 32%-62%, 11.5 min) to give 1-[6-[4-[3- chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilino]pyrido[3,2-d]p yrimidin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (15.0 mg, 0.023 mmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.37 (s, 1H), 8.07 - 7.89 (m, 2H), 7.12 (dd, J = 9.6, 13.6 Hz, 2H), 6.35 - 6.05 (m, 2H), 5.79 - 5.63 (m, 1H), 4.79 (br. d, J = 9.2 Hz, 2H), 4.73 (dd, J = 6.4, 7.6 Hz, 2H), 4.51 - 4.46 (m, 3H), 4.35 (d, J = 6.8 Hz, 2H), 4.28 (d, J = 9.6 Hz, 2H), 4.15 (br. t, J = 7.2 Hz, 2H), 3.81 (br. t, J = 7.2 Hz, 1H), 3.51 - 3.40 (m, 1H), 2.56 (br. s, 2H); m/z ES+ [M+H] ⁺ 511.2. Example 197. Preparation of 1-[6-[4-[3-Chloro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (Compound 332) Step 1. tert-Butyl 6-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-anilino]pyrido[3, 2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]pyri do[3,2- d]pyrimidin-4-amine (100 mg, 258 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (66.6 mg, 336 μmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added diisopropylethylamine (100 mg, 775 μmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was added water and filtered, the solid was collected to give tert-butyl 6-[4-[3-chloro-4-(1-methylpyrazol-3- yl)oxy-anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3 .3]heptane-1-carboxylate (140 mg, 0.26 mmol, 93%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.46 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 9.2 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.78 (d, J = 2.4 Hz, 1H), 4.76 - 4.50 (m, 2H), 4.40 - 4.23 (m, 2H), 3.84 - 3.66 (m, 5H), 2.54 (s, 2H), 1.38 (d, J = 3.6 Hz, 3H), 1.14 (s, 6H); m/z ES+ [M+H] ⁺ 549.3. Step 2. N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-(1,6-diaza spiro[3.3]heptan- 6-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept ane-1-carboxylate (140 mg, 255 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-[3- chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-(1,6-diazaspiro [3.3]heptan-6-yl)pyrido[3,2- d]pyrimidin-4-amine (110 mg, 0.25 mmol, 76%) as a yellow solid. m/z ES+ [M+H] ⁺ 449.3. Step 3.1-[6-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-anilino]pyri do[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of N-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (110 mg, 245 μmol) in tetrahydrofuran (0.75 mL) and water (0.75 mL) was added sodium bicarbonate (20.6 mg, 245 μmol) at 0 °C until pH stabilized at 8. After that, prop-2-enoyl chloride (22.2 mg, 245 μmol) was added in one portion. The mixture was stirred at 0 °C for 0.25 hr. On completion, the mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 17%-47%, 10 min) to give 1-[6-[4-[3-chloro-4-(1-methylpyrazol-3-yl)oxy-anilino]pyrido [3,2-d]pyrimidin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (49.3 mg, 0.098 mmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 - 9.31 (m, 1H), 8.51 - 8.45 (m, 1H), 8.33 - 8.30 (m, 1H), 8.00 - 7.88 (m, 2H), 7.61 (d, J = 2.4 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.18 - 7.07 (m, 1H), 6.66 - 6.05 (m, 2H), 5.78 (d, J = 2.4 Hz, 1H), 5.77 - 5.67 (m, 1H), 4.83 (d, J = 9.6 Hz, 1.5H), 4.59 - 4.48 (m, 1H), 4.30 (d, J = 9.6 Hz, 1.5H), 4.15 (t, J = 7.2 Hz, 1.5H), 3.82 (t, J = 7.2 Hz, 0.5H), 3.72 (s, 3H), 2.60 (t, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 503.3. Example 198. Preparation of N-(1-(4-((4-chloro-3-methoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide (Compound 379) Step 1. 6-Chloro-N-(4-chloro-3-methoxyphenyl)pyrido[3,2-d]pyrimidin- 4-amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.3 g, 1.50 mmol), 4-chloro-3- methoxy-aniline (212 mg, 1.35 mmol) in acetonitrile (5 mL) was stirred at 25 °C for 16 hr. On completion, the mixture was filtered and the filter cake was concentrated in vacuo to give 6-chloro- N-(4-chloro-3-methoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (0.45 g, 1.41 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 320.9. Step 2. tert-Butyl(1-(4-((4-chloro-3-methoxyphenyl) amino)pyrido[3,2-d]pyrimidin-6- yl)azetidin-3-yl)carbamate A solution of 6-chloro-N-(4-chloro-3-methoxy-phenyl)pyrido[3,2-d]pyrimidin -4-amine (0.25 g, 778μmol), tert-butyl N-(azetidin-3-yl)carbamate (134 mg, 778 μmol), diisopropylethylamine (301 mg, 2.34 mmol) in 1-methylpyrrolidin-2-one (3 mL) was stirred at 80 °C for 3 hr. On completion, the reaction mixture was quenched by addition water (30 mL) and stirred for 0.5 h. The mixture was filtered and the filter cake was concentrated in vacuo to give tert-butyl(1-(4-((4-chloro-3-methoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3- yl)carbamate (0.35 g, 0.77 mmol, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 457.3. Step 3.6-(3-aminoazetidin-1-yl)-N-(4-chloro-3-methoxyphenyl)pyrid o[3,2-d] pyrimidin- 4-amine To a solution of tert-butyl N-[1-[4-(4-chloro-3-methoxy-anilino)pyrido[3,2-d]pyrimidin- 6-yl] azetidin-3-yl]carbamate (0.3 g, 656 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (14.9 g, 656 μmol). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give 6-(3-aminoazetidin-1-yl)-N-(4-chloro-3- methoxyphenyl)pyrido[3,2-d] pyrimidin-4-amine (0.23 g, 0.65 mmol, crude, TFA) as a yellow solid. m/z ES+ [M+H] ⁺ 357.0 Step 4. N-(1-(4-((4-chloro-3- methoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(4-chloro-3-methoxy-phenyl)pyrido [3,2-d] pyrimidin-4-amine (0.2 g, 424 μmol, trifluoroacetic acid), sodium bicarbonate (107 mg, 1.27 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (38.4 mg, 424 μmol). The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM ammonium bicarbonate)- acetonitrile]; B%: 32%-62%,9min) to give N-(1-(4-((4-chloro-3- methoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl)acrylamide (0.038 g, 0.093 mmol, 21%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.48 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.29 - 6.10 (m, 2H), 5.69 - 5.62 (m, 1H), 4.82 - 4.68 (m, 1H), 4.52 (t, J = 8.4 Hz, 2H), 4.11 - 4.03 (m, 2H), 3.90 (s, 3H); m/z ES+ [M+H] ⁺ 411.1. Example 199. Preparation of 1-(6-(4-((4-Chloro-5-phenoxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 362) Step 1. 6-Chloro-N-(4-chloro-5-phenoxypyridin-2-yl)pyrido[3,2-d]pyri midin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 499 μmol) and 4-chloro- 5-phenoxy-pyridin-2-amine (110 mg, 499 μmol) in dimethyl sulfoxide (2 mL) was added potassium tert-butoxide (1 M, 1.5 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was diluted in water (30 mL) and filtered. The filter cake was washed with water (30 mL) and collected to give 6-chloro-N-(4-chloro-5-phenoxypyridin-2-yl)pyrido[3,2-d]pyri midin-4-amine (130 mg, 0.34 mmol, 58%) as a yellow solid. m/z ES+ [M+H] ⁺ 383.8. Step 2. tert-Butyl 6-(4-((4-chloro-5-phenolxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution 6-chloro-N-(4-chloro-5-phenoxy-2-pyridyl)pyrido[3,2-d]pyrimi din-4-amine (100 mg, 260 μmol) in 1-methylpyrrolidin-2-one (2 mL) was added tert-butyl 1,6- diazaspiro[3.3]heptanes-1-carboxylate (67 mg, 338 μmol) and diisopropylethylamine (67 mg, 520 μmol). The mixture was stirred at 100 °C for 5 h. The mixture was diluted in water (30 mL) and filtered. The filter cake was washed with water (30 mL) and collected to give tert-butyl 6-(4-((4- chloro-5-phenolxypyridin-2-yl)amino)pyrido[3,2-d]pyrimidin-6 -yl)-1,6-diazaspiro[3.3]heptane- 1-carboxylate (100 mg, 0.18 mmol, 70%) as a yellow solid. m/z ES+ [M+H] ⁺ 546.0. Step 3. N-(4-chloro-5-phenoxypyridin-2-yl)-6-(1,6-diazaspiro[3.3]hep tan-6- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[(4-chloro-5-phenoxy-2-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (100 mg, 183 μmol) in trifluoroacetic acid (1 mL) and dichloromethane (2 mL) was stirred at 15 °C for 0.5 hr. The mixture was concentrated to give N-(4-chloro-5-phenoxypyridin-2-yl)-6-(1,6-diazaspiro[3.3]hep tan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (0.1 g, 0.22 mmol, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 446.1. Step 4. 1-(6-(4-((4-Chloro-5-phenoxypyridin-2-yl)amino)pyrido[3,2-d] pyrimidin-6-yl)- 1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(4-chloro-5-phenoxy-2-pyridyl)-6-(1,6-diazaspiro[3.3]hepta n-6- yl)pyrido[3,2-d]pyrimidin-4-amine (54 mg, 122 μmol) and sodium bicarbonate (30 mg, 367 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (11 mg, 122 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.16 hr. On completion, the mixture was concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 45%-75%, 10 min) and (column: Phenomenex Synergi C18150 x 25 mm x 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 45%-75%, 10 min) to give 1-(6-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (13 mg, 0.026 mmol, 22%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.41 - 9.37 (m, 1H), 9.07 (s, 1H), 8.73 - 8.68 (m, 1H), 8.12 (s, 1H), 8.04 - 7.91 (m, 1H), 7.35 (t, J = 8.0 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.54 - 6.35 (m, 1H), 6.20 - 6.13 (m, 1H), 5.71 (d, J = 10.4 Hz, 1H), 5.07 - 4.64 (m, 2H), 4.49 - 4.27 (m, 2H), 4.21 - 4.00 (m, 2H), 2.69 - 2.57 (m, 2H); m/z ES+ [M+H] ⁺ 500.1. Example 200. Preparation of 1-(6-(4-((4-Chloro-5-phenoxypyridin-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 381) Step 1. 6-Chloro-N-(5-chloro-3-pyridyl)pyrido[3,2-d]pyrimidin-4-amin e A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (300 mg, 1.50 mmol), 5-chloropyridin- 3-amine (192 mg, 1.50 mmol), trifluoroacetic acid (17.10 mg, 149 μmol) in isopropanol (6 mL) was stirred at 60 °C for 3 hr. On completion, the reaction mixture was diluted with water (20 mL) and then filtered. The filter cake was collected to give 6-chloro-N-(5-chloro-3-pyridyl)pyrido[3,2- d]pyrimidin-4-amine (300 mg, 1.03 mmol, crude) as an orange solid. m/z ES+ [M+H] ⁺ 292.0. Step 2. tert-Butyl 6-[4-[(5-chloro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl] -1,6- diazaspiro[3.3]heptane-1-carboxylate A mixture of 6-chloro-N-(5-chloro-3-pyridyl)pyrido[3,2-d]pyrimidin-4-amin e (120 mg, 410 μmol) , tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (97.7 mg, 492 μmol), diisopropylethylamine (159 mg, 1.23 mmol) in N-methyl pyrrolidone (1 mL) was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 6-[4-[(5- chloro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diaz aspiro[3.3]heptane-1-carboxylate (220 mg, 0.44 mmol, crude) as yellow solid. m/z ES+ [M+H] ⁺ 454.2. Step 3. N-(5-chloro-3-pyridyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyr ido[3,2- d]pyrimidin-4-amine A solution of tert-butyl 6-[4-[(5-chloro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl] - 1,6-diazaspiro[3.3]heptane-1-carboxylate (200 mg, 440 μmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (1.5 mL) was stirred at 25 °C for 3 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(5-chloro-3-pyridyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 353.8. Step 4. 1-[6-[4-[(5-chloro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6- yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one A solution of N-(5-chloro-3-pyridyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyr ido[3,2- d]pyrimidin-4-amine (130 mg, 367 μmol), prop-2-enoyl chloride (33.2 mg, 367 μmol), sodium bicarbonate (92.6 mg, 1.10 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30mm, 3um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 18%-4%, 8 min) to give 1-[6-[4-[(5-chloro-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3. 3]heptan-1-yl]prop-2-en-1-one (20.0 mg, 49.0 μmol, 13%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 9.11 (s, 1H), 8.74 - 8.76 (m, 1H), 8.53 - 8.56 (m, 1H), 8.33 - 8.32 (m, 1H), 7.95 - 7.98 (m, 1H), 7.12 - 7.21 (m, 1H), 6.26 - 6.59 (m, 1H), 6.09 - 6.14 (m, 1H), 5.68 - 5.74 (m, 1H), 4.86 - 4.84 (m, 2H), 4.30 - 4.56 (m, 2H), 4.18 - 3.80 (m, 2H), 2.55 - 2.67 (m, 2H); m/z ES+ [M+H] ⁺ 408.1. Example 201. Preparation of 1-(6-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl) - 2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Compound 8) Step 1. tert-Butyl 6-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-2, 6- diazaspiro[3.3]heptane-2-carboxylate To a solution of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (500 mg, 1.29 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate;oxalic acid (446 mg, 1.55 mmol) in dioxane (5 mL) was added sodium tert-butoxide (372 mg, 3.88 mmol), RuPhos-Pd-G3 (108 mg, 129 μmol) and RuPhos (60.3 mg, 129 μmol). The mixture was stirred at 100 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was quenched by water (10 mL) and extracted with tetrahydrofuran (10 mL x 3). The combined organic layers was washed with brine (10 mL x 3), dried over anhydrous sodium sulphate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 6-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-2,6-dia zaspiro[3.3]heptane-2-carboxylate (220 mg, 436 μmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.52 (t, J = 8.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 2.0, 8.8 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.07 (dd, J = 2.4, 8.8 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.16 (d, J = 4.8 Hz, 8H), 1.47 (s, 9H). Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(2,6-diazaspiro[3.3]heptan -2-yl)quinazolin-4- amine To a solution of tert-butyl 6-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate (220 mg, 436 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.15 g, 750 μL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum to give N-(3,4-dichloro-2-fluorophenyl)-6- (2,6-diazaspiro[3.3]heptan-2-yl)quinazolin-4-amine (150 mg, crude, TFA salt) as a yellow solid. Step 3. 1-(6-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6-yl) -2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one To a mixture of 6-(2,6-diazaspiro[3.3]heptan-2-yl)-N-(3,4-dichloro-2-fluoro- phenyl)quinazolin-4-amine (150 mg, 371 μmol, TFA salt) and sodium bicarbonate (124 mg, 1.48 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added prop-2-enoyl chloride (40.3 mg, 445 μmol) dropwise at 0 °C. The mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150x50mm, 3 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 25%-45%, 10 min) to give compound 1-[6-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-2,6- diazaspiro[3.3]heptan-2-yl]prop-2-en-1-one (30 mg, 65.6 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 8.32 (d, J = 14.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.57 (s, 2H), 7.23 - 7.12 (m, 2H), 6.37 - 6.27 (m, 1H), 6.11 (dd, J = 2.4, 17.2 Hz, 1H), 5.72 - 5.65 (m, 1H), 4.46 (s, 2H), 4.17 (s, 2H), 4.13 (s, 4H); m/z ES+ [M+H] ⁺ 458.2. Example 202. Preparation of 1-(6-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1 -one (Compound 9) Step 1. tert-Butyl 6-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (250 mg, 727 μmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate;oxalic acid (251 mg, 873 μmol) in N-methyl pyrrolidone (3 mL) was added diisopropylethylamine (376 mg, 2.91 mmol). The mixture was stirred at 100 °C for 12 hr. On completion, the mixture was added into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over sodium sulphate, filtered and concentrated in vacuum to give tert-butyl 6-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (360 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11 (d, J = 2.4 Hz, 1H), 8.84 (t, J = 8.4 Hz, 1H), 8.63 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.33 (dd, J = 2.0, 9.2 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 4.33 (s, 4H), 4.18 (s, 4H). Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(2,6-diazaspiro[3.3]heptan -2-yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 593 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.15 g, 10.1 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum to give 6-(2,6-diazaspiro[3.3]heptan-2-yl)- N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-ami ne (300 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 405.2. Step 3. 1-(6-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-2,6- diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one To a mixture of 6-(2,6-diazaspiro[3.3]heptan-2-yl)-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 385 μmol, TFA salt) and sodium bicarbonate (129 mg, 1.54 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added prop-2-enoyl chloride (41.8 mg, 462 μmol) dropwise at 0 °C. The mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150x50mm, 3 um; mobile phase: [water (0.225% FA) - ACN]; B%: 40% - 60%, 10 min) to give 1-[6-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]-2,6-diazaspiro[3.3]heptan-2-yl]prop-2-en-1-one (40 mg, 87.1 μmol, 20.6%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.48 - 8.42 (m, 2H), 7.94 (d, J = 9.2 Hz, 1H), 7.57 (dd, J = 2.0, 9.2 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 6.37 - 6.26 (m, 1H), 6.11 (dd, J = 2.4, 16.8 Hz, 1H), 5.70 - 5.65 (m, 1H), 4.47 (s, 2H), 4.33 (s, 4H), 4.18 (s, 2H); m/z ES+ [M+H] ⁺ 459.2. Example 203. Preparation of N-(1-(4-(3-chloro-2-fluorophenoxy)pyrido[3,2-d]pyrimidin-6- yl)azetidin-3-yl)acrylamide (Compound 58) Step 1. tert-Butyl (1-(4-(3-chloro-2-fluorophenoxy)pyrido[3,2-d]pyrimidin-6-yl) azetidin- 3-yl)carbamate To a solution of tert-butyl N-[1-(4-chloropyrido[3,2-d]pyrimidin-6-yl)azetidin-3- yl]carbamate (70.0 mg, 208 μmol) in acetonitrile (1.0 mL) was added potassium carbonate (57.6 mg, 417 μmol) and 3-chloro-2-fluoro-phenol (36.7 mg, 250 μmol). The mixture was stirred at 60 °C for 12 hr. On completion, the reaction mixture was diluted with water (6 mL) and filtered. The filter cake was concentrated under reduced pressure to give tert-butyl N-[1-[4-(3-chloro -2- fluoro-phenoxy)pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]car bamate (60.0 mg, 135 μmol, 63%) as an orange solid. m/z ES+ [M+H] ⁺ 446.3. Step 2. 1-(4-(3-Chloro-2-fluorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)a zetidin-3-amine To a solution of tert-butyl N-[1-[4-(3-chloro-2-fluoro-phenoxy)pyrido[3,2-d]pyrimidin-6- yl] azetidin-3-yl]carbamate (50 mg, 112 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 1-[4-(3-chloro-2-fluoro-phenoxy)pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-amine (50 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 346.3. Step 3. N-(1-(4-(3-Chloro-2-fluorophenoxy)pyrido[3,2-d]pyrimidin-6-y l)azetidin-3- yl)acrylamide To a solution of 1-[4-(3-chloro-2-fluoro-phenoxy)pyrido[3,2-d]pyrimidin-6-yl] azetidin - 3-amine (45.0 mg, 97.9 μmol, TFA salt) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (24.7 mg, 294 μmol). The mixture was added prop-2-enoyl chloride (8.86 mg, 97.9 μmol) at 0 °C. Then the reaction was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition; column: Unisil 3-100 C18 Ultra 150 x 50mm x 3 um; mobile phase: [water (0.225% FA) - ACN]; B%: 35% - 55%, 10 min) to give N-[1-[4-(3-chloro-2-fluoro-phenoxy)pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]prop-2-enamide (20.1 mg, 50.4 μmol, 51%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J = 6.8 Hz, 1H), 8.48 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 8.4 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 6.28 - 6.19 (m, 1H), 6.18 - 6.11 (m, 1H), 5.66 (dd, J = 2.4, 10.0 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.49 (t, J = 8.4 Hz, 2H), 4.07 - 4.03 (m, 2H); m/z ES+ [M+H] ⁺ 400.1. Example 204. Preparation of 1-(6-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 66)

Step 1. tert-Butyl 6-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3-chloro-2,4-difluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (290 mg, 887 μmol) in N-methylpyrrolidone (3.0 mL) was added diisopropylethylamine (344 mg, 2.66 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (264 mg, 1.33 mmol). The mixture was stirred at 80 °C for 1.5 hr. And the mixture was added tert-butyl 1,6- diazaspiro[3.3]heptane-1-carboxylate (87.9 mg, 443 μmol) and stirred at 100 °C for 1 hr. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was concentrated under reduced pressure to give tert-butyl 6-[4-(3-chloro-2,4-difluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept ane-1-carboxylate (380 mg, 779 μmol, 84 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.40 (s, 1H), 8.23 - 8.15 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.68 - 4.51 (m, 2H), 4.35 - 4.24 (m, 2H), 3.82 - 3.69 (m, 2H), 2.54 (s, 2H), 1.14 (s, 9H); m/z ES+ [M+H] ⁺ 489.3. Step 2. N-(3-Chloro-2,4-difluorophenyl)-6-(1,6-diazaspiro[3.3]heptan -6-yl)pyrido[3,2- d]pyrimidin-4-amine A solution of tert-butyl 6-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]- 1,6-diazaspiro[3.3]heptane-1-carboxylate (180 mg, 368 μmol) in dichloromethane (2.0 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-2,4-difluoro-phenyl)-6-(1,6-diazaspiro[3.3]hepta n-6- yl)pyrido[3,2-d]pyrimidin-4-amine (185 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 388.8. Step 3. 1-(6-(4-((3-Chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2,4-difluoro-phenyl)-6-(1,6-diazaspiro[3.3]hepta n-6- yl)pyrido[3,2-d]pyrimidin-4-amine (180 mg, 463 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (117 mg, 1.39 mmol). The mixture was added prop-2-enoyl chloride (41.9 mg, 463 μmol) at 0 °C. Then the reaction was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Gemini-NX C1875 x 30mm, 3um; mobile phase: [water (0.225% FA) - ACN]; B%: 25% - 55%, 7min) to give 1-[6-[4-(3-chloro-2,4- difluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro [3.3]heptan-1-yl]prop-2-en-1-one (50.5 mg, 114 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 - 9.20 (m, 1H), 8.42 (s, 1H), 8.27 - 8.07 (m, 1H), 8.01 - 7.93 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 7.21 - 7.10 (m, 1H), 6.36 - 6.24 (m, 1H), 6.65 - 6.07 (m, 1H), 5.79 - 5.65 (m, 1H), 4.84 - 4.45 (m, 2H), 4.29 (d, J = 9.2 Hz, 1H), 4.15 (t, J = 7.2 Hz, 2H), 2.64 - 2.52 (m, 2H); m/z ES+ [M+H] ⁺ 443.1. Example 205. Preparation of 1-(6-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 22) Step 1. tert-Butyl 6-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (190 mg, 553 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate;oxalic acid (191 mg, 663 μmol) in N-methylpyrrolidone (2 mL) was added diisopropylethylamine (214 mg, 1.66 mmol), the mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was quenched with saturated ammonium chloride (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1 to 0/1) to give tert-butyl 6-[4- (3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]- 1,6-diazaspiro[3.3]heptane-1- carboxylate (240 mg, 476 μmol, 86%) as a yellow solid. m/z ES+ [M+H] ⁺ 505.0. Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan -6-yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (210 mg, 415 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(1,6- diazaspiro[3.3]heptan-6-yl)-N-(3,4-dichloro-2-fluoro-phenyl) pyrido[3,2-d]pyrimidin-4-amine (200 mg, crude) as a white solid. Step 3. 1-(6-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 452 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (152 mg, 1.81 mmol) and followed by prop-2-enoyl chloride (45.1 mg, 498 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875 x 30mm x 3um; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; B%: 30% - 50%, 7 min) to give 1-[6-[4- (3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]- 1,6-diazaspiro[3.3]heptan-1-yl]prop- 2-en-1-one (37.7 mg, 82.3 μmol, 18%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.72 (s, 1H), 8.72 - 8.53 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 2.03.6 Hz, 1H), 6.38 (d, J = 16.0 Hz, 1H), 6.17 (dd, J = 10.4, 16.8 Hz, 1H), 5.75 (d, J = 10.0 Hz, 1H), 5.11 (d, J = 7.2 Hz, 2H), 4.38 (d, J = 7.6 Hz, 2H), 4.22 (d, J = 6.4 Hz, 2H), 2.71 (s, 2H), 2.63 (s, 2H); m/z ES+ [M+H] ⁺ 459.0. Example 206. Preparation of 1-[6-[4-[(5-Fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one (Compound 81) Step 1. tert-Butyl 6-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrim idin-6- yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(5-fluoro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimi din-4- amine (180 mg, 489 μmol) in N-methyl pyrrolidone (2.0 mL) was added diisopropylethylamine (190 mg, 1.47 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (146 mg, 734 μmol). The mixture was stirred at 100 °C for 2 hr. Then the reaction was stirred at 100 °C for 1.5 hr. On completion, the reaction mixture was diluted with water 20 mL and filtered. The filter cake was concentrated in vacuo to give tert-butyl 6-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (240 mg, 0.45 mmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.67 - 8.60 (m, 2H), 8.51 (s, 1H), 8.10 (d, J = 4.2 Hz, 1H), 7.85 (s, 1H), 7.37 - 7.30 (m, 2H), 7.15 - 7.06 (m, 3H), 6.79 (d, J = 9.2 Hz, 1H), 4.85 - 4.50 (m, 2H), 4.19 (s, 2H), 3.82 (t, J = 6.8 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.19 (s, 9H); m/z ES+ [M+H] ⁺ 530.3. Step 2.6-(1,6-Diazaspiro[3.3]heptan-6-yl) -N-(5-fluoro-6-phenoxy-3-pyridyl)pyrido[3,2- d]pyrimidin-4-amine A solution of tert-butyl 6-[4-[(5-fluoro-6-phenoxy-3-pyridyl)aminopyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (190 mg, 359 μmol) in trifluoroacetic acid (0.4 mL) and dichloromethane (2.0 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(5- fluoro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (195 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 430.3. Step 3. 1-[6-[4-(5-Chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-(5-fluoro-6-phenoxy-3- pyridyl)pyrido[3,2-d]pyrimidin-4-amine (195 mg, 454 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (114 mg, 1.36 mmol). The mixture was added prop- 2-enoyl chloride (45.2 mg, 499 μmol) and stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition;column: Phenomenex Gemini-NX C1875x30mmx3um; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 7 min) and re-purified by prep-HPLC (neutral condition;column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 34%- 67%, 9 min) to give 1-[6-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]py rimidin-6-yl]- 1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (41.5 mg, 85.9 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 8.64 (dd, J = 2.4, 12.4 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.51 - 8.46 (m, 1H), 8.03 - 7.91 (m, 1H), 7.48 - 7.39 (m, 2H), 7.25 - 7.09 (m, 4H), 6.35 - 6.24 (m, 1H), 6.17 - 6.07 (m, 1H), 5.76 - 5.66 (m, 1H), 4.84 (d, J = 9.6 Hz, 1.5H), 4.59 - 4.48 (m, 1H), 4.31 (d, J = 9.6 Hz, 1.5H), 4.16 (t, J = 7.2 Hz, 1.5H), 3.83 (t, J = 7.6 Hz, 0.5H), 2.66 - 2.53 (m, 2H); m/z ES+ [M+H] ⁺ 484.2. Example 207. Preparation of 1-[6-[4-[4-([1,2,4]Triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3. 3]heptan-1-yl]prop-2-en-1-one (Compound 82) Step 1. tert-Butyl 6-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]pyrid o[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-[4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl] pyrido[3,2- d]pyrimidin-4-amine (100 mg, 256 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1- carboxylate;oxalic acid (88.7 mg, 307 μmol) in N-methyl pyrrolidone (3 mL) was added diisopropylethylamine (132 mg, 1.03 mmol), the mixture was stirred at 100 °C for 12 hr. On completion, The mixture was quenched by water (5 mL) and extracted with ethyl acetate (5 mL x 3), The combined organic layers was washed with brine (5 mL x 3), dried over sodium sulfate and concentrated in vacuum to give tert-butyl 6-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3. 3]heptane-1-carboxylate (150 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.48 - 8.38 (m, 2H), 8.13 (br .d, J = 8.8 Hz, 2H), 7.94 (d, J = 9.2 Hz, 1H), 7.30 (br .d, J = 8.8 Hz, 2H), 7.12 (br .d, J = 8.0 Hz, 1H), 7.06 - 6.97 (m, 2H), 4.78 - 4.52 (m, 2H), 4.42 - 4.23 (m, 2H), 3.90 - 3.69 (m, 2H), 2.54 (br .s, 2H), 1.47 - 1.04 (m, 9H). Step 2. 6-(1,6-Diazaspiro[3.3]heptan-6-yl)-N-[4-([1,2,4]triazolo[1,5 -a]pyridin-7- yloxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3. 3]heptane-1-carboxylate (150 mg, 271 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the mixture was stirred at 25 °C for 0.5 hr . On completion, the mixture was concentrated in vacuum to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[4-([1,2,4]triazolo[1,5 -a]pyridin-7- yloxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (150 mg, crude, TFA) as a yellow solid. Step 3. 1-[6-[4-[4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)anilino]py rido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1 -one To a solution of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-N-[4-([1,2,4]triazolo[1,5 -a]pyridin-7- yloxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (150 mg, 265 μmol) and sodium bicarbonate (89.1 mg, 1.06 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added prop-2-enoyl chloride (26.4 mg, 291 μmol), the mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 30%-50%, 10 min) and repurified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 30%-50%, 10 min) to give 1-[6-[4-[4-([1,2,4]triazolo[1,5-a]pyridin- 7-yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[ 3.3]heptan-1-yl]prop-2-en-1-one (19 mg, 36.1 μmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 - 9.30 (m, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.49 - 8.44 (m, 1H), 8.39 (s, 1H), 8.12 (d, J = 8.8 Hz, 2H), 8.01 - 7.92 (m, 1H), 7.33 - 7.25 (m, 2H), 7.19 - 7.07 (m, 1H), 7.06 - 6.97 (m, 2H), 6.37 - 6.23 (m, 1H), 6.17 - 6.08 (m, 1H), 5.80 - 5.66 (m, 1H), 4.84 (br. d, J = 9.6 Hz, 1.5H), 4.60 - 4.48 (m, 1H), 4.31 (d, J = 9.6 Hz, 1.5H), 4.16 (t, J = 7.6 Hz, 1.5H), 3.82 (t, J = 7.2 Hz, 0.5H), 2.64 - 2.54 (m, 2H); m/z ES+ [M+H] ⁺ 506.4. Example 208. Preparation of 1-[6-[4-(3,4-Dichloro-2-fluoro-phenoxy)pyrido[3,2-d] pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-o ne (Compound 83) Step 1. tert-Butyl 6-(4-hydroxypyrido[3,2-d] pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane- 1-carboxylate To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (100 mg, 551 μmol) in N-methyl pyrrolidone (2.0 mL) was added diisopropylethylamine (214 mg, 1.65 mmol) and bis(1-tert- butoxycarbonyl-1-aza-6-azoniaspiro[3.3]heptan-6-yl) oxalate (268 mg, 551 μmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC [ACN/(0.1% FA in water), 0% to 90%] to give tert-butyl 6-(4-hydroxypyrido[3,2-d] pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane- 1-carboxylate (150 mg, 0.44 mmol, 73%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.71 - 4.47 (m, 2H), 4.35 - 4.19 (m, 2H), 3.91 - 3.78 (m, 2H), 2.57 - 2.53 (m, 2H), 1.23 (s, 9H); m/z ES+ [M+H] ⁺ 344.2. Step 2. tert-Butyl 6-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]h eptane-1- carboxylate To a solution of phosphorus oxylchloride (201 mg, 1.31 mmol) in toluene (4.0 mL) was added tert-butyl 6-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3] heptane-1- carboxylate (150 mg, 437 μmol) and diisopropylethylamine (452 mg, 3.49 mmol) at 25 °C. The mixture was stirred at 110 °C for 4 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 6/1 to 3/1) to give tert-butyl 6-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-1,6- diazaspiro[3.3]heptane-1-carboxylate (100 mg, crude) as yellow solid. m/z ES+ [M+H] ⁺ 362.2. Step 3. tert-Butyl 6-[4-(3,4-dichloro-2-fluoro-phenoxy)pyrido[3,2-d]pyrimidin-6 -yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of tert-butyl 6-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-1,6- diazaspiro[3.3]heptane-1-carboxylate (85.0 mg, 235 μmol) in acetonitrile (1.0 mL) was added potassium carbonate (64.9 mg, 470 μmol) and 3,4-dichloro-2-fluoro-phenol (63.8 mg, 352 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to give tert-butyl 6-[4-(3,4-dichloro-2-fluoro-phenoxy)pyrido[3,2-d]pyrimidin-6 - yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (100 mg, 0.20 mmol, 81%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 1.6, 8.8 Hz, 1H), 7.51 - 7.42 (m, 1H), 7.22 (d, J = 9.2 Hz, 1H), 4.54 - 4.35 (m, 4H), 3.77 - 3.67 (m, 4H), 2.48 - 2.44 (m, 2H), 1.35 - 1.05 (m, 9H); m/z ES+ [M+H] ⁺ 506.0. Step 4.6-(1,6-Diazaspiro[3.3]heptan-6-yl)-4-(3,4-dichloro-2-fluor o-phenoxy)pyrido[3,2- d]pyrimidine To a mixture of tert-butyl 6-[4-(3,4-dichloro-2-fluoro-phenoxy)pyrido[3,2-d] pyrimidin- 6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (100 mg, 197 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.2 mL) in one portion at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give 6-(1,6-diazaspiro[3.3]heptan-6-yl)-4-(3,4-dichloro-2-fluoro- phenoxy)pyrido[3,2- d]pyrimidine (80 mg, 0.19 mmol, 99%) as yellow solid. m/z ES+ [M+H] ⁺ 406.0. Step 5. 1-[6-[4-(3,4-Dichloro-2-fluoro-phenoxy)pyrido[3,2-d]pyrimidi n-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a mixture of 6-(1,6-diazaspiro[3.3]heptan-6-yl)-4-(3,4-dichloro-2-fluoro- phenoxy)pyrido [3,2-d]pyrimidine (80.0 mg, 197 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (57.9 mg, 689 μmol). Then a solution of prop-2-enoyl chloride (17.8 mg, 197 μmol) in tetrahydrofuran (0.2 mL) was added dropwise at 0 °C over a period of 2 mins under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min. On completion, mixture was poured into water (5.0 mL) and the suspension was filtered. The filter cake was washed with water (2.0 mL x 3), dried in vacuum to give crude product. The crude product was triturated with water/methanol = 1/5 (twice) to give 1-[6-[4-(3,4-dichloro-2-fluoro- phenoxy)pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]hept an-1-yl]prop-2-en-1-one (28.15 mg, 61.3 μmol, 30%) as white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 - 8.45 (m, 1H), 8.19 - 8.08 (m, 1H), 7.72 - 7.55 (m, 2H), 7.32 - 7.23 (m, 1H), 6.60 - 6.24 (m, 2H), 5.76 - 5.68 (m, 1H), 4.78 (d, J = 9.6 Hz, 1.5H), 4.48 - 4.14 (m, 4H), 3.80 (t, J = 7.6 Hz, 0.5H), 2.62 - 2.54 (m, 2H); m/z ES+ [M+H] ⁺ 460.0. Example 209. Preparation of 1-[6-[4-(3-chloro -2-fluoro-anilino)quinazolin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (Compound 84) lino)quinazolin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-amine (140 mg, 397 μmol) and bis(1-tert-butoxycarbonyl-1-aza-6-azoniaspiro[3.3]heptan-6-y l) oxalate (116 mg, 238 μmol) in dioxane (3.0 mL) was added sodium tert-butoxide (153 mg, 1.59 mmol), palladium acetate (8.91 mg, 39.7 μmol and XantPhos (23.0 mg, 39.7 μmol. The mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 0/1) and repurified by reverse-phase HPLC [ACN/(0.1% FA in water), 0% to 90%] to give tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-1,6- diazaspiro[3.3]heptane-1-carboxylate (60 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 470.1. Step 2. N-(3-Chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)quinazolin-4- amine To a mixture of tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-1,6-diazasp iro [3.3]heptane-1-carboxylate (40.0 mg, 85.1 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.4 mL) in one portion at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)quinazolin-4-amine (32 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 370.1. Step 3. 1-[6-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-1,6-diaz aspiro[3.3]heptan-1- yl]prop-2-en-1-one To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)quinazolin-4-amine (30.0 mg, 81.1 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (23.8 mg, 284 μmol). Then a solution of prop-2-enoyl chloride (7.34 mg, 81.1 μmol) in tetrahydrofuran (0.2 mL) was added dropwise at 0 °C over a period of 2 mins under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by Prep-HPLC [column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 27% - 57%, 9 min] to give 1-[6-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-1,6- diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (14.2 mg, 32.3 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 8.30 (s, 1H), 7.75 - 7.60 (m, 1H), 7.56 - 7.45 (m, 1H), 7.30 - 7.17 (m, 3H), 6.33 - 6.06 (m, 2H), 5.77 - 5.67 (m, 2H), 4.61 (d, J = 8.4 Hz, 1.5H), 4.27 - 4.12 (m, 4H), 3.83 (t, J = 6.8 Hz, 0.5H), 2.68 - 2.54 (m, 2H); m/z ES+ [M+H] ⁺ 424.0. Example 210. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- methyl-azetidin-1-yl]prop-2-en-1-one (Compound 67)

Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quiazolin-6-yl]-3-methyl -azetidine- 1-carboxylate To a solution of 3,4-dichloro-2-fluoro-aniline (109 mg, 607 μmol) in tetrahydrofuran (5 mL) was added n-butyl lithium (2.5 M in toluene, 485 μL) dropwise at 0 °C, the mixture was stirred at 0 °C for 0.5 h. Tert-butyl 3-(4-methoxyquinazolin-6-yl)-3-methyl-azetidine-1- carboxylate (100 mg, 303 μmol) was added dropwise at 0 °C, the mixture was stirred at 25 °C for 12 h. On completion, the mixture was quenched with water (1 mL) and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether/Ethyl acetate=1/1) to give compound tert- butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-methy l-azetidine-1-carboxylate (70.0 mg, 146 μmol, 48%) as a yellow solid. m/z ES+ [M+H] ⁺ 477.0. Step 2. N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-methylazetidin-3-yl)qu inazolin-4-amine To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-methy l- azetidine-1-carboxylate (60 mg, 125 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol), the mixture was stirred at 25 °C for 0.5 h. On completion, The mixture was concentrated in vacuum to give compound N-(3,4-dichloro-2-fluoro-phenyl)-6-(3- methylazetidin-3-yl)quinazolin-4-amine (60.0 mg, crude, trifluoroacetic acid) as a yellow solid. m/z ES+ [M+H]+ 376.9 Step 3. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-me thyl-azetidin-1- yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-methylazetidin-3-yl)qu inazolin-4- amine (60 mg, 122 μmol, trifluoroacetic acid) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (41.0 mg, 488 μmol) and prop-2-enoyl chloride (13.2 mg, 146 μmol), the mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuum, the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30mm, 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 20%-50%, 7 min) to give compound 1-[3- [4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-methyl- azetidin-1-yl]prop-2-en-1-one (20 mg, 46.4 μmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 - 10.01 (m, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 7.92 - 7.78 (m, 2H), 7.60 (s, 2H), 6.37 (dd, J = 10.4, 17.2 Hz, 1H), 6.13 (dd, J = 2.0, 17.2 Hz, 1H), 5.73 - 5.67 (m, 1H), 4.56 (d, J = 8.4 Hz, 1H), 4.44 - 4.32 (m, 2H), 4.05 (d, J = 10.0 Hz, 1H), 1.69 (s, 3H); m/z ES+ [M+H] ⁺ 430.9. Example 211. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- methoxy-azetidin-1-yl]prop-2-en-1-one (Compound 209) Step 1. tert-Butyl 3-methoxy-3-(4-methoxyquinazolin-6-yl)azetidine-1-carboxylat e To a solution of tert-butyl 3-hydroxy-3-(4-methoxyquinazolin-6-yl)azetidine-1- carboxylate (200 mg, 604 μmol) in dimethylformamide (5 mL) was added sodium hydride (36.1 mg, 905 μmol, 60% in mineral oil) and methyl iodide (128 mg, 906 μmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition water (10 mL) at 25 °C and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% NH ₃ •water condition) to give tert-butyl 3-methoxy-3-(4-methoxyquinazolin-6-yl)azetidine-1- carboxylate (180 mg, 0.52 mmol, 86%) as a yellow solid. m/z ES+ [M+H] ⁺ 346.2. Step 2. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-metho xy- azetidine-1-carboxylate To a solution of tert-butyl 3-methoxy-3-(4-methoxyquinazolin-6-yl)azetidine-1- carboxylate (260 mg, 753 μmol) in tetrahydrofuran (10 mL) was added n-butyl lithium (2.5 M in toluene, 6.02 mL) dropwise at -78 °C. After addition, the mixture was stirred at this temperature for 4 h, and then 3,4-dichloro-2-fluoro-aniline (1.36 g, 7.53 mmol) in tetrahydrofuran (5 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by water (10 mL) at 25 °C, and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give compound tert-butyl3-[4-(3,4- dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-methoxy-azetidi ne-1-carboxylate (520 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 493.3. Step 3. N-(3,4-Dichloro-2-fluoro-phenyl)-6-(3-methoxyazetidin-3-yl) quinazolin-4- amine To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- methoxy-azetidine-1-carboxylate (500 mg, 1.01 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3,4-dichloro-2-fluoro-phenyl)-6-(3- methoxyazetidin-3-yl) quinazolin-4-amine (300 mg, trifluoroacetic acid salt, crude) as a white solid. m/z ES+ [M+H] ⁺ 392.9. Step 4. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-me thoxy-azetidin-1- yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-methoxyazetidin-3-yl)q uinazolin- 4-amine (120 mg, 237 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (397 mg, 4.73 mmol) and prop-2-enoyl chloride (21.4 mg, 236 μmol), the mixture was stirred at 0 °C for 0.1 hour. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition; column: Phenomenex Gemini-NX C18 75 x 30mm x 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - acetonitrile]; B%: 28%-58%, 8 min) to give compound 1-[3-[4-(3,4-dichloro-2- fluoro-anilino)quinazolin-6-yl]-3-methoxy-azetidin-1-yl]prop -2-en-1-one (12.9 mg, 28.9 μmol, 12%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 2 H), 7.89 - 7.84 (m, 2H), 7.59 (s, 2 H), 6.43 - 6.36 (m, 1 H), 6.16 (dd, J = 4.0, 16.8 Hz, 1 H), 5.74 - 5.71 (m, 1 H), 4.63 - 4.61 (m, 1 H), 4.56 - 4.49 (m, 2 H), 4.23 (d, J = 10.8 Hz, 1 H), 3.06 (s, 3 H); m/z ES+ [M+H] ⁺ 447.3. Example 212. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- fluoro-azetidin-1-yl]prop-2-en-1-one (Compound 275) Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-hydro xy- azetidine-1-carboxylate To a solution of 3,4-dichloro-2-fluoro-aniline (543 mg, 3.02 mmol) in tetrahydrofuran (3 mL) was added n-butyl lithium (2.5 M in toluene, 2.41 mL) dropwise at 25 °C. After addition, the mixture was stirred at this temperature for 4 hours, and then a solution of tert-butyl 3-hydroxy-3- (4-methoxyquinazolin-6-yl)azetidine-1-carboxylate (100 mg, 302 μmol) in tetrahydrofuran (1 mL) was added dropwise at 25 °C, the resulting mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched by water (10 mL) at 0 °C, and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine 30 mL (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] -3-hydroxy-azetidine-1-carboxylate (25.0 mg, 0.052 mmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 - 10.14 (m, 1H), 8.53 (d, J = 8.4 Hz, 1 H), 7.99 - 7.97 (m, 1H), 7.85 - 7.82 (m, 1H), 7.59 (s, 1H), 6.60 (s, 1H), 4.50 (d, J = 8.0 Hz, 2 H), 4.10 (d, J =8.4 Hz, 1 H), 1.49 (s, 9 H). Step 2. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluor o- azetidine-1-carboxylate To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- hydroxy-azetidine-1-carboxylate (25.0 mg, 52.2 μmol) in dichloromethane (3 mL) was added 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-l4-sulfanamine (23.1 mg, 104 μmol) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 1 hours. On completion, the reaction mixture was quenched by saturated sodium bicarbonate solution (10 mL) at 25 °C, and extracted with dichloromethane (15 mL x 2). The combined organic layers were washed with brine 30 mL (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluor o-azetidine-1-carboxylate (10.0 mg, 0.021 mmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.29 - 10.22 (m, 1H), 8.63 - 8.57 (m, 1 H), 8.00 - 7.89 (m, 2 H), 7.61 (s, 1H), 4.55 - 4.36 (s, 1H), 1.49 (s, 9 H). Step 3. N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-fluoroazetidin-3-yl)qu inazolin-4-amine To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluor o- azetidine-1-carboxylate (10.0 mg, 20.8 μmol) in dichloromethane (1 mL) was added hydrochloric acid/dioxane (4 M, 10.4 μL). The mixture was stirred at 25 °C for 0.1 hours. On completion, the mixture was concentrated in vacuo to give N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-fluoroazetidin- 3-yl)quinazolin-4-amine (7.00 mg, 0.018 mmol, 80%, hydrochloric acid) as a white solid. m/z ES+ [M+H] ⁺ 381.1. Step 4. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fl uoro-azetidin-1- yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-fluoroazetidin-3-yl)qu inazolin-4- amine (50.0 mg, 120 μmol, hydrochloric acid) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (10.1 mg, 120 μmol) at 0 °C, then prop-2-enoyl chloride (9.75 mg, 108 μmol) was added. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 35%-65%, 9 min) to give 1-[3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fl uoro-azetidin-1-yl]prop-2-en- 1-one (1.48 mg, 3.52 μmol, 2%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.42 - 10.05 (m, 1H), 8.68 - 8.44 (m, 2H), 8.06 - 7.84 (m, 2H), 7.65 - 7.54 (m, 2H), 6.46 - 6.36 (m, 1H), 6.29 - 6.11 (m, 1H), 5.85 - 5.68 (m, 1H), 4.88 - 4.76 (m, 2H), 4.73 - 4.57 (m, 1H), 4.53 - 4.38 (m, 1H); m/z ES+ [M+H]+ 421.9. Example 213. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-(2 - hydroxyethyl)azetidin-1-yl]prop-2-en-1-one (Compound 114) Step 1. tert-Butyl 3-(2-hydroxyethyl)-3-(4-methoxyquinazolin-6-yl)azetidine-1- carboxylate To a solution of tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-3-(4-methoxyquinazolin-6- yl)azetidine-1-carboxylate (250 mg, 622 μmol) in tetrahydrofuran (5 mL) was added DIBAL-H (1 M, 3.11 mL) dropwise at 0 °C and the mixture was stirred at 0 °C for 1 h. On completion, the mixture was quenched with methanol (10 mL) and filtered. The filtrate was concentrated to give compound tert-butyl 3-(2-hydroxyethyl)-3-(4-methoxyquinazolin-6-yl)azetidine-1-c arboxylate (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 360.4. Step 2. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-(2- hydroxyethyl)azetidine-1-carboxylate To a solution of 3,4-dichloro-2-fluoro-aniline (50.0 mg, 277 μmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (2.5 M in toluene, 222 μL) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then tert-butyl 3-(2-hydroxyethyl)-3-(4-methoxyquinazolin-6- yl)azetidine-1-carboxylate (49.9 mg, 138 μmol) was added at 0 °C. The mixture was stirred at 25 °C for 12 h. On completion, the mixture was quenched by water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic layers were washed with brine (2 mL x 3), dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by prep- TLC (Petroleum ether/Ethyl acetate=3/1) to give compound tert-butyl 3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-(2-hydroxyethyl)azetidine-1-carbo xylate (50.0 mg, 98.6 μmol, 70%) as a yellow solid. m/z ES+ [M+H] ⁺ 507.3 Step 3. 2-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]azeti din-3-yl]ethanol To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-(2- hydroxyethyl)azetidine-1-carboxylate (40.0 mg, 78.8 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol), the mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuum to give compound 2-[3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]azetidin-3-yl]ethanol (40.0 mg, crude, trifluoroacetic acid) as a yellow solid. Step 4. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-(2 - hydroxyethyl)azetidin-1-yl]prop-2-en-1-one To a solution of 2-[3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]azeti din-3- yl]ethanol (40.0 mg, 76.7 μmol, trifluoroacetic acid) in tetrahydrofuran (4 mL) and water (4 mL) was added sodium bicarbonate (32.2 mg, 383 μmol) and prop-2-enoyl chloride (8.33 mg, 92.0 μmol), the mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuum, the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 17%- 47%, 8 min) to give compound 1-[3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-(2 - hydroxyethyl)azetidin-1-yl]prop-2-en-1-one (15.0 mg, 32.5 μmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.30 (m, 1H), 8.25 (s, 1H), 7.69 (s, 2H), 7.59 - 7.42 (m, 2H), 6.35 (dd, J = 10.4, 17.2 Hz, 1H), 6.11 (dd, J = 2.0, 16.8 Hz, 1H), 5.75 - 5.63 (m, 1H), 4.62 - 4.44 (m, 3H), 4.35 (d, J = 9.6 Hz, 1H), 4.20 (d, J = 10.4 Hz, 1H), 3.26 - 3.21 (m, 2H), 2.17 (t, J = 6.8 Hz, 2H); m/z ES+ [M+H] ⁺ 461.2. Example 214. Preparation of 1-(3-(4-((3-Chloro-2-fluorophenyl) amino) quinazolin-6-yl)-3- methylazetidin-1-yl) prop-2-en-1-one (Compound 187) Step 1. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- methylazetidine-1-carboxylate To a solution of 3-chloro-2-fluoro-aniline (354 mg, 2.43 mmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (2.5 M in toluene, 1.94 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. tert-Butyl 3-(4-methoxyquinazolin-6-yl)-3-methyl-azetidine-1-carboxylat e (80 mg, 243 μmol) was added. The mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was quenched by saturated ammonium chloride solution (2 mL), then diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(4-((3- chloro-2-fluorophenyl) amino) quinazolin-6-yl)-3-methylazetidine-1-carboxylate (40.0 mg, 90.3 μmol, 33%) as a brown solid. m/z ES+ [M+H] ⁺ 443.0. Step 2. N-(3-Chloro-2-fluorophenyl)-6-(3-methylazetidin-3-yl) quinazolin-4-amine To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-methyl- azetidine-1-carboxylate (35.0 mg, 79.0 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL), the mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluorophenyl)-6-(3-methylazetidin-3- yl) quinazolin-4-amine (30.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 343.1. Step 3. 1-(3-(4-((3-Chloro-2-fluorophenyl) amino) quinazolin-6-yl)-3-methylazetidin-1- yl) prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-(3-methylazetidin-3-yl)quinaz olin-4- amine (30.0 mg, 65.7 μmol, trifluoroacetic acid salt) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (22.1 mg, 263 μmol) and prop-2-enoyl chloride (5.94 mg, 65.7 μmol) at 0 °C, the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 12%-42%, min) to give 1-(3-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-3-methylazetidin-1-yl) prop-2-en-1-one (14.0 mg, 35.3 μmol, 52%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.88 - 7.77 (m, 2H), 7.52 (d, J = 5.6 Hz, 2H), 7.36 - 7.25 (m, 1H), 6.36 (dd, J = 10.2, 17.2 Hz, 1H), 6.13 (dd, J = 2.4, 17.2 Hz, 1H), 5.74 - 5.66 (m, 1H), 4.56 (d, J = 8.4 Hz, 1H), 4.43 - 4.32 (m, 3H), 4.04 (d, J = 10.0 Hz, 1H), 1.69 (s, 3H); m/z ES+ [M+H] ⁺ 397.3. Example 215. Preparation of 1-(3-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6- yl)azetidin-1-yl)prop-2-en-1-one (Compound 4) Step 1. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)aze tidine-1- carboxylate To a 40 mL vial equipped with a stir bar was added 6-bromo-N-(3,4-dichloro-2-fluoro- phenyl)quinazolin-4-amine (2.00 g, 5.17 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (1.22 g, 5.17 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (58.0 mg, 51.7 μmol), NiCl ₂ .dtbbpy (10.3 mg, 25.8 μmol), sodium carbonate (1.10 g, 10.3 mmol) and 1,1,1,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane (1.28 g, 5.17 mmol) in 1,2-dimethoxyethane (30 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 5 hrs under nitrogen. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography [SiO ₂ , Petroleum ether/Ethyl acetate=2/1 to 1/1] to give tert- butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]azetidin e-1-carboxylate (1.30 g, 44%) as a yellow solid. m/z ES+ [M+H] ⁺ 463.3. Step 2. 4-(3,4-Dichlorophenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3 ,2-d]pyrimidine To a mixture of tert-butyl (3S)-3-[4-(3,4-dichlorophenoxy)pyrido[3,2-d]pyrimidin-6-yl] oxypyrrolidine-1-carboxylate (140 mg, 293 μmol) in dichloromethane (1.5 mL) was added hydrochloric acid/ethyl acetate (4 M, 73.3 μL) at 16 °C. The mixture was stirred at 16 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give 4-(3,4- dichlorophenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]py rimidine (140 mg, crude, hydrochloric acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 363.1. Step 3. 1-[3-[4-(3,4-Dichloro-2- fluoro-anilino)quinazolin-6-yl]azetidin-1-yl]prop-2-en- 1-one To a mixture of 6-(azetidin-3-yl)-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin -4-amine (940 mg, 2.59 mmol) in tetrahydrofuran (5.0 mL) and water (5.0 mL) was added sodium bicarbonate (652 mg, 7.76 mmol). Then a solution of prop-2-enoyl chloride (234 mg, 2.59 mmol) in tetrahydrofuran (0.5 mL) was added dropwise at 0 °C during a period of 2 mins under nitrogen. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by Prep-HPLC [column: Waters Xbridge C18 150x50mmx 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-60%, 11 min] to give 1-[3-[4-(3,4-dichloro-2- fluoro-anilino)quinazolin-6-yl]azetidin-1-yl]prop-2-en-1- one (341 mg, 0.82 mmol, 32%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.42 - 9.92 (m, 1H), 8.60 - 8.36 (m, 2H), 7.95 - 7.77 (m, 2H), 7.59 (s, 2H), 6.40 (dd, J = 10.0, 16.8 Hz, 1H), 6.16 (dd, J = 2.4, 17.2 Hz, 1H), 5.71 (dd, J = 2.4, 10.0 Hz, 1H), 4.73 (t, J = 8.4 Hz, 1H), 4.48 - 4.39 (m, 1H), 4.34 (dd, J = 6.0, 8.4 Hz, 1H), 4.20 - 4.09 (m, 2H); m/z ES+ [M+H] ⁺ 417.0. Example 216. Preparation of 1-[3-[4-(3-chloro-2-fluoro -anilino)quinazolin-6-yl]azetidin-1- yl]prop-2-en-1-one (Compound 21) Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]azetidine-1- carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-N-(3-chloro-2-fluoro-phenyl) quinazolin-4-amine (140 mg, 397 μmol), tert-butyl 3-bromoazetidine-1-carboxylate (122 mg, 516 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (4.45mg, 3.97 μmol), NiCl ₂ .dtbbpy (790 ug, 1.99 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (98.7 mg, 397 μmol) and sodium carbonate (84.2 mg, 794 μmol) in 1,2-dimethoxyethane (1.5 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hrs under nitrogen. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=20:1 to 1:2) to give tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]azetidine- 1-carboxylate (144 mg, 0.34 mmol, 84%) as a yellow solid. m/z ES+ [M+H] ⁺ 429.1. Step 2. 6-(Azetidin-3-yl)-N-(3-chloro-2-fluoro-phenyl) quinazolin-4-amine To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]azetidine-1- carboxylate (100 mg, 233 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(azetidin-3-yl)-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-a mine (76.0 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 329.0. Step 3. 1-[3-[4-(3-Chloro-2-fluoro -anilino)quinazolin-6-yl]azetidin-1-yl]prop-2-en-1- one To a solution of 6-(azetidin-3-yl)-N-(3-chloro-2-fluoro-phenyl)quinazolin-4-a mine (75.0 mg, 228 μmol) in tetrahydrofuran (1 mL) was added a solution of sodium bicarbonate (153 mg, 1.82 mmol) in water (0.3 mL). Then a solution of prop-2-enoyl chloride (18.6 mg, 205 μmol) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%: 9%-42%, 10 min) to give 1-[3-[4-(3- chloro-2-fluoro-anilino)quinazolin-6-yl]azetidin-1-yl]prop-2 -en-1-one (21.8 mg, 0.057 mmol, 25%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.50 ( d, J = 3.6 Hz, 2H), 7.90 - 7.76 (m, 2H), 7.58 - 7.47 (m, 2H), 7.30 ( t, J = 7.6 Hz, 1H), 6.39 (dd, J = 10.4, 16.8 Hz, 1H), 6.15 (dd, J = 2.4, 17.2 Hz, 1H), 5.77 - 5.61 (m, 1H), 4.73 ( t, J = 8.4 Hz, 1H), 4.46 - 4.30 (m, 2H), 4.21 - 4.08 (m, 2H); m/z ES+ [M+H] ⁺ 383.0. Example 217. Preparation of 1-(6-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-1- azaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 236)

Step 1. tert-Butyl 6-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-1- azaspiro[3.3]heptane-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-N-(3-chloro-2-fluoro- phenyl)quinazolin-4-amine (120 mg, 340 μmol), tert-butyl 6-bromo-1-azaspiro[3.3]heptane-1- carboxylate (75.2 mg, 272 μmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (3.82 mg, 3.40 μmol), NiCl ₂ .dtbbpy (828 ug, 2.08 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (84.6 mg, 340 μmol) and sodium carbonate (72.1 mg, 680 μmol) in 1,2-dimethoxyethane (4 mL). The vial was sealed and placed under nitrogen was added. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-TLC (petroleum ether:ethyl acetate = 3:1) to give tert-butyl 6-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-1-azaspiro[3.3]heptane-1 -carboxylate (88.0 mg, 0.19 mmol, 55%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.60 - 8.50 (m, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.80 - 7.70 (m, 2H), 7.67 (s, 1H), 7.22 - 7.16 (m, 2H), 3.92 - 3.85 (m, 1H), 3.83 (t, J = 7.2 Hz, 2H), 3.37 - 3.25 (m, 2H), 2.50 - 2.40 (m, 2H), 2.30 - 2.20 (m, 2H), 1.61 - 1.49 (m, 9H). Step 2. N-(3-Chloro-2-fluorophenyl)-6-(1-azaspiro[3.3]heptan-6-yl)qu inazolin-4-amine To a solution of tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-1- azaspiro[3.3]heptane-1-carboxylate (28.0 mg, 59.7 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated by blowing nitrogen to give N-(3-chloro-2-fluorophenyl)-6-(1- azaspiro[3.3]heptan-6-yl)quinazolin-4-amine (22.0 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 369.2. Step 3. 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6-yl)-1- azaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1-azaspiro[3.3]heptan-6-yl)-N-(3-chloro-2-fluoro-phenyl)q uinazolin- 4-amine (22.0 mg, 59.6 μmol) in tetrahydrofuran (0.6 mL) and water (0.2 mL) was added sodium bicarbonate (10.0 mg, 119 μmol) at 0 °C. Then prop-2-enoyl chloride (5.40 mg, 59.6 μmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 32%-62%, 8 min) to give 1-(6-(4-((3-chloro-2-fluorophenyl)amino)quinazolin- 6-yl)-1-azaspiro[3.3]heptan-1-yl)prop-2-en-1-one (4.4 mg, 10.4 μmol, 17%) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.29 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.27 - 7.23 (m, 1H), 6.35 - 6.29 (m, 2H), 5.75 - 5.72 (m, 1H), 4.23 (t, J = 7.6 Hz, 2H), 3.51 - 3.44 (m, 1H), 3.37 - 2.89 (m, 2H), 2.68 - 2.59 (m, 4H); m/z ES+ [M+H] ⁺ 423.4. Example 218. Preparation of 1-[3-[4-(3-Ethynyl-2-fluoro- anilino)quinazolin-6- yl]azetidin- 1-yl]prop-2-en-1-one (Compound 29) Step 1. tert-Butyl 3-(4-hydroxyquinazolin-6-yl)azetidine-1-carboxylate To an 40 mL vial equipped with a stir bar was added 6-bromoquinazolin-4-ol (1.00 g, 4.44 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (1.05 g, 4.44 mmol), sodium carbonate (941 mg, 8.89 mmol), NiCl ₂ .dtbbpy (8.84 mg, 22.2 μmol), 1,1,1,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane (1.1 g, 4.44 mmol) and Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (49.8 mg, 44.4 μmol) in 1,2-dimethoxyethane (15 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hrs under nitrogen. On completion, the reaction was filtered and the filter cake was washed with dichloromethane (10 mL × 3). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to give tert-butyl 3-(4-hydroxyquinazolin-6-yl)azetidine-1-carboxylate (700 mg, 2.33 mmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.26 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.79 (d, J = 1.2 Hz, 2H), 4.45 - 4.37 (m, 2H), 4.10 - 4.02 (m, 2H), 3.95 - 3.86 (m, 1H), 1.49 (s, 9H). Step 2. tert-Butyl 3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]azetidine-1-carboxylate To a solution of tert-butyl 3-(4-hydroxyquinazolin-6-yl)azetidine-1-carboxylate (50.0 mg, 165 μmol) in acetonitrile (0.5 mL) was added (benzotriazol1yloxy)tris(dimethylamino)phosphonium hexafluophosphate (95.4 mg, 215 μmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (50.5 mg, 331 μmol). The reaction mixture was stirred at 25 °C for 20 min.2-Fluoro-3-(2-trimethylsilylethynyl)aniline (51.6 mg, 248 μmol) was added and the reaction mixture was stirred at 60 °C for 2 hrs. On completion, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=3:1 to 1:1) to give tert-butyl 3-[4-[2-fluoro-3-(2- trimethylsilylethynyl)anilino]quinazolin-6-yl]azetidine-1-ca rboxylate (50.0 mg, 0.10 mmol, 61%) as an off-white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.68-8.56 (m, 1H), 8.01 - 7.96 (m, 1H), 7.89 (dd, J = 1.6, 8.8 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.23 (dd, J = 1.6, 6.4 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 4.47 (t, J = 8.8 Hz, 2H), 4.08 (dd, J = 5.6, 8.8 Hz, 2H), 3.99 - 3.92 (m, 1H), 1.51 (s, 9H), 0.29 (s, 9H); m/z ES+ [M+H] ⁺ 491.0. Step 3. 6-(Azetidin-3-yl)-N-(3-ethynyl-2-fluoro-phenyl)quinazolin-4- amine To a solution of tert-butyl 3-[4-(3-ethynyl-2-fluoro-anilino)quinazolin-6-yl]azetidine-1 - carboxylate (50 mg, 119 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol) and the reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give 6-(azetidin-3-yl)-N-(3-ethynyl-2-fluoro-phenyl)quinazolin-4- amine (50.0 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 319.4. Step 4. 1-[3-[4-(3-Ethynyl-2-fluoro- anilino)quinazolin-6- yl]azetidin-1-yl]prop-2-en-1- one To a solution of 6-(azetidin-3-yl)-N-(3-ethynyl-2-fluoro-phenyl)quinazolin-4- amine (40.0 mg, 92.5 μmol) in dichloromethane (1 mL) was added prop-2-enoyl chloride (7.54 mg, 83.2 μmol) and triethyl amine (9.4 mg, 92.5 μmol) at 0 °C dropwise and the reaction mixture was stirred at 0 °C for 1 hr. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 18%-48%, 8 min) to give 1-[3-[4-(3-ethynyl-2-fluoro- anilino)quinazolin-6- yl]azetidin-1-yl]prop- 2-en-1-one (7.8 mg, 20.9 μmol, 22%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.52 (dd, J = 1.6, 7.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.90 - 7.85 (m, 3H), 7.32 - 7.28 (m, 1H), 7.24 - 7.18 (m, 1H), 6.44 - 6.38 (m, 1H), 6.32 - 6.23 (m, 1H), 5.74 (dd, J = 2.0, 10.4 Hz, 1H), 4.76 (t, J = 8.8 Hz, 1H), 4.62 (t, J = 9.6 Hz, 1H), 4.36 - 4.27 (m, 2H), 4.16 - 4.05 (m, 1H), 3.37 (s, 1H); m/z ES+ [M+H] ⁺ 373.3. Example 219. Preparation of 1-(3-(4-((3-Ethynyl-2-fluorophenyl)amino)quinazolin-6-yl)-3- methylazetidin-1-yl)prop-2-en-1-one (Compound 299) Step 1. tert-Butyl 3-(4-((2-fluoro-3-((trimethylsilyl)ethynyl)phenyl)amino)quin azolin-6- yl)-3-methylazetidine-1-carboxylate To a solution of tert-butyl 3-methyl-3-(4-methylsulfanylquinazolin-6-yl)azetidine-1- carboxylate (50.0 mg, 145 μmol) in isopropanol (1 mL) was added 2-fluoro-3-(2- trimethylsilylethynyl)aniline (30 mg, 145 μmol) and hydrochloric acid (1 M, 29 μL). The mixture was stirred at 80 °C for 12 hours. The mixture was concentrated in vacuo to give tert-butyl 3-(4- ((2-fluoro-3-((trimethylsilyl)ethynyl)phenyl)amino)quinazoli n-6-yl)-3-methylazetidine-1- carboxylate (75.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 505.5. Step 2. N-(2-Fluoro-3-((trimethylsilyl)ethynyl)phenyl)-6-(3-methylaz etidin-3- yl)quinazolin-4-amine To a solution of tert-butyl 3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]-3-methyl-azetidine-1-carboxylate (73.0 mg, 145 μmol) in isopropanol (1 mL) was added hydrochloric acid (2 M, 730 μL). The mixture was stirred at 60 °C for 2 hours. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give N-(2-fluoro-3-((trimethylsilyl)ethynyl)phenyl)-6-(3-methylaz etidin-3- yl)quinazolin-4-amine (30.0 mg, 74.1 μmol, 46%) as a white solid. m/z ES+ [M+H] ⁺ 405.2. Step 3. N-(3-ethynyl-2-fluorophenyl)-6-(3-methylazetidin-3-yl)quinaz olin-4-amine To a solution of N-[2-fluoro-3-(2-trimethylsilylethynyl)phenyl]-6-(3-methylaz etidin-3- yl)quinazolin-4-amine (25.0 mg, 61.8 μmol) in acetonitrile (1 mL) was added cesium carbonate (40.3 mg, 124 μmol). The mixture was stirred at 60 °C for 2 h. The mixture was poured into tetrahydrofuran (5 mL) and then filtered to remove the solid. The organic phase was concentrated in vacuo to give N-(3-ethynyl-2-fluorophenyl)-6-(3-methylazetidin-3-yl)quinaz olin-4-amine (20.0 mg, crude) as a yellow oil. m/z ES+ [M+3] ⁺ 333.4. Step 4. 1-(3-(4-((3-Ethynyl-2-fluorophenyl)amino)quinazolin-6-yl)-3- methylazetidin-1- yl)prop-2-en-1-one To a solution of N-(3-ethynyl-2-fluoro-phenyl)-6-(3-methylazetidin-3-yl)quina zolin-4- amine (17.0 mg, 51.2 μmol) in tetrahydrofuran (0.2 mL) and water (0.2 mL) was added sodium bicarbonate (8.59 mg, 102 μmol) and prop-2-enoyl chloride (2.78 mg, 30.7 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 26%-56%, 9 min) to give 1-(3-(4-((3- ethynyl-2-fluorophenyl)amino)quinazolin-6-yl)-3-methylazetid in-1-yl)prop-2-en-1-one (6.0 mg, 15.5 μmol, 30%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 8.32 (d, J = 1.2 Hz, 1H), 7.91 - 7.83 (m, 2H), 7.65 (t, J = 6.8 Hz, 1H), 7.46 (t, J = 6.4 Hz, 1H), 7.29 - 7.19 (m, 1H), 6.50 - 6.37 (m, 1H), 6.34 - 6.23 (m, 1H), 5.78 (dd, J = 1.6, 10.2 Hz, 1H), 4.72 (d, J = 8.8 Hz, 1H), 4.46 (dd, J = 9.6, 19.6 Hz, 2H), 4.20 (d, J = 10.0 Hz, 1H), 3.85 (s, 1H), 1.79 (s, 3H); m/z ES+ [M+H] ⁺ 387.4. Example 220. Preparation of 1-(3-(4-((3-Chloro-2,4-difluorophenyl)amino)quinazolin-6-yl) - 3-methylazetidin-1-yl)prop-2-en-1-one (Compound 298)

Step 1. tert-Butyl 3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)-3- methylazetidine-1-carboxylate To a solution of tert-butyl 3-methyl-3-(4-methylsulfanylquinazolin-6-yl)azetidine-1- carboxylate (50.0 mg, 145 μmol) in isopropanol (1 mL) was added 3-chloro-2,4-difluoro-aniline (23.7 mg, 145 μmol) and hydrochloric acid (1 M, 30.0 μL). The mixture was stirred at 85 °C for 12 hours. The mixture was concentrated in vacuo to give tert-butyl 3-(4-((3-chloro-2,4- difluorophenyl)amino)quinazolin-6-yl)-3-methylazetidine-1-ca rboxylate (70.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 461.2. Step 2. N-(3-Chloro-2,4-difluorophenyl)-6-(3-methylazetidin-3-yl)qui nazolin-4-amine To a solution of tert-butyl 3-[4-(3-chloro-2,4-difluoro-anilino)quinazolin-6-yl]-3-methy l- azetidine-1-carboxylate (66.0 mg, 143 μmol) in isopropanol (1 mL) was added hydrochloric acid (2 M, 0.5 mL), the mixture was stirred at 85 °C for 0.5 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give N-(3-chloro-2,4-difluorophenyl)-6-(3-methylazetidin-3-yl)qui nazolin-4-amine (20.0 mg, 0.055 mmol, 31%) as a colorless oil. m/z ES+ [M+H] ⁺ 361.1. Step 3. 1-(3-(4-((3-Chloro-2,4-difluorophenyl)amino)quinazolin-6-yl) -3-methylazetidin- 1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2,4-difluoro-phenyl)-6-(3-methylazetidin-3-yl)qu inazolin-4- amine (20.0 mg, 44.4 μmol) in tetrahydrofuran (0.3 mL) and water (0.3 mL) was added sodium bicarbonate (14.9 mg, 177 μmol), then prop-2-enoyl chloride (2.41 mg, 26.6 μmol) was added in the mixture at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150x50 mmx3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 15%-45%, 10 min) to give 1-(3-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl) -3-methylazetidin-1-yl)prop- 2-en-1-one (4.3 mg, 10.4 μmol, 22%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 1H), 8.34 (s, 1H), 7.99 - 7.91 (m, 1H), 7.90 - 7.85 (m, 1H), 7.61-7.49 (m, 1H), 7.31-7.18 (m, 1H), 6.50 - 6.37 (m, 1H), 6.35 - 6.22 (m, 1H), 5.78 (dd, J = 1.6, 10.4 Hz, 1H), 4.71 (d, J = 8.8 Hz, 1H), 4.47 (dd, J = 9.6, 14.4 Hz, 2H), 4.21 (d, J = 10.0 Hz, 1H), 1.79 (s, 3H); m/z ES+ [M+H] ⁺ 415.4. Example 221. Preparation of 1-(3-(4-((5-Chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- methylazetidin-1-yl)prop-2-en-1-one (Compound 323) Step 1. tert-Butyl 3-(4-((5-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- methylazetidine-1-carboxylate To a solution of tert-butyl 3-methyl-3-(4-methylsulfanylquinazolin-6-yl)azetidine-1- carboxylate (100 mg, 289 μmol) in isopropanol (1.5 mL) was added 5-chloro-2-fluoro-aniline (42.1 mg, 289 μmol) and hydrochloric acid (1 M, 57.9 μL), the mixture was stirred at 85 °C for 12 hours. The mixture was concentrated in vacuo to give tert-butyl 3-(4-((5-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-3-methylazetidine-1-carb oxylate (130 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 443.3. Step 2. N-(5-Chloro-2-fluorophenyl)-6-(3-methylazetidin-3-yl)quinazo lin-4-amine To a solution of tert-butyl 3-[4-(5-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-methyl- azetidine-1-carboxylate (130 mg, 294 μmol) in isopropanol (1 mL) was added hydrochloric acid (2 M, 1.02 mL), the mixture was stirred at 85 °C for 0.5 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 1%-30%, 10 min) to give N-(5-chloro-2-fluorophenyl)-6-(3-methylazetidin-3-yl)quinazo lin-4-amine (15.0 mg, 43.7 μmol, 15%) as a colorless oil. m/z ES+ [M+H] ⁺ 343.3. Step 3. 1-(3-(4-((5-Chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3-m ethylazetidin-1- yl)prop-2-en-1-one To a solution of N-(5-chloro-2-fluoro-phenyl)-6-(3-methylazetidin-3-yl)quinaz olin-4- amine (14.0 mg, 40.8 μmol) in tetrahydrofuran (0.3 mL) and water (0.3 mL) was added sodium bicarbonate (13.7 mg, 163 μmol) and prop-2-enoyl chloride (2.22 mg, 24.5 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 32%-62%, 9 min) to give 1-(3-(4-((5-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-3-methylazetidin-1-yl)pr op-2-en-1-one (3.1 mg, 7.6 μmol, 18%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.93 - 7.83 (m, 2H), 7.78 (d, J = 5.2 Hz, 1H), 7.41 - 7.18 (m, 2H), 6.52 - 6.37 (m, 1H), 6.36 - 6.23 (m, 1H), 5.77 (dd, J = 2.0, 10.4 Hz, 1H), 4.71 (d, J = 8.8 Hz, 1H), 4.46 (dd, J = 9.6, 19.6 Hz, 2H), 4.20 (d, J = 10.4 Hz, 1H), 1.79 (s, 3H); m/z ES+ [M+H] ⁺ 397.1. Example 222. Preparation of 1-(3-(4-((2,3-Difluorophenyl)amino)quinazolin-6-yl)-3- methylazetidin-1-yl)prop-2-en-1-one (Compound 329) Step 1. tert-Butyl 3-(4-((2,3-difluorophenyl)amino)quinazolin-6-yl)-3-methylaze tidine- 1-carboxylate To a solution of tert-butyl 3-methyl-3-(4-methylsulfanylquinazolin-6-yl)azetidine-1- carboxylate (100 mg, 289 μmol) in isopropanol (1.5 mL) was added 2,3-difluoroaniline (41.1 mg, 318 μmol) and hydrochloric acid (1 M, 57.9 μL), the mixture was stirred at 85 °C for 12 hours. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=2/1 to 0/1) to give tert-butyl 3-(4-((2,3- difluorophenyl)amino)quinazolin-6-yl)-3-methylazetidine-1-ca rboxylate (40.0 mg, 93.7 μmol, 28%) as a yellow oil. m/z ES+ [M+H] ⁺ 427.3. Step 2. N-(2,3-Difluorophenyl)-6-(3-methylazetidin-3-yl)quinazolin-4 -amine To a solution of tert-butyl 3-[4-(2,3-difluoroanilino)quinazolin-6-yl]-3-methyl-azetidin e- 1-carboxylate (40 mg, 93.8 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (77.0 mg, 675 μmol), the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo to give N-(2,3-difluorophenyl)-6-(3-methylazetidin-3-yl)quinazolin-4 -amine (40.0 mg, crude) as a colorless oil. m/z ES+ [M+H] ⁺ 327.1. Step 3. 1-(3-(4-((2,3-Difluorophenyl)amino)quinazolin-6-yl)-3-methyl azetidin-1- yl)prop-2-en-1-one To a solution of N-(2,3-difluorophenyl)-6-(3-methylazetidin-3-yl)quinazolin-4 -amine (30.0 mg, 91.9 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (30.9 mg, 368 μmol) and prop-2-enoyl chloride (4.99 mg, 55.2 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 30%-60%, 9 min) to give 1-(3-(4-((2,3- difluorophenyl)amino)quinazolin-6-yl)-3-methylazetidin-1-yl) prop-2-en-1-one (5.7 mg, 15.0 μmol, 15%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.45 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 7.89 - 7.73 (m, 2H), 7.40 - 7.20 (m, 3H), 6.37 (dd, J = 10.4, 17.2 Hz, 1H), 6.13 (dd, J = 1.6, 16.8 Hz, 1H), 5.70 (dd, J = 1.6, 10.4 Hz, 1H), 4.56 (d, J = 8.4 Hz, 1H), 4.43 - 4.33 (m, 2H), 4.04 (d, J = 9.6 Hz, 1H), 1.69 (s, 3H); m/z ES+ [M+H] ⁺ 381.1. Example 223. Preparation of 1-(3-(4-((3-Chloro-2-fluoro-4- methoxyphenyl)amino)quinazolin-6-yl)-3-methylazetidin-1-yl)p rop-2-en-1-one (Compound 345)

Step 1. tert-Butyl 3-(4-((3-chloro-2-fluoro-4-methoxyphenyl)amino)quinazolin-6- yl)-3- methylazetidine-1-carboxylate To a solution of tert-butyl 3-methyl-3-(4-methylsulfanylquinazolin-6-yl)azetidine-1- carboxylate (90 mg, 0.26 mmol) in isopropanol (1 mL) was added 3-chloro-2-fluoro-4- methoxyaniline (50.3 mg, 0.29 mmol) and hydrochloric acid (1 M, 52 μL), the reaction mixture was stirred at 85 °C for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give tert-butyl 3-(4-((3-chloro-2-fluoro-4-methoxyphenyl)amino)quinazolin-6- yl)- 3-methylazetidine-1-carboxylate (60.0 mg, 0.13 mmol, 47%) as a white solid. m/z ES+ [M+H] ⁺ 473.3. Step 2. N-(3-Chloro-2-fluoro-4-methoxy -phenyl)-6-(3-methylazetidin-3-yl)quinazolin- 4-amine To a solution of tert-butyl 3-(4-((3-chloro-2-fluoro-4-methoxyphenyl)amino)quinazolin- 6-yl)-3-methylazetidine-1-carboxylate (60.0 mg, 0.13 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL), the reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2- fluoro-4-methoxy-phenyl)-6-(3-methylazetidin-3-yl)quinazolin -4-amine (50.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 373.0. Step 3. 1-(3-(4-((3-Chloro-2-fluoro-4-methoxyphenyl)amino)quinazolin -6-yl)-3- methylazetidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-4-methoxyphenyl)-6-(3-methylazetidin-3- yl)quinazolin-4-amine (50 mg, 0.13 mmol) and sodium bicarbonate (33.8 mg, 0.4 mmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added prop-2-enoyl chloride (7.3 mg, 80.5 μmol) at 0 °C. The reaction was stirred at 0 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 12%-42%, 10 min) to give 1-(3-(4-((3-chloro-2-fluoro-4- methoxyphenyl)amino)quinazolin-6-yl)-3-methylazetidin-1-yl)p rop-2-en-1-one (19.4 mg, 45.4 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.29 (s, 1H), 7.89 - 7.82 (m, 2H), 7.44 (t, J = 8.4 Hz, 1H), 7.01 (dd, J = 1.6, 8.8 Hz, 1H), 6.48 - 6.37 (m, 1H), 6.32 - 6.25 (m, 1H), 5.77 (dd, J = 1.6, 10.0 Hz, 1H), 4.71 (d, J = 8.4 Hz, 1H), 4.50 – 4.40 (m, 2H), 4.20 (d, J = 10.0 Hz, 1H), 3.97 (s, 3H), 1.79 (s, 3H); m/z ES+ [M+H] ⁺ 427.1. Example 224. Preparation of 1-(3-(4-((5-Chloro-2-fluorophenyl)amino)quinazolin-6- yl)azetidin-1-yl)prop-2-en-1-one (Compound 24) Step 1. 6-Bromo-N-(5-chloro-2-fluorophenyl)quinazolin-4-amine A solution of 6-bromo-4-chloro-quinazoline (300 mg, 1.23 mmol) and 5-chloro-2-fluoro- aniline (269 mg, 1.85 mmol) in acetonitrile (2 mL) was stirred at 60 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. Then the residue was recrystallized with methanol (5 mL) to give 6-bromo-N-(5-chloro-2-fluorophenyl)quinazolin- 4-amine (410 mg, 1.16 mmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (d, J = 1.6 Hz, 1H), 8.93 (s, 1H), 8.26 (dd, J = 2.0, 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 2.4, 6.4 Hz, 1H), 7.56 - 7.44 (m, 2H). Step 2. tert-Butyl 3-(4-((5-chloro-2-fluorophenyl)amino)quinazolin-6-yl)azetidi ne-1- carboxylate To an vial (8 mL) equipped with a stir bar was added 6-bromo-N-(5-chloro-2-fluoro- phenyl)quinazolin-4-amine (100 mg, 284 μmol), tert-butyl 3-bromoazetidine-1-carboxylate (87.1 mg, 369 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (3.18 mg, 2.84 μmol), NiCl ₂ .dtbbpy (564 ug, 1.42 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (70.5 mg, 284 μmol) and sodium carbonate (60.1 mg, 567 μmol) in 1,2-dimethoxyethane (1.5 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hours under nitrogen. On completion, the reaction mixture was diluted with water (5 mL), and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 25/1 to 3/1) to give tert-butyl 3-(4-((5-chloro-2- fluorophenyl)amino)quinazolin-6-yl)azetidine-1-carboxylate (70.0 mg, 0.16 mmol, 48%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 7.81 - 7.80 (m, 1H), 7.75 - 7.69 (m, 1H), 7.43 - 7.35 (m, 2H), 4.34 (m, 2H), 4.05 - 4.02 (m, 2H), 3.30 - 3.28 (m, 1H), 1.41 (s, 9H). Step 3. 6-(Azetidin-3-yl)-N-(5-chloro-2-fluorophenyl)quinazolin-4-am ine To a solution of tert-butyl 3-[4-(5-chloro-2-fluoro-anilino)quinazolin-6-yl]azetidine-1- carboxylate (70.0 mg, 163 μmol) in dichloromethane (0.5 mL) was addedd trifluoroacetic acid (770 mg, 6.75 mmol), the reaction mixture was stirred at 20 °C for 10 mins. On completion, the reaction mixture was concentrated in vacuo to give 6-(azetidin-3-yl)-N-(5-chloro-2- fluorophenyl)quinazolin- 4-amine (70.0 mg, crude, trifluoroacetic acid) as a yellow oil. Step 4. 1-(3-(4-((5-Chloro-2- fluorophenyl)amino)quinazolin-6-yl)azetidin-1-yl)prop-2- en-1-one To a solution of 6-(azetidin-3-yl)-N-(5-chloro-2-fluoro-phenyl)quinazolin-4-a mine (70.0 mg, 158 μmol, trifluoroacetic acid) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (39.8 mg, 474 μmol), then prop-2-enoyl chloride (12.9 mg, 142 μmol) was added dropwise into the mixture at 0 °C. The reaction mixture was stirred at 0 °C for 30 mins. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 23%-53%, 7 min) to give 1-(3-(4-((5-chloro-2-fluorophenyl)amino)quinazolin-6-yl)azet idin-1-yl)prop-2-en-1-one (14.6 mg, 38.1 μmol, 24%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 - 9.70 (m, 1H), 8.53 - 8.39 (m, 2H), 7.89 - 7.82 (m, 1H), 7.81 - 7.76 (m, 1H), 7.69 (m, 1H), 7.43 - 7.33 (m, 2H), 6.39 (dd, J = 10.4, 17.2 Hz, 1H), 6.15 (dd, J = 2.4, 17.2 Hz, 1H), 5.74 - 5.67 (m, 1H), 4.76 - 4.68 (m, 1H), 4.46 - 4.38 (m, 1H), 4.34 (dd, J = 6.0, 8.0 Hz, 1H), 4.20 - 4.08 (m, 2H); m/z ES+ [M+H] ⁺ 383.1. Example 225. Preparation of 1-[3-[4-(3-Chloro-2,4-difluoro-anilino)quinazolin-6- yl]azetidin-1-yl]prop-2-en-1-one (Compound 28) Step 1. tert-Butyl 3-[4-(3-chloro-2,4-difluoro-anilino)quinazolin-6-yl]azetidin e-1- carboxylate To an vial (8 mL) equipped with a stir bar was added 6-bromo-N-(3-chloro-2,4-difluoro- phenyl)quinazolin-4-amine (200 mg, 540 μmol), tert-butyl 3-bromoazetidine-1-carboxylate (166 mg, 702 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (6.05 mg, 5.40 μmol), NiCl ₂ .dtbbpy (1.07 mg, 2.70 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (134 mg, 540 μmol, 167 μL) and sodium carbonate (114 mg, 1.08 mmol) in 1,2-dimethoxyethane (20.0 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hrs under nitrogen. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=20/1 to 2/1) to give tert-butyl 3-[4-(3-chloro-2,4-difluoro- anilino)quinazolin-6-yl]azetidine-1-carboxylate (115 mg, 0.26 mmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 7.83 - 7.79 (m, 2H), 7.61 - 7.54 (m, 1H), 7.44 - 7.39 (m, 1H), 4.34 (s, 2H), 4.08 - 3.98 (m, 3H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 447.1. Step 2. 6-(Azetidin-3-yl)-N-(3-chloro-2,4-difluoro-phenyl)quinazolin -4-amine To a solution of tert-butyl 3-[4-(3-chloro-2,4-difluoro-anilino)quinazolin-6-yl]azetidin e- 1-carboxylate (115 mg, 257 μmol ) in dichloromethane (0.9 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol, 0.3 mL), the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated in vacuo to give 6-(azetidin-3-yl)-N-(3-chloro-2,4-difluoro-phenyl)quinazolin -4- amine (89.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 347.1. Step 3. 1-[3-[4-(3-Chloro-2,4-difluoro-anilino)quinazolin-6-yl]azeti din-1-yl]prop-2-en- 1-one To a solution of 6-(azetidin-3-yl)-N-(3-chloro-2,4-difluoro-phenyl)quinazolin -4-amine (89.0 mg, 257 μmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (173 mg, 2.05 mmol) in water (0.3 mL). Then a solution of prop-2-enoyl chloride (20.9 mg, 231 μmol) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 22%-52%,7min) to give 1-[3-[4-(3-chloro-2,4-difluoro-anilino)quinazolin-6-yl]azeti din-1-yl]prop-2-en-1-one (29.5 mg, 73.6 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 - 9.96 (m, 1H), 8.61 - 8.42 (m, 2H), 7.94 - 7.75 (m, 2H), 7.63 - 7.52 (m, 1H), 7.46-7.34 (m, 1H), 6.39 (dd, J = 10.4, 17.2 Hz, 1H), 6.15 (dd, J = 2.4, 17.2 Hz, 1H), 5.75 - 5.66 (m, 1H), 4.73 (t, J = 8.4 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.33 (dd, J = 6.0, 8.4 Hz, 1H), 4.22 - 4.05 (m, 2H); m/z ES+ [M+H] ⁺ 401.1. Example 226. Preparation of 1-[3-[4-(3-Chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin- 1- yl]prop-2-en-1-one (Compound 56) Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidine-1- carboxylate To a solution of 6-bromo-4-(3-chloro-2-fluoro-phenoxy)quinazoline (200 mg, 566 μmol) in 1,2-dimethoxyethane (3.0 mL) was added bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2-py ridyl)pyridine;hexafluorophosphate (6.35 mg, 5.66 μmol), bis(trimethylsilyl)silyl-trimethyl-silane (141 mg, 566 μmol), sodium carbonate (120 mg, 1.13 mmol), NiCl ₂ .dtbbpy (1.13 mg, 2.83 μmol) and tert-butyl 3- bromoazetidine-1-carboxylate (174 mg, 735 μmol). The mixture was stirred and irradiated with a 34 W blue LED lamp, with cooling fan to keep the reaction temperature at 25 °C for 1 h under nitrogen. On completion, the reaction mixture was filtered. The filtrate was poured into 10 mL water and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether : ethyl acetate = 20:1 to 1:1] to give tert- butyl 3-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidine-1- carboxylate (100 mg, 0.28 mmol, 70%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (s, 1H), 8.76 (s, 1H), 8.37 - 8.24 (m, 1H), 8.16 - 7.99 (m, 3H), 7.68 - 7.52 (m, 3H), 7.45 - 7.34 (m, 1H), 4.35 (t, J = 8.4 Hz, 2H), 4.05 - 3.93 (m, 2H), 3.27 (s, 1H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 430.1. Step 2. 6-(Azetidin-3-yl)-4-(3-chloro-2-fluoro-phenoxy)quinazoline To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidine-1- carboxylate (90.0 mg, 209 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (716 mg, 6.28 mmol), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was dried by blowing nitrogen to give 6-(azetidin-3-yl)-4-(3-chloro-2-fluoro-phenoxy)quinazoline (69.0 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 330.0. Step 3. 1-[3-[4-(3-Chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin- 1-yl]prop-2-en-1- one To a solution of 6-(azetidin-3-yl)-4-(3-chloro-2-fluoro-phenoxy)quinazoline (69 mg, 209 μmol) in tetrahydrofuran (2.0 mL) and water (0.50 mL) was added sodium bicarbonate (70.3 mg, 837 μmol), then prop-2-enoyl chloride (17.0 mg, 188 μmol) was added into the mixture at 0 °C. The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched by 2.0 mL methanol at 0 °C. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 25%-50%, 6 min) to give 1-[3-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]azetidin- 1-yl]prop-2-en-1-one (18.0 mg, 47.0 μmol, 22%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 8.34 (s, 1H), 8.19 - 8.14 (m, 1H), 8.10 - 8.05 (m, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 6.44 - 6.34 (m, 1H), 6.17 - 6.12 (m, 1H), 5.75 - 5.67 (m, 1H), 4.72 (t, J = 8.8 Hz, 1H), 4.49 - 4.36 (m, 2H), 4.31 - 4.20 (m, 1H), 4.10 - 4.03 (m, 1H); m/z ES+ [M+H] ⁺ 383.1. Example 227. Preparation of 1-[3-[4-(3-Chloro-2,4-difluoro-phenoxy)quinazolin-6- yl]azetidin-1-yl]prop-2-en-1-one (Compound 68) Step 1. 6-Bromo-4-(3-chloro-2,4-difluorophenoxy)quinazoline To a solution of 6-bromo-4-chloro-quinazoline (2.00 g, 8.23 mmol) in acetonitrile (20 mL) was added potassium carbonate (2.27 g, 16.46 mmol) and 3-chloro-2,4-difluorophenol (2.03 g, 12.35 mmol). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 6-bromo-4-(3-chloro- 2,4-difluorophenoxy)quinazoline (2.3 g, 6.20 mmol, 75%) as a yellow solid. m/z ES+ [M+H] ⁺ 371.0. Step 2. tert-Butyl 2-[4-(3,4-dichloro-2-fluoro-phenoxy)quinazolin-6-yl]morpholi ne-4- carboxylate To a solution of 6-bromo-4-(3,4-dichloro-2-fluoro-phenoxy)quinazoline (200 mg, 516 μmol) and tert-butyl 3-bromoazetidine-1-carboxylate (158.2 mg, 670 μmol) in 1,2- dimethoxyethane (8.0 mL) was added dtbbpy (0.69 mg, 2.58 μmol), bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridyl]phenyl]iridium(1+);4-tert-butyl- 2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (5.8 mg, 5.16 μmol), dichloronickel;1,2-dimethoxyethane (0.56 mg, 2.58 μmol), bis(trimethylsilyl)silyl-trimethyl-silane (128.2 mg, 516 μmol) and sodium carbonate (109.2 mg, 1.03 mmol). Then the reaction was stirred at 25 °C for 2 hrs with blue LEDs under nitrogen. On completion, the reaction was added brine (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 3/1] to give tert-butyl 2-[4-(3,4-dichloro-2-fluoro-phenoxy)quinazolin-6-yl]morpholi ne- 4-carboxylate (70.0 mg, 0.16 mmol, 22.0%) as a yellow oil. m/z ES+ [M+H] ⁺ 448.1. Step 3.6-(Azetidin-3-yl)-4-(3-chloro-2,4-difluoro-phenoxy)quinazo line To a solution of tert-butyl 3-[4-(3-chloro-2,4-difluoro-phenoxy)quinazolin-6- yl]azetidine-1-carboxylate (50.0 mg, 112 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol), then the reaction was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated by blowing nitrogen to give 6-(azetidin-3-yl)- 4-(3-chloro-2,4-difluoro-phenoxy)quinazoline (38.0 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 348.1. Step 4.1-[3-[4-(3-Chloro-2,4-difluoro-phenoxy)quinazolin-6-yl]aze tidin-1-yl]prop-2-en- 1-one To a solution of 6-(azetidin-3-yl)-4-(3-chloro-2,4-difluoro-phenoxy)quinazoli ne (38.0 mg, 109 μmol) in sodium bicarbonate (1.08 g, 12.8 mmol, 0.5 mL) and tetrahydrofuran (0.5 mL) was added prop-2-enoyl chloride (9.89 mg, 109 μmol) at 0 °C, then the reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-55%, 6 min) to give 1-[3-[4-(3-chloro- 2,4-difluoro-phenoxy)quinazolin-6-yl]azetidin-1-yl]prop-2-en -1-one (10.9 mg, 0.027 mmol, 25%) as a white solid. NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 8.34 (s, 1H), 8.17 - 8.06 (m, 2H), 7.69 - 7.63 (m, 1H), 7.53 - 7.47 (m, 1H), 6.39 (dd, J = 10.4, 16.8 Hz, 1H), 6.15 (d, J = 16.8 Hz, 1H), 5.70 (d, J = 10.4 Hz, 1H), 4.72 (t, J = 8.8 Hz, 1H), 4.42 (q, J = 9.6 Hz, 2H), 4.24 (t, J = 6.4 Hz, 1H), 4.09 - 4.04 (m, 1H); m/z ES+ [M+H] ⁺ 402.0. Example 228. Preparation of 1-((4r,6r)-6-(4-((3-Chloro-2,4- difluorophenyl)amino)quinazolin-6-yl)-1-azaspiro[3.3]heptan- 1-yl)prop-2-en-1-one (Compound 243)

Step 1. (4r,6r)-tert-Butyl 6-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)-1- azaspiro[3.3]heptane-1-carboxylate To an vial (8 mL) equipped with a stir bar was added 6-bromo-N-(3-chloro-2,4-difluoro- phenyl)quinazolin-4-amine (90.0 mg, 243 μmol), tert-butyl 6-bromo-1-azaspiro[3.3]heptane-1- carboxylate (60.3 mg, 218 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (2.72 mg, 2.43 μmol), NiCl ₂ .dtbbpy (0.483 mg, 1.21 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (60.4 mg, 243 μmol), sodium carbonate (51.5 mg, 485 μmol) in 1,2-dimethoxyethane (2 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-TLC (petroleum ether:ethyl acetate = 3:1) to give (4r,6r)-tert-butyl 6-(4-((3-chloro-2,4-difluorophenyl)amino)quinazolin-6-yl)-1- azaspiro[3.3]heptane-1-carboxylate (38.0 mg, 0.078 mmol, 32%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 3.90 - 3.69 (m, 1H), 3.67 - 3.57 (m, 2H), 3.11 - 3.02 (m, 2H), 2.63 - 2.51 (m, 2H), 2.25 - 2.15 (m, 2H), 1.43 - 1.30 (m, 9H). Step 2. (4r,6r)-N-(3-Chloro-2,4-difluorophenyl)-6-(1-azaspiro[3.3]he ptan-6- yl)quinazolin-4-amine A solution of tert-butyl 6-[4-(3-chloro-2,4-difluoro-anilino)quinazolin-6-yl]-1- azaspiro[3.3]heptane-1-carboxylate (38.0 mg, 78.0 μmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated by blowing nitrogen to give (4r,6r)-N-(3-chloro-2,4-difluorophenyl)-6-(1- azaspiro[3.3]heptan-6-yl)quinazolin-4-amine (30 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 387.2. Step 3. 1-((4r,6r)-6-(4-((3-Chloro-2,4-difluorophenyl)amino)quinazol in-6-yl)-1- azaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of 6-(1-azaspiro[3.3]heptan-6-yl)-N-(3-chloro-2,4-difluoro- phenyl)quinazolin-4-amine (30.0 mg, 77.5 μmol) in tetrahydrofuran (0.6 mL) and water (0.2 mL) was added sodium bicarbonate (20.0 mg, 232 μmol), then prop-2-enoyl chloride (7.02 mg, 77.5 μmol) was added at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-60%, 8 min) to give 1-((4r,6r)-6-(4-((3-chloro-2,4-difluorophenyl)amino)quinazol in-6-yl)-1- azaspiro[3.3]heptan-1-yl)prop-2-en-1-one (4.1 mg, 9.3 μmol, 11%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.27 - 8.21 (m, 1H), 7.90 - 7.80 (m, 2H), 7.58 - 7.57 (m, 1H), 7.26 - 7.21 (m, 1H), 6.43 - 6.29 (m, 2H), 5.78 - 5.76 (m, 1H), 4.30 - 4.18 (m, 2H), 3.54 - 2.73 (m, 3H), 2.62 - 2.40 (m, 3H), 2.35 - 2.05 (m, 1H); m/z ES+ [M+H] ⁺ 441.4. Example 229. Preparation of 1-[3-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6- yl]-3-methyl-azetidin-1-yl]prop-2-en-1-one (Compound 327) Step 1. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)-3- methylazetidine-1-carboxylate A mixture of tert-butyl 3-[5-cyano-4-[(E)-dimethylaminomethyleneamino]-2-methoxy- phenyl]-3-methyl-azetidine-1-carboxylate (120 mg, 322 μmol), 3-chloro-2-fluoro-aniline (46.9 mg, 322 μmol) in toluene (1 mL) and acetic acid (1 mL) was stirred at 115 °C for 2 hrs under nitrogen atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) give compound tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 3-methyl-azetidine-1-carboxylate (80.0 mg, 0.17 mmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 1H), 8.50 - 8.40 (m, 1H), 7.44 (s, 1H), 7.30 (s, 1H), 7.21 - 7.14 (m, 2H), 4.30 (d, J = 8.0 Hz, 2H), 4.02 - 3.98 (m, 5H), 1.70 (s, 3H), 1.47 (s, 9H). Step 2. N-(3-Chloro-2-fluoro-phenyl)-7-methoxy-6-(3-methylazetidin-3 -yl)quinazolin-4- amine A solution of 3-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 3-methyl- azetidine-1-carboxylate (50 mg, 106 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL) was stirred at 15 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give compound N-(3-chloro-2-fluoro-phenyl)-7-methoxy-6-(3-methylazetidin-3 -yl)quinazolin-4- amine (40.0 mg, crude, trifluoroacetic acid) as a yellow gum. Step 3. 1-[3-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-y l]-3-methyl- azetidin-1-yl]prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-7-methoxy-6-(3-methylazetidin-3 - yl)quinazolin-4-amine (40.0 mg, 108 μmol) and sodium bicarbonate (27.0 mg, 322 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (9.71 mg, 107 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 17%-47%, 10 min) to give compound 1-[3-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-y l]-3-methyl- azetidin-1-yl]prop-2-en-1-one (25.7 mg, 0.060 mmol, 54%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.30 - 8.20 (m, 1H), 8.15 - 7.93 (m, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.24 - 7.13 (m, 2H), 6.26 - 6.18 (m, 2H), 5.60 (dd, J = 3.6, 8.4 Hz, 1H), 4.63 (d, J = 10.4 Hz, 1H), 4.53 (d, J = 8.4 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 4.21 (d, J = 10.4 Hz, 1H), 4.01 (s, 3H), 1.74 (s, 3H); m/z ES+ [M+H] ⁺ 427.1. Example 230. Preparation of 1-(3-(4-((3-Chloro-4-(difluoromethoxy)phenyl)amino)-7- methoxyquinazolin-6-yl)-3-methylazetidin-1-yl)prop-2-en-1-on e (Compound 427)

(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)-7- methoxyquinazolin-6-yl)-3-methylazetidine-1-carboxylate A mixture of tert-butyl 3-(5-cyano-4-(((dimethylamino)methylene)amino)-2- methoxyphenyl)-3-methylazetidine-1-carboxylate (150 mg, 402 μmol) and 3-chloro-4- (difluoromethoxy)aniline (117 mg, 604 μmol) in toluene (0.5 mL) and acetic acid (0.5 mL) was stirred at 115 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)-7-methoxyqu inazolin-6-yl)- 3-methylazetidine-1-carboxylate (200 mg, 0.38 mmol, 81%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 7.96 (s, 1H), 7.70 - 7.58 (m, 1H), 7.31 (s, 1H), 7.27 - 7.17 (m, 2H), 4.52 - 4.12 (m, 2H), 4.00 (d, J = 8.0 Hz, 2H), 3.94 (s, 3H), 1.67 (s, 3H), 1.50 - 1.44 (m, 9H); m/z ES+ [M+H] ⁺ 521.0. Step 2. N-(3-Chloro-4-(difluoromethoxy)phenyl)-7-methoxy-6-(3-methyl azetidin-3- yl)quinazolin-4-amine A mixture of tert-butyl 3-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)-7- methoxyquinazolin-6-yl)-3-methylazetidine-1-carboxylate (150 mg, 288 μmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (1 mL) was stirred at 15 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-4- (difluoromethoxy)phenyl)-7-methoxy-6-(3-methylazetidin-3-yl) quinazolin-4-amine (200 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 421.0. Step 3. 1-(3-(4-((3-Chloro-4-(difluoromethoxy)phenyl)amino)-7-methox yquinazolin-6- yl)-3-methylazetidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-4-(difluoromethoxy)phenyl)-7-methoxy-6-(3- methylazetidin-3-yl)quinazolin-4-amine (120 mg, 285 μmol, trifluoroacetic acid) and sodium bicarbonate (95.8 mg, 1.14 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added acryloyl chloride (23.2 mg, 256 μmol) at 0 °C. The mixture was stirred at 0 °C for 15 min. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 40%- 70%, 9 min) to give 1-(3-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)-7-methox yquinazolin- 6-yl)-3-methylazetidin-1-yl)prop-2-en-1-one (45.2 mg, 0.095 mmol, 33%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 - 8.61 (m, 1H), 8.06 - 7.93 (m, 1H), 7.71 - 7.61 (m, 1H), 7.34 - 7.29 (m, 1H), 6.89 - 6.81 (m, 1H), 6.36 - 6.14 (m, 2H), 5.64 (d, J = 8.8 Hz, 1H), 4.93 (s, 2H), 4.67 - 4.56 (m, 3H), 4.56 - 4.48 (m, 1H), 4.35 - 4.26 (m, 3H), 4.24 - 4.15 (m, 1H), 4.00 (s, 3H), 3.61 - 3.41 (m, 1H), 1.73 (s, 3H); m/z ES+ [M+H] ⁺ 475.0. Example 231. Preparation of 1-[3-[4-(5-Ethynyl-2- fluoro-anilino)quinazolin-6-yl]azetidin-1- yl]prop-2-en-1-one (Compound 36) Step 1. tert-Butyl 3-(4-hydroxyquinazolin-6-yl)azetidine-1-carboxylate To an 40 mL vial equipped with a stir bar was added 6-bromoquinazolin-4-ol (1.00 g, 4.44 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (1.05 g, 4.44 mmol), sodium carbonate (941 mg, 8.89 mmol), NiCl ₂ .dtbbpy (8.84 mg, 22.2 μmol), 1,1,1,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane (1.1 g, 4.44 mmol) and Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (498 mg, 444 μmol) in 1,2-dimethoxyethane (15 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hrs under nitrogen. On completion, the reaction was filtered and the filter cake was washed with dichloromethane (10 mL × 3). The combined organic phase was dried in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give tert-butyl 3-(4- hydroxyquinazolin-6-yl)azetidine-1-carboxylate (0.7 g, 2.33 mmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.26 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.79 (d, J = 1.2 Hz, 2H), 4.45 - 4.37 (m, 2H), 4.10 - 4.02 (m, 2H), 3.95 - 3.86 (m, 1H), 1.49 (s, 9H). Step 2. tert-Butyl 3-(4-chloroquinazolin-6-yl)azetidine-1-carboxylate To a solution of tert-butyl 3-(4-hydroxyquinazolin-6-yl)azetidine-1-carboxylate (3 g, 9.96 mmol) in toluene (30 mL) was added N,N-diisopropylethylamine (6.43 g, 49.78 mmol) and phosphorus oxychloride (1.83 g, 11.95 mmol). The reaction mixture was stirred at 110 °C for 4 hrs. On completion, the mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/2 to 1/4) to give tert-butyl 3-(4-chloroquinazolin-6- yl)azetidine-1-carboxylate (2.9 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 320.3. Step 3. tert-Butyl 3-[4-[2-fluoro-5-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]azetidine-1-carboxylate To a solution of tert-butyl 3-(4-chloroquinazolin-6-yl)azetidine-1-carboxylate (100 mg, 313 μmol) in acetonitrile (1.0 mL) was added 2-fluoro-5-(2-trimethylsilylethynyl)aniline (97.3 mg, 469 μmol). The mixture was stirred at 60 °C for 12 hrs. The reaction mixture was dried in vacuo to give tert-butyl 3-[4-[2-fluoro-5-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]azetidine-1-carboxylate (153 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 491.3. Step 4. tert-Butyl 3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6-yl] azetidine-1- carboxylate To a solution of tert-butyl 3-[4-[2-fluoro-5-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]azetidine-1-carboxylate (153 mg, 312 μmol) in acetonitrile (1.0 mL) was added cesium carbonate (102 mg, 312 μmol), the mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether: Ethyl acetate=2:1) to give tert-butyl 3-[4-(5-ethynyl-2-fluoro- anilino)quinazolin-6-yl]azetidine-1-carboxylate (81.0 mg, 0.19 mmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.01 - 7.95 (m, 1H), 7.89 (dd, J = 1.6, 8.4 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.30 - 7.25 (m, 2H), 7.19 - 7.13 (m, 1H), 4.46 (t, J = 8.8 Hz, 2H), 4.07 (dd, J = 5.6, 8.4 Hz, 2H), 4.00 - 3.92 (m, 1H), 3.40 (d, J = 8.4 Hz, 1H), 3.10 (s, 1H), 1.50 (s, 9H); m/z ES+ [M+H] ⁺ 419.2. Step 5.6-(Azetidin-3-yl)-N-(5-ethynyl-2-fluoro-phenyl) quinazolin-4-amine To a solution of tert-butyl 3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6-yl]azetidine-1 - carboxylate (81.0 mg, 194 μmol) in dichloromethane (0.9 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol), the mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture concentrated in vacuo to give 6-(azetidin-3-yl)-N-(5-ethynyl-2-fluoro-phenyl)quinazolin-4- amine (55.0 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 319.1. Step 6. 1-[3-[4-(5-Ethynyl-2-fluoro-anilino)quinazolin-6-yl]azetidin -1-yl]prop-2-en-1- one To a solution of 6-(azetidin-3-yl)-N-(5-ethynyl-2-fluoro-phenyl)quinazolin-4- amine (55.0 mg, 173 μmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (116 mg, 1.38 mmol) in water (0.3 mL). Then a solution of prop-2-enoyl chloride (14.1mg, 156 μmol) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C, the reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether:Ethyl acetate=2:1) and re-purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mm, 10um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 9%-39%, 10 min) to give 1-[3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6-yl]azetidin -1-yl]prop-2-en-1-one (10.7 mg, 0.029 mmol, 17%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.34 (s, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.35-7.28 (m, 1H), 7.14 (dd, J = 8.8, 10.4 Hz, 1H), 6.38 - 6.31 (m, 1H), 6.28 - 6.19 (m, 1H), 5.73 - 5.67 (m, 1H), 4.74 (t, J = 8.8 Hz, 1H), 4.63 - 4.53 (m, 1H), 4.41 - 4.24 (m, 2H), 4.15 - 4.02 (m, 1H), 3.09 (s, 1H); m/z ES+ [M+H] ⁺ 373.1. Example 232. Preparation of 1-(3-(4-((5-Chloro-6-methoxypyridin-3-yl)amino)quinazolin-6- yl)-3-methylazetidin-1-yl)prop-2-en-1-one (Compound 436) Step 1. tert-Butyl 3-(4-((5-chloro-6-methoxypyridin-3-yl)amino)quinazolin-6-yl) -3- methylazetidine-1-carboxylate To a solution of 5-chloro-6-methoxy-pyridin-3-amine (241 mg, 1.52 mmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (2.5 M, 1.21 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Then tert-butyl 3-(4-methoxyquinazolin-6-yl)-3-methyl-azetidine-1- carboxylate (100 mg, 304 μmol) was added dropwise into the mixture at 25 °C, the mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was quenched by sat. ammonium chloride (5 mL), then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=3/1 to 1/1) to give tert-butyl 3-(4-((5-chloro-6-methoxypyridin-3- yl)amino)quinazolin-6-yl)-3-methylazetidine-1-carboxylate (100 mg, 0.22 mmol, 65%) as a yellow oil. m/z ES+ [M+H] ⁺ 455.9. Step 2. N-(5-Chloro-6-methoxypyridin-3-yl)-6-(3-methylazetidin-3-yl) quinazolin-4- amine To a solution of tert-butyl 3-[4-[(5-chloro-6-methoxy-3-pyridyl)amino] quinazolin-6-yl]- 3-methyl-azetidine-1-carboxylate (80 mg, 176 μmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.2 mL), the mixture was stirred at 20 °C for 20 min. On completion, the reaction mixture was concentrated under reduced pressure to give N-(5-chloro-6-methoxypyridin- 3-yl)-6-(3-methylazetidin-3-yl) quinazolin-4-amine (80 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 356.2. Step 3. 1-(3-(4-((5-Chloro-6-methoxypyridin-3-yl)amino)quinazolin-6- yl)-3- methylazetidin-1-yl)prop-2-en-1-one To a solution of N-(5-chloro-6-methoxy-3-pyridyl)-6-(3-methylazetidin-3-yl) quinazolin- 4-amine (80.0 mg, 170 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (71.5 mg, 851 μmol) and prop-2-enoyl chloride (15.4 mg, 170 μmol). The mixture was stirred at 0 °C for 10 min. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (0.2% FA)-acetonitrile]; B%: 14%-44%, 10 min) to give 1-(3-(4-((5-chloro-6-methoxypyridin-3-yl)amino)quinazolin-6- yl)-3-methylazetidin-1-yl)prop-2-en-1-one (37.7 mg, 0.092 mmol, 54%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.57 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.36 (s, 2H), 7.82 (d, J = 6.4 Hz, 2H), 6.37 (dd, J = 10.4, 17.2 Hz, 1H), 6.19 - 6.06 (m, 1H), 5.70 (dd, J = 2.0, 10.4 Hz, 1H), 4.57 (d, J = 8.4 Hz, 1H), 4.46 - 4.29 (m, 2H), 4.06 (d, J = 10.0 Hz, 1H), 3.97 (s, 3H), 1.69 (s, 3H); m/z ES+ [M+H] ⁺ 410.0. Example 233. Preparation of 1-(3-Methyl-3-(4-((2,3,4-trifluorophenyl)amino)quinazolin-6- yl)azetidin-1-yl)prop-2-en-1-one (Compound 414) Step 1. tert-Butyl 3-methyl-3-(4-((2,3,4-trifluorophenyl)amino)quinazolin-6- yl)azetidine-1-carboxylate To a solution of 2,3,4-trifluoroaniline (357 mg, 2.43 mmol) in tetrahydrofuran (5 mL) was added n-butyl lithium (2.5 M, 1.94 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. Then tert-butyl 3-(4-methoxyquinazolin-6-yl)-3-methyl-azetidine-1-carboxylat e (160 mg, 486 μmol) was added dropwise at 25 °C, the mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched by sat. ammonium chloride (5 mL), diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=5/1 to 1/1) to give tert- butyl 3-methyl-3-(4-((2,3,4-trifluorophenyl)amino)quinazolin-6-yl) azetidine-1-carboxylate (200 mg, 0.45 mmol, 93%) as a brown oil. m/z ES+ [M+H] ⁺ 444.9. Step 2. 6-(3-Methylazetidin-3-yl)-N-(2,3,4-trifluorophenyl) quinazolin-4-amine To a solution of tert-butyl 3-methyl-3-[4-(2,3,4-trifluoroanilino)quinazolin-6- yl]azetidine-1-carboxylate (200 mg, 450 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), the mixture was stirred at 25 °C for 20 min. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(3-methylazetidin-3-yl)-N-(2,3,4- trifluorophenyl) quinazolin-4-amine (200 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 345.1. Step 3. 1-(3-Methyl-3-(4-((2,3,4-trifluorophenyl)amino)quinazolin-6- yl)azetidin-1- yl)prop-2-en-1-one To a solution of 6-(3-methylazetidin-3-yl)-N-(2,3,4-trifluorophenyl) quinazolin-4-amine (200 mg, 436 μmol, trifluoroacetic acid salt) in tetrahydrofuran (2 mL) and water (1 mL) was added sodium bicarbonate (183 mg, 2.18 mmol) and prop-2-enoyl chloride (39.5 mg, 436 μmol). The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 20%-50%, 8 min) to give 1-(3-methyl-3-(4-((2,3,4- trifluorophenyl)amino)quinazolin-6-yl)azetidin-1-yl)prop-2-e n-1-one (69.7 mg, 0.17 mmol, 39%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.60 - 8.28 (m, 2H), 7.93 - 7.74 (m, 2H), 7.40 (d, J = 7.2 Hz, 2H), 6.37 (dd, J = 10.4, 17.2 Hz, 1H), 6.20 - 6.02 (m, 1H), 5.70 (d, J = 10.4 Hz, 1H), 4.56 (d, J = 8.4 Hz, 1H), 4.44 - 4.29 (m, 2H), 4.04 (d, J = 10.0 Hz, 1H), 1.70 (s, 3H); m/z ES+ [M+H] ⁺ 399.0. Example 234. Preparation of 1-(3-(4-((5-Chloropyridin-3-yl)amino)quinazolin-6-yl)-3- methylazetidin-1-yl)prop-2-en-1-one (Compound 418)

Step 1. tert-Butyl 3-(4-((5-chloropyridin-3-yl)amino)quinazolin-6-yl)-3-methyla zetidine- 1-carboxylate To a solution of 5-chloropyridin-3-amine (312 mg, 2.43 mmol) in tetrahydrofuran (5 mL) was added n-butyl lithium (2.5 M, 1.94 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. Then tert-butyl 3-(4-methoxyquinazolin-6-yl)-3-methyl-azetidine-1-carboxylat e (160 mg, 486 μmol) was added dropwise at 25 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was quenched by sat. ammonium chloride (5 mL), diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4- ((5-chloropyridin-3-yl)amino)quinazolin-6-yl)-3-methylazetid ine-1-carboxylate (70.0 mg, 0.16 mmol, 31%) as a brown solid. m/z ES+ [M+H] ⁺ 425.9. Step 2. N-(5-Chloropyridin-3-yl)-6-(3-methylazetidin-3-yl)quinazolin -4-amine To a solution of tert-butyl 3-[4-[(5-chloro-3-pyridyl)amino]quinazolin-6-yl]-3-methyl- azetidine-1-carboxylate (70.0 mg, 164 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL), the mixture was stirred at 20 °C for 20 min. On completion, the reaction mixture was concentrated under reduced pressure to give N-(5-chloropyridin-3-yl)-6-(3- methylazetidin-3-yl)quinazolin-4-amine (70.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 326.1. Step 3. 1-(3-(4-((5-Chloropyridin-3-yl)amino)quinazolin-6-yl)-3-meth ylazetidin-1- yl)prop-2-en-1-one To a solution of N-(5-chloro-3-pyridyl)-6-(3-methylazetidin-3-yl)quinazolin-4 -amine (70 mg, 159 μmol, trifluoroacetic acid salt) in tetrahydrofuran (0.5 mL) and water (0.2 mL) was added sodium bicarbonate (66.9 mg, 796 μmol) and prop-2-enoyl chloride (14.4 mg, 159 μmol), the mixture was stirred at 0 °C for 10 min . On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 29%-59%, 8 min) to give 1-(3-(4-((5-chloropyridin-3-yl)amino)quinazolin-6-yl)-3- methylazetidin-1-yl)prop-2-en-1-one (28.5 mg, 0.075 mmol, 46%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 - 9.96 (m, 1H), 8.96 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 8.39 (d, J = 2.0 Hz, 2H), 7.86 (d, J = 2.4 Hz, 2H), 6.37 (dd, J = 10.4, 17.2 Hz, 1H), 6.14 (dd, J = 2.4, 17.2 Hz, 1H), 5.76 - 5.63 (m, 1H), 4.58 (d, J = 8.4 Hz, 1H), 4.48 - 4.31 (m, 2H), 4.07 (d, J = 10.0 Hz, 1H), 1.70 (s, 3H); m/z ES+ [M+H] ⁺ 380.0. Example 235. Preparation of 1-(3-(4-((5-Fluoropyridin-3-yl)amino)quinazolin-6-yl)-3- methylazetidin-1-yl)prop-2-en-1-one (Compound 419) Step 1. tert-Butyl 3-(4-((5-fluoropyridin-3-yl)amino)quinazolin-6-yl)-3-methyla zetidine- 1-carboxylate To a solution of 5-fluoropyridin-3-amine (272 mg, 2.43 mmol) in tetrahydrofuran (5 mL) was added n-butyl lithium (2.5 M, 1.94 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. Then tert-butyl 3-(4-methoxyquinazolin-6-yl)-3-methyl-azetidine-1-carboxylat e (160 mg, 486 μmol) was added dropwise at 25 °C, the mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was quenched by sat. ammonium chloride (5 mL), then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4- ((5-fluoropyridin-3-yl)amino)quinazolin-6-yl)-3-methylazetid ine-1-carboxylate (100 mg, 0.24 mmol, 48%) as a brown solid. m/z ES+ [M+H] ⁺ 410.0. Step 2. N-(5-Fluoropyridin-3-yl)-6-(3-methylazetidin-3-yl) quinazolin-4-amine To a solution of tert-butyl 3-[4-[(5-fluoro-3-pyridyl)amino]quinazolin-6-yl]-3-methyl- azetidine-1-carboxylate (100 mg, 244 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL), the mixture was stirred at 20 °C for 20 min. On completion, the reaction mixture was concentrated under reduced pressure to give N-(5-fluoropyridin-3-yl)-6-(3- methylazetidin-3-yl) quinazolin-4-amine (100 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 310.1. Step 3. 1-(3-(4-((5-Fluoropyridin-3-yl)amino)quinazolin-6-yl)-3-meth ylazetidin-1- yl)prop-2-en-1-one To a solution of N-(5-fluoro-3-pyridyl)-6-(3-methylazetidin-3-yl)quinazolin-4 -amine (100 mg, 236 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (99.2 mg, 1.18 mmol) and prop-2-enoyl chloride (21.4 mg, 236 μmol), the mixture was stirred at 0 °C for 10 min. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 25%-55%, 8 min) to give 1-(3-(4-((5-fluoropyridin-3-yl)amino)quinazolin-6- yl)-3-methylazetidin-1-yl)prop-2-en-1-one (37.8 mg, 0.10 mmol, 42%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.85 (s, 1H), 8.68 (s, 1H), 8.47 - 8.30 (m, 3H), 7.96 - 7.79 (m, 2H), 6.37 (dd, J = 10.4, 17.2 Hz, 1H), 6.14 (dd, J = 2.0, 16.8 Hz, 1H), 5.70 (dd, J = 2.0, 10.4 Hz, 1H), 4.58 (d, J = 8.4 Hz, 1H), 4.48 - 4.35 (m, 2H), 4.07 (d, J = 10.0 Hz, 1H), 1.70 (s, 3H); m/z ES+ [M+H] ⁺ 364.1. Example 236. Preparation of 1-[3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-1-yl]prop-2-en-1-one (Compound 12)

Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] azetidine- 1-carboxylate To an vial (15 mL) equipped with a stir bar was added tert-butyl 3-bromoazetidine-1- carboxylate (397 mg, 1.68 mmol), 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (400 mg, 1.29 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (14.5 mg, 12.9 μmol), NiCl ₂ .dtbbpy (2.57 mg, 6.47 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (321 mg, 1.29 mmol) and sodium carbonate (274 mg, 2.59 mmol) in 1,2-dimethoxyethane (4 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] azetidine- 1-carboxylate (850 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 430.1 Step 2.6-(Azetidin-3-yl)-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d ]pyrimidin-4-amine To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidine-1-carboxylate (850 mg, 1.98 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.31 g, 20.2 mmol), the mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 6-(azetidin-3-yl)-N-(3-chloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (870 mg, crude, trifluoroacetic acid) as a brown solid. m/z ES+ [M+H] ⁺ 330.1 Step 3. 1-[3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-1- yl]prop-2-en-1-one To a solution of 6-(azetidin-3-yl)-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]p yrimidin- 4- amine (870 mg, 1.96 mmol, trifluoroacetic acid) in water (2 mL) and tetrahydrofuran (10 mL) was added sodium bicarbonate (164 mg, 1.96 mmol) and prop-2-enoyl chloride (195 mg, 2.16 mmol), the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875x30mm, 3um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 30%-60%, 7 min) to give 1-[3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-1-yl]prop-2-en-1- one (106 mg, 0.28 mmol, 14%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.63 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.00 - 7.86 (m, 2H), 7.57 - 7.47 (m, 1H), 7.38 - 7.25 (m, 1H), 6.45 - 6.31 (m, 1H), 6.19 - 6.07 (m, 1H), 5.75 - 5.64 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.48 - 4.31 (m, 3H); m/z ES+ [M+H] ⁺ 384.0. Example 237. Preparation of 1-[3-[4-(4-Phenoxyanilino)pyrido[3,2-d]pyrimidin-6- yl]azetidin-1-yl]prop-2-en-1-one (Compound 31) Step 1. tert-Butyl 3-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetidine -1- carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(4- phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 229 μmol), tert-butyl 3- bromoazetidine-1-carboxylate (70.4 mg, 298 μmol), Ir[dF(F)ppy] ₂ [dtbbpy](PF ₆ ) (2.34 mg, 2.29 μmol), NiCl ₂ .dtbbpy (456 μg, 1.15 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (57.0 mg, 229 μmol) and sodium carbonate (48.6 mg, 458 μmol) in 1,2-dimethoxyethane (1.5 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate= 1:1) and further purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/1) to give tert-butyl 3-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetidine -1- carboxylate (60.0 mg, 0.13 mmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.87 - 7.83 (m, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.13 - 7.07 (m, 1H), 7.04 - 6.98 (m, 5H), 4.40 ( d, J = 8.8 Hz, 2H), 4.32 (s, 2H), 4.22 - 4.13 (m, 1H), 1.47 (s, 10H); m/z ES ⁺ [M+H]+ 470.2. Step 2. 6-(Azetidin-3-yl)-N-(4-phenoxyphenyl)pyrido[3,2-d]pyrimidin- 4-amine To a solution of tert-butyl 3-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetidine - 1-carboxylate (55.0 mg, 117 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (13.3 mg, 117 μmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(azetidin-3-yl)-N-(4- phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, crude) as a yellow solid. Step 3. 1-[3-[4-(4-Phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetid in-1-yl]prop-2-en- 1-one To a solution of 6-(azetidin-3-yl)-N-(4-phenoxyphenyl)pyrido[3,2-d]pyrimidin- 4-amine (45.0 mg, 121 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (30.7 mg, 365 μmol) and prop-2-enoyl chloride (9.92 mg, 109 μmol), the mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-63%, 9 min) to give 1-[3-[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]azetid in-1-yl]prop-2-en-1-one (18.9 mg, 0.045 mmol, 36%) as a yellow solid. ¹ H NMR (400 MHz,CDCl ₃ ) δ 9.24 (s, 1H), 8.77 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.17 - 7.08 (m, 3H), 7.08 - 7.02 (m, 2H), 6.47 - 6.35 (m, 1H), 6.34 - 6.21 (m, 1H), 5.77 - 5.71 (m, 1H), 4.78 - 4.70 (m), 4.61 - 4.46 (m, 3H), 4.26 - 4.13 (m, 1H); m/z ES+ [M+H] ⁺ 424.1. Example 238. Preparation of 1-[3-[4-(4-Chloro-2,3-difluoro-anilino)pyrido[3,4-d]pyrimidi n- 6-yl]azetidin-1-yl]prop-2-en-1-one (Compound 399)

Step 1. 6-Chloro-N-(4-chloro-2,3-difluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (500 mg, 2.50 mmol) in acetonitrile (5 mL) was added 4-chloro-2,3-difluoro-aniline (490 mg, 3.00 mmol), the mixture was stirred at 25 °C for 12 hr. The reaction mixture was filtered and the solid was concentrated under reduced pressure to give 6-chloro-N-(4-chloro-2,3-difluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine (800 mg, 2.45 mmol, 97%) as a brown solid. m/z ES+ [M+H] ⁺ 326.9. Step 2. tert-Butyl 3-[4-(4-chloro-2,3-difluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]azetidine-1-carboxylate A mixture of 6-chloro-N-(4-chloro-2,3-difluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine (200 mg, 611 μmol), tert-butyl 3-bromoazetidine-1-carboxylate (288 mg, 1.22 mmol), NiCl2.glyme (13.4 mg, 61.1 μmol), pyridine-2-carboxamidine;hydrochloride (5.00 mg, 12.2 μmol) and zinc powder (399 mg, 6.11 mmol) in dimethyl acetamide (2 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 1 hr under nitrogen atmosphere. The reaction mixture was added into water (20 mL) and filtered. The filter cake was collected and futher purified by prep-HPLC (column: Phenomenex luna C18150x40mmx 15um; mobile phase: [water (0.1%trifluoroacetic acid)-acetonitrile]; B%: 22%-52%,11min) to give tert- butyl 3-[4-(4-chloro-2,3-difluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl]azetidine-1-carboxylate (30.0 mg, 0.067 mmol, 10%) as a white solid. m/z ES+ [M+H] ⁺ 447.9. Step 3. 6-(Azetidin-3-yl)-N-(4-chloro-2,3-difluoro-phenyl)pyrido[3,4 -d]pyrimidin-4- amine A mixture of tert-butyl 3-[4-(4-chloro-2,3-difluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]azetidine-1-carboxylate (25.0 mg, 55.8 μmol) in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-(azetidin-3-yl)-N-(4-chloro-2,3-difluoro-phenyl)pyrido[3,4 -d]pyrimidin-4- amine (25.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 348.0. Step 4. 1-[3-[4-(4-Chloro-2,3-difluoro-anilino)pyrido[3,4-d]pyrimidi n-6-yl]azetidin-1- yl]prop-2-en-1-one To a solution of 6-(azetidin-3-yl)-N-(4-chloro-2,3-difluoro-phenyl)pyrido[3,4 - d]pyrimidin-4-amine (20.0 mg, 57.5 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (4.83 mg, 57.5 μmol) and prop-2-enoyl chloride (5.21 mg, 57.5 μmol), the mixture was stirred at 0 °C for 1 hr. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 32%-62%,7 min) to give 1-[3-[4-(4-chloro-2,3-difluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]azetidin-1-yl]prop-2-en- 1-one (8.7 mg, 0.022 mmol, 37%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (s, 1H), 8.50 - 8.40 (m, 2H), 8.25 (s, 1H), 7.49 - 7.34 (m, 2H), 6.42-6.35 (m, 1H), 6.14 (d, J = 16.4 Hz, 1H), 5.70 (d, J = 10.4 Hz, 1H), 4.67 (t, J = 8.0 Hz, 1H), 4.45 - 4.33 (m, 2H), 4.22 - 4.14 (m, 2H); m/z ES+ [M+H] ⁺ 402.0. Example 239. Preparation of 1-[3-[4-(2,3-Difluoroanilino)pyrido[3,4-d]pyrimidin-6- yl]azetidin-1-yl]prop-2-en-1-one (Compound 402) Step 1. 6-Chloro-N-(2,3-difluorophenyl)pyrido[3,4-d]pyrimidin-4-amin e To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (500 mg, 2.50 mmol) in acetonitrile (5 mL) was add 2,3-difluoroaniline (387 mg, 3.00 mmol), the mixture was stirred at 25 °C for 12 hr. The reaction mixture was filtered and the solid was concentrated under reduced pressure to give 6-chloro-N-(2,3-difluorophenyl)pyrido[3,4-d]pyrimidin-4-amin e (700 mg, 2.39 mmol, 95%) as a brown solid. m/z ES+ [M+H] ⁺ 293.0. Step 2. tert-Butyl 3-[4-(2,3-difluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]azetid ine-1- carboxylate A mixture of 6-chloro-N-(2,3-difluorophenyl)pyrido[3,4-d]pyrimidin-4-amin e (670 mg, 2.29 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (1.08 g, 4.58 mmol), NiCl ₂ .glyme (50.3mg, 228 μmol), pyridine-2-carboxamidine;hydrochloride (50.0 mg, 45.7 μmol), zinc powder (74.8 mg, 1.14 mmol) in dimethyl acetamide (4 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 1 hr under nitrogen atmosphere. The reaction mixture was added water (10 mL) and then filtered. The filter cake was collected and further purified by prep-HPLC (column: Phenomenex luna C18150x40mmx 15um; mobile phase: [water (0.1%trifluoroacetic acid)-acetonitrile]; B%: 29%-59%,11min) to give tert-butyl 3-[4-(2,3- difluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]azetidine-1-carb oxylate (45.0 mg, 109 μmmol, 4%) as a white solid. m/z ES+ [M+H] ⁺ 414.1. Step 3. 6-(Azetidin-3-yl)-N-(2,3-difluorophenyl)pyrido[3,4-d]pyrimid in-4-amine To a solution of tert-butyl 3-[4-(2,3-difluoroanilino)pyrido[3,4-d]pyrimidin-6- yl]azetidine-1-carboxylate (43.0 mg, 104 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-(azetidin-3-yl)-N-(2,3-difluorophenyl)pyrido[3,4- d]pyrimidin-4-amine (40.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 314.2. Step 4. 1-[3-[4-(2,3-Difluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]aze tidin-1-yl]prop-2- en-1-one To a solution of 6-(azetidin-3-yl)-N-(2,3-difluorophenyl)pyrido[3,4-d]pyrimid in-4-amine (30.0 mg, 95.7 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (8.04 mg, 95.7 μmol) and prop-2-enoyl chloride (8.67 mg, 95.8 μmol). The mixture was stirred at 0 °C for 1 hr .The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30mmx3um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 22%-52%,7min) and further purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 22%-52%, 9 min) to give 1-[3- [4-(2,3-difluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]azetidin -1-yl]prop-2-en-1-one (7.5 mg, 20.4 μmol, 21%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.46 - 9.94 (m, 1H), 9.17 (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 7.43 - 7.18 (m, 3H), 6.42-6.36 (m, 1H), 6.17-6.12 (m, 1H), 5.71-5.68 (m, 1H), 4.73 - 4.66 (m, 1H), 4.46 - 4.35 (m, 2H), 4.23 - 4.16 (m, 2H); m/z ES+ [M+H] ⁺ 368.1. Example 240. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)-7-methoxy-pyrido[3,2 - d]pyrimidin-6-yl]azetidin-1-yl]prop-2-en-1-one (Compound 30) Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)-7-methoxy-pyrido[3,2- d]pyrimidin-6-yl]azetidine-1-carboxylate A mixture of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)-7-methoxy-pyrido[3 ,2- d]pyrimidin-4-amine (500 mg, 1.34 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (632 mg, 2.68 mmol), NiCl ₂ ·glyme (29.4 mg, 134 μmol), pyridine-2-carboxamidine;hydrochloride (42.2 mg, 268 μmol) and zinc powder (263 mg, 4.02 mmol) in dimethyl acetamide (6 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (50 mL) and filtered. The filtered cake was concentrated under reduced pressure to give a residue. The crude product was purified by trituration in ethyl acetate (50 mL) to give tert-butyl 3-[4-(3,4-dichloro- 2-fluoro-anilino)-7-methoxy-pyrido[3,2-d]pyrimidin-6-yl]azet idine-1-carboxylate (420 mg, 0.85 mmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.75 (s, 1H), 8.59 (t, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.28 (dd, J = 1.6, 9.2 Hz, 1H), 4.35 - 4.23 (m, 4H), 4.20 - 4.14 (m, 1H), 3.95 (s, 3H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 494.2. Step 2. 6-(Azetidin-3-yl)-N-(3,4-dichloro-2-fluoro-phenyl)-7-methoxy -pyrido[3,2- d]pyrimidin-4-amine A solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)-7-methoxy-pyrido[3,2- d]pyrimidin-6-yl]azetidine-1-carboxylate (200 mg, 405 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (2 mL) was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give 6-(azetidin-3-yl)-N-(3,4-dichloro-2-fluoro-phenyl)-7-methoxy - pyrido[3,2-d]pyrimidin-4-amine (200 mg, crude, trifluoroacetic acid) as a brown oil. m/z ES+ [M+H] ⁺ 394.2. Step 3. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)-7-methoxy-pyrido[3,2 -d]pyrimidin-6- yl]azetidin-1-yl]prop-2-en-1-one To a solution of 6-(azetidin-3-yl)-N-(3,4-dichloro-2-fluoro-phenyl)-7-methoxy - pyrido[3,2-d] pyrimidin-4-amine (200 mg, 507 μmol) and sodium bicarbonate (128 mg, 1.52 mmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added prop-2-enoyl chloride (45.9 mg, 507 μmol), the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filtered cake was washed with water (3 mL) and concentrated in vacuo to give a residue. The crude product was triturated in ethyl acetate (30 mL) and then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1 to ethyl acetate/dichloromethane = 50:1) to give 1-[3-[4-(3,4-dichloro-2-fluoro-anilino)-7-methoxy- pyrido[3,2-d]pyrimidin-6-yl]azetidin-1-yl]prop-2-en-1-one (40.8 mg, 0.091 mmol, 17%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.82 (s, 1H), 8.65 (t, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.39 (dd, J = 2.4, 9.2 Hz, 1H), 6.45 - 6.37 (m, 1H), 6.36 - 6.26 (m, 1H), 5.75 (dd, J = 2.4, 10.0 Hz, 1H), 4.69 (d, J = 7.6 Hz, 2H), 4.59 - 4.47 (m, 2H), 4.42 – 4.32 (m, 1H), 4.08 (s, 3H); m/z ES+ [M+H] ⁺ 448.1. Example 241. Preparation of 1-[3-[4-(3-Chloro-2,4-difluoro-anilino)pyrido[3,4-d]pyrimidi n- 6-yl]azetidin-1-yl]prop-2-en-1-one (Compound 401)

Step 1. tert-Butyl 3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]azetidine-1-carboxylate A mixture of 6-chloro-N-(3-chloro-2,4-difluoro-phenyl)pyrido[3,4-d]pyrimi din-4-amine (870 mg, 2.66 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (1.26 g, 5.32 mmol), NiCl ₂ .glyme (58.4 mg, 265 μmol), pyridine-2-carboxamidine;hydrochloride (50.0 mg, 53.1 μmol), zinc powder (86.9 mg, 1.33 mmol) in dimethyl acetamide (4 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 1 hr under nitrogen atmosphere. The reaction mixture was added water (10 mL) and then filtered. The filter cake was collected and further purified by prep-HPLC (column: Phenomenex luna C18150x40mmx 15um; mobile phase: [water (0.1%trifluoroacetic acid)-acetonitrile]; B%: 22%-52%,11min) to give tert-butyl 3-[4-(3- chloro-2,4-difluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]azet idine-1-carboxylate (60.0 mg, 0.13 mmol, 5%) as a white solid. m/z ES+ [M+H] ⁺ 448.2. Step 2. 6-(Azetidin-3-yl)-N-(3-chloro-2,4-difluoro-phenyl)pyrido[3,4 -d]pyrimidin-4- amine To a solution of tert-butyl 3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]azetidine-1-carboxylate (55.0 mg, 122 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-(azetidin-3-yl)-N-(3-chloro-2,4-difluoro- phenyl)pyrido[3,4-d]pyrimidin-4-amine (50.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 348.0. Step 3. 1-[3-[4-(3-Chloro-2,4-difluoro-anilino)pyrido[3,4-d]pyrimidi n-6-yl]azetidin-1- yl]prop-2-en-1-one To a solution of 6-(azetidin-3-yl)-N-(3-chloro-2,4-difluoro-phenyl)pyrido[3,4 - d]pyrimidin-4-amine (45 mg, 129 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (10.8 mg, 129 μmol) and prop-2-enoyl chloride (11.7 mg, 129 μmol), the mixture was stirred at 0 °C for 1 hr. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 30%-60%,7min) and further purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%) to give 1-[3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,4-d]pyrimidi n-6-yl]azetidin-1-yl]prop-2- en-1-one (34.7 mg, 0.085 mmol, 66%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 - 10.21 (m, 1H), 9.23 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 7.67 - 7.52 (m, 1H), 7.44-7.40 (m, 1H), 6.42-6.36 (m, 1H), 6.17-6.12 (m, 1H), 5.76 - 5.66 (m, 1H), 4.70 (t, J = 8.0 Hz, 1H), 4.48 - 4.33 (m, 2H), 4.26 - 4.14 (m, 2H); m/z ES+ [M+H] ⁺ 402.0. Example 242. Preparation of N-[1-[4-[(5-Fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-prop-2-enamide (Compound 215) Step 1. tert-Butyl N-[1-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-carbamate To a mixture of 6-chloro-N-(5-fluoro-6-phenoxy-3-pyridyl)pyrido[3,2-d]pyrimi din-4- amine (400 mg, 1.09 mmol) in N-methylpyrrolidone (6 mL) was added N,N-diisopropylethylamine (703 mg, 5.44 mmol) and tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate (291 mg, 1.31 mmol), the mixture was stirred at 100 °C for 1 hour. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate 100 mL (50 mL x 2). The combined organic layers were washed with brine 100 mL (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 1/1) give tert-butyl N-[1-[4-[(5- fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl ]azetidin-3-yl]-N-methyl- carbamate (500 mg, 0.97 mmol, 84%) as a yellow oil. m/z ES+ [M+H] ⁺ 518.1 Step 2. N-(5-Fluoro-6-phenoxy-3-pyridyl)-6-[3-(methylamino)azetidin- 1-yl]pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl N-[1-[4-[(5-fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]azetidin-3-yl]-N-methyl-carbamate (200 mg, 386 μmol) in dichloromethane (5 mL) was added zinc bromide (870 mg, 3.86 mmol), the mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to give N-(5-fluoro- 6-phenoxy-3-pyridyl)-6-[3-(methylamino)azetidin-1-yl]pyrido[ 3,2-d]pyrimidin-4-amine (160 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 418.4 Step 3. N-[1-[4-[(5-Fluoro-6-phenoxy-3-pyridyl)amino]pyrido[3,2-d]py rimidin-6- yl]azetidin-3-yl]-N-methyl-prop-2-enamide To a mixture of N-(5-fluoro-6-phenoxy-3-pyridyl)-6-[3-(methylamino)azetidin- 1- yl]pyrido[3,2-d]pyrimidin-4-amine (160 mg, 383 μmol) in tetrahydrofuran (5 mL) and water (1 mL) was added sodium bicarbonate (32.2 mg, 383 μmol), followed by prop-2-enoyl chloride (34.7 mg, 383 μmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , dichloromethane: methanol = 10:1) to give N-[1-[4-[(5-fluoro-6-phenoxy-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]-N-m ethyl-prop-2-enamide (8.3 mg, 17.6 μmol, 4%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 - 9.53 (m, 1H), 8.63 - 8.59 (m, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.47 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.24 - 7.20 (m, 1H), 7.17 - 7.12 (m, 3H), 6.83 - 6.76 (m, 1H), 6.19 - 6.15 (m, 1H), 5.74 (d, J = 10.0 Hz, 1H), 5.34 - 5.29 (m, 1H), 4.48 - 4.46 (m, 2H), 4.35 - 4.25 (m, 2H), 3.17 - 3.05 (m, 3H); m/z ES+ [M+H] ⁺ 472.4. Example 243. Preparation of 1-[6-[4-(3,4-Dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]-1-azaspiro[3.3]heptan-1-yl]prop-2-en-1-one (Compound 180)

Step 1. tert-Butyl 6-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]-1- azaspiro[3.3]heptane-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-chloro-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, 203 μmol), tert-butyl 6-bromo-1- azaspiro[3.3]heptane-1-carboxylate (70.0 mg, 253 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (2.29 mg, 2.04 μmol), NiCl ₂ .dtbbpy (0.41 mg, 1.02 μmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (50.7 mg, 203 μmol) and sodium carbonate (43.2 mg, 407 μmol) in 1,2-dimethoxyethane (2 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hr under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mm, 10um; mobile phase:[water (0.1%trifluoroacetic acid)- acetonitrile]; B%: 62%-92%, 10 min) to afford tert-butyl 6-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-1-azaspiro[3.3]heptane- 1-carboxylate (40.0 mg, 69.5 μmol, 34%) as a yellow solid. m/z ES+ [M+H] ⁺ 504.3. Step 2. 6-(1-Azaspiro[3.3]heptan-6-yl)-N-(3,4-dichloro-2-fluoro-phen yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]-1-azaspiro[3.3]heptane-1-carboxylate (40.0 mg, 79.3 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol), the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-(1-azaspiro[3.3]heptan-6-yl)- N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin-4-ami ne (30.0 mg, crude, trifluoroacetic acid) as a brown oil. m/z ES+ [M+H] ⁺ 404.2. Step 3. 1-[6-[4-(3,4-Dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n-6-yl]-1- azaspiro[3.3]heptan-1-yl]prop-2-en-1-one To a solution of 6-(1-azaspiro[3.3]heptan-6-yl)-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (30 mg, 57.9 μmol, trifluoroacetic acid) and sodium bicarbonate (9.73 mg, 115 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2- enoyl chloride (5.24 mg, 57.9 μmol) dropwise at 0 °C, the mixture was stirred at 25 °C for 15 min. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 65%-95%, 10 min) to afford 1-[6-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1-azaspiro[3.3]heptan-1-yl]prop-2-en-1-one (4 mg, 7.61 μmol, 13%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 - 9.64 (m, 1H), 8.63 - 8.58 (m, 1H), 8.21 (t, J = 8.4 Hz, 1H), 8.17 - 8.10 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.22 - 7.14 (m, 1H), 6.91 - 6.83 (m, 1H), 6.29 - 6.19 (m, 1H), 6.15 - 6.07 (m, 1H), 5.76 - 5.59 (m, 1H), 4.15 - 3.93 (m, 3H), 3.74 - 3.64 (m, 1H), 3.21 - 3.16 (m, 1H), 3.09 - 2.83 (m, 1H), 2.67 - 2.59 (m, 2H), 2.39 - 2.26 (m, 2H); m/z ES+ [M+H] ⁺ 458.2. Example 244. Preparation of 1-(3-(4-((5-Chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)azetidin-1-yl)prop-2-en-1-one (Compound 245) Step 1. 6-Chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (220 mg, 1.10 mmol) in acetonitrile (3.0 mL) was added 5-chloro-2-fluoro-aniline (208 mg, 1.43 mmol). The mixture was stirred at 40 °C for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 6-chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine (180 mg, 0.58 mmol, 49%) as a yellow solid. m/z ES+ [M+H] ⁺ 309.0. Step 2. tert-Butyl 3-[4-(5-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] azetidine- 1-carboxylate A mixture of 6-chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine (80.0 mg, 259 μmol), tert-butyl 3-bromoazetidine-1-carboxylate (122 mg, 516 μmol), NiCl ₂ .glyme (5.69 mg, 25.9 μmol), pyridine-2-carboxamidine;hydrochloride (8.16 mg, 51.9 μmol) and zinc powder (50.8 mg, 776 μmol) in dimethyl acetamide (2.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 15 hr under nitrogen. Then pyridine-2-carboxamidine;hydrochloride (8.16 mg, 51.8 μmol) and NiCl2.glyme (5.69 mg, 25.9 μmol) was added into the mixture and the mixture was stirred at 60 °C for further 2 hr. On completion, the reaction mixture was diluted with water (10 mL) and filtered. The filter cake was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 5/1) to give tert-butyl 3-[4-(5- chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]azetidin e-1-carboxylate (50.0 mg, 0.12 mmol, 27%) as a yellow oil. m/z ES+ [M+H] ⁺ 430.2. Step 3. 6-(Azetidin-3-yl)-N-(5-chloro-2-fluorophenyl)pyrido[3,4-d]py rimidin-4-amine A solution of tert-butyl 3-[4-(5-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] azetidine-1-carboxylate (40.0 mg, 93.0 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1 mL) was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(azetidin-3-yl)-N-(5-chloro-2-fluorophenyl)pyrido[3,4-d]py rimidin-4-amine (40.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 330.3. Step 4. 1-(3-(4-((5-Chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimid in-6-yl)azetidin- 1-yl)prop-2-en-1-one To a solution of 6-(azetidin-3-yl)-N-(5-chloro-2-fluoro-phenyl)pyrido[3,4-d]p yrimidin-4- amine (40.0 mg, 121 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (30.6 mg, 364 μmol). The mixture was added prop-2-enoyl chloride (11.0 mg, 121 μmol, 9.9 μL) and stirred at 0 °C for 1 min. Then the reaction was added prop-2-enoyl chloride (11.0 mg, 121 μmol, 9.9 μL) and stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150x25mmx 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 28%-58%, 10 min) to give 1-(3-(4-((5-chloro-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)azetidin-1-yl )prop-2-en-1-one (8.1 mg, 0.021 mmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 - 10.20 (m, 1H), 9.22 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 7.71 (d, J = 4.4 Hz, 1H), 7.42 - 7.40 (m, 2H), 6.39 (dd, J = 10.4, 16.8 Hz, 1H), 6.15 (dd, J = 2.0, 17.2 Hz, 1H), 5.72 - 5.69 (m, 1H), 4.70 (t, J = 8.0 Hz, 1H), 4.43 - 4.39 (m, 2H), 4.22 - 4.18 (m, 2H); m/z ES+ [M+H] ⁺ 384.3. Example 245. Preparation of 1-[3-[4-(3-Ethynyl-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]azetidin-1-yl]prop-2-en-1-one (Compound 260) Step 1. 6-Chloro-N-[2-fluoro-3-(2-trimethylsilylethynyl)phenyl]pyrid o[3,4-d]pyrimidin- 4-amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (530 mg, 2.65 mmol) in acetonitrile (5.0 mL) was added 2-fluoro-3-(2-trimethylsilylethynyl)aniline (494 mg, 2.38 mmol). The mixture was stirred at 40 °C for 1 hr. On completion, the reaction mixture was filtered and the filte cake was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 6-chloro-N-[2-fluoro-3-(2- trimethylsilylethynyl)phenyl]pyrido[3,4-d]pyrimidin-4-amine (280 mg, 0.75 mmol, 25%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 9.08 (s, 1H), 8.72 - 8.51 (m, 2H), 7.60 (t, J = 6.4 Hz, 1H), 7.49 (t, J = 6.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 0.25 (s, 9H). Step 2. tert-Butyl 3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]pyrido[3,4 - d]pyrimidin-6-yl]azetidine-1-carboxylate A mixture of 6-chloro-N-[2-fluoro-3-(2-trimethylsilylethynyl)phenyl]pyrid o[3,4- d]pyrimidin-4-amine (200 mg, 539 μmol), tert-butyl 3-bromoazetidine-1-carboxylate (255 mg, 1.08 mmol), NiCl ₂ .glyme (11.9 mg, 53.9 μmol), pyridine-2-carboxamidine;hydrochloride (17.0 mg, 108 μmol) and zinc powder (106 mg, 1.62 mmol) in dimethyl acetamide (3.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 40 °C for 6.5 hrs under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (10 mL) and filtered. The filter cake was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 3/1) and further purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-[4-[2- fluoro-3-(2-trimethylsilylethynyl)anilino]pyrido[3,4-d]pyrim idin-6-yl]azetidine-1-carboxylate (25 mg, 0.051 mmol, 7.5%) as an off-white oil. m/z ES+ [M+H] ⁺ 492.2. Step 3. tert-Butyl 3-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl]azetidine-1-carboxylate To a solution of tert-butyl 3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]pyrido[3,4 -d] pyrimidin-6-yl]azetidine-1-carboxylate (20.0 mg, 40.7 μmol) in acetonitrile (0.5 mL) was added cesium carbonate (39.8 mg, 122 μmol), the mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (4 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 3-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]azetidine-1-carboxylate (15 mg, crude) as an orange oil. m/z ES+ [M+H] ⁺ 420.2. Step 4. 6-(Azetidin-3-yl)-N-(3-ethynyl-2-fluoro-phenyl)pyrido[3,4-d] pyrimidin-4-amine A solution of tert-butyl 3-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl ] azetidine-1-carboxylate (15 mg, 35.8 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(azetidin-3-yl)-N-(3-ethynyl-2-fluoro-phenyl)pyrido[3,4-d] pyrimidin-4-amine (15 mg, crude, trifluoroacetic acid) as a red oil. Step 5. 1-[3-[4-(3-Ethynyl-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl]azetidin-1- yl]prop-2-en-1-one To a solution of 6-(azetidin-3-yl)-N-(3-ethynyl-2-fluoro-phenyl)pyrido[3,4-d] pyrimidin- 4- amine (15.0 mg, 47.0 μmol) and sodium bicarbonate (11.8 mg, 141 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added prop-2-enoyl chloride (4.25 mg, 47.0 μmol) and the mixture was stirred at 0 °C for 10 min. Then prop-2-enoyl chloride (4.25 mg, 47.0 μmol) was added into the mixture and the mixture was stirred at 0 °C for another 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150x25mm, 10um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 24%-54%, 10 min) to give 1-[3-[4-(3-ethynyl-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]azetidin-1-yl]prop-2-en-1-one (5.0 mg, 0.013 mmol, 28.6%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 - 10.14 (m, 1H), 9.23 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.62 - 7.59 (m, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.32 - 7.28 (m, 1H), 6.40 (dd, J = 10.4, 17.2 Hz, 1H), 6.16 (dd, J = 2.0, 17.2 Hz, 1H), 5.71 (dd, J = 2.0, 10.4 Hz, 1H), 4.73 - 4.69 (m, 1H), 4.57 (s, 1H), 4.46 - 4.40 (m, 2H), 4.23 - 4.20 (m, 2H); m/z ES+ [M+H] ⁺ 374.4. Example 246. Preparation of 1-(6-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 314) Step 1. tert-Butyl 6-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(2-fluoro-3-methylphenyl)pyrido[3,2-d]pyrimidin-4 -amine (80.0 mg, 277 μmol) in dimethylsulfoxide (1 mL) was added N,N-diisopropylethylamine (48.3 μL, 276 μmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (54.9 mg, 277 μmol). The mixture was heated to 80 °C using an oil bath and stirring was continued for 18 hours. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (3 x 10 mL). The combined organic layers were concentrated in vacuo to afford tert-butyl 6-(4- ((2-fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -1,6-diazaspiro[3.3]heptane-1- carboxylate as a brown residue (135 mg, crude) that was carried forward without further purification. m/z ES+ [M+H] ⁺ 451.1. Step 2. N-(2-Fluoro-3-methylphenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (135 mg, 277 μmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL, 25.9 mmol). Stirring was continued at room temperature for 2 hours, before the mixture was concentrated in vacuo to afford a residue that was redissolved in dichloromethane (8 mL). The mixture was concentrated in vacuo to afford N-(2-fluoro-3-methylphenyl)-6-(1,6-diazaspiro[3.3]heptan-6-y l)pyrido[3,2-d]pyrimidin- 4-amine as a brown residue (97.1 mg, crude) that was carried forward without further purification. m/z ES+ [M+H] ⁺ 351.1. Step 3. 1-(6-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one To a solution of N-(2-fluoro-3-methylphenyl)-6-(1,6-diazaspiro[3.3]heptan-6- yl)pyrido[3,2-d]pyrimidin-4-amine (97.1 mg, 277 μmol) in tetrahydrofuran (1 mL) was added N,N-diisopropylethylamine (145 μL, 831 μmol). Acryloyl chloride (22.4 μL, 277 μmol) was added to the mixture and stirring was continued at room temperature for 1 hour. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (40 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford 1-(6-(4-((2- fluoro-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6 -diazaspiro[3.3]heptan-1-yl)prop- 2-en-1-one as a white powder (23.8 mg, 58.2 μmol, 21% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (s, 1H), 8.48 (s, 1H), 8.39 (dd, J = 24.0, 16.1 Hz, 1H), 7.98 (dd, J = 14.9, 9.0 Hz, 1H), 7.21 – 7.09 (m, 2H), 7.03 (t, J = 7.3 Hz, 1H), 6.62 – 6.25 (m, 1H), 6.25 – 6.07 (m, 1H), 5.79 – 5.63 (m, 1H), 4.85 – 4.22 (m, 4H), 4.07 (m, 2H), 2.58 (dt, J = 13.5, 6.4 Hz, 2H), 2.30 (d, J = 1.3 Hz, 3H); m/z ES+ [M+H] ⁺ 405.1. Example 247. Preparation of 1-(6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]hep tan-1-yl)prop-2-en-1-one (Compound 308) 1-(6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 246, Compound 314, starting from intermediate Int-67 (white powder, 16.8 mg, 39.0 μmol, 12% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (d, J = 26.9 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 7.92 (dd, J = 17.9, 9.0 Hz, 1H), 7.66 (t, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.5 Hz, 1H), 7.10 (dd, J = 26.3, 9.1 Hz, 1H), 6.86 (dd, J = 8.7, 2.7 Hz, 1H), 6.62 – 6.26 (m, 1H), 6.27 – 6.05 (m, 1H), 5.78 – 5.63 (m, 1H), 4.81 (d, J = 9.6 Hz, 1H), 4.52 (d, J = 9.6 Hz, 1H), 4.26 (dt, J = 9.5, 7.6 Hz, 6H), 4.15 (t, J = 7.4 Hz, 2H), 2.57 (dt, J = 11.7, 6.2 Hz, 2H). Example 248. Preparation of 1-(6-(4-((2,3,4-trifluorophenyl)amino)pyrido[3,2-d]pyrimidin - 6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one (Compound 312) 1-(6-(4-((2,3,4-trifluorophenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 246, Compound 314, starting from intermediate Int-68 (white powder, 4.30 mg, 10.1 μmol, 4.3% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.41 (s, 1H), 8.06 – 7.89 (m, 2H), 7.38 (d, J = 9.5 Hz, 1H), 7.14 (dd, J = 22.2, 9.1 Hz, 1H), 6.60 – 6.24 (m, 1H), 6.25 – 6.00 (m, 1H), 5.68 (dd, J = 10.2, 2.2 Hz, 1H), 4.89 – 4.18 (m, 4H), 4.13 (t, J = 7.4 Hz, 2H), 2.57 (dd, J = 19.6, 12.3 Hz, 2H); m/z ES+ [M+H] ⁺ 427.1. Example 249. Preparation of 1-(6-(4-((2,4-difluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 313) 1-(6-(4-((2,4-difluoro-3-methylphenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 246, Compound 314, starting from intermediate Int-69 (white powder, 18.2 mg, 43.1 μmol, 17% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.44 (s, 1H), 8.23 – 8.06 (m, 1H), 7.97 (dd, J = 14.5, 9.0 Hz, 1H), 7.21 – 7.05 (m, 2H), 6.63 – 6.25 (m, 1H), 6.25 – 6.05 (m, 1H), 5.80 – 5.63 (m, 1H), 4.86 – 4.22 (m, 4H), 4.15 (t, J = 7.4 Hz, 2H), 2.59 (dd, J = 19.6, 12.2 Hz, 2H), 2.22 (s, 3H); m/z ES+ [M+H] ⁺ 423.1. Example 250. Preparation of 1-(6-(4-((2,3-difluoro-4-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)prop-2-en-1 -one (Compound 357) 1-(6-(4-((2,3-difluoro-4-methylphenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 246, Compound 314, starting from intermediate Int-70 (white powder, 15.0 mg, 35.5 μmol, 15% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (s, 1H), 8.43 (s, 1H), 8.09 – 7.77 (m, 2H), 7.29 – 7.04 (m, 2H), 6.20 (ddd, J = 19.2, 16.9, 6.2 Hz, 2H), 5.69 (dd, J = 10.2, 2.2 Hz, 1H), 4.79 (d, J = 9.5 Hz, 1H), 4.50 (d, J = 4.0 Hz, 1H), 4.29 (d, J = 9.5 Hz, 2H), 4.15 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.4 Hz, 2H), 2.29 (s, 3H); m/z ES+ [M+H] ⁺ 423.3. Example 251. Preparation of 1-(6-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)but-2-yn-1- one (Compound 248) Step 1. tert-Butyl 6-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 6-chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4- amine (100 mg, 291 μmol) in dimethylsulfoxide (1 mL) was added tert-butyl 1,6- diazaspiro[3.3]heptane-1-carboxylate (57.7 mg, 291 μmol). The mixture was heated to 120 °C using an oil bath. Stirring was continued for 1 hour. The oil bath was removed and the reaction mixture was allowed to come to room temperature. Tert-butyl 6-(4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspi ro[3.3]heptane-1-carboxylate was afforded as a brown solid by filtering the reaction mixture. Material (147 mg, crude) was carried forward without purification. m/z ES+ [M+H] ⁺ 505.2. Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan -6-yl)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl 6-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (147 mg, 291 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL, 12.9 mmol). Stirring was continued for 18 hours at room temperature. The mixture was concentrated in vacuo. The residue was redissolved in dichloromethane (20 mL) and concentrated in vacuo. N-(3,4-dichloro-2- fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d ]pyrimidin-4-amine was obtained as a crude brown residue (118 mg, crude) that was carried forward without further purification. m/z ES+ [M+H] ⁺ 405.1. Step 3. 1-(6-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)but-2-yn-1-one To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-(1,6-diazaspiro[3.3]heptan -6- yl)pyrido[3,2-d]pyrimidin-4-amine (58.8 mg, 145 μmol) in tetrahydrofuran (2 mL) was added acid chloride (0.25 M in dichloromethane, 580 μL, 145 μmol). Stirring was continued for 18 hours. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-90%) as an eluent. The pure fractions were collected and lyophilized to afford 1-(6-(4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspi ro[3.3]heptan-1-yl)but-2-yn-1-one (25.0 mg, 53.7 μmol, 37% over three steps) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 9.26 (s, 1H), 8.48 (s, 2H), 8.47 – 8.39 (m, 2H), 8.01 (d, J = 9.1 Hz, 1H), 7.97 (d, J = 9.1 Hz, 1H), 7.61 (dd, J = 3.1, 2.0 Hz, 1H), 7.58 (dd, J = 3.2, 2.0 Hz, 1H), 7.20 (d, J = 9.1 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 4.78 (s, 2H), 4.72 (d, J = 10.2 Hz, 2H), 4.44 (d, J = 10.5 Hz, 2H), 4.29 (d, J = 10.2 Hz, 2H), 4.05 (t, J = 7.3 Hz, 2H), 3.87 – 3.80 (m, 2H), 2.66 – 2.60 (m, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.01 (s, 3H), 1.27 (s, 3H); m/z ES+ [M+H] ⁺ 471.1. Example 252. Preparation of 1-(6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)but-2-yn-1- one (Compound 210) 1-(6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)but-2-yn-1-one was prepared according to the general scheme outlined in Example 251, Compound 248, starting from intermediate Int-29 (white powder, 8.50 mg, 19.5 μmol, 20% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 9.24 (s, 1H), 8.44 (s, 2H), 8.37 (dd, J = 10.1, 2.4 Hz, 1H), 8.35 – 8.28 (m, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.40 – 7.30 (m, 2H), 7.31 – 7.24 (m, 2H), 7.16 (d, J = 9.1 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H), 4.76 (s, 2H), 4.69 (d, J = 10.0 Hz, 2H), 4.41 (d, J = 9.8 Hz, 2H), 4.27 (d, J = 10.3 Hz, 2H), 4.02 (t, J = 7.5 Hz, 2H), 3.81 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.4 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.98 (s, 3H), 1.23 (s, 3H); m/z ES+ [M+H] ⁺ 437.1. Example 253. Preparation of 1-(6-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.3]heptan-1-yl)but-2-yn-1- one (Compound 212) 1-(6-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrido[3,2-d] pyrimidin-6-yl)-1,6- diazaspiro[3.3]heptan-1-yl)but-2-yn-1-one was prepared using the general scheme outlined in Example 251, Compound 248, starting from intermediate Int-7 (white powder, 23.4 mg, 45.7 μmol, 29% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 9.48 (s, 1H), 8.77 (dd, J = 4.3, 2.4 Hz, 2H), 8.67 (dd, J = 14.0, 2.3 Hz, 2H), 8.46 (d, J = 2.5 Hz, 2H), 7.98 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.43 (t, J = 7.8 Hz, 4H), 7.22 (t, J = 7.4 Hz, 2H), 7.19 – 7.06 (m, 6H), 4.84 (s, 2H), 4.75 (d, J = 9.9 Hz, 2H), 4.44 (d, J = 10.0 Hz, 2H), 4.30 (d, J = 9.9 Hz, 2H), 4.05 (t, J = 7.7 Hz, 2H), 3.85 (d, J = 7.1 Hz, 2H), 2.64 – 2.56 (m, 4H), 2.01 (s, 3H), 1.26 (s, 3H); m/z ES+ [M+H] ⁺ 512.2. Example 254. Preparation of N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)but-2-ynamide (Compound 211)

Step 1. tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)azetidin-3-yl)carbamate To a solution of 6-chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine (150 mg, 485 μmol) in N-methylpyrrolidinone (2 mL) was added 3-(boc-amino)azetidine (91.9 mg, 534 μmol). Triethylamine (205 μL, 1.46 mmol) was added and the mixture was heated to 100 °C. Stirring was continued for 18 hours. The oil bath was removed and the mixture was allowed to cool to room temperature. The mixture was purified using C18 reverse phase chromatography (40 g cartridge) with ammonium formate (10 mM) and acetonitrile (10-90% gradient) as an eluent. The pure fractions were collected and lyophilized to afford tert-butyl (1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl )carbamate as a white , 85.4 μmol, 18%). m/z ES+ [M+H] ⁺ 445.1. Step 2. 6-(3-Aminoazetidin-1-yl)-N-(3-chloro-2-fluorophenyl)pyrido[3 ,2-d]pyrimidin-4- amine To a solution of tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)carbamate (38.0 mg, 85.4 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (500 μL, 6.53 mmol). Stirring was continued for 2 hours at room temperature. The mixture was concentrated in vacuo and the residue was redissolved in dichloromethane (2 mL). The mixture was concentrated in vacuo once more to afford 6-(3- aminoazetidin-1-yl)-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d] pyrimidin-4-amine as a crude brown residue (29.4 mg, crude) that was carried forward without further purification. m/z ES+ [M+H] ⁺ 345.2. Step 3. N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)azetidin- 3-yl)but-2-ynamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(3-chloro-2-fluorophenyl)pyrido[3 ,2- d]pyrimidin-4-amine (7.72 mg, 22.4 μmol) in tetrahydrofuran (1 mL) was added triethylamine (9.46 μL, 67.2 μmol) and the mixture was cooled to 0 °C. But-2-ynoyl chloride (0.25 M in dichloromethane, 98.5 μL, 24.6 μmol) was added and the cooling bath was removed. Stirring was continued at room temperature for 1 hour. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (40 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-90% gradient) as eluent. The pure fractions were collected and lyophilized to afford N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)but-2-ynamide as a white powder (3.8 mg, 9.25 μmol, 41% over two steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 9.25 (d, J = 6.5 Hz, 1H), 8.44 (s, 1H), 8.29 (t, J = 6.9 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.40 – 7.33 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.43 (t, J = 8.4 Hz, 2H), 4.10 – 3.94 (m, 2H), 1.98 (s, 3H); m/z ES+ [M+H] ⁺ 411.1. Example 255. Preparation of (R)-N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 392) Step 1. (R)-tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)pyrrolidin-3-yl)carbamate To a solution of 6-chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine (150 mg, 485 μmol) in dimethylsulfoxide (2 mL) was added (R)-(+)-tert-butyl pyrrolidin-3-yl carbamate (92.2 mg, 495 μmol) and N,N-diisopropylethylamine (254 μL, 1.46 mmol). The mixture was heated to 100 ℃ and stirring was continued for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford (R)-tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin - 6-yl)pyrrolidin-3-yl)carbamate as a brown residue (223 that was carried forward without further purification. m/z ES+ [M+H] ⁺ 459.1. Step 2. (R)-6-(3-Aminopyrrolidin-1-yl)-N-(3-chloro-2-fluorophenyl)py rido[3,2- d]pyrimidin-4-amine To a solution of (R)-tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)carbamate (223 mg, 485 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL, 24.3 mmol). Stirring was continued for 2 hours. The mixture was concentrated in vacuo to afford a residue that was redissolved in dichloromethane (10 mL). The mixture was concentrated in vacuo to afford (R)-6-(3-aminopyrrolidin-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine as a brown residue (174 that was carried forward without further purification. m/z ES+ [M+H] ⁺ 359.1. Step 3. (R)-N-(1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)pyrrolidin-3-yl)acrylamide To a solution of (R)-6-(3-aminopyrrolidin-1-yl)-N-(3-chloro-2-fluorophenyl)py rido[3,2- d]pyrimidin-4-amine (174 mg, 485 μmol) in tetrahydrofuran (10 mL) was added N,N- diisopropylethylamine (253 μL, 1.45 mmol) and acryloyl chloride (39.2 μL, 485 μmol). Stirring was continued for 1 hour. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate (10 mM) and acetonitrile (10-100 % gradient) as an eluent. The pure fractions were collected and lyophilized to afford (R)-N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)pyrrolidin-3-yl)acrylamide as a white solid (24.1 mg, 58.2 μmol, 12% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.45 (d, J = 7.0 Hz, 1H), 8.43 (s, 1H), 8.35 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.45 – 7.12 (m, 3H), 6.19 (ddd, J = 19.5, 17.1, 6.2 Hz, 2H), 5.61 (dd, J = 9.9, 2.4 Hz, 1H), 4.54 (dd, J = 11.0, 5.5 Hz, 1H), 3.87 (dd, J = 10.9, 6.3 Hz, 1H), 3.70 (s, 2H), 3.53 (s, 1H), 2.27 (dt, J = 13.5, 6.6 Hz, 1H), 2.02 (dt, J = 11.6, 5.7 Hz, 1H); m/z ES+ [M+H] ⁺ 413.1. Example 256. Preparation of (S)-N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 393) (S)-N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)pyrrolidin-3- yl)acrylamide was prepared using the general scheme outlined in Example 255, Compound 392, starting from (S)-(+)-3-(Boc-amino)pyrrolidine in Step 1 (white powder, 32.1 mg, 77.8 μmol, 16% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.45 (d, J = 7.1 Hz, 1H), 8.43 (s, 1H), 8.34 (t, J = 6.9 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.43 – 7.17 (m, 3H), 6.18 (ddd, J = 19.5,17.1, 6.2 Hz, 2H), 5.61 (dd, J = 9.9, 2.4 Hz, 1H), 4.59 – 4.47 (m, 1H), 3.87 (dd, J = 11.0, 6.1 Hz, 1H), 3.71 (s, 2H), 3.52 (s, 1H), 2.28 (td, J = 13.9, 7.7 Hz, 1H), 2.01 (td, J = 12.4, 5.8 Hz, 1H); m/z ES+ [M+H] ⁺ 413.1. Example 257. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 250) Step 1. (1S,4S)-tert-Butyl 5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of 6-chloro-N-(3-chloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4 -amine (254 mg, 821 μmol) in dimethylsulfoxide (5 mL) was added (1S,4S)-tertbutyl-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (179 mg, 903 μmol) and N,N-diisopropylethylamine (431 μL, 2.46 mmol). The mixture was heated to 80 °C and stirring was continued for 18 hours. The mixture was cooled to room temperature and purified using C18 reverse phase chromatography (60 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford (1S,4S)-tert- butyl 5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (271 mg, 575 μmol, 70%) as a white solid. m/z ES+ [M+H] ⁺ 471.1. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 - fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of (1S,4S)-tert-butyl 5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (200 mg, 425 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL, 25.9 mmol). Stirring was continued for 2 hours. The mixture was concentrated in vacuo and the residue was redissolved in dichloromethane (10 mL). The mixture was concentrated in vacuo to afford 6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2-fluorophenyl)p yrido[3,2-d]pyrimidin-4-amine as a brown residue (157 mg, crude) that was carried forward without further purification. m/z ES+ [M+H] ⁺ 371.2. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 - fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, 323 μmol) in tetrahydrofuran (1 mL) was added triethylamine (136 μL, 969 μmol) and acryloyl chloride (26.1 μL, 323 μmol). Stirring was continued for 1 hour. The mixture was concentrated in vacuo and the residue was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford 1-((1S,4S)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (36.9 mg, 87.2 μmol, 27%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.40 (d, J = 3.3 Hz, 1H), 8.18 (s, 1H), 7.94 (dd, J = 9.2, 3.9 Hz, 1H), 7.55 – 7.10 (m, 3H), 6.62 (m, 1H), 6.14 (ddd, J = 16.8, 6.1, 2.3 Hz, 1H), 5.67 (ddd, J = 22.6, 10.3, 2.3 Hz, 1H), 5.27 (s, 1H), 5.01 (m, 1H), 3.84 – 3.39 (m, 4H), 2.05 (d, J = 30.5 Hz, 2H); m/z ES+ [M+H] ⁺ 425.2. Example 258. Preparation of 1-((1S,4S)-5-(4-((3,5-difluoro-4-methylpyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 415) 1-((1S,4S)-5-(4-((3,5-difluoro-4-methylpyridin-2-yl)amino)py rido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-82 in Step 1 (white powder, 7.00 mg, 16.5 μmol, 5% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77 (s, 1H), 8.36 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 9.2, 3.5 Hz, 1H), 6.84 – 6.29 (m, 1H), 6.14 (ddd, J = 16.7, 5.9, 2.2 Hz, 1H), 5.67 (ddd, J = 21.3, 10.3, 2.2 Hz, 1H), 4.99 (d, J = 54.7 Hz, 1H), 3.78 – 3.36 (m, 6H), 2.31 (s, 3H), 2.02 (d, J = 29.3 Hz, 2H); m/z ES+ [M+H] ⁺ 424.1. Example 259. Preparation of 3-((6-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluorobenzonitrile (Compound 398) 3-((6-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl )pyrido[3,2-d]pyrimidin-4- yl)amino)-2-fluorobenzonitrile was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-81 in Step 1 (white powder, 11.7 mg, 28.0 mmol, 32% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.49 (s, 1H), 8.41 (d, J = 4.0 Hz, 1H), 7.95 (dd, J = 9.2, 4.1 Hz, 1H), 7.72 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 6.62 (m, 1H), 6.14 (ddd, J = 16.8, 6.0, 2.3 Hz, 1H), 5.67 (ddd, J = 22.6, 10.3, 2.3 Hz, 1H), 5.01 (m, 1H), 3.83 – 3.25 (m, 6H), 2.06 (d, J = 30.9 Hz, 2H); m/z ES+ [M+H] ⁺ 416.1. Example 260. Preparation of 1-((1S,4S)-5-(4-((5-chloro-2,4- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 372) 1-((1S,4S)-5-(4-((5-chloro-2,4-difluorophenyl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-34 in Step 1 (white powder, 100 mg, 226 μmol, 37% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 8.40 (d, J = 2.2 Hz, 2H), 7.92 (dd, J = 9.2, 4.0 Hz, 1H), 7.69 (t, J = 10.0 Hz, 1H), 7.30 (s, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 6.0, 2.3 Hz, 1H), 5.67 (ddd, J = 22.6, 10.3, 2.3 Hz, 1H), 5.00 (m, 2H), 4.14 – 3.63 (m, 2H), 3.62 – 3.38 (m, 2H), 2.05 (d, J = 30.2 Hz, 2H); m/z ES+ [M+H] ⁺ 442.8. Example 261. Preparation of 1-((1S,4S)-5-(4-((5-fluoropyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 373) 1-((1S,4S)-5-(4-((5-fluoropyridin-3-yl)amino)pyrido[3,2-d]py rimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-80 in Step 1 (white powder, 83.4 mg, 218 μmol, 20% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 9.01 (d, J = 6.7 Hz, 1H), 8.62 – 8.51 (m, 1H), 8.48 (s, 1H), 8.29 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 9.2, 2.9 Hz, 1H), 7.22 (s, 1H), 6.62 (m, 1H), 6.15 (ddd, J = 16.8, 7.5, 2.2 Hz, 1H), 5.67 (ddd, J = 26.0, 10.3, 2.3 Hz, 1H), 5.02 (m, 1H), 4.09 (s, 1H), 3.79 – 3.41 (m, 4H), 2.05 (d, J = 28.3 Hz, 2H); m/z ES+ [M+H] ⁺ 391.9. Example 262. Preparation of 1-((1S,4S)-5-(4-((5-chloropyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 374) 1-((1S,4S)-5-(4-((5-chloropyridin-3-yl)amino)pyrido[3,2-d]py rimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-79 in Step 1 (white powder, 100 mg, 240 μmol, 20% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 9.24 – 9.05 (m, 1H), 8.70 (dd, J = 4.7, 2.5 Hz, 1H), 8.50 (d, J = 11.7 Hz, 1H), 8.38 – 8.11 (m, 1H), 7.94 (dd, J = 9.2, 2.9 Hz, 1H), 7.26 (s, 1H), 6.62 (m, 1H), 6.15 (ddd, J = 16.8, 7.3, 2.3 Hz, 1H), 5.67 (ddd, J = 25.6, 10.3, 2.3 Hz, 1H), 5.02 (m, 1H), 3.63 (m, 5H), 2.05 (d, J = 28.4 Hz, 2H); m/z ES+ [M+H] ⁺ 407.8. Example 263. Preparation of 1-((1S,4S)-5-(4-((5-chloro-6-methoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 375) 1-((1S,4S)-5-(4-((5-chloro-6-methoxypyridin-3-yl)amino)pyrid o[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-78 in Step 1 (white powder, 100 mg, 228 μmol, 19% over three steps. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.68 (dd, J = 5.5, 2.2 Hz, 1H), 8.48 (dd, J = 4.5, 2.3 Hz, 1H), 8.38 (s, 1H), 7.90 (dd, J = 9.2, 2.8 Hz, 1H), 7.23 (s, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 6.8, 2.2 Hz, 1H), 5.67 (ddd, J = 23.9, 10.2, 2.2 Hz, 2H), 5.01 (m, 1H), 3.96 (s, 3H), 3.81 – 3.36 (m, 4H), 2.04 (d, J = 28.5 Hz, 2H); ). m/z ES+ [M+H] ⁺ 437.8. Example 264. Preparation of 1-((1S,4S)-5-(4-((5-fluoro-6-methoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 376) 1-((1S,4S)-5-(4-((5-fluoro-6-methoxypyridin-3-yl)amino)pyrid o[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-77 in Step 1 (white powder, 100 mg, 239 μmol 21% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.51 (dd, J = 5.2, 2.1 Hz, 1H), 8.38 (s, 1H), 8.32 (ddd, J = 12.5, 4.4, 2.2 Hz, 1H), 7.90 (dd, J = 9.2, 2.8 Hz, 1H), 7.25 (s, 1H), 6.61 (m, 1H), 6.15 (ddd, J = 16.8, 6.9, 2.3 Hz, 1H), 5.67 (ddd, J = 24.2, 10.3, 2.3 Hz, 2H), 5.01 (m, 1H), 3.96 (s, 3H), 3.61 (m, 4H), 2.04 (d, J = 28.6 Hz, 2H); m/z ES+ [M+H] ⁺ 422.0. Example 265. Preparation of 1-((1S,4S)-5-(4-((3-fluoro-2-methoxyphenyl)amino)pyrido[3,2- (Compound 377) 1-((1S,4S)-5-(4-((3-fluoro-2-methoxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-76 in Step 1 (white powder, 100 mg, 239 μmol, 21% over three steps). ¹ H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.60 (dd, J = 8.3, 1.0 Hz, 1H), 8.51 (s, 1H), 7.96 (dd, J = 9.2, 2.8 Hz, 1H), 7.34 (s, 1H), 7.18 (td, J = 8.4, 6.0 Hz, 1H), 7.04 – 6.94 (m, 1H), 6.62 (m, 1H), 6.14 (ddd, J = 16.8, 4.4, 2.3 Hz, 1H), 5.67 (ddd, J = 25.7, 10.3, 2.3 Hz, 1H), 5.06 (t, J = 37.2 Hz, 2H), 4.02 (s, 3H), 3.86 – 3.50 (m, 4H), 2.10 (dd, J = 31.6, 6.3 Hz, 2H); m/z ES+ [M+H] ⁺ 421.0. Example 266. Preparation of 1-((1S,4S)-5-(4-((2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 378) 1-((1S,4S)-5-(4-((2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-75 in Step 1 (white powder, 100 mg, 254 μmol, 24% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 7.91 (dd, J = 9.2, 3.5 Hz, 1H), 7.45 – 7.02 (m, 4H), 6.59 (m, 1H), 6.12 (ddd, J = 16.9, 5.7, 2.3 Hz, 1H), 5.64 (ddd, J = 22.6, 10.3, 2.3 Hz, 1H), 4.98 (m, 2H), 3.63 (m, 4H), 2.03 (d, J = 30.3 Hz, 2H); m/z ES+ [M+H] ⁺ 391.0. Example 267. Preparation of 1-((1S,4S)-5-(4-((2,4-difluoro-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 311) 1-((1S,4S)-5-(4-((2,4-difluoro-3-methylphenyl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-69 in Step 1 (white powder, 24.8 mg, 57.4 μmol, 22% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.99 (s, 1H), 7.92 (dd, J = 9.2, 3.6 Hz, 1H), 7.28 (s, 1H), 7.13 (td, J = 9.0, 1.6 Hz, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 6.0, 2.3 Hz, 1H), 5.67 (ddd, J = 22.2, 10.3, 2.3 Hz, 1H), 5.25 (s, 1H), 5.00 (d, m, 1H), 3.80 – 3.40 (m, 4H), 2.22 (s, 3H), 2.05 (d, J = 30.6 Hz, 2H); m/z ES+ [M+H] ⁺ 423.2. Example 268. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 315) 1-((1S,4S)-5-(4-((2,3-difluoro-4-methylphenyl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-70 in Step 1 (white powder, 7.40 mg, 17.2 μmol, 8% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.35 (d, J = 3.1 Hz, 1H), 7.92 (dd, J = 9.2, 3.8 Hz, 1H), 7.78 (s, 1H), 7.28 (s, 1H), 7.15 (t, J = 7.7 Hz, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 5.9, 2.3 Hz, 1H), 5.67 (ddd, J = 22.1, 10.3, 2.3 Hz, 1H), 5.32 (s, 1H), 5.00 (m, 1H), 3.86 – 3.38 (m, 4H), 2.30 (d, J = 1.5 Hz, 3H), 2.05 (d, J = 30.6 Hz, 2H); m/z ES+ [M+H] ⁺ 423.2. Example 269. Preparation of 1-((1S,4S)-5-(4-((2,3,4-trifluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 316) 1-((1S,4S)-5-(4-((2,3,4-trifluorophenyl)amino)pyrido[3,2-d]p yrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-68 in Step 1 (white powder, 21.1 mg, 47.5 μmol, 15% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.34 (d, J = 3.0 Hz, 1H), 7.92 (dd, J = 9.2, 3.9 Hz, 1H), 7.81 (s, 1H), 7.39 (td, J = 10.3, 2.1 Hz, 1H), 7.27 (s, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 5.9, 2.3 Hz, 1H), 5.67 (ddd, J = 21.8, 10.3, 2.3 Hz, 1H), 5.32 (s,1H), 5.01 (m, 1H), 3.84 –3.37 (m, 4H), 2.04 (d, J = 30.6 Hz, 2H); m/z ES+ [M+H] ⁺ 427.0. Example 270. Preparation of 1-((1S,4S)-5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 307) 1-((1S,4S)-5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino) pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-67 in Step 1 (white powder, 13.1 mg, 30.5 μmol, 10% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.27 (m, 1H), 7.85 (dd, J = 9.2, 3.1 Hz, 1H), 7.60 (t, J = 2.7 Hz, 1H), 7.45 – 7.00 (m, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.59 (m, 1H), 6.12 (ddd, J = 16.8, 6.5, 2.3 Hz, 1H), 5.65 (ddd, J = 24.3, 10.3, 2.3 Hz, 2H), 4.98 (m, 1H), 4.23 (dt, J = 5.1, 3.8 Hz, 4H), 3.76 – 3.53 (m, 4H), 2.01 (d, J = 29.1 Hz, 2H); m/z ES+ [M+H] ⁺ 431.3. Example 271. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2,4- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 309) 1-((1S,4S)-5-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-52 in Step 1 (white powder, 17.3 mg, 39.8 μmol, 25% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.92 (dd, J = 9.2, 3.9 Hz, 1H), 7.40 (td, J = 9.0, 1.8 Hz, 1H), 7.28 (s, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 5.9, 2.3 Hz, 1H), 5.67 (ddd, J = 21.7, 10.2, 2.3 Hz, 1H), 5.32 (s, 1H), 5.00 (m, 1H), 3.83 – 3.36 (m, 4H), 2.06 (dd, J = 15.5, 15.1 Hz, 2H); m/z ES+ [M+H] ⁺ 443.0. Example 272. Preparation of 1-((1S,4S)-5-(4-((2,3-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 295) 1-((1S,4S)-5-(4-((2,3-difluorophenyl)amino)pyrido[3,2-d]pyri midin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-40 in Step 1 (white powder, 19.3 mg, 47.3 μmol, 21% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.40 (s, 1H), 7.94 (dd, J = 9.2, 3.9 Hz, 1H), 7.26 (t, J = 6.9 Hz, 1H), 6.81 (dd, J = 16.7, 10.3 Hz, 1H), 6.42 (dd, J = 16.8, 10.3 Hz, 1H), 6.14 (ddd, J = 16.8, 5.9, 2.3 Hz, 1H), 5.67 (ddd, J = 22.3, 10.3, 2.3 Hz, 1H), 5.01 (m, 2H), 3.81 – 3.36 (m, 6H), 2.05 (d, J = 30.8 Hz, 2H); m/z ES+ [M+H] ⁺ 409.2. Example 273. Preparation of 1-((1S,4S)-5-(4-((4-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 296) 1-((1S,4S)-5-(4-((4-chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-74 in Step 1 (white powder, 19.1 mg, 45.0 μmol, 19% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.39 (d, J = 2.9 Hz, 1H), 8.27 (br. s, 1H), 7.93 (dd, J = 9.2, 3.7 Hz, 1H), 7.57 (dd, J = 10.7, 2.3 Hz, 1H), 7.39 – 7.34 (m, 1H), 7.45 – 7.08 (br. s, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 5.9, 2.3 Hz, 1H), 5.67 (ddd, J = 22.9, 10.3, 2.3 Hz, 1H), 5.32 (br. s, 1H), 5.00 (m, 1H), 3.92 – 3.32 (m, 4H), 2.05 (d, J = 30.8 Hz, 2H); m/z ES+ [M+H] ⁺ 425.1. Example 274. Preparation of 1-((1S,4S)-5-(4-((4-chloro-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (Compound 297) 1-((1S,4S)-5-(4-((4-chloro-2,3-difluorophenyl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-73 in Step 1 (white powder, 13.3 mg, 30.0 μmol, 13% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.40 (d, J = 3.5 Hz, 1H), 8.05 (br. s, 1H), 7.94 (dd, J = 9.2, 4.3 Hz, 1H), 7.54 – 7.46 (m, 1H),7.30 (br. s, 1H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 6.0, 2.3 Hz, 1H), 5.67 (ddd, J = 22.8, 10.3, 2.3 Hz, 1H), 5.32 (br. s, 1H), 5.01 (m, 1H), 3.89 – 3.37 (m, 4H), 2.05 (d, J = 30.4 Hz, 2H); m/z ES+ [M+H] ⁺ 443.2. Example 275. Preparation of 1-((1S,4S)-5-(4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 249) 1-((1S,4S)-5-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-45 in Step 1 (white powder, 19.5 mg, 42.5 μmol, 15% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.40 (d, J = 3.8 Hz, 1H), 8.24 (s, 1H), 7.93 (dd, J = 9.2, 4.8 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.33 (s, 1H), 6.62 (m, 1H), 6.14 (ddd, J = 16.8, 6.1, 2.3 Hz, 1H), 5.67 (ddd, J = 23.3, 10.3, 2.3 Hz, 1H), 5.23 (s, 1H), 5.01 (m, 1H), 3.82 – 3.42 (m, 4H), 2.06 (d, J = 30.2 Hz, 2H); m/z ES+ [M+H] ⁺ 459.0. Example 276. Preparation of 1-((1S,4S)-5-(4-((5-chloro-6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 251) 1-((1S,4S)-5-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrid o[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-7 in Step 1 (white powder, 11.0 mg, 22.0 μmol, 38% over three steps). ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.67 (t, J = 2.3 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.27 – 7.16 (m, 2H), 7.16 – 7.04 (m, 2H), 6.87 – 6.36 (m, 1H), 6.28 (ddd, J = 16.8, 8.4, 1.9 Hz, 1H), 5.75 (ddd, J = 28.5, 10.4, 1.9 Hz, 1H), 5.43 (d, J = 41.6 Hz, 1H), 5.05 (d, J = 15.2 Hz, 1H), 3.86 – 3.49 (m, 5H), 2.17 – 2.06 (m, 2H); m/z ES+ [M+H] ⁺ 500.2. Example 277. Preparation of 1-((1S,4S)-5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 310) 1-((1S,4S)-5-(4-((2-fluoro-3-methylphenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-8 in Step 1 (white powder, 245 mg, 606 μmol, 24% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.41 (d, J = 1.9 Hz, 1H), 8.17 (m, 1H), 7.92 (dd, J = 9.2, 3.5 Hz, 1H), 7.30 (s, 1H), 7.16 (dd, J = 17.7, 10.0 Hz, 1H), 7.05 (t, J = 7.1 Hz, 1H), 6.62 (m, 1H), 6.14 (ddd, J = 16.8, 6.4, 2.3 Hz, 1H), 5.67 (ddd, J = 23.6, 10.3, 2.3 Hz, 1H), 5.20 (m, 1H), 5.00 (m, 1H), 3.82 – 3.38 (m, 4H), 2.30 (d, J = 1.4 Hz, 3H), 2.06 (d, J = 30.3 Hz, 2H); m/z ES+ [M+H] ⁺ 405.2. Example 278. Preparation of (E)-1-((1S,4S)-5-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)-4- (dimethylamino)but-2-en-1-one (Compound 417) 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluorophenyl)pyrido[3,2- d]pyrimidin-4-amine was prepared using the general scheme outlined in Example 257, Compound 250 for steps 1 and 2 starting from intermediate Int-29. Step 3. (E)-1-((1S,4S)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3 ,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(dimethylamino)but -2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 - fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (31.5 mg, 85.0 μmol) in tetrahydrofuran (5 mL) was added N,N-diisopropylethylamine (500 μL, 2.87 mmol) and (E)-4-bromobut-2-enoyl chloride (15.6 mg, 85.9 μmol). Stirring was continued for 5 minutes. Dimethylamine (46.8 μL, 93.5 μmol) was added to the mixture and stirring was continued for 1 hour. The solution was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford (E)-1-((1S,4S)- 5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4-(dimethylamino)but-2-en-1- one as a white solid (6.7 mg, 20.7 μmol, 24%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 18.6 Hz, 1H), 7.92 (dd, J = 9.2, 3.6 Hz, 1H), 7.30 (dd, J = 25.7, 17.7 Hz, 3H), 6.72 – 6.11 (m, 2H), 5.52 – 5.05 (m, 1H), 4.96 (m, 1H), 3.63 (m, 4H), 3.10 – 2.95 (m, 2H), 2.17 (s, 3H), 2.10 (s, 3H), 2.04 (t, J = 15.0 Hz, 2H); m/z ES+ [M+H] ⁺ 482.0. Example 279A and B. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2- en-1-one (Compound 394) and 1-((1R,4R)-5-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2- en-1-one (Compound 395) 1-((1S,4S)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one and 1-((1R,4R)-5-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2-en- 1-one were prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate as the piperazine in Step 1. The enantiomers were separated using an i-amylose-110 x 250 mm 5 um column with an i-amylose-1 10 x 10 mm 5 um pre column. Flow rate was 10 mL/min with an isocratic mobile phase at 30% isopropanol-0.1% NH ₄ OH / 70% supercritical CO ₂ . Run time was 25 minutes. Column pressure was 150 bar and column temperature was 40 °C. 1-((1S,4S)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one was obtained as a white solid (8.50 mg, 19.4 μmol, 7.9 % over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.36 (s, 1H), 7.98 (t, J = 30.5 Hz, 2H), 7.29 (dd, J = 28.8, 20.6 Hz, 3H), 6.71 (m, 1H), 6.25 – 6.02 (m, 1H), 5.68 (ddd, J = 14.2, 10.3, 2.4 Hz, 1H), 4.69 (m, 1H), 3.92 – 3.64 (m, 4H), 3.60 (s, 1H), 1.90 (d, J = 8.5 Hz, 4H); m/z ES+ [M+H] ⁺ 439.1. 1-((1R,4R)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one was obtained as a white solid (6.50 mg, 14.8 μmol, 6.0 % over three steps). The enantiomers were separated by chiral separation. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.36 (s, 1H), 7.98 (t, J = 30.5 Hz, 2H), 7.29 (dd, J = 28.8, 20.6 Hz, 3H), 6.71 (m, 1H), 6.25 – 6.02 (m, 1H), 5.68 (ddd, J = 14.2, 10.3, 2.4 Hz, 1H), 4.69 (m, 1H), 3.92 – 3.64 (m, 4H), 3.60 (s, 1H), 1.90 (d, J = 8.5 Hz, 4H); m/z ES+ [M+H] ⁺ 439.1. Example 280. Preparation of 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-e n-1-one (Compound 389) 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate as the piperazine in Step 1 (white powder, 24.1 mg, 54.4 μmol, 17% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.42 (s, 1H), 8.12 (t, J = 7.0 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.54 (d, J = 9.4 Hz, 1H), 7.46 – 7.36 (m, 1H), 7.30 (td, J = 8.1, 0.9 Hz, 1H), 6.84 (dd, J = 16.7, 10.3 Hz, 1H), 6.22 (dd, J = 16.7, 2.2 Hz, 1H), 5.74 (dd, J = 10.3, 2.2 Hz, 1H), 4.75 (d, J = 6.3 Hz, 2H), 4.57 – 4.24 (m, 2H), 3.10 (dd, J = 27.1, 12.1 Hz, 2H), 2.10 – 1.68 (m, 4H); m/z ES+ [M+H] ⁺ 438.9. Example 281. Preparation of 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-e n-1-one (Compound 390) 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 3,8- diazabicyclo[3.2.1]octane-3-carboxylate as the piperazine in Step 1 (white powder, 12.9 mg, 29.5 μmol, 6.1% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.41 (s, 1H), 8.08 (t, J = 7.0 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.3 Hz, 1H), 7.46 – 7.35 (m, 1H), 7.30 (td, J = 8.2, 1.2 Hz, 1H), 6.79 (dd, J = 16.7, 10.5 Hz, 1H), 6.11 (dd, J = 16.7, 2.3 Hz, 1H), 5.68 (dd, J = 10.5, 2.3 Hz, 1H), 4.96 (s, 2H), 4.25 (d, J = 13.1 Hz, 1H), 3.89 (d, J = 12.8 Hz, 1H), 3.44 (d, J = 12.7 Hz, 1H), 3.00 (d, J = 13.1 Hz, 1H), 1.99 (s, 2H), 1.73 (dd, J = 17.0, 7.0 Hz, 2H); m/z ES+ [M+H] ⁺ 439.0. Example 282. Preparation of 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)prop-2- en-1-one (Compound 371) 1-(3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 3,6- diazabicyclo[3.1.1]heptane-6-carboxylate as the piperazine in Step 1 (white powder, 50.4 mg, 116 μmol, 24% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.09 – 7.91 (m, 1H), 7.52 – 7.20 (m, 3H), 6.49 (dd, J = 16.9, 10.3 Hz, 1H), 6.12 (dd, J = 17.0, 2.0 Hz,1H), 5.68 (dd, J = 10.3, 2.0 Hz, 1H), 4.93 (s, 1H), 4.56 (s, 1H), 4.25 – 3.65 (m, 4H), 2.76 (d, J = 8.2 Hz, 1H), 1.69 (d, J = 8.8 Hz, 1H); m/z ES+ [M+H] ⁺ 425.0. Example 283. Preparation of 1-(4-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one (Compound 365) 1-(4-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-2- methylpiperazin-1-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 2- methylpiperazine-1-carboxylate as the piperazine in Step 1 (white powder, 13.0 mg, 30.2 μmol, 9% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.40 (s, 1H), 8.10 (t, J = 7.1 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.61 (d, J = 9.4 Hz, 1H), 7.35 (dtd, J = 17.3, 8.2, 1.2 Hz, 2H), 6.87 (dd, J = 16.6, 10.5 Hz, 1H), 6.16 (dd, J = 16.6, 1.9 Hz, 1H), 5.72 (dd, J = 10.4, 2.2 Hz, 1H), 4.61 – 4.28 (m, 4H), 3.54 – 3.34 (m, J = 10.0 Hz, 1H), 3.19 (t, J = 9.9 Hz, 2H), 1.21 (s, 3H); m/z ES+ [M+H] ⁺ 427.0. Example 284. Preparation of 1-(4-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Compound 366) 1-(4-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-3- methylpiperazin-1-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 3- methylpiperazine-1-carboxylate as the piperazine in Step 1 (white powder, 4.70 mg, 10.8 μmol, 4% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.42 (s, 1H), 8.15 (t, J = 7.5 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.40 (dd, J = 10.8, 4.2 Hz, 1H), 7.30 (t, J = 8.5 Hz, 1H), 6.91 (dd, J = 16.1, 10.6 Hz, 1H), 6.20 (d, J = 16.7 Hz, 1H), 5.74 (dd, J = 10.4, 2.3 Hz, 1H), 4.81 (s, 1H), 4.59 – 3.48 (m, 3H), 3.28 – 3.13 (m, J = 7.3 Hz, 2H), 3.09 – 2.88 (m, J = 12.5 Hz, 1H), 1.14 (d, J = 5.4 Hz, 3H); m/z ES+ [M+H] ⁺ 427.0. Example 285. Preparation of 1-(4-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,2-dimethylpiperazin-1-yl)prop-2-en-1-one (Compound 354) 1-(4-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-2,2- dimethylpiperazin-1-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 2,2- dimethylpiperazine-1-carboxylate as the piperazine in Step 1 (white powder, 28.4 mg, 64.3 μmol, 25% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.40 (s, 1H), 8.18 (t, J = 7.4 Hz, 1H), 7.98 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 9.3 Hz, 1H), 7.40 (t, J = 6.8 Hz, 1H), 7.30 (t, J = 8.2 Hz, 1H), 6.77 (dd, J = 16.7, 10.5 Hz, 1H), 6.03 (dd, J = 16.7, 2.3 Hz, 1H), 5.62 (dd, J = 10.5, 2.3 Hz, 1H), 4.04 (s, 2H), 4.00 – 3.93 (m, 2H), 3.74 (t, J = 5.4 Hz, 2H), 1.48 (s, 6H); m/z ES+ [M+H] ⁺ 441.2. Example 286. Preparation of 1-(7-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one (Compound 355) 1-(7-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 2,2- dimethylpiperazine-1-carboxylate as the piperazine in Step 1 (white powder, 18.7 mg, 42.0 μmol, 21% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.39 (s, 1H), 8.03 (t, J = 7.3 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 9.4 Hz, 1H), 7.49 – 7.37 (m, 1H), 7.37 – 7.23 (m, 1H), 6.92 (s, 1H), 6.17 (dd, J = 16.8, 2.3 Hz, 1H), 5.74 (d, J = 12.2 Hz, 1H), 3.78 (m, 6H), 1.05 (d, J = 29.3 Hz, 4H); m/z ES+ [M+H] ⁺ 439.1. Example 287. Preparation of 1-(6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)prop-2- en-1-one (Compound 356) 1-(6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 3,6- diazabicyclo[3.1.1]heptane-3-carboxylate as the piperazine in Step 1 (white powder, 22.0 mg, 51.0 μmol, 30% over three steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.41 (s, 1H), 8.10 (t, J = 7.1 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.44 – 7.34 (m, 1H), 7.34 – 7.20 (m, 2H), 6.56 (dd, J = 16.7, 10.4 Hz, 1H), 5.99 (dd, J = 16.7, 2.3 Hz, 1H), 5.58 (dd, J = 10.4, 2.3 Hz, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.51 – 3.86 (m, 2H), 3.77 (d, J = 11.5 Hz, 1H), 3.53 (d, J = 13.8 Hz, 1H), 2.76 (d, J = 7.6 Hz, 1H), 1.64 (d, J = 8.7 Hz, 1H); m/z ES+ [M+H] ⁺ 425.1. Example 288. Preparation of 1-((1R,4R)-5-(4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (Compound 252) 1-((1R,4R)-5-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-45 and (1R,4R)-tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate as the piperazine in Step 1 (white powder, 11.0 mg, 23.9 μmol, 41% over three steps). ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.51 (td, J = 8.7, 3.3 Hz, 1H), 8.39 (t, J = 2.2 Hz, 1H), 7.84 (dt, J = 9.2, 3.5 Hz, 1H), 7.33 (dt, J = 9.1, 4.5 Hz, 1H), 7.21 (s, 1H), 6.63 (m, 1H), 6.30 (ddd, J = 16.8, 8.2, 1.9 Hz, 1H), 5.76 (ddd, J = 29.6, 10.4, 1.9 Hz, 1H), 5.18 (d, J = 13.7 Hz, 1H), 5.08 (d, J = 13.8 Hz, 1H), 3.90 – 3.51 (m, 5H), 2.25 – 2.06 (m, 2H); m/z ES+ [M+H] ⁺ 459.1. Example 289. Preparation of 1-((1R,4R)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 253) 1-((1R,4R)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and (1R,4R)-tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate as the piperazine in Step 1 (white powder, 6.00 mg, 14.0 μmol, 24% over three steps). ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.57 – 8.46 (m, 1H), 8.41 (d, J = 1.3 Hz, 1H), 7.88 (dd, J = 9.3, 2.1 Hz, 1H), 7.33 – 7.13 (m, 3H), 6.62 (m, 1H), 6.28 (ddd, J = 16.8, 8.0, 1.9 Hz, 1H), 5.75 (ddd, J = 29.2, 10.4, 1.9 Hz, 1H), 5.25 (s, 1H), 5.09 (s, 1H), 3.88 – 3.51 (m, 5H), 2.14 (t, J = 13.5 Hz, 2H); m/z ES+ [M+H] ⁺ 425.2. Example 290. Preparation of 1-((1R,4R)-5-(4-((5-chloro-6-phenoxypyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 255) 1-((1R,4R)-5-(4-((5-chloro-6-phenoxypyridin-3-yl)amino)pyrid o[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-7 and (1R,4R)-tert- butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as the piperazine in Step 1 (white powder, 7.00 mg, 14.0 μmol, 51% over three steps). ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.70 (dd, J = 2.5, 1.1 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.46 – 7.35 (m, 2H), 7.28 – 7.15 (m, 2H), 7.15 – 7.08 (m, 2H), 6.61 (m, 1H), 6.28 (ddd, J = 16.8, 7.9, 1.9 Hz, 1H), 5.75 (ddd, J = 27.2, 10.4, 1.9 Hz, 1H), 5.45 (s, 1H), 5.08 (s, 1H), 3.73 (m, 5H), 2.13 (dd, J = 23.9, 9.2 Hz, 2H); m/z ES+ [M+H] ⁺ 500.2. Example 291. Preparation of 1-(4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)prop-2-en-1-one (Compound 1) Step 1. tert-Butyl 4-(3-(methoxycarbonyl)-4-nitrophenyl)hexahydropyrrolo[3,2- b]pyrrole-1(2H)-carboxylate To a solution of methyl 5-fluoro-2-nitrobenzoate (1.50 g, 7.53 mmol) and tert-butyl hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (1.76 g, 8.29 mmol) in dimethylsulfoxide (15.0 mL) was added N,N-diisopropylethylamine (2.92 g, 22.6 mmol) in portions. The mixture was stirred at 90 °C for 12 hr. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic layer was washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was triturated with petroleum ether / ethyl acetate (20 mL, 4/1) and filtered. The filter cake was dried in vacuum to give tert-butyl 4-(3-(methoxycarbonyl)-4-nitrophenyl)hexahydropyrrolo[3,2-b] pyrrole-1(2H)- carboxylate (1.90 g, 4.85 mmol, 64%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J = 9.2 Hz, 1H), 6.95 - 6.58 (m, 2H), 4.53 (s, 1H), 4.40 (s, 1H), 3.83 (s, 3H), 3.65 - 3.48 (m, 2H), 3.40 (d, J = 7.2 Hz, 1H), 3.15 - 3.05 (m, 1H), 2.18 - 2.02 (m, 3H), 1.89 (s, 1H), 1.43 (s, 9H). Step 2. tert-Butyl 4-(4-amino-3-(methoxycarbonyl)phenyl)hexahydropyrrolo[3,2- b]pyrrole-1(2H)-carboxylate To a solution of tert-butyl 4-(3-(methoxycarbonyl)-4-nitrophenyl)hexahydropyrrolo[3,2- b]pyrrole-1(2H)-carboxylate (1.90 g, 4.85 mmol) in methanol (20 mL) was added palladium on activated carbon (300 mg, 10 wt. % loading) in portions under hydrogen (15 psi). The mixture was stirred at 25 °C for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuum to give tert-butyl 4-(4-amino-3-(methoxycarbonyl)phenyl)hexahydropyrrolo[3,2-b] pyrrole-1(2H)- carboxylate (1.78 g, crude) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.90 (d, J = 2.8 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.77 - 6.70 (m, 1H), 6.01 (s, 2H), 4.30 (s, 1H), 4.19 (dt, J = 2.4, 6.0 Hz, 1H), 3.77 (s, 3H), 3.48 - 3.41 (m, 1H), 3.25 - 3.02 (m, 3H), 2.10 - 1.74 (m, 4H), 1.42 (s, 9H). Step 3. tert-Butyl 4-(4-hydroxyquinazolin-6-yl)hexahydropyrrolo[3,2-b] pyrrole-1(2H)- carboxylate To a solution of tert-butyl 4-(4-amino-3- (methoxycarbonyl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H) -carboxylate (800 mg, 2.21 mmol) in ethanol (10 mL) was added formamidine acetate (461 mg, 4.43 mmol) in portions. The mixture was stirred at 80 °C for 2 hr. The mixture was concentrated in vacuum to give a residue. The residue was triturated with water (2 × 6 mL) and filtered. The filter cake was dried in vacuum to give tert-butyl 4-(4-hydroxyquinazolin-6-yl)hexahydropyrrolo[3,2-b] pyrrole-1(2H)- carboxylate (630 mg, 1.77 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.06 - 11.65 (m, 1H), 7.82 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 2.8, 8.8 Hz, 1H), 7.08 (d, J = 2.8 Hz, 1H), 4.51 - 4.32 (m, 2H), 3.57 - 3.38 (m, 3H), 3.15 - 3.05 (m, 1H), 2.17 - 2.01 (m, 3H), 1.98 - 1.87 (m, 1H), 1.44 (s, 9H). Step 4. tert-Butyl 4-(4-chloroquinazolin-6-yl)hexahydropyrrolo[3,2-b]pyrrole-1( 2H)- carboxylate To a solution of tert-butyl 4-(4-hydroxyquinazolin-6-yl)hexahydropyrrolo[3,2-b]pyrrole- 1(2H)-carboxylate (500 mg, 1.40 mmol) in toluene (8.00 mL) was added N,N- diisopropylethylamine (907 mg, 7.01 mmol) and phosphorus oxychloride (645 mg, 4.21 mmol) dropwise. The mixture was stirred at 100 °C for 2 hr. The mixture was diluted with saturated sodium bicarbonate (60 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuum to give tert-butyl 4-(4-chloroquinazolin-6-yl)hexahydropyrrolo[3,2-b]pyrrole-1( 2H)- carboxylate (760 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 375.0. Step 5. tert-Butyl 4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate To a solution of tert-butyl 4-(4-chloroquinazolin-6-yl)hexahydropyrrolo[3,2-b]pyrrole- 1(2H)-carboxylate (660 mg, 1.76 mmol), 3,4-dichloro-2-fluoroaniline (349 mg, 1.94 mmol) in acetonitrile (10 mL) was added hydrochloric acid / ethyl acetate (4 M, 44.0 μL) dropwise. The mixture was stirred at 20 °C for 2 hr. On completion, the mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/3) to give tert-butyl 4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (250 mg, 482 μmol, 27%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.66 (s, 1H), 8.28 (s, 1H), 7.73 - 7.56 (m, 3H), 7.47 - 7.14 (m, 2H), 4.59 - 4.41 (m, 2H), 3.58 - 3.41 (m, 3H), 3.09 (dt, J = 6.8, 10.0 Hz, 1H), 2.20 - 2.07 (m, 3H), 1.96 – 1.85 (s, 1H), 1.45 (s, 9H). Step 6. N-(3,4-Dichloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,2-b]py rrol-1(2H)- yl)quinazolin-4-amine To a solution of tert-butyl 4-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (200 mg, 386 μmol) in methanol (1.00 mL) was added hydrochloric acid / ethyl acetate (4 M, 1.0 mL) dropwise. The mixture was stirred at 20 °C for 1 hr. The mixture was concentrated in vacuum to give N-(3,4-dichloro-2-fluorophenyl)-6- (hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)quinazolin-4-amine (161 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 418.0. Step 7. 1-(4-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,2-b]py rrol- 1(2H)-yl)quinazolin-4-amine (161 mg, 385 μmol), triethylamine (117 mg, 1.15 mmol) in dimethyformamide (2.00 mL) was added acryloyl chloride (45.3 mg, 500 μmol) dropwise. The mixture was stirred at 20 °C for 2 hr. The mixture was filtered. The filtrate was purified by prep- HPLC (column: UniSil 3-100 C18 UItra (150 x 25 mm x 3 um); mobile phase: [water (0.225% FA) - acetonitrile]; B%: 22% - 52%, 10 min) to give 1-(4-(4-((3,4-dichloro-2- fluorophenyl)amino)quinazolin-6-yl)hexahydropyrrolo[3,2-b]py rrol-1(2H)-yl)prop-2-en-1-one (48.1 mg, 99.8 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 8.30 - 8.17 (m, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 6.78 - 6.54 (m, 1H), 6.26 - 6.12 (m, 1H), 5.78 - 5.63 (m, 1H), 4.90 - 4.56 (m, 2H), 3.83 - 3.73 (m, 1H), 3.59 - 3.47 (m, 2H), 2.38 - 2.30 (m, 1H), 2.23 - 2.15 (m, 2H), 2.12 - 1.90 (m, 2H); m/z ES+ [M+H] ⁺ 472.0. Example 292. Preparation of 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)prop-2-en-1-one (Compound 2) Step 1. tert-Butyl 1-(3-(methoxycarbonyl)-4-nitrophenyl)hexahydropyrrolo[3,4- b]pyrrole-5(1H)-carboxylate To a solution of methyl 5-fluoro-2-nitrobenzoate (938 mg, 4.71 mmol) and tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.00 g, 4.71 mmol) in dimethylsulfoxide (20 mL) was added N,N-diisopropylethylamine (1.22 g, 9.42 mmol) dropwise. The mixture was stirred at 90 °C for 12 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (20 mL) and dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give tert-butyl 1-(3- (methoxycarbonyl)-4-nitrophenyl)hexahydropyrrolo[3,4-b]pyrro le-5(1H)-carboxylate (1.80 g, 4.60 mmol, 98%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 8.8 Hz, 1H), 6.45 - 6.38 (m, 2H), 4.23 (s, 1H), 3.87 (s, 3H), 3.80 - 3.63 (m, 1H), 3.62 - 3.51 (m, 2H), 3.48 - 3.39 (m, 1H), 3.37 - 3.18 (m, 2H), 3.00 (d, J = 4.4 Hz, 1H), 2.25 - 2.08 (m, 1H), 1.96 - 1.87 (m, 1H), 1.37 (s, 9H). Step 2. tert-Butyl 1-(4-amino-3-(methoxycarbonyl)phenyl)hexahydropyrrolo[3,4- b]pyrrole-5(1H)-carboxylate To a solution of tert-butyl 1-(3-(methoxycarbonyl)-4-nitrophenyl)hexahydropyrrolo[3,4- b]pyrrole-5(1H)-carboxylate (1.80 g, 4.60 mmol) in methanol (20 mL) was added palladium on activated carbon (400 mg, 10 wt. % loading) in one portion under hydrogen. The mixture was stirred at 25 °C under hydrogen (15 psi) for 1 hr. The mixture was filtered and the filtrate was concentrated to give tert-butyl 1-(4-amino-3-(methoxycarbonyl)phenyl)hexahydropyrrolo[3,4- b]pyrrole-5(1H)-carboxylate (1.6 g, 4.43 mmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 362.1. Step 3. tert-Butyl 1-(4-hydroxyquinazolin-6-yl)hexahydropyrrolo[3,4-b]pyrrole-5 (1H)- carboxylate To a solution of tert-butyl 1-(4-amino-3- (methoxycarbonyl)phenyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H) -carboxylate (700 mg, 1.94 mmol) in ethanol (5.00 mL) was added formamidine acetate (403 mg, 3.87 mmol) in portions. The mixture was stirred at 80 °C for 2 hr. The mixture was concentrated to give crude product. The crude product was triturated with water (10 mL) and filtered. The filter cake was dried to give tert- butyl 1-(4-hydroxyquinazolin-6-yl)hexahydropyrrolo[3,4-b]pyrrole-5 (1H)-carboxylate (660 mg, 1.85 mmol, 96%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.89 - 10.56 (m, 1H), 7.92 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.12 - 7.01 (m, 1H), 4.33 (s, 1H), 3.95 - 3.75 (m, 1H), 3.74 - 3.68 (m, 1H), 3.68 - 3.60 (m, 1H), 3.54 - 3.35 (m, 3H), 3.07 (s, 1H), 2.29 - 2.19 (m, 1H), 2.05 - 1.95 (m, 1H), 1.45 (s, 9H). Step 4. tert-Butyl 1-(4-chloroquinazolin-6-yl)hexahydropyrrolo[3,4-b]pyrrole-5( 1H)- carboxylate To a solution of tert-butyl 1-(4-hydroxyquinazolin-6-yl)hexahydropyrrolo[3,4-b]pyrrole- 5(1H)-carboxylate (100 mg, 281 μmol) and N,N-diisopropylethylamine (181 mg, 1.40 mmol) in toluene (5 mL) was added phosphorus oxychloride (129 mg, 842 μmol) dropwise. The mixture was stirred at 100 °C for 2 hr. The mixture was diluted with saturated sodium bicarbonate solution (30.0 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give tert-butyl 1-(4- chloroquinazolin-6-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-c arboxylate (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 375.0. Step 5. tert-Butyl 1-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,4-b]pyrrole-5 To a solution of tert-butyl 1-(4-chloroquinazolin-6-yl)hexahydropyrrolo[3,4-b]pyrrole- 5(1H)-carboxylate (100 mg, 267 μmol) and 3,4-dichloro-2-fluoroaniline (48.0 mg, 267 μmol) in acetonitrile (3.0 mL) was added hydrochloric acid / ethyl acetate (4 M, 6.67 μL) dropwise. The mixture was stirred at 25 °C for 2 hr. The mixture was added sat. ammonium hydroxide to adjust pH = 7. The mixture was concentrated to give crude product. The crude product was triturated with ethyl acetate and filtered. The filter cake was dried to give tert-butyl 1-(4-((3,4-dichloro-2- fluorophenyl)amino)quinazolin-6-yl)hexahydropyrrolo[3,4-b]py rrole-5(1H)-carboxylate (210 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (d, J = 2.4 Hz, 1H), 8.74 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.56 (dd, J = 2.4, 9.2 Hz, 1H), 4.55 - 4.32 (m, 1H), 3.86 (dd, J = 6.4, 11.2 Hz, 1H), 3.74 - 3.63 (m, 1H), 3.55 - 3.50 (m, 2H), 3.30 - 3.19 (m, 2H), 3.12 (s, 1H), 2.23 - 2.13 (m, 1H), 2.00 - 1.87 (m, 1H), 1.37 (d, J = 14.0 Hz, 9H). Step 6. N-(3,4-Dichloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,4-b]py rrol-1(2H)- yl)quinazolin-4-amine To a solution of tert-butyl 1-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (120 mg, 231 μmol) in methanol (2.0 mL) was added hydrochloric acid / ethyl acetate (4.00 M, 3.00 mL) dropwise. The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated to give crude product. The crude product was purified by reverse-phase HPLC (0.1% FA condition) to give N-(3,4-dichloro-2-fluorophenyl)-6- (hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)quinazolin-4-amine (50.0 mg, 120 μmol, 52%) as a yellow solid. Step 7. 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6- yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,4-b]py rrol- 1(2H)-yl) quinazolin-4-amine (40.0 mg, 95.6 μmol) and triethylamine (38.7 mg, 383 μmol) in dimethyl formamide (2.0 mL) was added acryloyl chloride (11.3 mg, 124 μmol) dropwise. The mixture was stirred at 25 °C for 0.5 hr. The mixture was filtered and the filtrate was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 28%-58%, 10 min) to give 1-(1-(4-((3,4-dichloro-2- fluorophenyl)amino)quinazolin-6-yl)hexahydropyrrolo[3,4-b]py rrol-5(1H)-yl)prop-2-en-1-one (10.6 mg, 22.0 μmol, 23%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.29 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.59 (s, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.67 - 6.49 (m, 1H), 6.12 (ddd, J = 2.4, 8.4, 16.8 Hz, 1H), 5.72 - 5.57 (m, 1H), 4.54 - 4.35 (m, 1H), 4.14 (dd, J = 6.8, 11.0 Hz, 1H), 3.95 - 3.83 (m, 1H), 3.73 - 3.56 (m, 2H), 3.51 - 3.45 (m, 2H), 3.23 - 3.08 (m, 1H), 2.24 - 2.17 (m, 1H), 1.97 - 1.88 (m, 1H); m/z ES+ [M+H]+ 471.9. Example 293. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 6) Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolid ine-1- carboxylate To a solution of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (0.5 g, 1.3 mmol) and tert-butyl 3-bromopyrrolidine-1-carboxylate (388 mg, 1.55 mmol) in dimethoxyethane (10 mL) were added Ir[dF(CF3)ppy]2(dtbpy)(PF6) (14.5 mg, 12.9 μmol), sodium carbonate (274 mg, 2.6 mmol), tris(trimethylsilyl)silane (321 mg, 1.3 mmol) and NiCl ₂ .dtbbpy (2.6 mg, 6.46 μmol). The mixture was degassed and purged with nitrogen for 3 times and then it was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 6 hr. On completion, the reaction was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate from 10: 1 to 1:1) to afford tert-butyl 3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]pyrrolidine-1-carboxylate (0.5 g, 890 μmol, 69%) as a yellow solid. Step 2. N-(3,4-Dichloro-2-fluoro-phenyl)-6-pyrrolidin-3-yl-quinazoli n-4-amine To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate (0.4 g, 838 μmol) in dichloromethane (3 mL) was added hydrochloric acid/ethyl acetate (4 M, 1 mL). The mixture was stirred at 20 °C for 1 hr. On completion, the organic solvent was removed under vacuum to afford N-(3,4-dichloro-2-fluoro-phenyl)-6- pyrrolidin-3-yl-quinazolin-4-amine (0.3 g, crude, HCl salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.80 - 11.97 (m, 1H), 9.81 - 9.59 (m, 2H), 9.14 (s, 1H), 8.99 (s, 1H), 8.22 (dd, J = 1.2, 8.8 Hz, 1H), 8.09 - 8.03 (m, 1H), 7.79 - 7.74 (m, 1H), 7.71 - 7.64 (m, 1H), 3.81 (d, J = 3.2 Hz, 2H), 3.35 (d, J = 3.6 Hz, 2H), 2.22 - 2.12 (m, 1H), 1.30 (s, 1H), 1.16 - 1.06 (m, 1H); m/z ES+ [M+H] ⁺ 377.0. Step 3. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrro lidin-1-yl]prop-2- en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-pyrrolidin-3-yl-quinazoli n-4-amine (0.1 g, 242 μmol, HCl salt) in tetrahydrofuran (4 mL) and water (1 mL) was added sodium bicarbonate (61 mg, 726 μmol) and prop-2-enoyl chloride (43.8 mg, 483 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the organic solvent was removed under vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge (150 x 25 mm x 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-methanol]; B%: 40% - 70%, 10 min) to afford 1-[3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrro lidin-1-yl]prop-2-en-1-one (11 mg, 25.1 μmol, 10.4%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 8.46 (s, 1H), 8.37 (d, J = 14.4 Hz, 1H), 7.94 - 7.72 (m, 2H), 7.65 - 7.47 (m, 2H), 6.66 (dd, J = 10.0, 16.8 Hz, 1H), 6.18 (ddd, J = 2.4, 5.2, 16.8 Hz, 1H), 5.70 (dt, J = 2.4, 10.0 Hz, 1H), 4.23 - 4.05 (m, 1H), 3.95 - 3.74 (m, 1H), 3.70 - 3.56 (m, 2H), 3.48 - 3.42 (m, 1H), 2.41 - 2.30 (m, 1H), 2.21 - 2.08 (m, 1H); m/z ES+ [M+H] ⁺ 431.0. Example 294. Preparation of 1-[(3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 17) Step 1. tert-Butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] pyrrolidine- 1-carboxylate and tert-butyl (3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolid ine-1-carboxylate (470 mg, 984 μmol) was separated by SFC (column: DAICEL CHIRALPAK IC(250 mm*30 mm,10um); mobile phase: [0.1% ammonium hydroxide ethanol]; B %: 45% - 45%, 3; 50 min) to give tert-butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] pyrrolidine-1- carboxylate (180 mg, 0.38 mmol, 38%, >99% ee) as a white solid and tert-butyl (3R)-3-[4-(3,4- dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolidine-1-carb oxylate (180 mg, 0.38 mmol, 38%, 98.7% ee) as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.61 - 8.46 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.83 - 7.62 (m, 3H), 7.36 (dd, J = 1.6, 9.2 Hz, 1H), 3.99 - 3.32 (m, 6H), 2.47 - 2.31 (m, 1H), 2.24 - 2.02 (m, 1H), 1.50 (s, 10H); m/z ES+ [M+H] ⁺ 477.0. 1H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.61 - 8.48 (m, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.81 - 7.54 (m, 3H), 7.36 (dd, J = 1.6, 9.2 Hz, 1H), 3.99 - 3.38 (m, 6H), 2.46 - 2.35 (m, 1H), 2.19 - 2.03 (m, 1H), 1.51 (s, 10H); m/z ES+ [M+H] ⁺ 477.0. Step 2. N-(3,4-Dichloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]qui nazolin-4-amine To a solution of tert-butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate (150 mg, 314 μmol) in dichloromethane (3 mL) was added HCl/ethyl acetate (4 M, 3.00 mL), the mixture was stirred at 25 °C for 1 hr. On completion, the reaction was filtered and concentrated in vacuo to give N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3- yl]quinazolin-4-amine (150 mg, crude, HCl salt) as a yellow solid. Step 3.1-[(3S)-3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-y l]pyrrolidin-1-yl]prop- 2-en-1-one To a solution of prop-2-enoyl chloride (36.1 mg, 399 μmol) and sodium bicarbonate (152 mg, 1.81 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added N-(3,4-dichloro-2-fluoro- phenyl)-6-[(3S)-pyrrolidin-3-yl]quinazolin-4-amine (150 mg, 363 μmol, HCl) at 0 °C, the mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 28% - 48%, 10 min) to give 1-[(3S)-3- [4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolidin -1-yl]prop-2-en-1-one (85 mg, 178 μmol, 49%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 - 8.71 (m, 1H), 8.46 - 8.25 (m, 1H), 8.22 - 8.02 (m, 1H), 8.00 - 7.85 (m, 2H), 7.50 - 7.45 (m, 1H), 7.40 - 7.30 (m, 1H), 6.66 - 6.38 (m, 2H), 5.76 - 5.71 (m, 1H), 4.23 - 4.10 (m, 1H), 4.02 - 3.84 (m, 1H), 3.70 - 3.56 (m, 3H), 2.56 - 2.41 (m, 1H), 2.26 - 2.08 (m, 1H); m/z ES+ [M+H] ⁺ 431.2. Example 295. Preparation of 1-[(3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 18) Step 1. N-(3,4-Dichloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]qui nazolin-4-amine To a solution of tert-butyl (3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate (150 mg, 314 μmol) in dichloromethane (3 mL) was added hydrochloric acid/ethyl acetate (4 M, 3.00 mL), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give N-(3,4-dichloro-2-fluoro-phenyl)-6- [(3R)-pyrrolidin-3-yl]quinazolin-4-amine (150 mg, crude, HCl salt) as a yellow solid. Step 2. 1-[(3R)-3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl] pyrrolidin-1- yl]prop-2-en-1-one To a solution of prop-2-enoyl chloride (36.1 mg, 399 μmol) and sodium bicarbonate (152 mg, 1.81 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added N-(3,4-dichloro-2-fluoro- phenyl)-6-[(3R)-pyrrolidin-3-yl]quinazolin-4-amine (150 mg, 363 μmol, HCl salt) at 0 °C, the mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: UniSil 3-100 C18 UItra (150 x 25 mm x 3 um); mobile phase: [water (0.225% FA) - acetonitrile]; B%: 28% - 48%, 10min) to give 1-[(3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] pyrrolidin-1-yl]prop-2-en-1-one (95 mg, 199 μmol, 55%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 - 8.74 (m, 1H), 8.46 - 8.15 (m, 2H), 8.00 - 7.87 (m, 2H), 7.80 - 7.72 (m, 1H), 7.36 - 7.32 (m, 1H), 6.56 - 6.48 (m, 2H), 5.76 - 5.68 (m, 1H), 4.23 - 4.08 (m, 1H), 4.02 - 3.84 (m, 1H), 3.76 - 3.56 (m, 3H), 2.56 - 2.44 (m, 1H), 2.26 - 2.11 (m, 1H); m/z ES+ [M+H] ⁺ 431.2. Example 296. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6- yl]imidazolidin-1-yl]prop-2-en-1-one (Compound 45) Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]imidazol idine-1- carboxylate A mixture of 6-bromo-N-(3,4-dichloro-2-fluoro-phenyl)quinazolin-4-amine (200 mg, 517 μmol), tert-butyl imidazolidine-1-carboxylate (134 mg, 775 μmol), 1,4-diazabicyclo[2.2.2]octane (104 mg, 930 μmol), Ir(ppy) ₂ (dtbbpy)PF ₆ (9.45 mg, 10.3 μmol) and dibromo nickel 1,2- dimethoxyethane (7.97 mg, 25.8 μmol) in dimethyl acetamide (30 mL) was degassed and purged with nitrogen for three times. The reaction vial was then sealed with parafilm, placed 2 cm away from one blue LED, and irradiated at 55 °C for 14 hr under nitrogen. The reaction mixture was filtered. The filtrate was then diluted with water (90 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel. Petroleum ether/Ethyl acetate=50:1 to 2:1) to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin- 6-yl]imidazolidine-1-carboxylate (161 mg, 337 μmol, 65%) as a yellow solid. m/z ES+ [M+H] ⁺ 478.1. Step 2. N-(3,4-Dichloro-2-fluoro-phenyl)-6-imidazolidin-1-yl-quinazo lin-4-amine To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]imidazolidine -1-carboxylate (80.0 mg, 167 μmol) in dichloromethane (1.2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol, 0.4 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated in vacuo to give N-(3,4-dichloro-2-fluoro-phenyl)-6- imidazolidin-1-yl-quinazolin-4-amine (60 mg, 159 μmol, 95%) as a yellow solid. m/z ES+ [M+H] ⁺ 378.1. Step 3. 1-[3-[4-(3,4-Dichloro-2-fluoro- anilino)quinazolin-6-yl]imidazolidin-1-yl]prop- 2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-imidazolidin-1-yl-quinazo lin-4- amine (60.0 mg, 159 μmol) in tetrahydrofuran (1.0 mL) was added sodium bicarbonate (107 mg, 1.27 mmol) in water (0.3 mL). And then a solution of prop-2-enoyl chloride (12.9 mg, 143 μmol) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm x 10 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 16% - 46%, 10 min) to give 1-[3-[4-(3,4- dichloro-2-fluoro-anilino)quinazolin-6-yl]imidazolidin-1-yl] prop-2-en-1-one (18.9 mg, 43.8 μmol, 28%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.57 - 7.49 (m, 1H), 7.49 - 7.40 (m, 2H), 6.70 - 6.65 (m, 1H), 6.25 (dd, J = 2.4, 16.8 Hz, 1H), 5.81 - 5.72 (m, 1H), 4.96 (s, 2H), 3.95 (d, J = 4.4 Hz, 2H), 3.79 - 3.71 (m, 2H); m/z ES+ [M+H] ⁺ 432.1. Example 297. Preparation of 1-[1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (Compound 53) Step 1. 6-(3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3,4-dichloro-2-fluoro-p henyl)quinazolin- 4-amine A solution of benzyl 1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 191 μmol) in trifluoroacetic acid (5.0 mL) was stirred at 60 °C for 1 hr. The mixture was dried by blowing nitrogen to give 6-(3- azabicyclo[3.1.0]hexan-1-yl)-N-(3,4-dichloro-2-fluoro-phenyl )quinazolin-4-amine (74 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 389.0. Step 2. 1-[1-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one To a solution of 6-(3-azabicyclo[3.1.0]hexan-1-yl)-N-(3,4-dichloro-2-fluoro-p henyl) quinazolin-4-amine (74.0 mg, 190 μmol) in tetrahydrofuran (0.40 mL) and water (0.10 mL) was added saturated sodium bicarbonate (63.8 mg, 760 μmol) and prop-2-enoyl chloride (13.7 mg, 152 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The mixture was quenched by addition methanol (0.50 mL). The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 x 30 mm x 3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -acetonitrile]; B%: 30% - 55%, 6 min) to give 1-[1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-az abicyclo[3.1.0]hexan- 3-yl]prop-2-en-1-one (19.8 mg, 44.7 μmol, 24%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.09 (s, 1H), 8.48 (s, 1H), 8.38 - 8.26 (m, 1H), 7.76 (d, J = 13.6 Hz, 2H), 7.68 - 7.54 (m, 2H), 6.72 - 6.57 (m, 1H), 6.21 - 6.12 (m, 1H), 5.70 (dd, J = 2.4, 10.0 Hz, 1H), 4.37 - 4.21 (m, 1H), 4.07 - 3.58 (m, 3H), 2.33 - 2.15 (m, 1H), 1.39 - 1.21 (m, 1H), 0.99 - 0.87 (m, 1H); m/z ES+ [M+H] ⁺ 443.0. Example 298. Preparation of 1-(3-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6-yl) - 3-methylpyrrolidin-1-yl)prop-2-en-1-one (Compound 324)

Step 1. tert-Butyl (4-(1-benzyl-2,5-dioxopyrrolidin-3-yl)phenyl)carbamate A solution of [4-(tert-butoxycarbonylamino)phenyl]boronic acid (22.8 g, 96.2 mmol), 1- benzylpyrrole-2,5-dione (9.00 g, 48.1 mmol), palladium acetate (0.54 g, 2.40 mmol), acetic acid (94.5 g, 1.57 mol, 90 mL) and 2-(2-pyridyl)pyridine (1.50 g, 9.62 mmol) in tetrahydrofuran (180 mL) and water (54 mL) was stirred at 80 °C for 20 hr under air. On completion, the solution was diluted with water (200 mL) and adjusted to pH 7~8 with saturated sodium bicarbonate solution. The solution was extracted with dichloromethane (400 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel. Petroleum ether: Ethyl acetate = 1 : 0 to 0 : 1) to give tert- butyl (4-(1-benzyl-2,5-dioxopyrrolidin-3-yl)phenyl)carbamate (13.0 g, 34.2 mmol, 71%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.26 (m, 5H), 7.16 - 7.14 (m, 2H), 4.61 (s, 2H), 4.18-4.15 (m, 1H), 3.27 - 3.20 (m, 1H), 2.81 (dd, J = 4.8, 18.0 Hz, 1H), 1.48 (s, 9 H). Step 2. tert-Butyl (4-(1-benzyl-3-methyl-2,5-dioxopyrrolidin-3-yl)phenyl)carbam ate To a solution of tert-butyl N-[4-(1-benzyl-2,5-dioxo-pyrrolidin-3-yl)phenyl]carbamate (13.0 g, 34.2 mmol) and cesium carbonate (33.4 g, 103 mmol) in N,N-dimethylformamide (65 mL) at 0 °C was added a solution of methyl iodide (3.90 g, 27.3 mmol, 1.70 mL) in N,N- dimethylformamide (6.5 mL) dropwise. Then the mixture solution was stirred at 25 °C for 2 hr. On completion, the solution was poured into ice-water (400 mL) and extracted with ethyl acetate (400 mL x 2). The organic layer was concentrated to give a residue. The residue was purified by column chromatography (silica gel. Petroleum ether: Ethyl acetate = 1 : 0 to 0 : 1) to give tert- butyl (4-(1-benzyl-3-methyl-2,5-dioxopyrrolidin-3-yl)phenyl)carbam ate (10.0 g, 25.4 mmol, 74%) as a yellow solid. m/z ES+ [M-Boc] ⁺ 295.2. Step 3. 3-(4-Aminophenyl)-1-benzyl-3-methylpyrrolidine-2,5-dione To a solution of tert-butyl N-[4-(1-benzyl-3-methyl-2,5-dioxo-pyrrolidin-3- yl)phenyl]carbamate (10.0 g, 25.6 mmol) in tetrahydrofuran (100 mL) was added hydrochloric acid/dioxane (4 M, 50.0 mL) and the reaction mixture was stirred at 60 °C for 5 hr. On completion, the reaction mixture was concentrated to give a residue. The residue was diluted with ethyl acetate (300 mL) and then basified with 5 M aq. sodium hydroxide solution to pH ~ 8. The layers were then separated. The organic layer was washed with brine (40 mL), dried over sodium sulphate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ ethyl acetate = 1 : 0 to 1 : 1) to give 3-(4- aminophenyl)-1-benzyl-3-methylpyrrolidine-2,5-dione (7.00 g, 23.8 mmol, 94%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.32 - 7.21 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 8.4 Hz, 1H), 5.07 (s, 2H), 4.60 (s, 2H), 2.98 (s, 2H), 1.55 (s, 3H). Step 4. 4-(1-Benzyl-3-methylpyrrolidin-3-yl)aniline To a stirred solution of lithium aluminum hydride (4.31 g, 114 mmol) in tetrahydrofuran (40 mL) was added a solution of 3-(4-aminophenyl)-1-benzyl-3-methyl-pyrrolidine-2,5-dione (7.00 g, 23.8 mmol) in tetrahydrofuran (100 mL) portionwise at 25 °C. Then the reaction mixture was stirred at 70 °C for 1 hr. On completion, the mixture was cooled to 0 °C and carefully quenched by water (4.3 mL), 10% sodium hydroxide solution (4.3 mL) and water (13 mL). The mixture was stirred at room temperature for 0.5 hour and then filtered. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel. petroleum ether/ ethyl acetate = 1/0 to 1/1) to give 4-(1-benzyl-3-methylpyrrolidin-3- yl)aniline (6.00 g, 22.5 mmol, 95%) as a yellow oil. m/z ES+ [M+H] ⁺ 267.0. Step 5. 4-(3-Methylpyrrolidin-3-yl)aniline To a solution of 4-(1-benzyl-3-methyl-pyrrolidin-3-yl)aniline (4.70 g, 17.6 mmol) in methanol (90 mL) was added ammonium formate (5.56 g, 88.2 mmol) and palladium on activated carbon (1.00 g, 10 wt. % loading) under nitrogen. The mixture solution was stirred at 90 °C for 2 hr under nitrogen. On completion, the solution was filtered and the filtrate was concentrated to give 4-(3-methylpyrrolidin-3-yl)aniline (3.00 g, crude) as a white solid. m/z ES+ [M+H] ⁺ 176.9. Step 6. tert-Butyl 3-(4-aminophenyl)-3-methylpyrrolidine-1-carboxylate To a solution of 4-(3-methylpyrrolidin-3-yl)aniline (3.00 g, 17.0 mmol) in dioxane (50 mL) and water (50 mL) was added sodium bicarbonate (1.72 g, 20.4 mmol) and di-tert-butyl dicarbonate (3.71 g, 17.0 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-aminophenyl)-3-methylpyrrolidine-1-carboxylate (3.30 g, 11.9 mmol, 70%) as a yellow oil. m/z ES+ [M+H] ⁺ 277.3. Step 7. tert-Butyl 3-(4-amino-3-bromophenyl)-3-methylpyrrolidine-1-carboxylate To a solution of tert-butyl 3-(4-aminophenyl)-3-methyl-pyrrolidine-1-carboxylate (3.30 g, 11.9 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (2.13 g, 11.9 mmol) portion-wise. The mixture solution was stirred at 15 °C for 16 hr. On completion, the solution was poured into water (80 mL) and extracted with dichloromethane (100 mL x 2). The organic layer was washed with brine (50 mL) and concentrated to give a residue. The residue was purified by reversed-phase HPLC (FA condition) to give tert-butyl 3-(4-amino-3-bromophenyl)-3- methylpyrrolidine-1-carboxylate (2.80 g, 7.88 mmol, 66%) as a brown oil. Step 8. tert-Butyl 3-(4-amino-3-cyanophenyl)-3-methylpyrrolidine-1-carboxylate A solution of tert-butyl 3-(4-amino-3-bromo-phenyl)-3-methyl-pyrrolidine-1-carboxylat e (2.80 g, 7.88 mmol), propanedinitrile (1.04 g, 15.8 mmol), copper iodide (751 mg, 3.94 mmol), 4- ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropalladiu m (112 mg, 158 μmol), 1,10- phenanthroline (355 mg, 1.97 mmol), sodium tert-butoxide (1.51 g, 15.8 mmol) and potassium fluoride (916 mg, 15.8 mmol) in N,N-dimethylformamide (50 mL) was stirred at 130 °C for 16 hr under nitrogen. On completion, the solution was poured into water (50 mL) and extracted with dichloromethane (60 mL x 2). The organic layer was washed with brine (30 mL) and concentrated to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ethyl acetate = 1 / 0 to 0 / 1) and repurified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-amino-3-cyanophenyl)-3-methylpyrrolidine-1-carboxylate (0.50 g, 1.67 mmol, 21%) as a pale solid. Step 9. tert-Butyl 3-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl)-3- methylpyrrolidine-1-carboxylate A solution of tert-butyl 3-(4-amino-3-cyano-phenyl)-3-methyl-pyrrolidine-1-carboxylat e (100 mg, 332 μmol) and N,N-dimethylformamide-dimethyl acetamide (119 mg, 995 μmol) in toluene (2 mL) was stirred at 120 °C for 2 hr. On completion, the solution was concentrated to give tert-butyl 3-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl)-3-meth ylpyrrolidine-1- carboxylate (110 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 357.1. Step 10. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- methylpyrrolidine-1-carboxylate A solution of tert-butyl 3-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl)-3- methylpyrrolidine-1-carboxylate (110 mg, 309 μmol) and 3,4-dichloro-2-fluoro-aniline (61.1 mg, 339 μmol) in toluene (3 mL) and acetic acid (1 mL) was stirred at 120 °C for 3 hr. On completion, the solution was concentrated to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)-3-methylpyrrolidine-1-carboxylate (40 mg, 81.4 μmol, 26%) as a white solid. m/z ES+ [M+H] ⁺ 491.3. Step 11. N-(3,4-Dichloro-2-fluorophenyl)-6-(3-methylpyrrolidin-3-yl)q uinazolin-4- amine A solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-methy l- pyrrolidine-1-carboxylate (40 mg, 81.4 μmol) in dichloromethane (2 mL) and trifluoroacetic acid (308 mg, 2.70 mmol) was stirred at 15 °C for 1 hr. On completion, the solution was concentrated to give N-(3,4-dichloro-2-fluorophenyl)-6-(3-methylpyrrolidin-3-yl)q uinazolin-4-amine (35 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 391.2. Step 12. 1-(3-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6-yl) -3- methylpyrrolidin-1-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-methylpyrrolidin-3-yl) quinazolin- 4-amine (35.0 mg, 69.3 μmol, TFA salt) in tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (46.6 mg, 554 μmol) followed by prop-2-enoyl chloride (5.64 mg, 62.3 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.25 hr. On completion, the solution was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 x 30mm x 3um; mobile phase: [water (10mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30% - 60%, 8 min) to give 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl) -3-methylpyrrolidin-1- yl)prop-2-en-1-one (24.0 mg, 53.9 μmol, 77%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.15 - 10.14 (m, 1H), 8.47 - 8.35 (m, 2H), 7.92 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.61 - 7.59 (m, 2H), 6.70 - 6.60 (m, 1H), 6.21 - 6.16 (m, 1H), 5.72 - 5.69 (m, 1H), 4.00 - 3.93 (m, 1H), 3.85 - 3.57 (m, 3H), 2.36 - 2.19 (m, 2H), 1.39 (d, J = 10.0 Hz, 1H); m/z ES+ [M+H] ⁺ 445.0. Example 299. Preparation of 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl) - 3-fluoropyrrolidin-1-yl)prop-2-en-1-one (Compound 55) Step 1. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- fluoropyrrolidine-1-carboxylate To a mixture of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-hydro xy -pyrrolidine-1-carboxylate (200 mg, 0.41 mmol) in dichloromethane (4 mL) was added diethylaminosulfur trifluoride (131 mg, 0.81 mmol) slowly at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was quenched with saturated sodium carbonate (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 10/1 to 1/1] to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-fluoro-pyrrolidine-1-carboxylate (130 mg, 0.26 mmol, 65%) as a brown solid. Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(3-fluoropyrrolidin-3-yl)q uinazolin-4-amine To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluor o- pyrrolidine-1-carboxylate (130 mg, 260 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove solvent to give N-(3,4-dichloro-2- fluorophenyl)-6-(3-fluoropyrrolidin-3-yl)quinazolin-4-amine (130 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 394.9. Step 3. 1-(3-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6-yl) -3- fluoropyrrolidin-1-yl)prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-(3-fluoropyrrolidin-3-yl)q uinazolin- 4-amine (128 mg, 254 μmol) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (108 mg, 1.29 mmol) and prop-2-enoyl chloride (27.8 mg, 307 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched by addition methanol (0.6 mL). The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (0.2% FA) - acetonitrile]; B%: 20% - 50%, 8 min) to give 1-[(3R)-3-[4-(3,4- dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluoro-pyrrolid in-1-yl]prop-2-en-1-one (16.1 mg, 40.0 μmol, 11%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.11 - 8.00 (m, 1H), 7.92 - 7.82 (m, 1H), 7.60 (s, 2H), 6.72 - 6.58 (m, 1H), 6.25 - 6.22 (m, 1H), 5.80 - 5.74 (m, 1H), 4.42 - 3.60 (m, 4H), 2.71 - 2.51 (m, 2H); m/z ES+ [M+H] ⁺ 449.0. Example 300. Preparation of 1-[(3S)-3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl] -3- fluoro-pyrrolidin-1-yl]prop-2-en-1-one (Compound 178)

Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluor o- pyrrolidine-1-carboxylate To a mixture of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-hydro xy -pyrrolidine-1-carboxylate (600 mg, 1.22 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (392 mg, 2.43 mmol) slowly at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was quenched with saturated sodium carbonate (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 10/1 to 1/1] to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-fluoro-pyrrolidine-1-carboxylate (500 mg, 1.01 mmol, 83%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 - 8.79 (m, 1H), 8.57 - 8.43 (m, 1H), 8.07 - 7.94 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 2.0, 9.2 Hz, 1H), 4.72 - 4.59 (m, 0.5H), 4.41 (d, J = 18.0 Hz, 0.5H), 4.09 - 3.63 (m, 3.5H), 2.56 - 2.32 (m, 2H), 1.55 - 1.43 (m, 9H). Step 2. tert-Butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- fluoro- pyrrolidine-1-carboxylate and tert-butyl (3R)-3-[4- (3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]-3-fluoro-pyrrolidine-1-carboxylate tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluor o-pyrrolidine-1- carboxylate (500 mg) was further separated by SFC (column: DAICEL CHIRALPAK AD(250 mm*30 mm,10 um);mobile phase:[0.1%NH ₃ H ₂ O methanol];B%: 42%-42%,5min) to give tert- butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- fluoro-pyrrolidine-1- carboxylate (205 mg, 414 μmol, 41%) as a white solid and tert-butyl (3R)-3-[4- (3,4-dichloro-2- fluoro-anilino)quinazolin-6-yl]-3-fluoro-pyrrolidine-1-carbo xylate (165 mg, 333 μmol, 33%) as a white solid. Step 3. N-(3,4-Dichloro-2-fluoro-phenyl)-6-[(3S)-3- fluoropyrrolidin-3-yl]quinazolin-4- amine To a solution of tert-butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- fluoro -pyrrolidine-1-carboxylate (200 mg, 404 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove solvent to give N-(3,4-dichloro-2-fluoro- phenyl)-6-[(3S)-3-fluoropyrrolidin-3-yl]quinazolin-4-amine (160 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 394.9. Step 4. 1-[(3S)-3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl] -3-fluoro-pyrrolidin- 1-yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3S)-3-fluoropyrrolidin- 3- yl]quinazolin-4-amine (160 mg, 404 μmol) in tetrahydrofuran (0.8 mL) and water (0.2 mL) was added sodium bicarbonate (136 mg, 1.61 mmol) and prop-2-enoyl chloride (34.7 mg, 383 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched by methanol (0.6 mL). The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40 mm*10 um; mobile phase: [water (0.2% FA)-acetonitrile]; B%: 20%-60%, 8 min) to give 1-[(3S)-3-[4- (3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluoro-pyr rolidin-1-yl]prop-2 -en-1-one (29 mg, 64.7 μmol, 16%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (d, J = 19.2 Hz, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.8, 3.2 Hz, 1H), 7.62 (s, 2H), 6.73 - 6.63 (m, 1H), 6.26 - 6.19 (m, 1 H), 5.79 - 5.72 (m, 1H), 4.46 - 3.52 (m, 4H), 2.75 - 2.65 (m, 2 H); m/z ES+ [M+H] ⁺ 449.0. Example 301. Preparation of 1-[(3R)-3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl] -3- fluoro-pyrrolidin-1-yl]prop-2-en-1-one (Compound 179) Step 1. N-(3,4-Dichloro-2-fluoro-phenyl)-6-[(3R)-3-fluoropyrrolidin- 3-yl]quinazolin-4- amine To a solution of tert-butyl (3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- fluoro-pyrrolidine-1-carboxylate (160 mg, 323 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove solvent to give N-(3,4-dichloro-2-fluoro- phenyl)-6-[(3R)-3-fluoropyrrolidin-3-yl]quinazolin-4-amine (128 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 394.9. Step 2.1-[(3R)-3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-y l]-3-fluoro-pyrrolidin- 1-yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3R)-3-fluoropyrrolidin- 3- yl]quinazolin-4-amine (128 mg, 323 μmol) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (108 mg, 1.29 mmol) and prop-2-enoyl chloride (27.8 mg, 307 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched by methanol (0.6 mL). The residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [water (0.2% FA)-acetonitrile]; B%: 20%-50%, 8 min) to give 1-[(3R)-3-[4-(3,4- dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluoro-pyrrolid in-1-yl]prop-2-en-1-one (35 mg, 64.7 μmol, 24%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.26 - 10.16 (m, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.62 (s, 2H), 6.75 - 6.63 (m, 1H), 6.26 - 6.19 (m, 1H), 5.79 - 5.72 (m, 1H), 4.41 - 4.13 (m, 2H), 4.11 - 3.83 (m, 4 H), 3.70 - 3.58 (m, 1H); m/z ES+ [M+H] ⁺ 449.0. Example 302. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- hydroxy-pyrrolidin-1-yl]prop-2-en-1-one (Compound 48) Step 1. 3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolid in-3-ol To a mixture of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- hydroxy-pyrrolidine-1-carboxylate (10.0 mg, 20.2 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (138 mg, 1.22 mmol) in one portion at 20 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 2 hr. On completion, the mixture was concentrated under reduced pressure to remove solvent to give 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolid in- 3-ol (10.0 mg, crude, TFA salt) as a brown oil. m/z ES+ [M+H] ⁺ 393.2. Step 2. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-hy droxy-pyrrolidin-1- yl]prop-2-en-1-one To a mixture of 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolid in-3-ol (10.0 mg, 19.7 μmol, TFA salt) in tetrahydrofuran (0.2 mL) and water (50 μL) was added sodium bicarbonate (13.2 mg, 157 μmol) in one portion at 0 °C under nitrogen atmosphere. Then prop-2- enoyl chloride (1.43 mg, 15.7 μmol) in tetrahydrofuran (50 μL) was added at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (0.2% FA) - acetonitrile]; B%: 10% - 45%, 8 min) to give 1-[3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-hy droxy-pyrrolidin-1-yl]prop-2-en-1- one (2.2 mg, 4.9 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 8.61 - 8.50 (m, 2H), 8.16 - 8.00 (m, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.59 (s, 2H), 6.80 - 6.46 (m, 1H), 6.15 - 6.22 (m, 1H), 5.88 - 5.59 (m, 2H), 3.98 - 3.70 (m, 3H), 3.68 - 3.55 (m, 1H), 2.41 - 2.21 (m, 2H); m/z ES+ [M+H] ⁺ 447.0. Example 303. Preparation of 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- hydroxy-pyrrolidin-1-yl]prop-2-en-1-one (Compound 164)

Step 1. tert-Butyl 3-hydroxy-3-(4-methoxyquinazolin-6-yl)pyrrolidine-1-carboxyl ate To a mixture of 6-bromo-4-methoxy-quinazoline (1.00 g, 4.18 mmol) in tetrahydrofuran (40 mL) was added n-butyl lithium (2.5 M in toluene, 1.67 mL) slowly at -65 °C ~ -60 °C under nitrogen atmosphere. The mixture was stirred at -65 °C for 2 min. Then tert-butyl 3- oxopyrrolidine-1-carboxylate (1.55 g, 8.37 mmol) in tetrahydrofuran (5 mL) was added slowly at -65 °C ~ -60 °C. The resulting mixture was stirred at -60 °C for 0.5 hr, then -30 °C for 0.5 hr and 20 °C for 1 hr. On completion, the mixture was quenched with saturated ammonium chloride (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 6/1 to 0/1] to afford tert-butyl 3-hydroxy-3-(4-methoxyquinazolin-6- yl)pyrrolidine-1-carboxylate (1.10 g, 3.19 mmol, 76%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.29 (s, 1H), 8.02 - 7.91 (m, 2H), 4.20 (s, 3H), 3.85 - 3.64 (m, 4H), 2.52 - 2.19 (m, 3H), 1.50 (d, J = 4.4 Hz, 9H). Step 2. tert-Butyl 3-methoxy-3-(4-methoxyquinazolin-6-yl)pyrrolidine-1-carboxyl ate To a mixture of tert-butyl 3-hydroxy-3-(4-methoxyquinazolin-6-yl)pyrrolidine-1- carboxylate (660 mg, 1.91 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (305 mg, 7.64 mmol, 60% in mineral oil) in one portion at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 60 min. Then iodomethane (1.08 g, 7.64 mmol) was added at 0 °C and the mixture was stirred at 20 °C for 1 hr. On completion, the mixture was quenched with saturated ammonium chloride (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (15 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 10/1 to 1/1] to give tert-butyl 3-methoxy-3-(4-methoxyquinazolin-6- yl)pyrrolidine-1-carboxylate (420 mg, 1.17 mmol, 61%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.12 (s, 1H), 8.06 - 7.98 (m, 1H), 7.96 - 7.88 (m, 1H), 4.22 (d, J = 4.4 Hz, 3H), 4.01 (d, J = 11.6 Hz, 0.5H), 3.88 (d, J = 11.6 Hz, 0.5H), 3.75 (d, J = 12.0 Hz, 0.5H), 3.66 - 3.49 (m, 2.5H), 3.05 (d, J = 4.4 Hz, 3H), 2.51 (d, J = 12.4 Hz, 1H), 2.38 - 2.17 (m, 1H), 1.50 (d, J = 1.2 Hz, 9H). Step 3. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-metho xy- pyrrolidine-1-carboxylate To a mixture of 3,4-dichloro-2-fluoro-aniline (125 mg, 695 μmol) in tetrahydrofuran (1 mL) was added n-butyl lithium (2.5 M in toluene, 0.56 μL) slowly at 20 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 6 hr. Then tert-butyl 3-methoxy-3-(4- methoxyquinazolin-6-yl)pyrrolidine-1-carboxylate (100 mg, 278 μmol) was added at 0 °C and the mixture was stirred at 20 °C for 16 hr. On completion, the mixture was quenched by saturated ammonium chloride (30 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 10/1 to 1/1] to afford tert-butyl 3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-methoxy-pyrrolidine-1-carboxylate (90 mg, 178 μmol, 63%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (d, J = 4.0 Hz, 1H), 8.56 - 8.40 (m, 1H), 8.05 - 7.98 (m, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.86 (s, 1H), 7.74 - 7.57 (m, 1H), 7.37 (d, J = 9.2 Hz, 1H), 4.01 - 3.46 (m, 4H), 3.17 - 3.06 (m, 3H), 2.51 (s, 1H), 2.38 - 2.21 (m, 1H), 1.50 (s, 9H). Step 4. N-(3,4-Dichloro-2-fluoro-phenyl)-6-(3-methoxypyrrolidin-3-yl )quinazolin-4- amine To a solution of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- methoxy -pyrrolidine-1-carboxylate (60.0 mg, 118 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (405 mg, 3.55 mmol). The mixture was stirred at 25 °C for 30 min. On completion, the residue was dried by blowing nitrogen to give N-(3,4-dichloro-2-fluoro-phenyl)- 6-(3-methoxypyrrolidin-3-yl)quinazolin-4-amine (48 mg, 118 μmol, 99%) as a brownish red solid. m/z ES+ [M+H] ⁺ 407.0. Step 5. 1-[3-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-me thoxy-pyrrolidin-1- yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-(3-methoxypyrrolidin-3- yl)quinazolin-4-amine (48.0 mg, 92.1 μmol) in tetrahydrofuran (1 mL) and water (0.20 mL) was added sodium bicarbonate (30.9 mg, 368 μmol) to adjust pH = 8. Then prop-2-enoyl chloride (7.50 mg, 82.9 μmol) was added at 0 °C .The mixture was stirred at 0 °C for 30 min. On completion, the mixture was quenched by 1.0 mL methanol at 0 °C. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 35%-65%, 8 min) to give 1-[3-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-methoxy-pyrrolidin-1-yl]prop-2-en -1-one (7.4 mg, 16.0 μmol, 17%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 8.52 (d, J = 15.6 Hz, 2H), 8.01 - 7.76 (m, 2H), 7.60 (s, 1H), 7.69 - 7.50 (m, 1H), 6.65 (ddd, J = 2.8, 10.4, 16.0 Hz, 1H), 6.24 - 6.13 (m, 1H), 5.76 - 5.66 (m, 1H), 4.31 - 4.17 (m, 1H), 3.92 - 3.53 (m, 3H), 3.01 - 2.89 (m, 3H), 2.74 - 2.58 (m, 1H), 2.44 - 2.31 (m, 1H); m/z ES+ [M+H] ⁺ 461.1. Example 304. Preparation of 1-[(1S,5R)-1-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6- yl]-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (Compound 246) Step 1. Benzyl (1S,5R)-1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] -3- azabicyclo[3.1.0]hexane-3-carboxylate and benzyl (1R,5S)-1-[4-(3,4-dichloro-2-fluoro- anilino)quinazolin-6-yl]-3-azabicyclo[3.1.0]hexane-3-carboxy late Benzyl 1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3-azabi cyclo[3.1.0]hexane- 3-carboxylate (85 mg, 162 μmol) was separated by SFC (condition: Column: Chiralpak AY-350 × 4.6mm I.D, 3um; Mobile phase:Phase A for CO ₂ , and Phase B for IPA(0.05%DEA); Gradient elution: 40%B in A; Flow rate: 3mL/min; Detector:DAD; Column Temp: 35C; Back Pressure: 100Bar) to give benzyl (1S,5R)-1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] -3- azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 75.6 μmol, 47%) as a white solid and benzyl (1R,5S)-1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] -3-azabicyclo[3.1.0]hexane-3- carboxylate (40 mg, 75.6 μmol, 47%) as a white solid. Step 2. 6-[(1S,5R)-3-Azabicyclo[3.1.0]hexan-1-yl]-N-(3,4-dichloro-2- fluoro- phenyl)quinazolin-4-amine A solution of benzyl (1S, 5R)-1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 76.4 μmol) in trifluoroacetic acid (0.5 mL) was stirred at 60 °C for 1 hr. The mixture was concentrated under reduced pressure to give 6-[(1S,5R)- 3-azabicyclo[3.1.0]hexan-1-yl]-N-(3,4-dichloro-2-fluoro-phen yl)quinazolin-4-amine (38 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 389.3. Step 3. 1-[(1S,5R)-1-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6- yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one To a solution of 6-[(1S,5R)-3-azabicyclo[3.1.0]hexan-1-yl]-N-(3,4-dichloro-2- fluoro- phenyl)quinazolin-4-amine (38 mg, 75.5 μmol) in water (0.5 mL) and tetrahydrofuran (1 mL) at 0 °C was added potassium carbonate (10 mg, 75.5 μmol) and prop-2-enoyl chloride (6.8 mg, 76 μmol). The mixture was stirred at 0 °C for 0.2 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (neutral:column: Waters Xbridge 150 x 25mm x 5um; mobile phase: [water(10 mM NH ₄ HCO ₃ ) - acetonitrile]; B%: 38% - 68%, 8min) to give 1-[(1S,5R)-1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (13.2 mg, 29.3 μmol, 39%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.15 - 10.04 (m, 1H), 8.48 ( s, 1H), 8.31 (d, J = 25.6 Hz, 1 H), 7.79 – 7.74 (m, 1H), 7.68 - 7.66 (m, 1H), 7.60 ( s, 2H), 6.71 - 6.59 (m, 1H), 6.21 - 6.16 (m, 1H), 5.71 (d, J = 10.4 Hz, 1H), 4.32 - 4.26 (m, 1H), 4.02 - 3.57 (m, 3H), 2.33 - 2.17 (m, 1H), 1.32 - 1.27 (m, 1H), 0.95 - 0.91 (m, 1H); m/z ES+ [M+H] ⁺ 443.3. Example 305. Preparation of 1-[(1R,5S)-1-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6- yl]-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (Compound 247) Step 1. 6-[(1R,5S)-3-Azabicyclo[3.1.0]hexan-1-yl]-N-(3,4-dichloro-2- fluoro- phenyl)quinazolin-4-amine A solution of benzyl (1R,5S)-1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6-yl] -3- azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 38.2 μmol) in trifluoroacetic acid (0.6 mL) was stirred at 60 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give 6-[(1R,5S)-3-azabicyclo[3.1.0]hexan-1-yl]-N-(3,4-dichloro-2- fluoro-phenyl)quinazolin-4- amine (20 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 389.2. Step 2. 1-[(1R,5S)-1-[4-(3,4-Dichloro-2-fluoro-anilino)quinazolin-6- yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one To a solution of 6-[(1R,5S)-3-azabicyclo[3.1.0]hexan-1-yl]-N-(3,4-dichloro-2- fluoro- phenyl)quinazolin-4-amine (19 mg, 37.7 μmol, TFA salt) in water (0.5 mL) and tetrahydrofuran (0.5 mL) was added potassium carbonate (5.2 mg, 37.8 μmol) and prop-2-enoyl chloride (3.4 mg, 38 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.2 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral column: Waters Xbridge 150 x 25mm x 5um; mobile phase: [water(10 mM NH ₄ HCO ₃ ) - acetonitrile]; B%: 38% - 68%, 8min) to give 1-[(1R,5S)-1-[4-(3,4-dichloro-2-fluoro-anilino)quinazolin-6- yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (5.46 mg, 11.45 μmol, 30%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 - 10.00 (m, 1H), 8.45 - 8.27 (m, 2H), 7.74 - 7.56 (m, 4H), 6.68 - 6.59 (m, 1H), 6.20 - 6.15 (m, 1H), 5.73 - 5.69 (m, 1H), 4.32 - 4.25 (m, 1H), 3.98 – 3.58 (m, 3H), 2.31 - 2.17 (m, 1H), 1.31 - 1.24 (m, 1H), 0.95 - 0.90 (m, 1H); m/z ES+ [M+H] ⁺ 443.3. Example 306. Preparation of 1-[(3R)-3-[4-(4-Chloro-3-ethynyl-2-fluoro-anilino)quinazolin - 6-yl]pyrrolidi-1-yl]prop-2-en-1-one (Compound 44) Step 1. tert-Butyl 3-[4-[4-chloro-2-fluoro-3-(2-trimethylsilylethynyl)anilino]q uinazolin- 6-yl]pyrrolidine-1-carboxylate To a solution of tert-butyl 3-(4-chloroquinazolin-6-yl)pyrrolidine-1-carboxylate (250 mg, 748 μmol) in acetonitrile (2 mL) was added 4-chloro-2-fluoro-3-(2-trimethylsilylethynyl)aniline (271 mg, 1.12 mmol) and the reaction mixture was stirred at 60 °C for 12 hr. The mixture was added water (10 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 * 25 m * 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 67%-97%, 9 min) to give tert-butyl 3-[4-[4-chloro-2- fluoro-3-(2-trimethylsilylethynyl)anilino]quinazolin-6-yl]py rrolidine-1-carboxylate (150 mg, 278 μmol, 37%) as an off-white solid. m/z ES+ [M+H] ⁺ 539.2. Step 2. tert-Butyl 3-(4-((4-chloro-3-ethynyl-2-fluorophenyl)amino)quinazolin-6- yl)pyrrolidine-1-carboxylate To a solution of tert-butyl 3-[4-[4-chloro-2-fluoro-3-(2- trimethylsilylethynyl)anilino]quinazolin-6-yl]pyrrolidine-1- carboxylate (120 mg, 222 μmol) in acetonitrile (2 mL) was added cesium carbonate (217 mg, 667 μmol) and the reaction mixture was stirred at 25 °C for 2 hr. On completion, the mixture was added water (10 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: DAICEL CHIRALPAK IC(250 mm * 30 mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 40%-40%, 2.3; 30 min) to give tert-butyl 3-(4-((4-chloro-3-ethynyl-2- fluorophenyl)amino)quinazolin-6-yl)pyrrolidine-1-carboxylate (120 mg, 139 μmol, 77%) as a light yellow solid. m/z ES+ [M+H]+ 467.2. Step 3. tert-Butyl (3R)-3-[4-(4-chloro-3-ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1- carboxylate 3-(4-((4-chloro-3-ethynyl-2-fluorophenyl)amino)quinazolin-6- yl)pyrrolidine-1- carboxylate (120 mg, 139 μmol) was separated by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O-ethanol];B%: 40%-40%,2.3;30min) to give tert-butyl (3R)-3-[4-(4-chloro-3-ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1- carboxylate (80.0 mg, 172 μmol, 77%) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 4.06 - 3.85 (m, 1H), 3.68 (s, 1H), 3.65 - 3.53 (m, 2H), 3.50 - 3.34 (m, 2H), 2.47 - 2.38 (m, 1H), 2.21 - 2.15 (m, 1H), 1.48 (s, 9H). Step 4. N-(4-Chloro-3-ethynyl-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3- yl]quinazolin-4- amine To a solution of tert-butyl (3R)-3-[4-(4-chloro-3-ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate (70.0 mg, 149 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (6.22 g, 54.5 mmol) and the reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-(4-chloro-3-ethynyl-2-fluoro-phenyl)-6- [(3R)-pyrrolidin-3-yl]quinazolin-4-amine (70.0 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 366.9. Step 5. 1-[(3R)-3-[4-(4-Chloro-3-ethynyl-2-fluoro-anilino)quinazolin -6-yl]pyrrolidi-1- yl]prop-2-en-1-one To a solution of N-(4-chloro-3-ethynyl-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3- yl]quinazolin-4-amine (53.4 mg, 145 μmol) in tetrahydrofuran (1 mL) and water (0.2 mL) was added sodium bicarbonate (44.1 mg, 436 μmol). Then prop-2-enoyl chloride (11.8 mg, 131 μmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 * 30 mm * 3 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%: 15%-45%, 7 min) to give 1-[(3R)-3-[4-(4-chloro-3-ethynyl-2-fluoro- anilino)quinazolin-6-yl]pyrrolidi-1-yl]prop-2-en-1-one (14.7 mg, 34.9 μmol, 22%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 8.51 - 8.36 (m, 2H), 7.89 - 7.73 (m, 2H), 7.62 (d, J = 5.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 6.65 (dd, J = 10.4, 16.8 Hz, 1H), 6.21 - 6.16 (m, 1H), 5.72 – 5.69 (m, 1H), 4.94 (s, 1H), 4.24 - 4.04 (m, 1H), 3.95 - 3.50 (m, 4H), 2.45 - 2.30 (m, 1H), 2.20 - 2.02 (m, 1H); m/z ES+ [M+H] ⁺ 421.2. Example 307. Preparation of 1-[(3S)-3-[4-(3-Ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 59) Step 1. tert-Butyl 3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]pyrrolidine-1-carboxylate To a solution of tert-butyl 3-(4-chloroquinazolin-6-yl)pyrrolidine-1-carboxylate (600 mg, 1.8 mmol) in acetonitrile (3 mL) was added 2-fluoro-3-(2-trimethylsilylethynyl)aniline (558 mg, 2.7 mmol) and the reaction mixture was stirred at 60 °C for 12 hrs. On completion, the mixture was added water (10 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18150 * 50 mm * 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 58% - 88%, 11 min) to give tert-butyl 3-[4- [2-fluoro-3-(2-trimethylsilylethynyl)anilino]quinazolin-6-yl ]pyrrolidine-1-carboxylate (200 mg, 396 μmol, 22%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (d, J = 10.4 Hz, 1H), 8.48 (s, 1H), 8.38 ( s, 1H), 7.86 - 7.82 (m, 1H), 7.78 - 7.74 (m, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.29 - 7.22 (m, 1H), 3.91 - 3.79 (m, 1H), 3.63 - 3.50 (m, 2H), 3.41 - 3.34 (m, 2H), 2.40 - 2.22 (m, 1H), 2.15 - 2.01 (m, 1H), 1.42 (d, J = 5.6 Hz, 9H), 0.25 (s, 9H). Step 2. tert-Butyl (3S)-3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]quina zolin-6- yl]pyrrolidine-1-carboxylate and tert-butyl (3R)-3-[4-[2-fluoro-3-(2- trimethylsilylethynyl)anilino]quinazolin-6-yl]pyrrolidine-1- carboxylate tert-Butyl 3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]quinazolin -6-yl]pyrrolidine- 1-carboxylate (200 mg, 396 μmol) was purified by prep-HPLC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O ethanol]; B%: 50%-50%, 2.5; 40 min) to give tert-butyl (3S)-3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]quina zolin-6- yl]pyrrolidine-1-carboxylate (100 mg, 198 μmol, 50%) as a light yellow solid and tert-butyl (3R)- 3-[4-[2-fluoro-3-(2-trimethylsilylethynyl)anilino]quinazolin -6-yl]pyrrolidine-1-carboxylate (100 mg, 198 μmol, 50%) as a light yellow solid. Step 3. N-(3-Ethynyl-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinaz olin-4-amine To a solution of tert-butyl (3S)-3-[4-[2-fluoro-3-(2- trimethylsilylethynyl)anilino]quinazolin-6-yl]pyrrolidine-1- carboxylate (90.0 mg, 178 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (13.8 g, 121 mmol) and the reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-(3- ethynyl-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinazolin- 4-amine (79 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 333.1. Step 4. 1-[(3S)-3-[4-(3-Ethynyl-2-fluoro-anilino)quinazolin-6-yl]pyr rolidin-1-yl]prop-2- en-1-one To a solution of N-(3-ethynyl-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinaz olin-4- amine (79 mg, 177 μmol, TFA salt) in tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (44.6 mg, 531 μmol). Then prop-2-enoyl chloride (14.4 mg, 159 μmol) was added at 0 °C. The reaction mixture was stirred at 0°C for 1 hr. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 * 25 mm * 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 10% - 40%, 10 min) to give 1-[(3S)-3-[4-(3-ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (22.2 mg, 57.4 μmol, 24%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (m, 1H), 8.48 (s, 1H), 8.44 - 8.39 (m, 1H), 7.92 - 7.71 (m, 2H), 7.66 - 7.42 (m, 2H), 7.33 - 7.21 (m, 1H), 6.65 (dd, J = 10.4, 16.8 Hz, 1H), 6.28 - 6.08 (m, 1H), 5.69 (dt, J = 2.4, 10.0 Hz, 1H), 4.54 (s, 1H), 4.25 - 4.04 (m, 1H), 3.94 - 3.73 (m, 1H), 3.71 - 3.54 (m, 2H), 3.49 - 3.45 (d, J = 11.6 Hz, 1H), 2.47 - 2.29 (m, 1H), 2.21 - 2.03 (m, 1H); m/z ES+ [M+H] ⁺ 387.2. Example 308. Preparation of 1-[(3R)-3-[4-(3-Ethynyl-2-fluoro-anilino)quinazolin-6- Step 1. N-(3-Ethynyl-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]quinaz olin-4-amine To a solution of tert-butyl (3R)-3-[4-[2-fluoro-3-(2- trimethylsilylethynyl)anilino]quinazolin-6-yl]pyrrolidine-1- carboxylate (90 mg, 178 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol) and the reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give N-(3- ethynyl-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]quinazolin- 4-amine (79.0 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 333.4. Step 2. 1-[(3R)-3-[4-(3-Ethynyl-2-fluoro-anilino)quinazolin-6-yl]pyr rolidin-1-yl]prop-2- en-1-one To a solution of N-(3-ethynyl-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]quinaz olin-4- amine (79 mg, 177 μmol, TFA salt) in tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (44.6 mg, 531 μmol). Then prop-2-enoyl chloride (14.4 mg, 159 μmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 * 25 mm * 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 10%-40%, 10 min) to give 1-[(3R)-3-[4-(3-ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (20.5 mg, 53.1 μmol, 24%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (m, 1H), 8.47 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.93 - 7.70 (m, 2H), 7.65 - 7.41 (m, 2H), 7.32 - 7.20 (m, 1H), 6.65 (dd, J = 10.4, 16.8 Hz, 1H), 6.23 - 6.12 (m, 1H), 5.69 (dt, J = 2.0, 10.0 Hz, 1H), 4.54 (s, 1H), 4.23 - 4.05 (m, 1H), 3.94 - 3.73 (m, 1H), 3.71 - 3.55 (m, 2H), 3.49 - 3.45 (m, 1H), 2.46 - 2.28 (m, 1H), 2.24 - 1.99 (m, 1H); m/z ES+ [M+H] ⁺ 387.2. Example 309. Preparation of (S)-1-(3-(4-((5-Ethynyl-2-fluoropyridin-3-yl)amino)quinazoli n- 6-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 109) Step 1. 6-Bromo-N-(2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-yl) quinazolin-4-amine To a solution of 2-fluoro-5-(2-trimethylsilylethynyl) pyridin-3-amine (2.17 g, 10.4 mmol) in acetonitrile (19 mL) was added 6-bromo-4-chloro-quinazoline (1.95 g, 8.01 mmol). The mixture was stirred at 60 °C for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=5/1 to dichloromethane/methanol=20/1) to give 6-bromo-N-(2-fluoro-5- ((trimethylsilyl)ethynyl)pyridin-3-yl)quinazolin-4-amine (3.0 g, 7.19 mmol, 86%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 8.79 (s, 1H), 8.34 - 8.10 (m, 3H), 7.85 (d, J = 8.8 Hz, 1H), 0.26 (s, 9H); m/z ES+ [M+H] ⁺ 417.1. Step 2. tert-Butyl 3-(4-((2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3- yl)amino)quinazolin-6-yl)pyrrolidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-N-[2-fluoro-5-(2- trimethylsilylethynyl)-3-pyridyl] quinazolin-4-amine (1.00 g, 2.41 mmol), tert-butyl 3- bromopyrrolidine-1-carboxylate (783 mg, 3.13 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (27.0 mg, 24.1 μmol), NiCl ₂ .dtbbpy (4.79 mg, 12.0 μmol), tris(trimethylsilyl)silane (599 mg, 2.41 mmol), sodium carbonate (510 mg, 4.82 mmol) in dimethoxyethane (15 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hr under nitrogen. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (dichloromethane: methanol = 100:1) to give tert-butyl 3-(4-((2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3- yl)amino)quinazolin-6-yl)pyrrolidine-1-carboxylate (500 mg, 712 μmol, 30%) as a yellow solid. m/z ES+ [M+H] ⁺ 506.3. Step 3. tert-Butyl 3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6- yl)pyrrolidine-1-carboxylate A solution of tert-butyl 3-[4-[[2-fluoro-5-(2-trimethylsilylethynyl)-3- pyridyl]amino]quinazolin-6-yl]pyrrolidine-1-carboxylate (420 mg, 831 μmol) in tetrabutylammonium fluoride (1 M in THF, 4.15 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=1/1 to 0/1) and repurified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6- yl)pyrrolidine-1-carboxylate (290 mg, 642 μmol, 77%) as a colorless oil. m/z ES+ [M+H] ⁺ 434.1. Step 4. (S)-tert-Butyl 3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6- yl)pyrrolidine-1-carboxylate tert-Butyl 3-[4-[(5-ethynyl-2-fluoro-3-pyridyl)amino]quinazolin-6-yl]py rrolidine-1- carboxylate (290 mg, 669 μmol) was purified by SFC (column: Daicel ChiralPak IG (250*30 mm, 10 um); mobile phase: [0.1%NH ₃ H ₂ O methanol]; B%: 50%-50%, 2.9; 45 min) to give (S)-tert- butyl 3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazolin-6-yl) pyrrolidine-1-carboxylate (100 mg, 231 μmol, 34%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 - 9.84 (m, 1H), 8.60 - 8.44 (m, 1H), 8.38 - 8.14 (m, 3H), 7.91 - 7.70 (m, 2H), 4.51 - 4.39 (m, 1H), 3.92 - 3.78 (m, 1H), 3.65 - 3.52 (m, 4H), 2.39 - 2.30 (m, 1H), 2.16 - 1.96 (m, 1H), 1.41 (d, J = 5.6 Hz, 9H); m/z ES+ [M+H] ⁺ 434.1. Step 5. (S)-N-(5-Ethynyl-2-fluoropyridin-3-yl)-6-(pyrrolidin-3-yl) quinazolin-4-amine To a solution of tert-butyl (3S)-3-[4-[(5-ethynyl-2-fluoro-3-pyridyl)amino]quinazolin-6- yl]pyrrolidine-1-carboxylate (100 mg, 231 μmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25°C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to (S)-N-(5-ethynyl-2-fluoropyridin-3- yl)-6-(pyrrolidin-3-yl) quinazolin-4-amine (80 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 334.3. Step 6. (S)-1-(3-(4-((5-Ethynyl-2-fluoropyridin-3-yl)amino)quinazoli n-6-yl)pyrrolidin-1- yl)prop-2-en-1-one To a solution of N-(5-ethynyl-2-fluoro-3-pyridyl)-6-[(3S)-pyrrolidin-3-yl] quinazolin-4- amine (80 mg, 179 μmol, TFA salt) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (52.6 mg, 626 μmol) and prop-2-enoyl chloride (16.2 mg, 179 μmol). The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um;mobile phase: [water (0.225% FA) - acetonitrile]; B%: 11% - 41%, 10 min) to give (S)-1-(3-(4-((5-ethynyl-2-fluoropyridin-3-yl)amino)quinazoli n- 6-yl)pyrrolidin-1-yl)prop-2-en-1-one (31.1 mg, 80.4 μmol, 45%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.43 - 9.92 (m, 1H), 8.56 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.30 (s, 2H), 7.98 - 7.89 (m, 1H), 7.83 d, J = 8.4 Hz, 1H), 6.72 (dd, J = 10.4, 16.8 Hz, 1H), 6.24 (ddd, J = 2.4, 5.6, 16.8 Hz, 1H), 5.76 (dt, J = 2.4, 10.4 Hz, 1H), 4.55 (s, 1H), 4.30 - 4.10 (m, 1H), 3.98 - 3.80 (m, 1H), 3.78 - 3.60 (m, 3H), 2.53 - 2.36 (m, 1H), 2.27 - 2.10 (m, 1H); m/z ES+ [M+H] ⁺ 388.4. Example 310. Preparation of 1-[(3S)-3-[4-[(7-Fluoro-1,2-benzothiazol-6- yl)amino]quinazolin-6-yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 225) Step 1. tert-Butyl -3-[4-[(7-fluoro-1,2-benzothiazol -6-yl)amino]quinazolin-6- yl]pyrrolidine-1-carboxylate To an 8 mL vial equipped with a stir bar was added N-(6-bromoquinazolin-4-yl) -7-fluoro- 1,2-benzothiazol-6-amine (800 mg, 2.13 mmol), tert-butyl 3-bromopyrrolidine -1-carboxylate (800 mg, 3.20 mmol), Ir[dF(CF ₃ )ppy]2(dtbpy)(PF ₆ ) (23.9 mg, 21.3 μmol), NiCl ₂ .dtbbpy (8.52 mg, 21.3 μmol), tris(trimethylsilyl)silane (530 mg, 2.13 mmol), sodium carbonate (452 mg, 4.26 mmol) in dimethoxyethane (20 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=3/1 to 0/1) to give tert-butyl -3-[4-[(7-fluoro-1,2-benzothiazol -6-yl)amino]quinazolin-6- yl]pyrrolidine-1-carboxylate (300 mg, 0.65 mmol, 33%) as a yellow solid. m/z ES+ [M+H] ⁺ 466.2. Step 2. tert-Butyl (3S)-3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazolin- 6- yl]pyrrolidine-1-carboxylate and tert-butyl (3R)-3-[4-[(7-fluoro-1,2-benzothiazol -6- yl)amino]quinazolin-6-yl]pyrrolidine-1-carboxylate tert-Butyl -3-[4-[(7-fluoro-1,2-benzothiazol -6-yl)amino]quinazolin-6-yl]pyrrolidine-1- carboxylate (300 mg, 0.65 mmol) was separated by SFC [column: DAICEL CHIRALCEL OJ- H(250mm x 30mm, 5 um); mobile phase: [0.1% NH3H2O ethanol]; B%: 30% - 30%, 5.0 min; 40 min] to give tert-butyl (3S)-3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazolin- 6- yl]pyrrolidine-1-carboxylate (100 mg, 0.21 mmol, 33%) and tert-butyl (3R)-3-[4-[(7-fluoro-1,2- benzothiazol -6-yl)amino]quinazolin-6-yl]pyrrolidine-1-carboxylate (100 mg, 0.21 mmol, 33%) as a yellow solid. m/z ES+ [M+H] ⁺ 466.1. Step 3. 7-Fluoro-N-[6-[(3S)-pyrrolidin-3-yl]quinazolin -4-yl]-1,2-benzothiazol-6-amine To a solution of tert-butyl (3S)-3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazolin- 6-yl]pyrrolidine-1-carboxylate (90.0 mg, 193 μmol) in dichloromethane (0.5 mL) was added hydrochloric acid/dioxane (4 M, 49.0 μL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 7-fluoro-N-[6-[(3S)-pyrrolidin-3- yl]quinazolin -4-yl]-1,2-benzothiazol-6-amine (75.0 mg, 187 μmol, 97%, HCl salt) as a yellow solid. m/z ES+ [M+H] ⁺ 366.1. Step 4. 1-[(3S)-3-[4-[(7-Fluoro-1,2-benzothiazol-6-yl)amino]quinazol in-6-yl]pyrrolidin- 1-yl]prop-2-en-1-one To a solution of 7-fluoro-N-[6-[(3S)-pyrrolidin-3-yl]quinazolin-4-yl]-1,2-ben zothiazol - 6-amine (75.0 mg, 187 μmol, HCl salt) in tetrahydrofuran (1 mL) and water (0.2 mL) was added sodium bicarbonate (78.4 mg, 933 μmol) and prop-2-enoyl chloride (13.5 mg, 149 μmol). The mixture was stirred at 0 °C for 0.1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water(0.225% FA)-acetonitrile]; B%: 12% - 42%, 7 min) to give 1-[(3S)-3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazol in- 6-yl]pyrrolidin-1-yl]prop-2-en-1-one (12.8 mg, 78.3 μmol, 16%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 - 10.20 (m, 1H), 9.23 (d, J = 4.00 Hz, 1 H), 8.50 - 8.42 (m, 2 H), 8.14 (d, J = 8.40 Hz, 1 H), 7.89 - 7.88 (m, 1H), 7.80 - 7.74 (m, 2H), 6.70 - 6.64 (m, 1H), 6.22 - 6.17 (m, 1H), 5.73 - 5.67 (m, 1H), 4.23 - 4.09 (m, 1H), 3.91 - 3.67 (m, 1 H), 3.65 - 3.60 (m, 2 H), 3.51 -3.48 (m, 1H), 2.41 - 2.33 (m, 1 H), 2.19 - 2.12 (m, 1 H); m/z ES+ [M+H] ⁺ 420.3. Example 311. Preparation of 1-[(3R)-3-[4-[(7-Fluoro-1,2-benzothiazol-6- yl)amino]quinazolin-6-yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 226) Step 1. 7-Fluoro-N-[6-[(3R)-pyrrolidin-3-yl]quinazolin-4-yl]-1,2-ben zothiazol-6-amine To a solution of tert-butyl (3R)-3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazolin- 6-yl] pyrrolidine-1-carboxylate (90.0 mg, 193 μmol) in dichloromethane (0.5 mL) was added hydrochloric acid/dioxane (4 M, 48.3 μL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 7-fluoro-N-[6-[(3R)-pyrrolidin-3- yl]quinazolin-4-yl]-1,2-benzothiazol-6-amine (75.0 mg, crude, HCl salt) as a yellow solid. Step 2. 1-[(3R)-3-[4-[(7-Fluoro-1,2-benzothiazol-6-yl)amino]quinazol in-6-yl]pyrrolidin- 1-yl]prop-2-en-1-one To a solution of 7-fluoro-N-[6-[(3R)-pyrrolidin-3-yl]quinazolin-4-yl]-1,2-ben zothiazol-6- amine (68.2 mg, 187 μmol, HCl salt) in tetrahydrofuran (1 mL) and water (0.2 mL) was added sodium bicarbonate (78.4 mg, 933 μmol) and prop-2-enoyl chloride (13.5 mg, 149 μmol). The mixture was stirred at 0 °C for 0.1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Gemini-NX C1875 x 30mm x 3um;mobile phase: [water(0.225%FA)-acetonitrile]; B%: 12%-42%, 7 min) to give 1-[(3R)-3-[4-[(7-fluoro-1,2-benzothiazol-6-yl)amino]quinazol in-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (16.9 mg, 40.3 μmol, 22%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 - 10.20 (m, 1H), 9.23 (d, J = 4.00 Hz, 1 H), 8.50 - 8.43 (m, 2 H), 8.14 (d, J = 8.40 Hz, 1 H), 7.89 - 7.88 (m, 1H), 7.81 - 7.75 (m, 2H), 6.70 - 6.64 (m, 1H), 6.22 - 6.18 (m, 1H), 5.73 - 5.68 (m, 1H), 4.23 - 4.09 (m, 1H), 3.91 - 3.67 (m, 1 H), 3.65 - 3.60 (m, 2 H), 3.51 - 3.45 (m, 1H), 2.39 - 2.34 (m, 1 H), 2.19 - 2.12 (m, 1 H); m/z ES+ [M+H] ⁺ 420.3. Example 312. Preparation of 1-[(3R)-3-[4-(3,4-Dichloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 240) Step 1. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl]-2,5- dihydropyrrole-1-carboxylate To a mixture of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimi din-4- amine (1 g, 2.91 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydropyrrole-1-carboxylate (816 mg, 2.77 mmol) in dioxane (24 mL) and water (4 mL) was added potassium carbonate (1.21 g, 8.73 mmol) and Pd(dppf)Cl ₂ (212 mg, 291 μmol). The mixture was stirred at 80 °C for 2 hr under nitrogen. The mixture was cooled to room temperature and poured into water (30 mL). The mixture was filtered. The filter cake was dried in vacuo to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 -yl]-2,5-dihydropyrrole-1- carboxylate (1.3 g, 2.73 mmol, 93%) as a brown solid. m/z ES+ [M+H] ⁺ 476.0. Step 2. tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]pyrrolidine-1-carboxylate To a mixture of tert-butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6 - yl]-2,5-dihydropyrrole-1-carboxylate (1 g, 2.10 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added palladium on activated carbon (100 mg, 10 wt. % loading) and magnesium oxide (676 mg, 16.8 mmol). The mixture was stirred at 20 °C for 3 hr under hydrogen. The mixture was filtered and the filtrate was concentrated in vacuum. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl 3-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]pyrrolidine-1-carboxylat e (350 mg, 731 μmol, 35%) as a brown solid. m/z ES+ [M+H] ⁺ 478.3. Step 3. tert-Butyl (3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimi din-6- yl]pyrrolidine-1-carboxylate and tert-Butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidine-1-carboxylate tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido [3,4-d]pyrimidin-6-yl]pyrrolidine- 1-carboxylate (350 mg, 731 μmol) was purified by SFC (column: DAICEL CHIRALCEL OJ- H(250mm*30mm,5um);mobile phase: [0.1%NH3water MEOH];B%: 25%-25%,4.2 min;200 min) to afford tert-butyl (3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimi din-6- yl]pyrrolidine-1-carboxylate (85.0 mg, 178 μmol, 28%) as a yellow solid and tert-butyl (3S)-3-[4- (3,4-dichloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]p yrrolidine-1-carboxylate (100 mg, 209 μmol, 33%) as a yellow solid. Step 4. N-(3,4-Dichloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyr ido[3,4- d]pyrimidin-4-amine To a solution of tert-butyl 3R)-3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidine-1-carboxylate (70.0 mg, 146 μmol) in ethyl acetate (2 mL) was added hydrochloric acid/Ethyl acetate (4 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give N-(3,4-dichloro-2-fluoro- phenyl)-6-[(3R)-pyrrolidin-3-yl]pyrido[3,4-d]pyrimidin-4-ami ne (50 mg, 132 μmol, 90%) as a yellow solid. m/z ES+ [M+H] ⁺ 378.0. Step 5. 1-[(3R)-3-[4-(3,4-Dichloro-2-fluoro-anilino)pyrido[3,4-d]pyr imidin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyr ido[3,4- d]pyrimidin-4-amine (50 mg, 132 μmol) and sodium bicarbonate (11.1 mg, 132 μmol) in tetrahydrofuran (2 mL) and water (0.5 mL) was added prop-2-enoyl chloride (10.8 mg, 119 μmol) in tetrahydrofuran (2 mL) at 0 °C. Then the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase:[water(10mM NH ₄ HCO ₃ )- acetonitrile]; B%: 25%-55%, 8 min) to afford 1-[(3R)-3-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]pyrrolidin-1-yl]prop-2-e n-1-one (31.2 mg, 72.2 μmol, 54%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.49 - 10.28 (m, 1H), 9.17 (s, 1H), 8.58 - 8.55 (m, 1H), 8.28 (s, 1H), 7.63 - 7.60 (m, 2H), 6.66 - 6.61 (m, 1H), 6.20 - 6.16 (m, 1H), 5.72 - 5.66 (m, 1H), 4.16 - 4.01 (m, 1H), 3.88 - 3.45 (m, 4H), 2.41 - 2.16 (m, 2H); m/z ES+ [M+H] ⁺ 432.1. Example 313. Preparation of 1-[(3R)-3-[4-(3,4-Dichloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 239) Step 1. N-(3,4-Dichloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]pyr ido[3,4- d]pyrimidin-4-amine To a solution of tert-butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidine-1-carboxylate (90 mg, 188 μmol) in ethyl acetate (2 mL) was added HCl/Ethyl acetate (4 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3S)- pyrrolidin-3-yl]pyrido[3,4-d]pyrimidin-4-amine (65 mg, 172 μmol, 91%) as a yellow solid. m/z ES+ [M+H]+378.0. Step 2. 1-[(3S)-3-[4-(3,4-Dichloro-2-fluoro-anilino)pyrido[3,4-d]pyr imidin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one To a solution of N-(3,4-dichloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]pyr ido[3,4- d]pyrimidin-4-amine (60 mg, 159 μmol) and sodium bicarbonate (13.3 mg, 159 μmol) in tetrahydrofuran (2.0 mL) and water (0.5 mL) was added prop-2-enoyl chloride (12.9 mg, 143 μmol) in tetrahydrofuran (2.0 mL) at 0 °C. Then the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase:[water(10mM NH ₄ HCO ₃ )-acetonitrile]; B%: 25%-55%, 8 min) to afford 1-[(3S)-3-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]pyrrolidin-1-yl]prop-2-e n-1-one (38.0 mg, 87.9 μmol, 55%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.48 - 10.37 (m, 1H), 9.16 (d, J = 2.4 Hz, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.62 - 7.60 (m, 2H), 6.69 - 6.61 (m, 1H), 6.20 - 6.16 (m, 1H), 5.72 - 5.69 (m, 1H), 4.15 – 4.04 (m, 1H), 3.88 - 3.61 (m, 4H), 2.46 - 2.18 (m, 2H); m/z ES+ [M+H] ⁺ 432.1. Example 314. Preparation of 6-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] - 2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-7-one (Compound 290) Step 1. tert-Butyl 6-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -7-oxo- 2,6-diazaspiro[3.4]octane-2-carboxylate To a mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine (110 mg, 355 μmol), tert-butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate (121 mg, 534 μmol) and Pd ₂ (dba) ₃ (16.3 mg, 17.8 μmol) in dioxane (3.0 mL) was added cesium carbonate (347 mg, 1.06 mmol) and Xantphos (10.3 mg, 17.8 μmol) in one portion at 25 °C. The mixture was stirred at 100 °C for 3 hr under nitrogen. On completion, the mixture was filtered and concentrated to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -7-oxo- 2,6-diazaspiro[3.4]octane-2-carboxylate (127 mg, 254 μmol 71%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H), 9.10 (s, 1H), 8.95 (s, 1H), 8.56 (s, 1H), 7.60 - 7.46 (m, 2H), 7.30 (t, J = 8.0 Hz, 1H), 4.31 (s, 2H), 3.99 - 3.91 (m, 4H), 3.01 (s, 2H), 1.39 (s, 9H); m/z ES+ [M+H] ⁺ 499.1. Step 2. 6-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6-yl)-2,6- diazaspiro[3.4]octan-7-one To a solution of tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] - 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (90.0 mg, 180 μmol) in dichloromethane (4.5 mL) was added trifluoroacetic acid (1.25 g, 10.8 mmol), the mixture was stirred at 25 °C for 1 hr. The mixture was concentrated to give 6-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6-yl)-2,6-diazaspiro[3.4]octan-7-one (92.0 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 399.0. Step 3. 6-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -2-prop-2-enoyl- 2,6-diazaspiro[3.4]octan-7-one To a mixture of 6-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -2,6- diazaspiro[3.4]octan-7-one (92.0 mg, 179 μmol) and sodium bicarbonate (96.9 mg, 897 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (20.9 mg, 179 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The crude product was purified by Prep–HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (0.225%formic acid)- acetonitrile]; B%: 24%-54%, 11.5 min) to give 6-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-7- one (61.3 mg, 135 μmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.63 - 10.40 (m, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.65 - 8.47 (m, 1H), 7.64 - 7.40 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 6.38 - 6.23 (m, 1H), 6.17 - 6.07 (m, 1H), 5.75 - 5.63 (m, 1H), 4.43 - 4.28 (m, 4H), 4.11 - 3.99 (m, 2H), 3.05 (s, 2H); m/z ES+ [M+H] ⁺ 453.1. Example 315. Preparation of 1-[(3R)-3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 221)

Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -2,5- dihydropyrrole-1-carboxylate A solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine (1 g, 3.23 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydrop yrrole-1- carboxylate (907 mg, 3.07 mmol), Pd(dppf)Cl ₂ (236 mg, 323 μmol), potassium carbonate (1.34 g, 9.70 mmol) in dioxane (12 mL) and water (2 mL) was stirred at 100 °C for 2 hr under nitrogen. The reaction mixture was quenched by addition water (3 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 3-[4-(3-chloro-2-fluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]-2,5-dihydropyrrole-1-ca rboxylate (1.2 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 442.0. Step 2. tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6- yl]pyrrolidine-1-carboxylate To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] - 2,5- dihydropyrrole-1-carboxylate (0.8 g, 1.81 mmol), magnesium oxide (583 mg, 14.4 mmol) in tetrahydrofuran (15 mL) was added palladium on activated carbon (0.3 g, 10 wt. % loading), the mixture was stirred at 25 °C for 2 hr under hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% NH ₃ •water conditions) to give tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6-yl]pyrrolidine-1-carboxylate (0.2 g, 450 μmol, 24%) as a yellow solid. m/z ES+[M+H] ⁺ 444.1. Step 3. tert-Butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6- yl]pyrrolidine-1-carboxylate and tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidine-1-carboxylate tert-Butyl 3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] pyrrolidine-1- carboxylate (0.2 g, 450 μmol) was separated by SFC (column: DAICEL CHIRALCEL OJ- H(250mm*30mm,5um);mobile phase: [0.1%NH ₃ water-methanol]; B%: 25%-25%, 3.3 min; 45 min) to give tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6- yl]pyrrolidine-1-carboxylate (0.1 g, 225 μmol, 50%) as a yellow solid and tert-butyl (3S)-3-[4- (3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl]pyrro lidine-1-carboxylate (0.1 g, 225 μmol, 50%) as a yellow solid. Step 4. N-(3-Chloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyrido[ 3,4-d]pyrimidin-4- amine A solution of tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6- yl] pyrrolidine-1-carboxylate (0.1 g, 225 μmol) in hydrochloric acid/Ethyl acetate (4 M, 5 mL) was stirred at 25 °C for 0.5 hr. The mixture was concentrated in vacuo to give N-(3-chloro-2- fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyrido[3,4-d]pyrimidi n-4-amine (0.08 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 344.0. Step 5. 1-[(3R)-3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in-6-yl]pyrrolidin- 1-yl]prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyrido[ 3,4- d]pyrimidin -4-amine (0.07 g, 184 μmol), sodium bicarbonate (46.3 mg, 552 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added prop-2-enoyl chloride (16.6 mg, 184 μmol) at 0 °C, the mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(0.225%formic acid)-acetonitrile]; B%: 30%-60%,7 min) to give 1-[(3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in-6-yl]pyrrolidin-1-yl]prop-2- en-1-one (29.0 mg, 72.9 μmol, 39%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 - 10.31 (m, 1H), 9.17 (s, 1H), 8.59 (s, 1H), 8.30 (s, 1H), 7.55 - 7.52 (m, 2H), 7.33 - 7.29 (m, 1H), 6.68 - 6.61 (m, 1H), 6.20 - 6.14 (m, 1H), 5.71 - 5.66 (m, 1H), 4.15 - 4.03 (m, 1H), 3.88 - 3.73 (m, 3H), 3.71 - 3.49 (m, 1H), 2.38 - 2.26 (m, 1H), 2.23 - 2.19 (m, 1H); m/z ES+[M+H] ⁺ 398.3. Example 316. Preparation of 1-[(3S)-3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 222) Step 1. N-(3-Chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]pyrido[ 3,4-d]pyrimidin-4- amine A solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6- yl] pyrrolidine-1-carboxylate (0.1 g, 225 μmol) in hydrochloric acid/Ethyl acetate (4 M, 5 mL) was stirred at 25 °C for 0.5 hr. The mixture was concentrated in vacuo to give N-(3-chloro-2- fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyrido[3,4-d]pyrimidi n-4-amine (0.08 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 344.0. Step 2. 1-[(3S)-3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in-6-yl]pyrrolidin- 1-yl]prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyrido[ 3,4- d]pyrimidin -4-amine (0.07 g, 184 μmol) and sodium bicarbonate (46.3 mg, 552 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added prop-2-enoyl chloride (16.6 mg, 184 μmol) at 0 °C, the mixture was stirred at 0 °C for 0.5 hr. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 30%-60%,7min) to give 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in-6-yl]pyrrolidin-1-yl]prop-2- en-1-one (32.0 mg, 80.6 μmol, 39%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.52 - 10.19 (m, 1H), 9.17 (s, 1H), 8.59 (s, 1H), 8.30 (s, 1H), 7.55 - 7.51 (m, 2H), 7.33 - 7.29 (m, 1H), 6.68 - 6.61 (m, 1H), 6.20 - 6.15 (m, 1H), 5.71 - 5.66 (m, 1H), 4.15 - 4.06 (m, 1H), 3.80 - 3.46 (m, 4H), 2.46 - 2.36 (m, 1H), 2.28 - 2.16 (m, 1H); m/z ES+[M+H] ⁺ 398.3. Example 317. Preparation of 1-[3-[4-(3-Chloro-2-fluoro-phenoxy)quinazolin-6- yl]imidazolidin-1-yl]prop-2-en-1-one (Compound 69)

Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]imidazolidin e-1- carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-4-(3-chloro-2-fluoro- phenoxy)quinazoline (300 mg, 848 μmol), tert-butyl imidazolidine-1-carboxylate (190 mg, 1.10 mmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4- tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (9.52 mg, 8.48 μmol), NiCl ₂ .dtbbpy (1.69 mg, 4.24 μmol), bis(trimethylsilyl)silyl-trimethyl-silane (211 mg, 848 μmol), sodium carbonate (180 mg, 1.70 mmol) in 1,2-dimethoxyethane (3 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hr under nitrogen. On completion, the reaction mixture was diluted with water (10 mL), and then extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel. Petroleum ether/Ethyl acetate = 5:1 to 3:1) to give tert-butyl 3-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6-yl]imidazolidin e-1- carboxylate (140 mg, 341 μmol, 31%) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.56 - 7.50 (m, 1H), 7.39 - 7.35 (m, 1H), 7.15 (m, 1H), 4.75 (s, 2H), 3.99 (s, 2H), 2.78 (s, 2H), 1.46 (s, 9H). Step 2. 4-(3-Chloro-2-fluoro-phenoxy)-6-imidazolidin-1-yl-quinazolin e To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-phenoxy)quinazolin-6- yl]imidazolidine-1-carboxylate (120 mg, 270 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol), the mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give 4-(3-chloro-2-fluoro-phenoxy)-6- imidazolidin-1-yl-quinazoline (120 mg, crude, TFA salt) as a yellow oil. Step 3. 1-[3-[4-(3-Chloro-2-fluoro-phenoxy)quinazolin-6-yl]imidazoli din-1-yl]prop-2- en-1-one To a solution of 4-(3-chloro-2-fluoro-phenoxy)-6-imidazolidin-1-yl-quinazolin e (120 mg, 262 μmol) and sodium bicarbonate (65.9 mg, 785 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added prop-2-enoyl chloride (21.3 mg, 235 μmol) at 0 °C, the reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um; mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 41%-71%, 10min) to give 1-[3-[4-(3- chloro-2-fluoro-phenoxy)quinazolin-6-yl]imidazolidin-1-yl]pr op-2-en-1-one (22.5 mg, 55.0 μmol, 21%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 7.95 (dd, J = 6.0, 9.2 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.64 - 7.57 (m, 1H), 7.54 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.33 - 7.19 (m, 1H), 6.83 - 6.62 (m, 1H), 6.32 - 6.20 (m, 1H), 5.78 (m, 1H), 5.10 (s, 1H), 4.92 (s, 1H), 4.03 (t, J = 6.4 Hz, 1H), 3.84 - 3.78 (m, 2H), 3.72 (t, J = 6.4 Hz, 1H); m/z ES+ [M+H] ⁺ 399.2. Example 318. Preparation of (R)-1-(3-(4-(3,4-Dichloro-2-fluorophenoxy)quinazolin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 25) Step 1. tert-Butyl 3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)pyrrolidi ne-1- carboxylate To an 8 mL vial equipped with a stir bar was added 6-bromo-4-(3,4-dichloro-2-fluoro- phenoxy)quinazoline (200 mg, 515 μmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (168 mg, 670 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (5.78 mg, 5.15 μmol), NiCl ₂ ·dtbbpy (1.03 mg, 2.58 μmol), tris(trimethylsilyl)silane (128 mg, 515 μmol), sodium carbonate (109 mg, 1.03 mmol) and 1,2-dimethoxyethane (1.5 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 hr under nitrogen. On completion, the reaction mixture was diluted with water (5 mL), and then extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ethyl acetate = 25/1 to 3/1) and repurified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl 3-(4-(3,4- dichloro-2-fluorophenoxy)quinazolin-6-yl)pyrrolidine-1-carbo xylate (86.0 mg, 180 μmol, 35%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1H), 8.24 (s, 1H), 8.10 - 8.01 (m, 2H), 7.74 - 7.64 (m, 2H), 3.82 (dd, J = 7.6, 10.0 Hz, 1H), 3.72 - 3.62 (m, 1H), 3.55 - 3.49 (m, 1H), 3.41 - 3.33 (m, 2H), 3.30 - 3.25 (m, 2H), 1.42 (d, J = 4.0 Hz, 9H); m/z ES+ [M+H] ⁺ 478.1. Step 2. (R)-tert-Butyl 3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)pyrrolidi ne-1- carboxylate and (S)-tert-Butyl3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin- 6-yl)pyrrolidine-1- carboxylate tert-Butyl 3-[4-(3,4-dichloro-2-fluoro-phenoxy)quinazolin-6-yl]pyrrolid ine-1- carboxylate (86.0 mg, 180 μmol) was separated by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10 um);mobile phase: [0.1%NH ₃ water methanol];B%: 35%-35%,4.5 min;35 min) to give (R)-tert-butyl 3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)pyrrolidi ne-1- carboxylate (30.0 mg, 62.8 μmol, 35%) as a yellow oil and (S)-tert-butyl3-(4-(3,4-dichloro-2- fluorophenoxy)quinazolin-6-yl)pyrrolidine-1-carboxylate (30.0 mg, 62.8 μmol, 35%) as a yellow oil. m/z ES+ [M+H] ⁺ 478.1. Step 3. (R)-4-(3,4-Dichloro-2-fluorophenoxy)-6-(pyrrolidin-3-yl)quin azoline To a solution of tert-butyl (3R)-3-[4-(3,4-dichloro-2-fluoro-phenoxy)quinazolin-6- yl]pyrrolidine-1-carboxylate (30 mg, 62.7 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the reaction mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give (R)-4-(3,4-dichloro-2- fluorophenoxy)-6-(pyrrolidin-3-yl)quinazoline (30.0 mg, crude, trifluoroacetic acid) as a yellow oil. Step 4. (R)-1-(3-(4-(3,4-Dichloro-2-fluorophenoxy)quinazolin-6-yl)py rrolidin-1-yl)prop- 2-en-1-one To a solution of 4-(3,4-dichloro-2-fluoro-phenoxy)-6-[(3R)-pyrrolidin-3-yl]qu inazoline (30 mg, 60.9 μmol, trifluoroacetic acid) and sodium bicarbonate (15.4 mg, 183 μmol) in tetrahydrofuran (1 mL) and water (0.1 mL) was added prop-2-enoyl chloride (4.96 mg, 54.9 μmol) at 0 °C, the reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10um; mobile phase: [water(0.225%formic acid)- acetonitrile]; B%: 45%-75%,10 min) and repurified by prep-TLC (Petroleum ether/Ethyl acetate = 0/1) to give (R)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6-yl)py rrolidin-1-yl)prop-2- en-1-one (14.4 mg, 32.9 μmol, 54%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 8.29 (dd, J = 2.0, 11.6 Hz, 1H), 8.15 - 7.99 (m, 2H), 7.76 - 7.61 (m, 2H), 6.70 - 6.60 (m, 1H), 6.20 - 6.13 (m, 1H), 5.73 - 5.65 (m, 1H), 4.22 - 4.01 (m, 1H), 3.89 - 3.65 (m, 3H), 3.47 - 3.42 (m, 1H), 2.46 - 2.34 (m, 1H), 2.28 - 1.93 (m, 1H); m/z ES+ [M+H] ⁺ 432.1. Example 319. Preparation of (S)-1-(3-(4-(3,4-Dichloro-2-fluorophenoxy)quinazolin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 26) Step 1. (S)-4-(3,4-Dichloro-2-fluorophenoxy)-6-(pyrrolidin-3-yl)quin azoline To a solution of tert-butyl (3S)-3-[4-(3,4-dichloro-2-fluoro-phenoxy)quinazolin-6- yl]pyrrolidine-1-carboxylate (30 mg, 62.7 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the reaction mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give (S)-4-(3,4-dichloro-2- fluorophenoxy)-6-(pyrrolidin-3-yl)quinazoline (30.0 mg, crude, trifluoroacetic acid) as a yellow oil. Step 2. (S)-1-(3-(4-(3,4-Dichloro-2-fluorophenoxy)quinazolin-6-yl)py rrolidin-1-yl)prop- 2-en-1-one To a solution of 4-(3,4-dichloro-2-fluoro-phenoxy)-6-[(3S)-pyrrolidin-3-yl]qu inazoline (23.1 mg, 61.0 μmol, trifluoroacetic acid) and sodium bicarbonate (15.4 mg, 183 μmol) in tetrahydrofuran (1 mL) and water (0.1 mL) was added prop-2-enoyl chloride (4.96 mg, 54.9 μmol) at 0 °C, the reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 0/1) to give (S)-1-(3-(4-(3,4-dichloro-2-fluorophenoxy)quinazolin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one (9.68 mg, 22.4 μmol, 37%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.29 (dd, J = 1.6, 11.6 Hz, 1H), 8.15 - 8.08 (m, 1H), 8.07 - 8.01 (m, 1H), 7.73 - 7.62 (m, 2H), 6.70 - 6.60 (m, 1H), 6.20 - 6.13 (m, 1H), 5.73- 5.65 (m, 1H), 4.22 - 4.02 (m, 1H), 3.91 - 3.65 (m, 3H), 3.48 - 3.42 (m, 1H), 2.46 - 2.34 (m, 1H), 2.28 - 2.02 (m, 1H); m/z ES+ [M+H] ⁺ 432.1 Example 320. Preparation of 2-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 7-prop-2-enoyl-2,7-diazaspiro[4.4]nonan-3-one (Compound 288) Step 1. tert-Butyl 2-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 3-oxo- 2,7-diazaspiro[4.4]nonane-7-carboxylate A solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-methoxy-quinazolin-4- amine (400 mg, 1.05 mmol), tert-butyl 8-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (300 mg, 1.25 mmol), Pd ₂ (dba) ₃ (100 mg, 109 μmol), Xantphos (120 mg, 207 μmol) and cesium carbonate (1.00 g, 3.07 mmol) in dioxane (1.0 mL) was stirred at 100 °C for 12 hr under nitrogen. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2-[4-(3-chloro-2-fluoro- anilino)-7-methoxy-quinazolin-6-yl]-3-oxo-2,7-diazaspiro[4.4 ]nonane-7-carboxylate (260 mg, 480 μmol, 32%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 7.61 (s, 2H), 7.53 - 7.47 (m, 2H), 7.32 (s, 1H), 7.30 - 7.26 (m, 1H), 3.97 (s, 3H), 3.31 - 3.26 (m, 4H), 3.22 - 3.19 (m, 2H), 3.16-3.10 (m, 2H), 2.18-2.14 (m, 2H), 1.41 (s, 9H); m/z ES+[M+H] ⁺ 542.0. Step 2. 2-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 2,7- diazaspiro[4.4]nonan-3-one To a solution of tert-butyl 2-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 3-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (100 mg, 184 μmol) in dichloromethane (5.00 mL) was added hydrochloride/dioxane (4 M, 1.00 mL). The reaction mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was concentrated to give 2-[4-(3-chloro-2-fluoro- anilino)-7-methoxy-quinazolin-6-yl]-2,7-diazaspiro[4.4]nonan -3-one (80.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 442.3. Step 3. 2-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 7-prop-2-enoyl- 2,7-diazaspiro[4.4]nonan-3-one To a solution of 2-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 2,7- diazaspiro[4.4]nonan-3-one (80.0 mg, 181 μmol) and sodium bicarbonate (53.2 mg, 633 μmol) in tetrahydrofuran (1.00 mL) and dioxane (1.00 mL) was added prop-2-enoyl chloride (16.3 mg, 181 μmol). The mixture was stirred at 20 °C for 0.25 hr. The reaction mixture was concentrated to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 8%-38%, 10 min) to give 2-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 7-prop-2-enoyl-2,7- diazaspiro[4.4]nonan-3-one (14.0 mg, 28.2 μmol, 15%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (d, J = 5.6 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.35 - 7.24 (m, 2H), 6.65-6.50 (m, 1H), 6.15 (dd, J = 2.4, 16.8 Hz, 1H), 5.72 - 5.65 (m, 1H), 3.98 - 3.92 (m, 3H), 3.79 - 3.46 (m, 6H), 2.62-2.54 (m, 2H), 2.18 - 1.95 (m, 2H); m/z ES+[M+H]+ 496.2. Example 321. Preparation of 1-[1-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (Compound 76) Step 1. 6-(3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2-fluoro-pheny l)pyrido[3,2- d]pyrimidin-4-amine A solution of benzyl 1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -3- azabicyclo[3.1.0]hexane-3-carboxylate (170 mg, 346 μmol) in trifluoroacetic acid (3 mL) was stirred at 60 °C for 2 hr. The mixture was dried by blowing nitrogen to give 6-(3- azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2-fluoro-phenyl)pyr ido[3,2-d]pyrimidin-4-amine (145 mg, crude) as a brown oil. Step 2. 1-[1-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azabic yclo[3.1.0]hexan-3- yl]prop-2-en-1-one To a solution of 6-(3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2-fluoro- phenyl)quinazolin-4-amine (145 mg, 408 μmol) in tetrahydrofuran (2.0 mL) and water (0.50 mL) was added sodium bicarbonate (137 mg, 1.63 mmol) at 0 °C. Then prop-2-enoyl chloride (33.3 mg, 367 μmol) was added into the mixture at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched with methanol (1 mL) and filtered. The filtrate was bubbled by nitrogen to remove the tetrahydrofuran. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-acetonitrile];B%: 30%- 60%, 10 min) to give 1-[1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (33.9 mg, 82.9 μmol, 20%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 - 9.86 (m, 1H), 8.48 (s, 1H), 8.40 - 8.24 (m, 1H), 7.82 - 7.63 (m, 2H), 7.53 (d, J = 5.2 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 6.74 - 6.56 (m, 1H), 6.23 - 6.13 (m, 1H), 5.76 - 5.67 (m, 1H), 4.29 (t, J = 6.8 Hz, 1H), 4.05 - 3.93 (m, 1H), 3.92 - 3.80 (m, 1.5H), 3.59 (dd, J = 4.0, 12.0 Hz, 1H), 2.36 - 2.17 (m, 1H), 1.35 - 1.24 (m, 1H), 0.96 - 0.92 (m, 1H); m/z ES+ [M+H] ⁺ 409.0. Example 322. Preparation of 1-[(1S)-1-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (Compound 142)

Step 1. Benzyl (1S,5R)-1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl )-3- azabicyclo[3.1.0]hexane-3-carboxylate and benzyl (1R,5S)-1-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-3-azabicyclo[3.1.0]hexan e-3-carboxylate Benzyl 1-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-azabicycl o[3.1.0]hexane-3- carboxylate (250 mg, 511 μmol) was purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase:[0.1%NH3water ETOH];B%: 53%-53%,6min) to give benzyl (1S,5R)-1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl )-3- azabicyclo[3.1.0]hexane-3-carboxylate (98 mg, 200 μmol, 39%) as a yellow oil and benzyl (1R,5S)-1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl )-3-azabicyclo[3.1.0]hexane-3- carboxylate (93 mg, 200 μmol, 37%) as a yellow oil. Step 2. 6-((1S,5R)-3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)quinazolin-4-amine A solution of benzyl (1S,5R)-1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl )-3- azabicyclo[3.1.0]hexane-3-carboxylate (93.0 mg, 190 μmol) in trifluoroacetic acid (1 mL) was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give 6- ((1S,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2-fluoro phenyl)quinazolin-4-amine (67.5 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 354.9. Step 3. 1-((1S,5R)-1-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6 -yl)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one To a solution of 6-((1S,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)quinazolin-4-amine (67.5 mg, 190 μmol) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (63.9 mg, 761 μmol) and prop-2-enoylchloride (16.4 mg, 181 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched by addition of methanol (0.6 mL). The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*25mm*5um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 25%-55%,10 min) to give 1-((1S,5R)-1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6 -yl)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one (26.8 mg, 65.5 μmol, 35%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 - 9.88 (m, 1H), 8.45 (s, 1H), 8.35 - 8.26 (m, 1H), 7.77 - 7.63 (m, 2H), 7.51 (s, 2H), 7.33 - 7.26 (m, 1H), 6.69 - 6.57 (m, 1H), 6.21 - 6.10 (m, 1H), 5.70 - 5.66 (m, 1H), 4.30 - 4.23 (m, 1H), 4.01 - 3.91 (m, 1H), 3.88 - 3.77 (m, 1.5H), 3.56 (dd, J = 4.0, 12.0 Hz, 1H), 2.31 - 2.17 (m, 1H), 1.31 - 1.24 (m, 1H), 0.92 - 0.87 (m, 1H); m/z ES+ [M+H] ⁺ 409.0. Example 323. Preparation of 1-[(1R)-1-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3- azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (Compound 143) Step 1. 6-((1R,5S)-3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)quinazolin-4-amine A solution of benzyl (1R,5S)-1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl )-3- azabicyclo[3.1.0]hexane-3-carboxylate (88.0 mg, 180 μmol) in trifluoroacetic acid (1 mL) was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give 6- ((1R,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2-fluoro phenyl)quinazolin-4-amine (63.9 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 354.9. Step 2. 1-((1R,5S)-1-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6 -yl)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one To a solution of 6-((1R,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)quinazolin-4-amine (63.9 mg, 179 μmol) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (60.3 mg, 718 μmol) and prop-2-enoylchloride (15.4 mg, 171 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched by addition of methanol (0.6 mL). The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX 80*40mm*3um; mobile phase: [water(10 Mm NH ₄ HCO ₃ )-acetonitrile]; B%: 20%-50%, 8 min) to give 1-((1R,5S)-1-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6 -yl)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one (36.9 mg, 90.3 μmol, 50%) a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.08 - 9.81 (m, 1H), 8.46 - 8.51 (m, 1H), 8.39 - 8.29 (m, 1H), 7.80 - 7.74 (m, 1H), 7.74 - 7.64 (m, 1H), 7.54 (t, J = 7.2, 2H), 7.36 - 7.29 (m, 1H), 6.70 - 6.57 (m, 1H), 6.21 - 6.15 (m, 1H), 5.74 - 5.69 (m, 1H), 4.33 - 4.25 (m, 1H), 4.04 - 3.95 (m, 1H), 3.91 - 3.80 (m, 1.5H), 3.59 (dd, J = 4.0, 12.0 Hz, 1H), 2.35 - 2.27 (m, 1H), 1.34 - 1.26 (m, 1H), 0.96 - 0.88 (m, 1H); m/z ES+ [M+H] ⁺ 409.0. Example 324. Preparation of 1-[(3S)-3-[4-(5-Ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 61) Step 1. tert-Butyl 3-[4-[2-fluoro-5-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]pyrrolidine-1-carboxylate To a solution of tert-butyl 3-(4-chloroquinazolin-6-yl)pyrrolidine-1-carboxylate (387 mg, 1.16 mmol) in acetonitrile (10.0mL) was added 2-fluoro-5-(2-trimethylsilylethynyl)aniline (240 mg, 1.16 mmol), the mixture was stirred at 60 °C for 12 hr. The reaction mixture was filtered and the filter cake was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl 3-[4-[2-fluoro-5-(2- trimethylsilylethynyl)anilino]quinazolin-6-yl]pyrrolidine-1- carboxylate (170 mg, 337 μmol, 29%) as a yellow solid. m/z ES+ [M+H] ⁺ 505.2. Step 2. tert-Butyl 3-(4-((5-ethynyl-2-fluorophenyl)amino)quinazolin-6-yl)pyrrol idine-1- carboxylate To a solution of tert-butyl 3-[4-[2-fluoro-5-(2-trimethylsilylethynyl)anilino]quinazolin -6- yl]pyrrolidine-1-carboxylate (170 mg, 337 μmol) in acetonitrile (5.0 mL) was added cesium carbonate (329 mg, 1.01 mmol). The mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl 3-(4-((5-ethynyl-2- fluorophenyl)amino)quinazolin-6-yl)pyrrolidine-1-carboxylate (165 mg, crude) as an off-white solid. m/z ES+ [M+H] ⁺ 433.2. Step 3. tert-Butyl (3S)-3-[4-(5-ethynyl-2-fluoro-anilino) quinazolin-6-yl]pyrrolidine-1- carboxylate and tert-butyl (3R)-3-[4- (5-ethynyl-2-fluoro-anilino)quinazolin-6-yl]pyrrolidine-1- carboxylate tert-Butyl 3-(4-((5-ethynyl-2-fluorophenyl)amino)quinazolin-6-yl)pyrrol idine-1- carboxylate (165 mg, 381 μmol) was separated by SFC (column: DAICEL CHIRALPAKIC(250mm*30mm,10um);mobile phase: [0.1%NH ₃ water-ethanol];B%: 40%- 40%,2.4 min; 50 min) to give tert-butyl (3S)-3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate (95 mg, 220 μmol, 57%) and tert-butyl (3R)-3-[4-(5-ethynyl-2- fluoro-anilino)quinazolin-6-yl]pyrrolidine-1-carboxylate (70 mg, 162 μmol, 43%) as off-white solids. m/z ES+ [M+H] ⁺ 433.2. Step 4. N-(5-Ethynyl-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinaz olin-4-amine To a solution of tert-butyl (3S)-3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6-yl] pyrrolidine-1-carboxylate (95.0 mg, 220 μmol) in dichloromethane (1.2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol), the mixture was stirred at 25 °C for 1 hr . On completion, the reaction mixture was concentrated in vacuo to give N-(5-ethynyl-2-fluoro-phenyl)-6-[(3S)- pyrrolidin-3-yl]quinazolin-4-amine (85 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 333.1. Step 5. 1-[(3S)-3-[4-(5-Ethynyl-2-fluoro-anilino)quinazolin-6-yl]pyr rolidin-1-yl]prop-2- en-1-one To a solution of N-(5-ethynyl-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinaz olin-4- amine (85.0 mg, 256 μmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (172 mg, 2.05 mmol) in water (0.3 mL), and then a solution of prop-2-enoyl chloride (20.8 mg, 230 μmol) in tetrahydrofuran (1.0 mL) was dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um; mobile phase:[water(0.225% formic acid)-acetonitrile]; B%: 11%-41%, 10 min) to give 1- [(3S)-3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6-yl]pyrro lidin-1-yl]prop-2-en-1-one (13.1 mg, 33.9 μmol, 13%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (d, J = 20.0 Hz, 1H), 8.49 (s, 1H), 8.41 - 8.32 (m, 1H), 7.92 - 7.82 (m, 1H), 7.82 - 7.66 (m, 2H), 7.51 - 7.29 (m, 2H), 6.65 (dd, J = 10.4, 16.8 Hz, 1H), 6.26 - 6.10 (m, 1H), 5.76 - 5.62 (m, 1H), 4.22 (s, 1H), 4.20 - 4.04 (m, 1H), 3.92 - 3.75 (m, 1H), 3.70 - 3.56 (m, 2H), 3.50-3.45 (m, 1H), 2.46 - 2.25 (m, 1H), 2.19 - 2.04 (m, 1H); m/z ES+ [M+H] ⁺ 387.1 Example 325. Preparation of 1-[(3R)-3-[4-(5-Ethynyl-2-fluoro-anilino)quinazolin-6- yl]pyrrolidin-1-yl]prop-2-en-1-one (Compound 62) Step 1. N-(5-Ethynyl-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]quinaz olin-4-amine To a solution of tert-butyl (3R)-3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6-yl] pyrrolidine-1-carboxylate (65.0 mg, 150 μmol) in dichloromethane (1.2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(5-ethynyl-2-fluoro-phenyl)-6-[(3R)- pyrrolidin-3-yl]quinazolin-4-amine (60 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 333.1. Step 2. 1-[(3R)-3-[4-(5-Ethynyl-2-fluoro-anilino)quinazolin-6-yl]pyr rolidin-1-yl]prop-2- en-1-one To a solution of N-(5-ethynyl-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]quinaz olin-4- amine (60.0 mg, 181 μmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium bicarbonate (121 mg, 1.44 mmol) in water (0.3 mL), and then a solution of prop- 2-enoyl chloride (14.7 mg, 162 μmol, 13.3 μL) in tetrahydrofuran (1.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um; mobile phase:[water(0.225% formic acid)-acetonitrile]; B%: 11%-41%, 10 min) to give 1-[(3R)-3-[4-(5-ethynyl-2-fluoro-anilino)quinazolin-6-yl]pyr rolidin-1-yl]prop-2- en-1-one (10.5 mg, 27.2 μmol, 15%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (m, 1H), 8.49 (s, 1H), 8.41 - 8.35 (m, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.81 - 7.66 (m, 2H), 7.51 - 7.28 (m, 2H), 6.65 (dd, J = 10.4, 16.8 Hz, 1H), 6.24 - 6.10 (m, 1H), 5.76 - 5.62 (m, 1H), 4.22 (s, 1H), 4.20 - 4.05 (m, 1H), 3.92 - 3.75 (m, 1H), 3.69 - 3.56 (m, 2H), 3.50-3.45 (m, 1H), 2.46 - 2.28 (m, 1H), 2.19 - 2.06 (m, 1H); m/z ES+ [M+H] ⁺ 387.1 Example 326. Preparation of (S)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 208) Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolidine- 1- carboxylate To an 25 mL vial equipped with a stir bar was added 6-bromo-N-(3-chloro-2-fluoro- phenyl)quinazolin-4-amine (1 g, 2.84 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (0.92 g, 3.69 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (31.8 mg, 28.4 μmol), NiCl ₂ .dtbbpy (5.64 mg, 14.2 μmol), tris(trimethylsilyl)silane (0.7 g, 2.84 mmol), sodium carbonate (0.6 g, 5.67 mmol) in 1,2- dimethoxyethane (10 mL). The vial was sealed, stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 14 hr under nitrogen. The reaction mixture was diluted with water 10 mL and extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silica gel. Petroleum ether/Ethyl acetate=1:1) to give tert- butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolidine- 1-carboxylate (400 mg, 903 μmol, 31%) as a yellow solid. m/z ES+ [M+H] ⁺ 443.4. Step 2. tert-Butyl (S)-3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)pyr rolidine- 1-carboxylate and tert-butyl (R)-3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)pyrrolidine-1-carboxylate tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]pyrrolidine- 1-carboxylate (400 mg, 903 μmol) was purified by SFC (column: Phenomenex-Cellulose- 2(250mm*30mm,10um);mobile phase:[0.1%NH ₃ water-methanol]; B%:35%-35%,5.8 min;80 min) to give tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]pyrroli dine-1- carboxylate (200 mg, 451 μmol, 50%) as a yellow solid and tert-butyl (3R)-3-[4-(3-chloro-2- fluoro-anilino)quinazolin-6-yl]pyrrolidine-1-carboxylate (170 mg, 384 μmol, 43%) as a yellow solid. Step 3. N-(3-Chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinazo lin-4-amine To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate (0.2 g, 0.45 mmol) in ethyl acetate (2 mL) was added 4 M HCl/dioxane (4 M, 2 mL). The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated in vacuum to give N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinazo lin-4-amine (170 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 343.0. Step 4. (S)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6-yl) pyrrolidin-1- yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinazo lin-4- amine (60 mg, 0.18 mmol) and sodium bicarbonate (44.1 mg, 0.53 mmol) in tetrahydrofuran (0.5 mL), water (0.5 mL) was added prop-2-enoyl chloride (19.0 mg, 0.21 mmol) at 0 °C, the mixture was stirred at 0 °C for 10 min. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-acetonitrile]; B%: 27%-57%,10 min) and then purified by prep-HPLC (column:Waters Xbridge 150*25mm*5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-acetonitrile]; B%: 27%-57%, 10 min) to give (S)-1-(3-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)pyrrolidin-1-yl)prop-2-en -1-one (25.8 mg, 65.0 μmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 - 9.88 (m, 1H), 8.53 - 8.33 (m, 2 H), 7.92 - 7.82 (m, 1H), 7.76 (d, J = 8.8 Hz. 1H), 7.50 (d, J = 6.0 Hz. 2H), 7.35 - 7.25 (m, 1H), 6.66 (dd, J = 10.4 Hz, 16.8 Hz), 6.23 - 6.12 (m, 1H), 5.72 - 5.63 (m, 1H), 4.21 - 4.06 (m, 1H), 3.90 - 3.75 (m, 1H), 3.69 - 3.57 (m, 1H), 3.48 (s, 1H), 2.40 - 2.32 (m, 1H), 2.27 - 2.07 (m, 1H); m/z ES+ [M+H]+ 397.3 Example 327. Preparation of (R)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 207) Step 1. N-(3-Chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]quinazo lin-4-amine To a solution of tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6- yl]pyrrolidine-1-carboxylate (170 mg, 0.38 mmol) in ethyl acetate (1.5 mL) was added HCl/dioxane (4 M, 1.5 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuum to give N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]quinazo lin- 4-amine (145 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 343.0. Step 2. (R)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6-yl) pyrrolidin-1- yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]quinazo lin-4- amine (100 mg, 0.29 mmol) and sodium bicarbonate (73.5 mg, 0.88 mmol) in tetrahydrofuran (0.5 mL), water (0.5 mL) was added prop-2-enoyl chloride (31.7 mg, 0.35 mmol) at 0 °C, the mixture was stirred at 0 °C for 10 min. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(10mM NH ₄ HCO ₃ )-acetonitrile]; B%: 27%-57%, 10 min) and then purified by prep- HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(10mM NH ₄ HCO ₃ )- acetonitrile];B%: 39%-69%, 10 min) to give (R)-1-(3-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)pyrrolidin-1-yl)prop-2-en -1-one (25.8 mg, 65.0 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 - 9.83 (m, 1H), 8.52 - 8.35 (m, 2 H), 7.88 - 7.83 (m, 1H), 7.79 - 7.74 (m. 1H), 7.55 - 7.45 (m. 1H), 7.32 - 7.26 (m, 1H), 6.65 (dd, J = 10.4 Hz, 16.8 Hz), 6.23 - 6.13 (m, 1H), 5.72 - 5.62 (m, 1H), 4.24 - 4.04 (m, 1H), 3.92 - 3.75 (m, 1H), 3.69 - 3.55 (m, 1H), 3.48 - 3.42 (m, 1H), 2.47 - 2.30 (m, 1H), 2.17 - 2.06 (m, 1H); m/z ES+ [M+H] ⁺ 397.1. Example 328. Preparation of 1-[(3S)-3-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3- fluoro-pyrrolidin-1-yl]prop-2-en-1-one (Compound 190) Step 1. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- hydroxypyrrolidine-1-carboxylate To a mixture of 6-bromo-N-(3-chloro-2-fluorophenyl)quinazolin-4-amine (2.00 g, 5.68 mmol) in tetrahydrofuran (20 mL) was added n-butyl lithium (2.5 M in toluene, 4.54 mL) over 30 min slowly at -60 °C under nitrogen atmosphere. The mixture was stirred at -60 °C for 30 min. Then tert-butyl 3-oxopyrrolidine-1-carboxylate (3.16 g, 17.04 mmol) in tetrahydrofuran (6 mL) was added slowly at -60 °C and the resulting mixture was stirred at -60 °C for 0.5 hr and 20 °C for 1 hr. On completion, the mixture was quenched with saturated ammonium chloride (40 mL). The aqueous phase was extracted with ethyl acetate (35 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 5/1 to 1/1] to afford tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- hydroxypyrrolidine-1-carboxylate (560 mg, 1.22 mmol, 21%) as a brown solid. m/z ES+ [M+H] ⁺ 459.0. Step 2. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- fluoropyrrolidine-1-carboxylate To a mixture of tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- hydroxypyrrolidine-1-carboxylate (420 mg, 0.92 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (296 mg, 1.84 mmol) slowly at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was quenched with saturated sodium carbonate (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography [Petroleum ether/Ethyl acetate = 10/1 to 1/1] to give tert-butyl 3-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-3-fluoropyrrolidine-1-ca rboxylate (360 mg, 0.78 mmol, 85%) as a brown solid. m/z ES+ [M+H] ⁺ 461.1. Step 3. tert-Butyl (S)-3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- fluoropyrrolidine-1-carboxylate and tert-butyl (R)-3-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-3-fluoropyrrolidine-1-ca rboxylate tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3-fluo ropyrrolidine-1- carboxylate (360 mg, 0.78 mmol) was further separated by SFC (column: DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um); mobile phase:[0.1%NH ₃ H ₂ O methanol]; B%: 42%-42%, 5 min) to give tert-butyl (S)-3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- fluoropyrrolidine-1- carboxylate (136 mg, 295 μmol, 38%) as a white solid and tert-butyl (R)-3-(4-((3-chloro-2- fluorophenyl)amino)quinazolin-6-yl)-3-fluoropyrrolidine-1-ca rboxylate (148 mg, 321 μmol, 41%) as a white solid. Step 4. N-(3-Chloro-2-fluoro-phenyl)-6-[(3S)-3-fluoropyrrolidin-3-yl ]quinazolin-4- amine A solution of (S)-3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-3- fluoropyrrolidine-1-carboxylate (110 mg, 239 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL) was stirred at 20 °C for 8 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-3- fluoropyrrolidin-3-yl]quinazolin-4-amine (186 mg, crude, trifluoroacetic acid) as a light yellow oil. m/z ES+ [M+H] ⁺ 361.2. Step 5. 1-[(3S)-3-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3-f luoro-pyrrolidin-1- yl]prop-2-en-1-one To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-3-fluoropyrrolidin-3-yl ] quinazolin-4-amine (120 mg, 253 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.25 mL) was added sodium bicarbonate (127 mg, 1.52 mmol) in one portion at 0 °C under nitrogen. Then prop-2-enoyl chloride (22.9 mg, 253 μmol) was added at 0 °C and the mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel. dichloromethane: methanol = 10:1) to give 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-f luoro-pyrrolidin-1- yl]prop-2-en-1-one (25.2 mg, 60.7 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ 8.85 - 8.76 (m, 1H), 8.28 (s, 1H), 8.24 - 8.15 (m, 1H), 8.05 - 7.97 (m, 1H), 7.86 - 7.80 (m, 1H), 7.26 - 7.12 (m, 2H), 6.59 - 6.32 (m, 2H), 5.84 - 5.68 (m, 1H), 4.36 - 3.79 (m, 4H), 2.71 - 2.40 (m, 2H); m/z ES+ [M+H] ⁺ 415.2. Example 329. Preparation of 1-[(3R)-3-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3- fluoro-pyrrolidin-1-yl]prop-2-en-1-one (Compound 189) Step 1. N-(3-Chloro-2-fluoro-phenyl)-6-[(3R)-3-fluoropyrrolidin-3-yl ]quinazolin-4- amine A solution of tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluo ro- pyrrolidine-1-carboxylate (200 mg, 434 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1 mL) was stirred at 20 °C for 8 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-3- fluoropyrrolidin-3-yl]quinazolin-4-amine (190 mg, crude, trifluoroacetic acid) as a light yellow oil. m/z ES+ [M+H] ⁺ 361.2. Step 2. 1-[(3R)-3-[4-(3-Chloro-2-fluoro-anilino)quinazolin-6-yl]-3-f luoro-pyrrolidin-1- yl]prop-2-en-1-one To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-3-fluoropyrrolidin-3- yl]quinazolin-4-amine (190 mg, 400 μmol, trifluoroacetic acid) in tetrahydrofuran (2 mL) and water (0.5 mL) was added sodium bicarbonate (201 mg, 2.40 mmol) in one portion at 0 °C under nitrogen. Then prop-2-enoyl chloride (36.2 mg, 400 μmol) was added at 0 °C and the mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, dichloromethane: methanol = 10:1) to give 1-[(3R)- 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]-3-fluoro-py rrolidin-1-yl]prop-2-en-1-one (39.3 mg, 94.8 μmol, 23%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 - 8.77 (m, 1H), 8.28 (s, 1H), 8.26 - 8.14 (m, 1H), 8.06 - 7.96 (m, 1H), 7.89 - 7.81 (m, 1H), 7.26 - 7.13 (m, 2H), 6.59 - 6.34 (m, 2H), 5.86 - 5.67 (m, 1H), 4.38 - 3.79 (m, 4H), 2.71 - 2.41 (m, 2H); m/z ES+ [M+H] ⁺ 415.2. Example 330. Preparation of 1-(3-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6- yl)imidazolidin-1-yl)prop-2-en-1-one (Compound 138) Step 1. tert-Butyl (2-((3-cyano-4-nitrophenyl)amino)ethyl)carbamate To a solution of 5-fluoro-2-nitro-benzonitrile (2 g, 12.0 mmol) in N-methyl pyrrolidone (20 mL) was added tert-butyl N-(2-aminoethyl)carbamate (2.12 g, 13.2 mmol) and diisopropylethylamine (3.11 g, 24.08 mmol), the mixture was stirred at 80 °C for 12 h. The mixture was poured into water (50 mL). The solid was collected by filtration and dried in vacuo to give tert-butyl (2-((3-cyano-4-nitrophenyl)amino)ethyl)carbamate (3.7 g, crude) as a white solid. m/z ES+ [M+Na] ⁺ 329.2. Step 2. tert-Butyl (2-((4-amino-3-cyanophenyl)amino)ethyl)carbamate To a solution of tert-butyl N-[2-(3-cyano-4-nitro-anilino)ethyl]carbamate (3.69 g, 12.1 mmol) in ethyl acetate (50 mL) was added Pt/V/C (1.5 g, 172 μmol, 3 wt. % loading). The mixture was stirred at 25 °C for 12 hr under hydrogen atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (2-((4-amino-3- cyanophenyl)amino)ethyl)carbamate (3.4 g, crude) as a yellow oil. m/z ES+ [M-55]+ 221.3. Step 3. tert-Butyl (2-((3-cyano-4- (((dimethylamino)methylene)amino)phenyl)amino)ethyl)carbamat e To a solution of tert-butyl N-[2-(4-amino-3-cyano-anilino)ethyl]carbamate (1.9 g, 6.88 mmol) in toluenen (20 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (2.46 g, 20.6 mmol). The mixture was stirred at 115 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give tert-butyl (2-((3-cyano-4- (((dimethylamino)methylene)amino)phenyl)amino)ethyl)carbamat e (2.3 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 332.0. Step 4. tert-Butyl (2-((4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)amino)ethyl)carbamate To a solution of tert-butyl N-[2-[3-cyano-4- (dimethylaminomethyleneamino)anilino]ethyl]carbamate (2.28 g, 6.88 mmol) in toluene (15 mL) and acetic acid (15 mL) was added 3-chloro-2-fluoro-aniline (1.00 g, 6.88 mmol), the mixture was stirred at 110 °C for 3 hr. The mixture was concentrated in vacuo to give tert-butyl (2-((4-((3- chloro-2-fluorophenyl)amino)quinazolin-6-yl)amino)ethyl)carb amate (0.6 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 432.4. Step 5. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)imidazo lidine- 1-carboxylate To a solution of tert-butyl N-[2-[[4-(3-chloro-2-fluoro-anilino)quinazolin-6- yl]amino]ethyl]carbamate (0.3 g, 695 μmol) in water (3 mL) and tetrahydrofuran (3 mL) was added formaldehyde (3 mL). The mixture was stirred at 70 °C for 12 hr. The mixture was concentrated in vacuo to give tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)imidazolidine-1-carboxylate (0.3 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.32 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.63 - 7.53 (m, 1H), 7.51 - 7.41 (m, 2H), 7.33 (d, J = 1.6 Hz, 1H), 7.29 - 7.23 (m, 1H), 4.80 (s, 2H), 3.85 - 3.79 (m, 2H), 3.77 - 3.73 (m, 2H), 1.56 (s, 12H); m/z ES+ [M+H] ⁺ 444.3. Step 6. N-(3-Chloro-2-fluorophenyl)-6-(imidazolidin-1-yl)quinazolin- 4-amine To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)quinazolin-6-yl]imidazolidin e- 1-carboxylate (0.3 g, 676 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (924 mg, 8.10 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to give N-(3-chloro-2-fluorophenyl)-6-(imidazolidin-1-yl)quinazolin- 4-amine (0.18 g, crude) as a yellow oil. m/z ES+ [M+H]+344.1. Step 7. 1-(3-(4-((3-Chloro-2-fluorophenyl)amino)quinazolin-6-yl)imid azolidin-1- yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-imidazolidin-1-yl-quinazolin- 4-amine (0.17 g, 494 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (208 mg, 2.47 mmol) and prop-2-enoyl chloride (35.8 mg, 396 μmol) at 0 °C, the mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in acetonitrile (2 mL) & water (2 mL) and then filtered. The filter cake was concentrated in vacuo to give 1-(3-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6- yl)imidazolidin-1-yl)prop-2-en-1-one (57.63 mg, 0.15 mmol, 29%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 - 9.75 (m, 1H), 8.32 (s, 1H), 7.74 - 7.71 (m, 1H), 7.53 - 7.42 (m, 4H), 7.29 (t, J = 8.0 Hz, 1H), 6.74 - 6.62 (m, 1H), 6.27 (dd, J = 2.0, 16.8 Hz, 1H), 5.80 (dd, J = 2.0, 10.0 Hz, 1H), 4.95 (d, J = 64.4 Hz, 2H), 4.02 (t, J = 6.4 Hz, 1H), 3.83 - 3.74 (m, 2H), 3.68 - 3.59 (m, 1H); m/z ES+ [M+H] ⁺ 398.1. Example 331. Preparation of 6-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 2- prop-2-enoyl-2,6-diazaspiro[3.4]octan-7-one (Compound 286) Step 1. tert-Butyl 6-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 7-oxo- 2,6-diazaspiro[3.4]octane-2-carboxylate A solution of 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-methoxy-quinazolin-4- amine (400 mg, 1.05 mmol), tert-butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate (270 mg, 1.19 mmol), Pd ₂ (dba) ₃ (100 mg, 109 μmol), XantPhos (120 mg, 207 μmol) and cesium carbonate (1.00 g, 3.07 mmol) in dioxane (2.00 mL) was stirred at 100 °C for 12 hr under nitrogen. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed- phase HPLC (0.1% formic acid condition) to give tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)-7- methoxy-quinazolin-6-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-c arboxylate (220 mg, 417 μmol, 37%) as a brown solid. m/z ES+[M+H] ⁺ 528.1. Step 2. 6-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 2,6- diazaspiro[3.4]octan-7-one To a solution of tert-butyl 6-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (100 mg, 189 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL), the reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated in vacuo to give 6-[4-(3-chloro-2-fluoro-anilino)-7-methoxy- quinazolin-6-yl]-2,6-diazaspiro[3.4]octan-7-one (80.0 mg, crude) as a yellow solid. m/z ES+[M+H] ⁺ 428.2. Step 3. 6-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 2-prop-2-enoyl- 2,6-diazaspiro[3.4]octan-7-one To a solution of 6-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 2,6- diazaspiro[3.4]octan-7-one (80.0 mg, 186 μmol) and sodium bicarbonate (54.9 mg, 654 μmol) in tetrahydrofuran (1.00 mL) and dioxane (1.00 mL) was added prop-2-enoyl chloride (16.9 mg, 187 μmol) in one portion, the mixture was stirred at 20 °C for 0.25 hr. The reaction mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(0.225%formic acid)-acetonitrile]; B%: 5%- 35%, 10 min) to give 6-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 2-prop-2- enoyl-2,6-diazaspiro[3.4]octan-7-one (7.43 mg, 15.4 μmol, 7.9%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.33 (s, 1H), 7.31 - 7.23 (m, 1H), 6.43 - 6.27 (m, 1H), 6.12 (dd, J = 2.4, 17.0 Hz, 1H), 5.69 (dd, J = 2.4, 10.2 Hz, 1H), 4.33 (s, 2H), 4.04 (s, 2H), 4.00 - 3.95 (m, 5H), 2.85 (s, 2H); m/z ES+ [M+H] ⁺ 482.1. Example 332. Preparation of N-(1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 331) Step 1. tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin -6- yl)pyrrolidin-3-yl)carbamate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin- 4-amine (200 mg, 646 μmol) in diisopropylethylamine (5.0 mL) was added tert-butyl N-pyrrolidin-3- ylcarbamate (480 mg, 2.58 mmol). The mixture was stirred at 130 °C for 16 hr. On completion, the reaction mixture was quenched by water (5 mL) at 25 °C, and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% condition) to give tert-butyl (1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)pyrrolidin-3- yl)carbamate (50.0 mg, 109 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 8.85 (s, 1H), 8.29 (s, 1H), 7.65 - 7.46 (m, 2H), 7.37 - 7.21 (m, 2H), 7.09 (s, 1H), 4.24 - 4.16 (m, 1H), 3.79 - 3.59 (m, 2H), 3.57 - 3.46 (m, 1H), 3.31 - 3.26 (m, 1H), 2.28 - 2.12 (m, 1H), 1.97 (dd, J = 6.4, 12.8 Hz, 1H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 459.2. Step 2. 6-(3-Aminopyrrolidin-1-yl)-N-(3-chloro-2-fluorophenyl)pyrido [3,4-d]pyrimidin- 4-amine To a solution of tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)pyrrolidin-3-yl)carbamate (35.0 mg, 76.2 μmol) in dichloromethane (0.42 mL) was added trifluoroacetic acid (123 mg, 1.08 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(3-aminopyrrolidin-1-yl)-N- (3-chloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimidin-4-amine (35.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 359.1. Step 3. N-(1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimid in-6- yl)pyrrolidin-3-yl)acrylamide To a solution of 6-(3-aminopyrrolidin-1-yl)-N-(3-chloro-2-fluoro-phenyl)pyrid o[3,4-d] pyrimidin-4-amine (40.0 mg, 111 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (46.8 mg, 557 μmol) and prop-2-enoyl chloride (10.1 mg, 111 μmol). The mixture was stirred at 0 °C for 30 minutes. On completion, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (neutral condition, column: waters xbridge 150ൈ25mm 10um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 20%- 50%, 11min) to give N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimid in-6- yl)pyrrolidin-3-yl)acrylamide (14.6 mg, 35.4 μmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.86 (s, 1H), 8.46 (d, J = 6.4 Hz, 1H), 8.29 (s, 1H), 7.54 (d, J = 13.6 Hz, 2H), 7.35 - 7.25 (m, 1H), 7.13 (s, 1H), 6.31 - 6.20 (m, 1H), 6.18 - 6.04 (m, 1H), 5.61 (dd, J = 2.4, 10.0 Hz, 1H), 4.60 - 4.46 (m, 1H), 3.76 (dd, J = 6.4, 10.8 Hz, 1H), 3.72 - 3.57 (m, 2H), 3.41 (m, 1H), 2.28 (m, 1H), 2.08 - 1.96 (m, 1H); m/z ES+ [M+H] ⁺ 413.2. Example 333. Preparation of N-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 359) Step 1. tert-Butyl (1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrim idin-6- yl)pyrrolidin-3-yl)carbamate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,4-d]pyrimi din-4- amine (500 mg, 1.46 mmol) in diisopropylethylamine (15 mL) was added tert-butyl N-pyrrolidin- 3-ylcarbamate (1.08 g, 5.82 mmol). The mixture was stirred at 130 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% NH ₃ •H ₂ O condition) to give tert-butyl (1-(4-((3,4- dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)py rrolidin-3-yl)carbamate (130 mg, 264 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 8.86 (s, 1H), 8.30 (s, 1H), 7.69 - 7.54 (m, 2H), 7.30 (s, 1H), 7.08 (s, 1H), 4.36 - 4.11 (m, 1H), 3.76 - 3.44 (m, 2H), 3.30 (s, 1H), 2.28 - 2.14 (m, 1H), 2.03 - 1.89 (m, 1H), 1.42 - 1.42 (m, 1H), 1.41 (s, 9H); m/z ES+ [M+H] ⁺ 493.1. Step 2. 6-(3-Aminopyrrolidin-1-yl)-N-(3,4-dichloro-2-fluorophenyl)py rido[3,4- d]pyrimidin-4-amine To a solution of tert-butyl (1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)pyrrolidin-3-yl)carbamate (130 mg, 264 μmol) in dichloromethane (0.42 mL) was added trifluoroacetic acid (800 mg, 7.02 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-(3-aminopyrrolidin-1-yl)-N- (3,4-dichloro-2-fluorophenyl)pyrido[3,4-d]pyrimidin-4-amine (100 mg ^crude) as a brown oil. m/z ES+ [M+H] ⁺ 393.1. Step 3. N-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyr imidin-6- yl)pyrrolidin-3-yl)acrylamide To a solution of 6-(3-aminopyrrolidin-1-yl)-N-(3,4-dichloro-2-fluorophenyl)py rido[3,4- d]pyrimidin-4-amine (100 mg, 254 μmol) in tetrahydrofuran (0.25 mL) and water (0.25 mL) was added sodium bicarbonate (64.0 mg, 762 μmol) and prop-2-enoyl chloride (18.4 mg, 203 μmol). Then the mixture was stirred at 0 °C for 30 minutes. On completion, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (FA condition. column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(0.225%FA)-ACN]; B%: 27%-57%,10 min) to give N-(1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyr imidin- 6-yl)pyrrolidin-3-yl)acrylamide (30.0 mg, 67.1 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.87 (s, 1H), 8.46 (d, J = 6.4 Hz, 1H), 8.31 (s, 1H), 7.67 - 7.52 (m, 2H), 7.12 (s, 1H), 6.33 - 6.19 (m, 1H), 6.18 - 6.07 (m, 1H), 5.62 (dd, J = 2.4, 9.6 Hz, 1H), 4.51 (td, J = 4.8, 1.2 Hz, 1H), 3.76 (dd, J = 6.0, 10.8 Hz, 1H), 3.70 - 3.58 (m, 2H), 3.45 - 3.38 (m, 1H), 2.31 - 2.26 (m, 1H), 2.07 - 1.99 (m, 1H); m/z ES+ [M+H] ⁺ 447.0. Example 334. Preparation of (R)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 10) Step 1. tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]pyrrolidine-1-carboxylate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (5 g, 16.2 mmol) and tert-butyl 3-bromopyrrolidine-1-carboxylate (5.26 g, 21.0 mmol) in 1,2- dimethoxyethane (10 mL) was added nickel chloride glyme (17.8 mg, 80.9 μmol), tris(trimethylsilyl)silane (4.02 g, 16.2 mmol) and pyridine-2-carboxamidine;hydrochloride (25.5 mg, 162 μmol). The mixture was degassed and purged with nitrogen for 3 times and then it was stirred at 20 °C for 2 hr. On completion, the reaction was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate from 10:1 to 1:1) and then repurified by reversed-phase HPLC (0.1% FA condition) to afford tert-butyl 3-[4-(3-chloro-2- fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]pyrrolidine-1-car boxylate (3.5 g, 7.10 mmol, 44%) as a yellow solid. m/z ES+ [M+H] ⁺ 444.1. Step 2. (R)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one and (S)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one tert-Butyl 3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] pyrrolidine-1- carboxylate (8.0 g, 18 mmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm*50 mm,10 um); mobile phase: [0.1% NH ₃ H ₂ O ethanol]; B%: 60%-60%, 4.2; 370min.) to afford tert-butyl (3R)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin- 6-yl]pyrrolidine-1- carboxylate (4.1 g, 9.1 mmol, 50%) as a yellow solid and tert-butyl (3S)-3-[4-(3-chloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]pyrrolidine-1-carboxylat e (4 g, 8.9 mmol, 49%) as a yellow solid. Step 3. (R)-N-(3-Chloro-2-fluorophenyl)-6-(pyrrolidin-3-yl)pyrido[3, 2-d]pyrimidin-4- amine A solution of (R)-tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidine-1-carboxylate (3.5 g, 7.88 mmol) in hydrochloride/ethyl acetate (4 M, 30 mL) and dichloromethane (30 mL) was stirred at 20 °C for 0.5 hr. On completion, the reaction was concentrated in vacuum to afford N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin- 3-yl]pyrido[3,2-d]pyrimidin-4-amine (2.7 g, crude) as a yellow solid. Step 4. (R)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3R)-pyrrolidin-3-yl]pyrido[ 3,2- d]pyrimidin-4-amine (2.7 g, 7.85 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added sodium bicarbonate (2.64 g, 31.4 mmol) at 0 °C to adjust pH =8, then a solution of prop-2-enoyl chloride (711 mg, 7.85 mmol) in tetrahydrofuran (10 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the reaction was concentrated in vacuum and then filtered. The filtered cake was washed with water (50 mL x 3). The crude product was triturated with ethyl acetate: petroleum ether (100 mL, 1:10) to afford (R)-1-(3-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pyrrolidin-1- yl)prop-2-en-1-one (1.2 g, 2.93 mmol, 37%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.27 (dd, J = 3.6, 8.8 Hz, 1H), 8.11 - 7.94 (m, 2H), 7.59 - 7.48 (m, 1H), 7.42 - 7.31 (m, 1H), 6.75 - 5.65 (m, 1H), 6.22 (td, J = 2.4, 16.8 Hz, 1H), 5.74 (td, J = 2.4, 10.2 Hz, 1H), 4.25 - 4.15 (m, 1H), 4.13 - 4.02 (m, 1H), 4.00 - 3.70 (m, 3H), 3.58 - 3.48 (m, 1H), 2.50 - 2.25 (m, 2H); m/z ES+ [M+H] ⁺ 398.1. Example 335. Preparation of (S)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 11) Step 1. N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]pyrido[ 3,2-d]pyrimidin-4- amine A solution of (S)-tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidine-1-carboxylate (4.0 g, 9.01 mmol) in hydrochloride/ethyl acetate (4 M, 40 mL) and dichloromethane (40 mL) was stirred at 20 °C for 0.5 hr. On completion, the reaction was concentrated in vacuum to afford N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3- yl]pyrido[3,2-d]pyrimidin-4-amine (3.0 g, crude) as a yellow solid. Step 2. (S)-1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)pyrrolidin-1-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]pyrido[ 3,2- d]pyrimidin-4-amine (3.00 g, 8.73 mmol) in tetrahydrofuran (30 mL) and water (15 mL) was added sodium bicarbonate (2.93 g, 34.9 mmol) at 0 °C to adjust pH = 8. Then a solution of prop-2-enoyl chloride (790 mg, 8.73 mmol) in tetrahydrofuran (15 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the reaction was concentrated in vacuum and then filtered. The filtered cake was washed with water (50 mL x 3). The crude product was triturated with ethyl acetate: petroleum ether (100 mL, 1:10) to afford (S)-1-(3-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pyrrolidin-1- yl)prop-2-en-1-one (2.2 g, 5.3 mmol, 60%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.91 (d, J = 3.6 Hz, 1H), 8.62 (d, J = 4.4 Hz, 1H), 8.22 (dd, J = 3.6, 8.8 Hz, 1H), 8.07 - 7.89 (m, 2H), 7.53 - 7.44 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.71 - 6.61 (m, 1H), 6.17 (td, J = 2.0, 16.8 Hz, 1H), 5.69 (td, J = 2.4, 10.2 Hz, 1H), 4.20 - 4.10 (m, 1H), 4.08 - 3.97 (m, 1H), 3.95 - 3.85 (m, 1H), 3.84 - 3.65 (m, 2H), 3.54 - 3.43 (m, 1H), 2.47 - 2.19 (m, 2H); m/z ES+ [M+H] ⁺ 398.1. Example 336. Preparation of 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1- one (Compound 78)

Step 1. Benzyl 1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate A solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (254 mg, 824 μmol), (3-benzyloxycarbonyl-3-azabicyclo[3.1.0]hexan-1-yl)-trifluor o- boron;potassium hydride (296 mg, 915 μmol), cesium carbonate (895 mg, 2.75 mmol) and [2-(2- aminophenyl) phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methan esulfonate (66.7 mg, 91.6 μmol) in toluene (5 mL) and water (1 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by water (10 mL), and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel. Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give benzyl 1- (4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (280 mg, 571 μmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 - 9.81 (m, 1H), 8.59 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.04 - 7.91 (m, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.44 - 7.31 (m, 6H), 5.13 (d, J = 8.0 Hz, 2H), 4.23 (dd, J = 4.0, 10.8 Hz, 1H), 4.08 (dd, J = 11.2, 17.6 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.67 - 3.57 (m, 1H), 1.66 (dd, J = 4.8, 8.0 Hz, 1H), 1.36 - 1.21 (m, 1H), 1.08 (d, J = 4.0 Hz, 1H). Step 2. 6-(3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2-fluorophenyl )pyrido[3,2- d]pyrimidin-4-amine A mixture of benzyl 1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -3- azabicyclo[3.1.0]hexane-3-carboxylate (280 mg, 569 μmol) in trifluoroacetic acid (3 mL) was stirred at 60 °C for 2 hr. On completion, the mixture was concentrated to give 6-(3- azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2-fluorophenyl)pyri do[3,2-d]pyrimidin-4-amine (202 mg, 568 μmol, 99%) as a brown oil. Step 3. 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one To a solution of 6-(3-azabicyclo[4.1.0]heptan-1-yl)-N-(3-chloro-2-fluoro-phen yl)pyrido [3,2-d]pyrimidin-4-amine (130 mg, 351 μmol) in tetrahydrofuran (0.8 mL) and water (0.2 mL) was added saturated sodium bicarbonate (118 mg, 1.41 mmol) and prop-2-enoyl chloride (25.4 mg, 281 μmol). The mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched by addition methanol (0.5 mL). The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 40%-60%,8min) to give 1-[1-[4-(3-chloro-2-fluoro-anilino)pyrido [3,2-d]pyrimidin-6-yl]-3-azabicyclo[4.1.0]heptan- 3-yl]prop-2-en-1-one (28.3 mg, 69.0 μmol, 19%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.89 - 9.78 (m, 1H), 8.58 (s, 1H), 8.17 - 8.12 (m, 1H), 7.96 (t, J = 7.2 Hz, 1H), 7.76 (t, J = 8.8 Hz, 1H), 7.55 - 7.45 (m, 1H), 7.36 - 7.30 (m, 1H), 6.75 - 6.55 (m, 1H), 6.76 - 6.66 (m, 1H), 5.76 - 5.67 (m, 1H), 4.48 - 4.19 (m, 2H), 3.98 - 3.86 (m, 1H), 3.86 - 3.78 (m, 0.5H), 3.58 - 3.53 (m, 0.5H), 2.26 - 2.12 (m, 1H), 1.68 - 1.63 (m, 1H), 1.09 - 1.05 (m, 1H); m/z ES+ [M+H] ⁺ 410.0. Example 337. Preparation of 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.4]octan-1-yl)prop-2-en-1- one (Compound 101) Step 1. tert-Butyl 6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 1,6-diazaspiro[3.4]octane-1-carboxylate To a mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 323 μmol) and tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate (100 mg, 194 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (167 mg, 1.29 mmol) at 20 °C under nitrogen. The mixture was stirred at 100 °C for 3 hr. On completion, the solution was poured into water (10 mL), then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl 6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (140 mg, 289 μmol, 86%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.42 (s, 1H), 8.35 – 8.31 (m, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.37 – 7.20 (m, 3H), 4.00 – 3.30 (m, 6H), 2.28 – 2.19 (m, 4H), 1.40 – 1.24 (m, 9H); m/z ES+ [M+H] ⁺ 485.1. Step 2. N-(3-Chloro-2-fluorophenyl)-6-(1,6-diazaspiro[3.4]octan-6-yl )pyrido[3,2- d]pyrimidin-4-amine To a mixture of tert-butyl 7-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] - 1,7-diazaspiro[3.4]octane-1-carboxylate (140 mg, 289 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (988 mg, 8.66 mmol) at 20 °C, the mixture was stirred at 40 °C for 3 hours. On completion, the mixture was concentrated in vacuum to give N-(3-chloro-2-fluoro- phenyl)-6-(1,7-diazaspiro[3.4]octan-7-yl)pyrido[3,2-d]pyrimi din-4-amine (110 mg, 283 μmol, 73%) as a yellow solid. m/z ES+ [M+H] ⁺ 385.0. Step 3. 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-1,6- diazaspiro[3.4]octan-1-yl)prop-2-en-1-one To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-(1,7-diazaspiro[3.4]octan-7- yl)pyrido[3,2-d]pyrimidin-4-amine (110 mg, 286 μmol) and sodium bicarbonate (72.0 mg, 858 μmol) in water (2 mL) was added a solution of prop-2-enoyl chloride (24.6 mg, 272 μmol) in tetrahydrofuran (2 mL) dropwise at 0 °C under nitrogen. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by water (5 mL) and then extracted with ethyl acetate (5 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Neutral condition; column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 42%-72%,9min) to give 1-(6-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-diazaspi ro[3.4]octan-1-yl)prop-2-en-1-one (55.0 mg, 125 μmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 - 9.27 (m, 1H), 8.42 (s, 1H), 8.39 - 8.20 (m, 1H), 7.99 - 7.91 (m, 1H), 7.38 - 7.20 (m, 3H), 6.37 - 6.26 (m, 1H), 6.20 - 6.06 (m, 1H), 5.70 - 5.62 (m, 1H), 4.22 - 4.15 (m, 3H), 3.93 - 3.80 (m, 2H), 3.65 - 3.53 (m, 1H), 2.82 - 2.73 (m, 1H), 2.45 - 2.35 (m, 2H), 2.33 - 2.22 (m, 1H); m/z ES+ [M+H] ⁺ 439.1. Example 338. Preparation of 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,6-diazaspiro[3.4]octan-2-yl)prop-2-en-1- one (Compound 103) Step 1. tert-Butyl 6-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)- 2,6-diazaspiro[3.4]octane-2-carboxylate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 323 μmol) in 1-methylpyrrolidin-2-one (1 mL) was added diisopropylethylamine (125 mg, 970 μmol) and tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate (103 mg, 485 μmol). The mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was diluted with water (20 mL) and filtered. The filter cake was concentrated in vacuo to give tert-butyl 6-(4-((3- chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,6 -diazaspiro[3.4]octane-2- carboxylate (200 mg, crude) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.13 (d, J = 2.0 Hz, 1H), 8.82 - 8.73 (m, 1H), 8.55 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.05 - 7.00 (m, 1H), 6.92 (d, J = 9.2 Hz, 1H), 3.95 - 3.91 (m, 2H), 3.73 (s, 2H), 3.31 (t, J = 7.2 Hz, 2H), 2.31 (t, J = 8.0 Hz, 2H), 1.96 (d, J = 7.6 Hz, 2H), 1.40 (s, 9H); m/z ES+ [M+H] ⁺ 485.1. Step 2. N-(3-Chloro-2-fluorophenyl)-6-(2,6-diazaspiro[3.4]octan-6-yl )pyrido[3,2- d]pyrimidin-4-amine A mixture of tert-butyl 7-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -2,7- diazaspiro[3.4]octane-2-carboxylate (200 mg, 412 μmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (1 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-2-fluoro-phenyl)-6-(2,6-diazaspiro[3.4]octan-6-y l) pyrido[3,2-d]pyrimidin-4-amine (200 mg, crude, TFA salt) as a brown oil. m/z ES+ [M+H] ⁺ 385.2. Step 3. 1-(6-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)-2,6- diazaspiro[3.4]octan-2-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-(2,6-diazaspiro[3.4]octan-6- yl)pyrido[3,2-d] pyrimidin-4-amine (200 mg, 520 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (131 mg, 1.56 mmol). Then prop-2-enoyl chloride (47.0 mg, 520 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (FA condition; column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water (0.225% FA)-ACN]; B%: 33%-53%, 10 min) to give 1-(6-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,6-diazaspi ro[3.4]octan-2-yl)prop-2-en-1-one (39.7 mg, 90.5 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.43 (s, 1H), 8.36 (t, J = 7.2 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.22 (d, J = 9.2 Hz, 1H), 6.34 (dd, J = 10.4, 17.2 Hz, 1H), 6.13 (dd, J = 2.0, 16.8 Hz, 1H), 5.69 (dd, J = 2.4, 10.4 Hz, 1H), 4.32 - 4.20 (m, 2H), 4.03 - 3.92 (m, 2H), 3.90 - 3.75 (m, 2H), 3.66 (d, J = 4.0 Hz, 2H), 2.32 - 2.23 (m, 2H); m/z ES+ [M+H] ⁺ 439.1. Example 339. Preparation of 1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)imidazolidin-1-yl)prop-2-en-1-one (Compound 122) Step 1. tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)imidazolidine-1-carboxylate A mixture of tert-butyl 3-[6-cyano-5-[(E)-dimethylaminomethyleneamino]-2-pyridyl] imidazolidine-1-carboxylate (160 mg, 465 μmol) and 3-chloro-2-fluoro-aniline (135 mg, 929 μmol) in toluene (2.0 mL) and acetic acid (2.0 mL) was stirred at 90 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with methanol (3.0 mL) and then filtered. The filter cake was dried under reduced pressure to give tert- butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)imidazolidine-1- carboxylate (60 mg, 135 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 - 9.07 (m, 1H), 8.91 - 8.79 (m, 1H), 8.68 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.15 - 7.09 (m, 1H), 7.08 - 6.99 (m, 1H), 5.03 (s, 2H), 4.04 - 3.73 (m, 4H), 1.58 (s, 9H). Step 2. N-(3-Chloro-2-fluorophenyl)-6-(imidazolidin-1-yl)pyrido[3,2- d]pyrimidin-4- amine To a mixture of tert-butyl 3-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)imidazolidine-1-carboxylate (40.0 mg, 89.9 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.4 mL) at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-2- fluoro-phenyl)-6-imidazolidin-1-yl-pyrido[3,2-d]pyrimidin-4- amine (40 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 345.2. Step 3. 1-(3-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6- yl)imidazolidin-1-yl)prop-2-en-1-one To a mixture of N-(3-chloro-2-fluoro-phenyl)-6-imidazolidin-1-yl-pyrido[3,2- d] pyrimidin-4-amine (30 mg, 87.01 μmol) in tetrahydrofuran (0.1 mL) and water (0.1 mL) was added sodium bicarbonate (25.6 mg, 304 μmol). Then a solution of prop-2-enoyl chloride (7.88 mg, 87.0 μmol) in tetrahydrofuran (0.1 mL) was added dropwise at 0 °C over 2 min under nitrogen. Then the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by Prep-HPLC [column: Phenomenex Gemini- NX C1875*30mm*3um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN]; B%: 25%-55%, 8 min] to give 1-[3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]imidazolidin-1-yl]prop-2- en-1-one (17.4 mg, 43.6 μmol, 50%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.22 - 8.04 (m, 2H), 7.47 - 7.27 (m, 3H), 6.85 - 6.61 (m, 1H), 6.32 - 6.22 (m, 1H), 5.82 (dt, J = 1.6, 10.4 Hz, 1H), 5.27 (s, 1H), 5.12 (s, 1H), 4.08 - 3.96 (m, 2H), 3.93 - 3.83 (m, 2H); m/z ES+ [M+H] ⁺ 399.3. Example 340. Preparation of 1-((1R)-1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1- one (Compound 144) Step 1. Benzyl (1R,5R)-1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]py rimidin-6- yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and Benzyl (1S,5S)-1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-3-azabicyclo [3.1.0]hexane-3-carboxylate Benzyl 1-[4-(3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] -3-azabicyclo[3.1.0] hexane-3-carboxylate (320 mg, 653 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase:[0.1%NH ₃ H ₂ O IPA]; B%: 50%-50%, 8 min) to give benzyl (1R,5R)-1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]py rimidin-6-yl)- 3-azabicyclo[3.1.0]hexane-3-carboxylate (107 mg, 218 μmol, 33%) as a yellow oil and benzyl (1S,5S)-1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]py rimidin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (103 mg, 210 μmol, 32%) as a yellow oil. Step 2. 6-((1R,5R)-3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine A mixture of benzyl (1R,5R)-1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (102 mg, 209 μmol) in trifluoroacetic acid (1 mL) was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (74.2 mg, crude) as a yellow oil. Step 3. 1-((1R,5R)-1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one To a solution of 6-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (74.2 mg, 209 μmol) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (70.1 mg, 834 μmol) and prop-2-enoyl chloride (17.0 mg, 188 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was quenched by methanol (0.6 mL) and then concentrated. The residue was purified by prep- HPLC (column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN]; B%: 35%-65%,10 min) to give 1-((1R)-1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-3-azabicyclo [3.1.0]hexan-3-yl)prop-2-en-1- one (53.1 mg, 0.13 mmol, 62%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 - 9.79 (m, 1 H), 8.56 (d, J = 2.8 Hz, 1 H), 8.14 (dd, J = 8.8, 7.2 Hz, 1 H), 7.96 - 7.86 (m, 1 H), 7.73 (t, J = 8.8 Hz, 1 H), 7.53 - 7.41 (m, 1 H), 7.35 – 7.24 (m, 1 H), 4.45 (d, J = 10.8 Hz, 1 H), 4.28 - 4.14 (m, 2 H), 3.96 - 3.77 (m, 1 H), 3.80 (dd, J = 10. 4, 4.0 Hz, 1 H), 3.54 (dd, J =12.0, 4.4 Hz, 1 H), 2.47 - 2.42 (m, 1 H), 1.64 (dt, J = 8.4, 4.4 Hz, 1 H), 1.05 (q, J = 4.8 Hz, 1 H); m/z ES+ [M+H] ⁺ 410.0. Example 341. Preparation of 1-((1S)-1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1- one (Compound 145) Step 1. 6-((1S,5S)-3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine A mixture of benzyl (1S,5S)-1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (98.0 mg, 200 μmol) in trifluoroacetic acid (1 mL) was stirred at 60 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-((1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (71.1 mg, crude) as a yellow oil. Step 2. 1-((1S,5S)-1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one A solution of 6-((1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (71.1 mg,199 μmol) in tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (67.2 mg, 800 μmol) and prop-2-enoyl chloride (16.3 mg, 180 μmol) at 0°C, and then the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was quenched by methanol (0.6 mL). The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water(10 mM NH ₄ HCO ₃ )- ACN]; B%: 25%-55%, 8 min) to give 1-((1S,5S)-1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-3-azabicyclo [3.1.0]hexan-3-yl)prop-2-en-1- one (28.8 mg, 70.2 μmol, 35%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 - 9.80 (m, 1 H), 8.56 (d, J = 2.4 Hz, 1 H), 8.18 - 8.10 (m, 1 H), 7.91 (dt, J = 20.0, 7.6 Hz, 1 H), 7.74 (t, J = 8.8 Hz, 1 H), 7.53 - 7.40 (m, 1 H), 7.31 (td, J = 8.0, 4.0 Hz, 1 H), 6.75 - 6.56 (m, 1 H), 6.21 - 6.12 (m, 1 H), 5.74 - 5.64 (m, 1 H), 4.45 (d, J = 10.80 Hz, 1 H), 4.28 - 4.15 (m, 2 H), 3.97 - 3.78 (m, 2 H), 3.54 (dd, J = 12.0, 4.0 Hz, 1 H), 2.47 - 2.42 (m, 1 H), 1.64 (dt, J = 8.4, 4.4 Hz, 1 H), 1.05 (q, J = 5.2 Hz, 1 H); m/z ES+ [M+H] ⁺ 410.0. Example 342. Preparation of 1-((3aR,6aS)-5-(4-((3-Chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)hexahydropyrr olo[3,4-c]pyrrol-2(1H)- yl)prop-2-en-1-one (Compound 301) Step 1. tert-Butyl (3aR,6aS)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbox ylate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 324 μmol) and tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (103 mg, 485 μmol) in 1-methylpyrrolidin-2-one (1.00 mL) was added diisopropylethylamine (105 mg, 809 μmol, 0.14 mL). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was quenched by 10 mL water and then filtered. The filter cake was collected to give tert- butyl (3aR,6aS)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d] pyrimidin-6- yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (80.0 mg, 165 μmol, 46%) as a brick-red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (d, J = 1.2 Hz, 1H), 8.36 (s, 1H), 8.33 - 8.26 (m, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.16 (d, J = 9.2 Hz, 1H), 3.75 (s, 2H), 3.60 - 3.36 (m, 4H), 3.16 (d, J = 10.4 Hz, 2H), 3.00 (s, 2H), 1.33 (s, 9H); m/z ES+ [M+H] ⁺ 485.2. Step 2. N-(3-Chloro-2-fluorophenyl)-6-((3aR,6aS)-hexahydropyrrolo[3, 4-c]pyrrol- 2(1H)-yl)pyrido[3,2-d]pyrimidin-4-amine A mixture of (3aR,6aS)-tert-butyl 5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbox ylate (60.0 mg, 124 μmol) in dichloromethane (1.00 mL) and trifluoroacetic acid (0.20 mL) was stirred at 25 °C for 3 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(3-Chloro-2-fluorophenyl)- 6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[3 ,2-d]pyrimidin-4-amine (40 mg, 104 μmol, 76%) as a yellow oil; m/z ES+ [M+H] ⁺ 385.3. Step 3. 1-((3aR,6aS)-5-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2 -d]pyrimidin-6- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluorophenyl)-6-((3aR,6aS)-hexahydropyrrolo[3, 4- c]pyrrol-2(1H)-yl)pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, 104 μmol) in tetrahydrofuran (0.50 mL) and water (0.50 mL) was added sodium bicarbonate (30.6 mg, 364 μmol). Then prop-2-enoyl chloride (4.70 mg, 51.97 μmol) was added to the above mixture. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(0.225%FA)-ACN];B%: 22%-52%, 10 min) to give 1-((3aR,6aS)-5-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)hexahydropyrr olo[3,4-c]pyrrol-2(1H)-yl)prop- 2-en-1-one (35.7 mg, 79.7 μmol, 77% ) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.44 (s, 1H), 8.41 - 8.35 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.32 - 7.27 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 6.60 (dd, J = 10.0, 16.8 Hz, 1H), 6.18 - 5.63 (m, 2H), 3.94 - 3.82 (m, 3H), 3.73 (dd, J = 7.6, 12.8 Hz, 1H), 3.56 (tt, J = 5.2, 10.4 Hz, 3H), 3.41 (dd, J = 4.8, 12.8 Hz, 1H), 3.19 - 3.04 (m, 2H); m/z ES+ [M+H] ⁺ 439.3. Example 343. Preparation of N-(1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 302)

Step 1. tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)pyrrolidin-3-yl)carbamate A mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (100 mg, 323 μmol) and tert-butyl N-pyrrolidin-3-ylcarbamate (90.4 mg, 485 μmol) in 1- methylpyrrolidin-2-one (2.00 mL) and diisopropylethylamine (104 mg, 809 μmol) was stirred at 80 °C for 12 hr. On completion, the reaction mixture was quenched by water (10.0 mL) and filtered. The filter cake was collected to give tert-butyl (1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pyrrolidin-3- yl)carbamate (140 mg, 305 μmol, 85%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (d, J = 1.2 Hz, 1H), 8.35 (s, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.34 - 7.16 (m, 3H), 7.13 (d, J = 9.2 Hz, 1H), 4.15 (d, J = 5.6 Hz, 1H), 3.79 - 3.31 (m, 4H), 3.26 - 3.21 (m, 2H), 1.34 (s, 9H); m/z ES+ [M+2H] ⁺ 459.0. Step 2. 6-(3-Aminopyrrolidin-1-yl)-N-(3-chloro-2-fluorophenyl)pyrido [3,2-d]pyrimidin- 4-amine A mixture of tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)pyrrolidin-3-yl)carbamate (120 mg, 261 μmol) in dichloromethane (2.00 mL) and trifluoroacetic acid (0.40 mL) was stirred at 25 °C for 3 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give 6-(3-aminopyrrolidin-1-yl)-N-(3-chloro-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (90.0 mg, 251 μmol, 77%) as a yellow oil. m/z ES+ [M+H] ⁺ 359.1. Step 3. N-(1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6- yl)pyrrolidin-3-yl)acrylamide To a solution of 6-(3-aminopyrrolidin-1-yl)-N-(3-chloro-2-fluorophenyl)pyrido [3,2- d]pyrimidin-4-amine (90.0 mg, 251 μmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL) was added sodium bicarbonate (63.2 mg, 753 μmol). Then prop-2-enoyl chloride (11.4 mg, 125 μmol) was added, the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (0.225%FA)-ACN];B%: 18%-48%, 10min) to give N-(1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)pyrrolidin-3- yl)acrylamide (14.4 mg, 34.9 μmol, 14%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.44 (s, 1H), 8.36 (t, J = 6.4 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 6.31 - 6.21 (m, 1H), 6.19 - 5.59 (m, 2H), 4.64 - 4.39 (m, 1H), 3.95 - 3.53 (m, 4H), 2.29 - 1.98 (m, 2H); m/z ES+ [M+H] ⁺ 415.1. Example 344. Preparation of N-(1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)-N-methylacrylamide (Compound 382) Step 1. tert-Butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)pyrrolidin-3-yl)(methyl)carbamate To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (150 mg, 485 μmol) in 1-methylpyrrolidin-2-one (1.0 mL) was added diisopropylethylamine (188 mg, 1.46 mmol) and tert-butyl N-methyl-N-pyrrolidin-3-yl-carbamate (106 mg, 533 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was quenched by water (10.0 mL) and filtered. The filter cake was collected to give tert-butyl (1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pyrrolidin-3- yl)(methyl)carbamate (200 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 8.34 - 8.21 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.45 - 7.15 (m, 3H), 4.98 - 4.66 (m, 1H), 3.97 - 3.75 (m, 2H), 3.63 - 3.44 (m, 2H), 2.79 (s, 3H), 2.22 - 2.14 (m, 2H), 1.43 (s, 9H). Step 2. N-(3-Chloro-2-fluorophenyl)-6-(3-(methylamino)pyrrolidin-1-y l)pyrido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl (1-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)(methyl)carbamate (150 mg, 317 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.16 g, 10.1 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give N-(3-chloro-2-fluorophenyl)-6- (3-(methylamino)pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-4-ami ne (118 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 373.1. Step 3. N-(1-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6- yl)pyrrolidin-3-yl)-N-methylacrylamide To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[3-(methylamino)pyrrolidin-1- yl]pyrido[3,2-d]pyrimidin-4-amine (100 mg, 268 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (67.6 mg, 804 μmol). Then prop-2-enoyl chloride (24.2 mg, 268 μmol) was added at 0 °C, the mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(0.225%FA)-ACN];B%: 25%-55%, 11.5 min) to give N-(1-(4-((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)pyrrolidin-3- yl)-N-methylacrylamide (30.0 mg, 70.3 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.54 - 8.14 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.44 - 7.16 (m, 3H), 7.05 - 6.48 (m, 1H), 6.29 - 5.57 (m, 2H), 5.39 - 4.80 (m, 1H), 3.86 (s, 2H), 3.68 - 3.49 (m, 2H), 3.10 - 2.84 (m, 3H), 2.22 (d, J = 1.6 Hz, 2H); m/z ES+ [M+H] ⁺ 427.1. Example 345. Preparation of 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1- one (Compound 64)

Step 1. Benzyl 1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)- 3-azabicyclo[3.1.0]hexane-3-carboxylate A mixture of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4-amine (321 mg, 934 μmol), (3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-1-yl)-triflu oro-boron; potassium hydride (300 mg, 1.04 mmol), cesium carbonate (1.01 g, 3.11 mmol) and [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phos phane;methanesulfonate (75.6 mg, 103 μmol) in toluene (4.0 mL) and water (0.40 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by water (5.0 mL) and then extracted with ethyl acetate (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel. petroleum ether/ethyl acetate = 10/1 to 5/1) to give tert-butyl 1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (230 mg, 0.44 mmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.95 - 9.83 (m, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.09 - 7.98 (m, 1H), 7.79 - 7.73 (m, 1H), 7.79 - 7.73 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.44 - 7.34 (m, 5H), 5.13 (d, J = 8.0 Hz, 2H), 4.22 (d, J = 10.4 Hz, 1H), 4.10 - 4.03 (m, 1H), 3.75 - 3.68 (m, 2H), 1.75 - 1.59 (m, 2H), 1.09 (s, 1H). Step 2. 6-(3-Azabicyclo[3.1.0]hexan-1-yl)-N-(3,4-dichloro-2-fluoroph enyl)pyrido[3,2- d]pyrimidin-4-amine A mixture of benzyl 1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 -yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 381 μmol) in trifluoroacetic acid (3.0 mL) was stirred at 60 °C for 2 hr. On completion, the mixture was concentrated to give 6-(3- azabicyclo[3.1.0]hexan-1-yl)-N-(3,4-dichloro-2-fluorophenyl) pyrido[3,2-d]pyrimidin-4-amine (148 mg, 0.38 mmol, 99%) as a brown oil. Step 3. 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-3- azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one To a solution of 6-(3-azabicyclo[3.1.0]hexan-1-yl)-N-(3,4-dichloro-2-fluoro- phenyl)pyrido [3,2-d]pyrimidin-4-amine (148 mg, 379 μmol) in tetrahydrofuran (0.80 mL) and water (0.20 mL) was added sodium bicarbonate (127 mg, 1.52 mmol) and prop-2-enoyl chloride (34.3 mg, 379 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was quenched by methanol (0.60 mL) and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 30%-60%, 10 min) to give 1-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1- one (15.8 mg, 35.6 μmol, 19%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 - 9.84 (m, 1H), 8.59 (s, 1H), 8.17 (t, J = 8.4 Hz, 1H), 8.03-7.96 (m, 1H), 7.79-7.74 (m, 1H), 7.66 - 7.61 (m, 1H), 6.76 - 6.57 (m, 1H), 6.22 - 6.14 (m, 1H), 5.76 - 5.67 (m, 1H), 4.46 (d, J = 10.8 Hz, 0.5H), 4.31 - 4.17 (m, 1.5H), 3.96 (d, J = 10.4 Hz, 0.5H), 3.91 - 3.79 (m, 1H), 3.58 - 3.53 (m, 0.5H), 2.50 - 2.40 (m, 1H), 1.66 (s, 1H), 1.07 (q, J = 4.8 Hz, 1H); m/z ES+ [M+H] ⁺ 444.0. Example 346. Preparation of 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)prop -2-en-1-one (Compound 14) Step 1. tert-Butyl 1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate To a solution of 6-chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimid in-4- amine (250 mg, 727 μmol) and tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrole-5- carboxylate (185 mg, 873 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (376 mg, 2.91 mmol), the mixture was stirred at 100 °C for 12 hr. On completion, the mixture was poured into water (10 mL) and extracted with ethyl estate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over sodium sulfate and concentrated in vacuum to give compound tert-butyl 1-[4-(3,4-dichloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,3,3a,4,6,6a-hexahydro pyrrolo[2,3-c]pyrrole-5- carboxylate (310 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 519.2. Step 2. N-(3,4-Dichloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,4-b]py rrol-1(2H)- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6 - yl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carboxyla te (200 mg, 385 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the mixture was stirred at 25 °C for 0.5 hr. On completion, The mixture was concentrated in vacuum to give compound N-(3,4-dichloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,4-b]py rrol-1(2H)- yl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, crude, TFA) as a yellow solid. Step 3. 1-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)prop-2-en-1-one To a mixture of N-(3,4-dichloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,4-b]py rrol- 1(2H)-yl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 477 μmol) and sodium bicarbonate (160 mg, 1.91 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added prop-2-enoyl chloride (51.8 mg, 572 μmol) dropwise at 0 °C, the mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(0.225% FA)-ACN]; B%: 40%- 70%, 10 min) to give 1-(1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)prop-2-en-1-one (65 mg, 137 μmol, 26%, FA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 8.53 - 8.40 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.28 (dd, J = 2.4, 9.2 Hz, 1H), 6.69 - 6.48 (m, 1H), 6.19 - 6.05 (m, 1H), 5.77 - 5.57 (m, 1H), 4.86 - 4.57 (m, 1H), 4.20 (dd, J = 7.2, 11.2 Hz, 1H), 3.95 (dd, J = 6.8, 13.2 Hz, 1H), 3.86 (dd, J = 8.0, 10.8 Hz, 1H), 3.79 - 3.74 (m, 1H), 3.69 (dd, J = 8.0, 12.8 Hz, 2H), 3.62 (dd, J = 4.8, 11.2 Hz, 1H), 3.47 (dd, J = 4.4, 12.8 Hz, 1H), 3.21 - 3.04 (m, 1H), 2.26 - 2.13 (m, 1H), 1.96 - 1.88 (m, 1H); m/z ES+ [M+H] ⁺ 473.2. Example 347. Preparation of 1-(1-(4-((5-Chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)prop -2-en-1-one (Compound 15) Step 1. tert-Butyl 1-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate A mixture of 6-chloro-N-(5-chloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimidin- 4-amine (250 mg, 808 μmol) and tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (206 mg, 970 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (418 mg, 3.23 mmol), the mixture was stirred at 100 °C for 12 hr. On completion, The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over sodium sulfate and concentrated in vacuum to give compound tert-butyl 1-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (320 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 485.2. Step 2. N-(5-Chloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,4-b]pyrrol -1(2H)- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 1-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (200 mg, 412 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuum to give compound N-(5-chloro-2- fluorophenyl)-6-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyri do[3,2-d]pyrimidin-4-amine (150 mg, crude) as a yellow solid. Step 3. 1-(1-(4-((5-Chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6- yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)prop-2-en-1-one To a mixture of N-(5-chloro-2-fluorophenyl)-6-(hexahydropyrrolo[3,4-b]pyrrol -1(2H)- yl)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 519 μmol) and sodium bicarbonate (174 mg, 2.08 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added prop-2-enoyl chloride (56.4 mg, 623 μmol) dropwise at 0 °C. The mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water(0.225%FA)-ACN]; B%: 32%-62%, 10 min) to give 1-(1-(4-((5-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimid in-6-yl)hexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)prop-2-en-1-one (15 mg, 34.2 μmol, 6.0%, FA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (d, J = 2.4 Hz, 1H), 8.77 - 8.67 (m, 1H), 8.55 (d, J = 3.6 Hz, 1H), 8.46 (s, 1H), 8.00 (dd, J = 1.2, 9.2 Hz, 1H), 7.44 (dd, J = 8.8, 10.8 Hz, 1H), 7.32 (dd, J = 2.4, 9.2 Hz, 1H), 7.25 - 7.19 (m, 1H), 6.68 - 6.50 (m, 1H), 6.12 (td, J = 2.8, 16.8 Hz, 1H), 5.72 - 5.59 (m, 1H), 4.82 - 4.61 (m, 1H), 4.23 - 4.13 (m, 1H), 3.99 - 3.91 (m, 1H), 3.87 (dd, J = 8.0, 10.8 Hz, 1H), 3.82 - 3.74 (m, 2H), 3.73 - 3.66 (m, 1H), 3.62 (dd, J = 5.2, 10.8 Hz, 1H), 3.48 (dd, J = 4.4, 12.8 Hz, 1H), 3.20 - 3.09 (m, 1H), 2.27 - 2.15 (m, 1H), 1.98 - 1.85 (m, 1H); m/z ES+ [M+H] ⁺ 439.2. Example 348. Preparation of 1-(3-(4-((5-Ethynyl-2-Fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)imidazolidin-1-yl)prop-2-en-1-one (Compound 137) Step 1. tert-Butyl 3-(4-((5-ethynyl-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6- yl)imidazolidine-1-carboxylate A solution of tert-butyl 3-[6-cyano-5-[(E)-dimethylaminomethyleneamino]-2-pyridyl] imidazolidine-1-carboxylate (150 mg, 436 μmol) and 5-ethynyl-2-fluoro-aniline (118 mg, 871 μmol) in acetic acid (1.0 mL) and toluene (1.0 mL) was stirred at 90 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to give tert-butyl 3-[4-(5- ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]imidazo lidine-1-carboxylate (60 mg, 138 μmol, 32%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 - 9.08 (m, 1H), 8.60 - 8.34 (m, 2H), 8.04 (d, J = 9.6 Hz, 1H), 7.48 - 7.30 (m, 3H), 4.94 (s, 2H), 4.25 - 4.20 (m, 1H), 3.94 - 3.81 (m, 2H), 3.77 - 3.64 (m, 2H), 1.48 (s, 9H). Step 2. N-(5-ethynyl-2-fluorophenyl)-6-(imidazolidin-1-yl)pyrido[3,2 -d]pyrimidin-4- amine To a mixture of tert-butyl 3-[4-(5-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl ] imidazolidine-1-carboxylate (50.0 mg, 115 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.1 mL) at 25 °C. Then the mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give N-(5-ethynyl-2-fluoro- phenyl)-6-imidazolidin-1-yl-pyrido[3,2-d]pyrimidin-4-amine (40 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 345.2. Step 3. 1-(3-(4-((5-Ethynyl-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6- yl)imidazolidin-1-yl)prop-2-en-1-one To a mixture of N-(5-ethynyl-2-fluoro-phenyl)-6-imidazolidin-1-yl-pyrido[3,2 - d]pyrimidin-4-amine (40.0 mg, 120 μmol) in tetrahydrofuran (0.1 mL)and water (0.1 mL) was added sodium bicarbonate (35.2 mg, 419 μmol). Then a solution of prop-2-enoyl chloride (10.8 mg, 120 μmol) in tetrahydrofuran (0.05 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC [column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN]; B%: 28%-58%, 8 min] to give 1- [3-[4-(5-ethynyl-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-y l]imidazolidin-1-yl]prop-2-en-1- one (6.6 mg, 16.9 μmol, 14%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.56 - 8.27 (m, 1H), 8.61 - 8.23 (m, 1H), 8.10 - 7.98 (m, 1H), 7.54 - 7.22 (m, 3H), 6.81 - 6.61 (m, 1H), 6.34 - 6.20 (m, 1H), 5.89 - 5.68 (m, 1H), 5.32 - 5.05 (m, 2H), 4.24 (d, J = 2.4 Hz, 1H), 4.11 - 3.81 (m, 4H); m/z ES+ [M+H] ⁺ 389.4. Example 349. Preparation of N-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 336) Step 1. tert-Butyl (1-(4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrim idin-6- yl)pyrrolidin-3-yl)carbamate To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrido[3,2-d]pyrimi din-4- amine (136 mg, 396 μmol) in 1-methylpyrrolidin-2-one (1 mL) was added diisopropylethylamine (153 mg, 1.19 mmol) and tert-butyl N-pyrrolidin-3-ylcarbamate (162 mg, 871 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was diluted with water (10 mL) and then filtered. The filter cake was concentrated in vacuo to give tert-butyl N-[1-[4-(3,4- dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]pyrrol idin-3-yl]carbamate (195 mg, 395 μmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 493.2. Step 2. 6-(3-Aminopyrrolidin-1-yl)-N-(3,4-dichloro-2-fluorophenyl)py rido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidi n- 6-yl]pyrrolidin-3-yl]carbamate (120 mg, 243 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6-(3-aminopyrrolidin-1-yl)-N-(3,4-dichloro-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (100 mg crude) as a yellow oil. m/z ES+ [M+H] ⁺ 393.1. Step 3. N-(1-(4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)pyrrolidin-3-yl)acrylamide To a solution of 6-(3-aminopyrrolidin-1-yl)-N-(3,4-dichloro-2-fluoro-phenyl)p yrido[3,2- d]pyrimidin-4-amine (95.0 mg, 242 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (20.3 mg, 242 μmol) in water (0.3 mL) at 0 °C. Then prop-2-enoyl chloride (32.8 mg, 362 μmol) in tetrahydrofuran (0.5 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 5 minutes. On completion, the residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(0.225% FA)- ACN]; B%: 32%-62%, 10 min) to give N-[1-[4-(3,4-dichloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]pyrrolidin-3-yl]prop-2-enamide (20.2 mg, 45.2 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.48 - 8.43 (m, 2H), 8.42 - 8.35 (m, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.60 (dd, J = 2.0, 8.8 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 6.29 - 6.10 (m, 2H), 5.62 (dd, J = 2.4, 10.0 Hz, 1H), 4.58 - 4.51 (m, 1H), 3.92 - 3.84 (m, 1H), 3.78 - 3.68 (m, 2H), 3.59 - 3.49 (m, 1H), 2.32 - 2.26 (m, 1H), 2.05 - 1.99 (m, 1H); m/z ES+ [M+H] ⁺ 447.1. Example 350. Preparation of N-(1-(4-((3-Bromo-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 384) Step 1. tert-Butyl (1-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6- yl)pyrrolidin-3-yl)carbamate To a solution of N-(3-bromo-2-fluoro-phenyl)-6-chloro-pyrido[3,2-d]pyrimidin- 4-amine (280 mg, 792 μmol) and tert-Butyl N-pyrrolidin-3-ylcarbamate (295 mg, 1.58 mmol) in 1- methylpyrrolidin-2-one (1.0 mL) was added diisopropylethylamine (307 mg, 2.38 mmol, 0.42 mL). The mixture was stirred at 100 °C for 3 hr. On completion, the reaction mixture was quenched by water (10 mL) and then filtered. The filter cake was concentrated in vacuo to give tert-butyl N- [1-[4-(3-bromo-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] pyrrolidin-3-yl]carbamate (300 mg, 596 μmol, 74%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (s, 1H), 8.37 (d, J = 6.8 Hz, 1H), 8.33 (s, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.33 (t, J = 6.8 Hz, 1H), 7.21 (d, J = 6.0 Hz, 1H), 7.13 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 4.15 (d, J = 5.2 Hz, 1H), 3.78 - 3.42 (m, 3H), 3.23 (d, J = 7.2 Hz, 1H), 2.13 (td, J = 6.4, 12.4 Hz, 1H), 1.89 (dd, J = 6.4, 12.4 Hz, 1H), 1.40 - 1.26 (m, 9H); m/z ES+ [M+H] ⁺ 503.3. Step 2. 6-(3-Aminopyrrolidin-1-yl)-N-(3-bromo-2-fluorophenyl)pyrido[ 3,2-d]pyrimidin- 4-amine A mixture of tert-Butyl N-[1-[4-(3-bromo-2- fluoro-anilino)pyrido[3,2-d]pyrimidin-6- yl]pyrrolidin-3-yl]carbamate (130 mg, 258 μmol) in trifluoroacetic acid (0.40 mL) and dichloromethane (2.0 mL) was stirred at 25 °C for 3 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give 6-(3-aminopyrrolidin-1-yl)-N-(3-bromo-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, 248 μmol, 94%) as a brown oil. m/z ES+ [M+H] ⁺ 402.9. Step 3. N-(1-(4-((3-Bromo-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6- yl)pyrrolidin-3-yl)acrylamide To a solution of 6-(3-Aminopyrrolidin-1-yl)-N-(3-bromo-2-fluorophenyl)pyrido[ 3,2- d]pyrimidin-4-amine (100 mg, 248 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added sodium bicarbonate (62.5 mg, 744 μmol). Then prop-2-enoyl chloride (18.0 mg, 198 μmol) was added to the above mixture. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase:[water(0.225% FA)- ACN] ;B%: 23%-53%, 10 min) to give N-(1-(4-((3-bromo-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (105 mg, 0.23 mmol, 91%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (d, J = 1.6 Hz, 1H), 8.50 - 8.39 (m, 3H), 7.94 (d, J = 9.2 Hz, 1H), 7.46 (m, 1H), 7.30 - 7.21 (m, 2H), 6.29 - 6.20 (m, 1H), 6.17 - 6.10 (m, 1H), 5.65 - 5.57 (m, 1H), 4.64 - 4.45 (m, 1H), 3.93 - 3.80 (m, 1H), 3.77 - 3.47 (m, 3H), 2.37 - 2.21 (m, 1H), 2.02 (m, 1H); m/z ES+ [M+H] ⁺ 459.0. Example 351. Preparation of N-(1-(4-((3-Chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)acrylamide (Compound 367)

Step 1. tert-Butyl (1-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrim idin-6- yl)pyrrolidin-3-yl)carbamate To a solution of 6-chloro-N-(3-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimid in-4- amine (100 mg, 305 μmol) and tert-butyl N-pyrrolidin-3-ylcarbamate (113 mg, 611 μmol) in 1- methylpyrrolidin-2-one (0.5 mL) was added diisopropylethylamine (118 mg, 917 μmol). The mixture was stirred at 100 °C for 2 hr. On completion, The reaction mixture was quenched by water (2 mL) at 0 °C and then filtered. The filter cake was collected to give tert-butyl (1-(4-((3- chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) pyrrolidin-3-yl)carbamate (140 mg, 294 μmol, 96%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.37 (dt, J = 1.6, 9.2 Hz, 1H), 7.28 (d, J = 6.4 Hz, 1H), 7.17 (d, J = 9.2 Hz, 1H), 4.22 -4.21 (m, 1H), 3.39 - 3.37 (m, 1H), 3.82 - 3.37 (m, 4H), 2.22 - 2.14 (m, 1H), 2.01 - 1.90 (m, 1H), 1.41 (s, 9H). Step 2. 6-(3-Aminopyrrolidin-1-yl)-N-(3-chloro-2,4-difluorophenyl)py rido[3,2- d]pyrimidin-4-amine To a solution of tert-butyl (1-(4-((3-chloro-2,4-difluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)pyrrolidin-3-yl)carbamate (120 mg, 251 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol, 2 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give 6-(3-aminopyrrolidin-1-yl)-N-(3-chloro-2,4- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (180 mg, crude) as a light yellow solid. m/z ES+ [M+H] ⁺ 377.0. Step 3. N-(1-(4-((3-Chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyr imidin-6- yl)pyrrolidin-3-yl)acrylamide To a mixture of 6-(3-aminopyrrolidin-1-yl)-N-(3-chloro-2,4-difluorophenyl)py rido[3,2- d]pyrimidin-4-amine (180 mg, 477 μmol) and sodium bicarbonate (200 mg, 2.39 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (30.2 mg, 334 μmol) at 0 °C. The reaction was stirred at 0 °C for 15 min. On completion, the mixture was concentrated. The residue was purified by Prep-HPLC (Neu: column: Phenomenex luna C18 150 x 25mm x 10um;mobile phase: [water(0.225%FA)-ACN];B%: 20%-50%,11.5min) to give N-(1-(4-((3- chloro-2,4-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) pyrrolidin-3-yl)acrylamide (17.9 mg, 41.6 μmol, 8%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.52 (s, 1H), 8.47 (d, J = 6.8 Hz, 1H), 7.97 (d, J = 9.2 Hz, 2H), 7.45 (dt, J = 1.6, 8.8 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 6.29 - 6.09 (m, 2H), 5.62 (dd, J = 2.4, 10.0 Hz, 1H), 4.61 - 4.49 (m, 1H), 3.97 - 3.84 (m, 1H), 3.80 - 3.66 (m, 2H), 3.61 - 3.53 (m, 1H), 2.32 - 2.23 (m, 1H), 2.08 - 1.96 (m, 1H); m/z ES+ [M+H] ⁺ 431.0. Example 352. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)but-2-y n-1-one (Compound 437) 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluorophenyl)pyrido[3,2- d]pyrimidin-4-amine was prepared using the general scheme outlined in Example 257, Compound 250 for steps 1 and 2 starting from intermediate Int-29. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)but-2-yn-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 - fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (31.5 mg, 85.0 μmol) in tetrahydrofuran (5 mL) was added a 0.25 M solution of but-2-ynoyl chloride (357 μL, 85.0 μmol) along with N,N- diisopropylethylamine (14.8 μL, 85.0 μmol). Stirring was continued for 1 hour. The solution was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate (10 mM) and acetonitrile (0-100% gradient) as an eluent. The pure fractions were collected and lyophilized to afford 1-((1S,4S)-5- (4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)but-2-yn-1-one as a white solid (16.6 mg, 38.3 μmol, 45%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 17.4 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.35 (dt, J = 16.3, 7.5 Hz, 3H), 5.25 (s, 1H), 4.91 (m, 1H), 3.82 – 3.45 (m, 4H), 2.14 – 2.00 (m, 5H); m/z ES+ [M+H] ⁺ 437.1. Example 353. Preparation of 1-((1R,5S)-7-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)pr op-2-en-1-one (Compound 438) 1-((1R,5S)-7-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-3-oxa- 7,9-diazabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one was prepared using the general scheme outlined in Example 257, Compound 250, starting from intermediate Int-29 and tert-butyl 3-oxa- 7,9-diazabicyclo[3.3.1]nonane-9-carboxylate as the piperazine in Step 1 (white powder, 16.0 mg, 35.0 μmol, 24% over three steps). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.40 (s, 1H), 8.16 (t, J = 7.1 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.40 (ddd, J = 8.3, 6.8, 1.6 Hz, 1H), 7.31 (td, J = 8.2, 1.3 Hz, 1H), 6.92 (dd, J = 16.7, 10.5 Hz, 1H), 6.25 (dd, J = 16.7, 2.2 Hz, 1H), 5.79 (dd, J = 10.4, 2.2 Hz, 1H), 4.79 (s, 2H), 4.49 (m, 2H), 4.00 (dd, J = 11.2, 6.9 Hz, 2H), 3.66 (t, J = 12.3 Hz, 2H), 3.35 (s, 1H), 3.28 (s, 1H); m/z ES+ [M+H] ⁺ 455.0. Example 354. Preparation of 1-((1S,4S)-5-(4-((6-(cyclopropylmethoxy)pyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (Compound 439) 1-((1S,4S)-5-(4-((6-(cyclopropylmethoxy)pyridin-3-yl)amino)p yrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in example 39, starting from intermediate Int-71 in Step 1 (white powder, 11.0 mg, 24.5 μmol, 30% over two steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.56 (t, J = 2.7 Hz, 1H), 8.32 (s, 1H), 8.17 (dd, J = 8.9, 2.9 Hz, 1H), 7.88 (dd, J = 9.2, 3.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.61 (m, 1H), 5.91 (m, 2H), 5.00 (m, 1H), 4.10 (d, J = 7.1 Hz, 2H), 3.82 – 3.35 (m, 6H), 2.03 (d, J =29.8 Hz, 2H), 1.31 – 1.18 (m, 2H), 0.55 (dt, J = 8.0, 2.9 Hz, 2H), 0.34 (dd, J = 4.7, 1.6 Hz, 2H); m/z ES+ [M+H] ⁺ 444.3. Example 355. Preparation of 1-((1S,4S)-5-(4-(3-chloro-2-fluorophenoxy)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (Compound 440) 1-((1S,4S)-5-(4-(3-chloro-2-fluorophenoxy)pyrido[3,2-d]pyrim idin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared using the general scheme outlined in example 39, starting from intermediate Int-72 in Step 1 (white powder, 10.1 mg, 23.7 μmol, 52% over two steps). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 8.07 (dd, J = 9.4, 2.8 Hz, 1H), 7.71 – 7.20 (m, 4H), 6.61 (m, 1H), 6.14 (dd, J = 16.7, 1.9 Hz, 1H), 5.67 (ddd, J = 16.3, 10.3, 2.2 Hz, 1H), 5.14 (d, m, 1H), 4.97 (m, 1H), 3.86 – 3.63 (m, 2H), 3.63 – 3.47 (m, 2H), 2.18 – 1.89 (m, 2H); m/z ES+ [M+H] ⁺ 426.0. Example 356. Preparation of 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)piperidin-1-yl)but-2-yn-1-one (Compound 441) Step 1. (E)-N'-(6-Chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimidam ide A solution of 3-amino-6-chloropicolinonitrile (3.00 g, 19.5 mmol) was suspended in N,N- dimethylformamide dimethyl acetal (6.62 mL, 48.8 mmol). The mixture was heated to 90 °C and stirring was continued for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo to afford (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide as a brown solid (3.95 g, 18.9 mmol, 97%). m/z ES+ [M+H] ⁺ 208.9. Step 2.6-Bromo-N-(3,4-dichloro-2-fluorophenyl)quinazolin-4-amine To a solution of (E)-N’-(6-chloro-2-cyanopyridin-3-yl)-N,N-dimethylformimid amide (300 mg, 1.19 mmol) in toluene (2 mL) was added 3,4-dichloro-2-fluoroaniline (146 μL, 1.19 mmol) and acetic acid (1 mL, 17.8 mmol). The mixture was heated to 120 ℃ and stirring was continued for 4 hours. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a crude residue that was purified using C18 reverse phase chromatography (25 g cartridge) with ammonium formate (10 mM) and acetonitrile (10-90% gradient) as an eluent. The pure fractions were combined and lyophilized to afford 6- bromo-N-(3,4-dichloro-2-fluorophenyl)quinazolin-4-amine as a white solid (215 mg, 417 μmol, 35%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.01 (dd, J = 8.9, 2.0 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.57 (s, 2H); m/z ES+ [M+H] ⁺ 388.0. Step 3. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)-5, 6- dihydropyridine-1(2H)-carboxylate To a solution of 6-bromo-N-(3,4-dichloro-2-fluorophenyl)quinazolin-4-amine (300 mg, 775 μmol) in dioxane (6.5 mL) and water (1.3 mL) was added tert-butyl 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxyla te (245 mg, 775 μmol), 1,1'- bis(diphenylphosphino)ferrocene dichloropalladium (II) (56.7 mg, 77.5 μmol) and potassium carbonate (321 mg, 2.33 mmol). The mixture was heated to 80 ℃ and stirring was continued for 16 hours. The mixture was cooled to room temperature, filtered through celite, diluted in water (25 mL), and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine and concentrated in vacuo to afford tert-butyl 3-(4-((3,4-dichloro-2- fluorophenyl)amino)quinazolin-6-yl)-5,6-dihydropyridine-1(2H )-carboxylate (415 mg, crude) as a brown residue that was carried forward without further purification. m/z ES+ [M+H] ⁺ 489.2. Step 4. tert-Butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip eridine- 1-carboxylate To a solution of tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)- 5,6-dihydropyridine-1(2H)-carboxylate (130 mg, 266 μmol) in methanol (7 mL) was added 10% palladium on carbon (56.5 mg, 531 μmol). Stirring was continued for 48 hours before the hydrogen balloon was removed and the mixture purged with nitrogen. The mixture was filtered through Celite®, and concentrated in vacuo to afford a brown residue that was purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate (10 mM) and acetonitrile (10-90% gradient) as an eluent. The pure fractions were combined and lyophilized to afford tert- butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6-yl)pip eridine-1-carboxylate as a light yellow solid (48.0 mg, 98.4 μmol, 37%). m/z ES+ [M+H] ⁺ 491.2. Step 5. N-(3,4-Dichloro-2-fluorophenyl)-6-(piperidin-3-yl)quinazolin -4-amine To a solution of tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)quinazolin-6- yl)piperidine-1-carboxylate (53.0 mg, 108 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (200 μL, 2.59 mmol). Stirring was continued for 1 hour. The mixture was concentrated in vacuo to afford a residue that was redissolved in dichloromethane (1 mL). The mixture was concentrated in vacuo to afford N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3- yl)quinazolin-4-amine (42.2 mg, crude) as a brown residue that was carried forward without further purification. m/z ES+ [M+H] ⁺ 391.1. Step 6. 1-(3-(4-((3,4-Dichloro-2-fluorophenyl)amino)quinazolin-6-yl) piperidin-1-yl)but- 2-yn-1-one A solution of N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl)quinazolin -4- amine (42.2 mg, 108 μmol) in tetrahydrofuran (2 mL) was cooled to 0 ℃ using an ice bath. A 0.25 M solution of but-2-ynoyl chloride in dichloromethane (29.8 μL, 119 μmol) and triethylamine (75.9 μL, 639 μmol) were added to the mixture and stirring was continued for 1 hour at room temperature. The mixture was diluted in water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate and acetonitrile (10-80% gradient) as an eluent. The pure fractions were combined and lyophilyzed to afford 1-(3-(4-((3,4- dichloro-2-fluorophenyl)amino)quinazolin-6-yl)piperidin-1-yl )but-2-yn-1-one as a white solid (9.10 mg, 19.4 μmol, 18%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.52 (s, 1H), 8.35 (d, J = 9.8 Hz, 1H), 7.83 (dt, J = 15.8, 8.2 Hz, 2H), 7.60 (s, 2H), 4.60 – 4.29 (m, 2H), 3.38 (t, J = 12.4 Hz, 1H), 3.18 (td, J = 13.0, 2.4 Hz, 1H), 2.95 – 2.64 (m, 2H), 2.02 (d, J = 25.9 Hz, 3H), 1.93 – 1.78 (m, 2H), 1.68 – 1.40 (m, 1H); m/z ES+ [M+H] ⁺ 457.1. Example 357. Preparation of 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-(((R)-tetrahydrofuran- 3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one and 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-(((S)-tetrahydrofuran- 3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. 2-Chloro-5-fluoro-4-nitrophenol To a solution of 2-chloro-5-fluoro-phenol (15.0 g, 102.3 mmol) in dichloromethane (200 mL) was added concentrated nitric acid (10.5 g, 117 mmol, 70%) dropwise at 0 °C. The mixture was stirred at 25 °C for 0.25 hs. On completion, the mixture was carefully quenched with water (200 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was purified by reversed-phase HPLC (0.1% Formic acid condition) and further purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5:1 to 2:1) to give 2-chloro-5- fluoro-4-nitro-phenol (5.81 g, 30.42 mmol, 29%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 11.6 Hz, 1H), 6.34 (s, 1H). Step 2. 3-((2-Chloro-5-fluoro-4-nitrophenoxy)methyl)tetrahydrofuran To a solution of 2-chloro-5-fluoro-4-nitro-phenol (500 mg, 2.61 mmol) and tetrahydrofuran-3-ylmethanol (400 mg, 3.92 mmol) in tetrahydrofuran (9.00 mL) was added triphenylphosphene (822 mg, 3.13 mmol) and diisopropyl azodicarboxylate (581 mg, 2.87 mmol). The mixture was stirred at 60 °C for 2 hs. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5:1 to 1:1) to give 3-[(2-chloro-5-fluoro-4-nitro- phenoxy)methyl]tetrahydrofuran (1.13 g, crude) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 13.6 Hz, 1H), 4.18 (dd, J = 7.2, 13.6 Hz, 2H), 3.81 - 3.76 (m, 2H), 3.71 - 3.66 (m, 1H), 3.55 (dd, J = 5.2, 8.8 Hz, 1H), 2.74 - 2.70 (m, 1H), 2.07 - 2.01 (m, 1H), 1.71 - 1.67 (m, 1H). Step 3. 5-Chloro-2-fluoro-4-((tetrahydrofuran-3-yl)methoxy)aniline To a solution of 3-[(2-chloro-5-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran (1.13 g, 4.10 mmol) in methanol (6.00 mL) and water (6.00 mL) was added iron powder (916 mg, 16.4 mmol) and ammonium chloride (2.19 g, 41.0 mmol). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was filtered and the fitrate was concentrated to give 5-chloro-2-fluoro-4- (tetrahydrofuran-3-ylmethoxy)aniline (1.00 g, 3.70 mmol, 90%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 - 8.68 (m, 1H), 7.13 - 6.70 (m, 1H), 5.00 - 4.71 (m, 2H), 3.88 - 3.67 (m, 2H), 2.07 - 1.92 (m, 1H), 1.80 - 1.45 (m, 2H), 1.21 - 1.14 (m, 4H); m/z ES+ [M+H] ⁺ 246.1. Step 4. 6-Chloro-N-(5-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine A solution of 5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline (200 mg, 814 μmol) and 4,6-dichloropyrido[3,2-d]pyrimidine (148 mg, 740 μmol) in acetonitrile (3.00 mL) was stirred at 40 °C for 2 hs. On completion, the mixture was filtered and the filtered cake was collected to give 6-chloro-N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy )phenyl]pyrido[3,2- d]pyrimidin-4-amine (170 mg, 0.42 mmol, 51%) as a yellow solid. m/z ES+ [M+H] ⁺ 408.9. Step 5. tert-Butyl (1S,4S)-5-(4-((5-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (170 mg, 415 μmol) and tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (107 mg, 540 μmol) in N-methylpyrrolidone (2.00 mL) was added diisopropylethylamine (161 mg, 1.25 mmol). The mixture was stirred at 100 °C for 14 hs. On completion, the mixture was quenched with water (10 mL) and filtered. The solid was collected to give tert-butyl (1S,4S)-5-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (220 mg, 0.39 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.25 - 9.08 (m, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 12.4 Hz, 2H), 4.53 (d, J = 17.2 Hz, 1H), 4.11 - 3.97 (m, 2H), 3.85 - 3.75 (m, 2H), 3.75 - 3.74 (m, 1H), 3.66 (J = 7.6, 14.0 Hz, 2H), 3.57 (dd, J = 5.6, 8.4 Hz, 1H), 2.19 - 2.15 (m, 2H), 2.09 - 1.94 (m, 3H), 1.92 - 1.87 (m, 2H), 1.69 (J = 6.4, 13.2 Hz, 1H), 1.41 - 1.33 (m, 9H); m/z ES+ [M+H] ⁺ 571.3. Step 6. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-2 -fluoro-4- ((tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin -4-amine To a solution of tert-butyl (1S,4S)-5-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (190 mg, 333 μmol) in dichloromethane (2.00 mL) was added trifluoroacetic acid (2.00 mL). The mixture was stirred at 25 °C for 0.5 hs. On completion, the mixture was concentrated to give 6- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-2-f luoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 0.32 mmol, 88%) as a brown oil. m/z ES+ [M+H] ⁺ 471.2. Step 7. 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (150 mg, 318 μmol) in tetrahydrofuran (0.75 mL) and water (0.75 mL) was added sodium bicarbonate (26.8 mg, 0.32 mmol) and prop-2-enoyl chloride (28.8 mg, 0.32 mmol) at 0 ºC. The mixture was stirred at 0 °C for 0.25 hs. On completion, the mixture was filtered and concentrated to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(0.225%FA)-ACN];B%: 20%-50%,10 min) to give 1-[(1S,4S)-5-[4-[5-chloro-2- fluoro-4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d]p yrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (70.1 mg, 0.13 mmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 - 9.10 (m, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 7.91 (dd, J = 3.2, 9.2 Hz, 1H), 7.31 (d, J = 12.4 Hz, 2H), 6.85 - 6.37 (m, 1H), 6.14 (ddd, J = 2.4, 5.6, 16.8 Hz, 1H), 5.73 - 5.60 (m, 1H), 5.48 - 5.14 (m, 1H), 5.08 - 4.92 (m, 1H), 4.10 - 3.99 (m, 2H), 3.84 - 3.77 (m, 2H), 3.76 - 3.65 (m, 3H), 3.59 (s, 3H), 2.75 - 2.68 (m, 1H), 2.09 - 1.99 (m, 3H), 1.74 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 525.3. Step 8. 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-(((R)-tetrahydrofuran- 3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one and 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-(((S)-tetrahydrofuran- 3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one The product 1-[(1S,4S)-5-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylme thoxy)anilino] pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2 -yl]prop-2-en-1-one (60 mg, 114 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [0.1%NH ₃ water MEOH]; B%: 50%-50%, 7.6; 790min) to give crude 1-((1S,4S)-5- (4-((5-chloro-2-fluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy) phenyl)amino)pyrido [3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one, which was further purified by Prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10um; mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 24%-51%, 8 min) to give 1-[(1S,4S)-5-[4-[5-chloro- 2-fluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]anilino]pyrid o[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (7.28 mg, 13.9 μmol, 12%) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 7.85 - 7.77 (m, 1H), 7.27 - 7.11 (m, 1H), 7.05 - 6.97 (m, 1H), 6.85 - 6.40 (m, 1H), 6.34 - 6.24 (m, 1H), 5.83 - 5.70 (m, 1H), 5.26 - 5.10 (m, 1H), 5.06 (d, J = 12.0 Hz, 1H), 4.05 - 4.00 (m, 1H), 3.98 - 3.89 (m, 3H), 3.89 - 3.70 (m, 5H), 3.69 - 3.54 (m, 2H), 2.86 - 2.72 (m, 1H), 2.23 - 2.05 (m, 3H), 1.89 - 1.77 (m, 1H). m/z ES+ [M+H] ⁺ 525.0. The SFC also gave another crude 1-((1S,4S)-5-(4-((5-chloro-2-fluoro-4-(((S)- tetrahydrofuran-3-Yl)methoxy)phenyl) amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, which was further purified by Prep-HPLC (column: Phenomenex luna C18 250*50mm*15um;mobile phase: [water(0.2%formic acid)- acetonitrile];B%: 22%-52%,10 min) to give 1-[(1S,4S)-5-[4-[5-chloro-2-fluoro-4-[[(3S)- tetrahydrofuran-3-yl]methoxy]anilino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (17.4 mg, 33.1 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 7.85 - 7.78 (m, 1H), 7.26 - 7.11 (m, 1H), 7.06 - 6.98 (m, 1H), 6.85 - 6.41 (m, 1H), 6.34 - 6.24 (m, 1H), 5.84 - 5.69 (m, 1H), 5.25 - 5.10 (m, 1H), 5.06 (d, J = 12.0 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.99 - 3.89 (m, 3H), 3.87 - 3.72 (m, 5H), 3.69 - 3.54 (m, 2H), 2.84 - 2.71 (m, 1H), 2.23 - 2.07 (m, 3H), 1.89 - 1.78 (m, 1H); m/z ES+ [M+H] ⁺ 525.0. Example 358. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -2,5- diazabicyclo[2.2.1]heptane-2-carboxylate A mixture of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (258 mg, 714 μmol) and 3-chloro-2-fluoro-4-(1- methylcyclopropoxy)aniline (220 mg, 714 μmol) in acetonitrile (5 mL) was stirred at 60 °C for 4 hr. On completion, the reaction mixture was filtered and the filtered cake was washed with acetonitrile (20 mL), dried in vacuo to give tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(1- methylcyclopropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2- carboxylate (331 mg, 612 μmol, 86%) as a yellow solid. m/z ES+ [M+H] ⁺ 541.0. Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-(1- methylcyclopropoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(1- methylcyclopropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2- carboxylate (150 mg, 277 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl]-6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (185 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 441.0. Step 3. 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -2,5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl]-6-[(1S, 4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (185 mg, 333 μmol) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (224 mg, 2.67 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (27.2 mg, 300 μmol) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by water (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];B%: 29%-59%,10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-(1- methylcyclopropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one (87.9 mg, 178 μmol, 53%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 - 9.18 (m, 1H), 8.29 (d, J = 3.2 Hz, 1H), 7.89 (dd, J = 4.4, 9.2 Hz, 1H), 7.81 (q, J = 9.2 Hz, 1H), 7.26 (dd, J = 1.6, 9.2 Hz, 2H), 6.85 - 6.36 (m, 1H), 6.21-6.07 (m, 1H), 5.74 - 5.60 (m, 1H), 5.59 - 4.87 (m, 2H), 3.81 - 3.62 (m, 2H), 3.61 - 3.49 (m, 2H), 2.13 - 1.92 (m, 2H), 1.55 (s, 3H), 1.03 - 0.93 (m, 2H), 0.89 - 0.79 (m, 2H); m/z ES+ [M+H] ⁺ 494.9. Example 359. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5-diazabicyclo[2.2.2]octan- 2-yl)prop-2-en-1-one

Step 1. 6-Chloro-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrido[3,2-d] pyrimidin-4- amine A solution of 4,6-dichloropyrido[3,2-d]pyrimidine (1.00 g, 5.00 mmol), 3-chloro-4- (difluoromethoxy)aniline (1.16 g, 6.00 mmol) in acetonitrile (15 mL) was stirred at 25 °C for 16 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 20/1 to 20/3) to give 6-chloro-N-[3-chloro-4-(difluorometh oxy)phenyl]pyrido[3,2- d]pyrimidin-4-amine (500 mg, 1.40 mmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.39 (s, 1H), 8.79 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.10 - 8.02 (m, 2H), 7.50 - 7.44 (m, 1H), 7.35 - 7.08 (m, 1H); m/z ES+ [M+H] ⁺ 357.0. Step 2. tert-Butyl 5-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e To a solution of 6-chloro-N-[3-chloro-4-(difluoromethoxy)phenyl]pyrido[3,2- d]pyrimidin-4-amine (220 mg, 616 μmol) in 1-methylpyrrolidin-2-one (1.5 mL) was added diisopropylethylamine (238 mg, 1.85 mmol). Then tert-butyl 2,5-diazabicyclo[2.2.2]octane-2- carboxylate (196 mg, 924 μmol) was added in the mixture. The mixture was stirred at 100 °C for 4 hr. On completion, mixture was poured into water (6.0 mL) and the suspension was filtered. The filtered cake was washed with water (1.0 mL x 2), dried in vacuo to give tert-butyl 5-[4-[3-chloro- 4-(difluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabi cyclo[2.2.2]octane-2- carboxylate (300 mg, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 - 9.26 (m, 1H), 8.45 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.12 - 8.03 (m, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.42 (s, 1H), 7.38 - 7.05 (m, 2H), 4.44 - 4.13 (m, 1H), 3.49 - 3.49 (m, 2H), 3.77 - 3.35 (m, 3H), 2.24 - 2.16 (m, 2H), 1.94 - 1.87 (m, 2H), 1.43 (d, J = 10.4 Hz, 9H); m/z ES+ [M+H] ⁺ 533.3. Step 3. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyri do[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e The crude product was purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3water MEOH];B%: 45%-45%,3.5;30min) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2 -d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (140 mg, 0.26 mmol, 47%) as a yellow soild and tert- butyl (1R,4R)-5-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyri do[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (130 mg, 0.24 mmol, 43%) as a yellow solid. m/z ES+ [M+H] ⁺ 533.3; m/z ES+ [M+H] ⁺ 533.1. Step 4. 6-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,2 - d] pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (100 mg, 187 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(difluoromethoxy)phenyl]-6-[(1S,4S)-2,5-diazab icyclo[2.2.2]octan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (75.0 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 433.3. Step 5. 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)p yrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-e n-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (75.0 mg, 173 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (43.6 mg, 519 μmol). And then prop-2-enoyl chloride (26.6 mg, 294 μmol) was added in the mixture. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid condition: column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(0.225%formic acid)- acetonitrile];B%: 24%-54%,10 min) to give a crude product. The product was further triturated with methanol (10 mL) for 15 min and then filtered. The filtered cake was collected to give 1- [(1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3, 2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one (34.6 mg, 71.0 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.45 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 2.4, 9.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.42 (s, 1H), 7.39 - 7.04 (m, 2H), 6.74 (m, 1H), 6.26 - 6.09 (m, 1H), 5.75 - 5.69 (m, 1H), 4.71 (m, 1H), 3.93 - 3.81 (m, 2H), 3.75 - 3.75 (m, 1H), 3.80 - 3.67 (m, 1H), 3.63 (s, 1H), 2.03 - 1.91 (m, 4H); m/z ES+ [M+H] ⁺ 487.3. Example 360. Preparation of 1-((1R,4R)-5-(4-((3-chloro-4- (difluoromethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5-diazabicyclo[2.2.2]octan- 2-yl)prop-2-en-1-one Step 1. 6-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1R,4R)-5-[4-[3-chloro-4- (difluoromethoxy)anilino]pyrido[3,2-d] pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2- carboxylate (100 mg, 187 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid ( 0.1 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(difluoromethoxy)phenyl]-6-[(1R,4R)- 2,5-diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-a mine (75.0 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 433.3. Step 2. 1-((1R,4R)-5-(4-((3-chloro-4-(difluoromethoxy)phenyl)amino)p yrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-e n-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-6-[(1R,4R)-2,5- diazabicyclo[2.2.2] octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (75.0 mg, 173 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (14.5 mg, 173 μmol). And then prop-2-enoyl chloride (21.9 mg, 242 μmol) was added in the mixture. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid condition, column: Phenomenex Luna C18 100*30mm*5um;mobile phase: [water(0.225%formic acid)- acetonitrile];B%: 28%-58%, 8 min) to give 1-[(1R,4R)-5-[4-[3-chloro-4- (difluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-di azabicyclo[2.2.2]octan-2-yl]prop- 2-en-1-one (28.5 mg, 58.5 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.45 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.05 (dd, J = 2.4, 9.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.42 (s, 1H), 7.38 - 7.04 (m, 2H), 6.74 (m, 1H), 6.26 - 6.11 (m, 1H), 5.75 - 5.69 (m, 1H), 4.71 (m, 1H), 3.92 - 3.81 (m, 2H), 3.80 - 3.65 (m, 2H), 3.63 (s, 1H), 2.04 - 1.90 (m, 4H); m/z ES+ [M+H] ⁺ 487.3. Example 361. Preparation of 1-(7-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one Step 1. tert-Butyl 7-(4-((3-chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin- 6-yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 266 μmol) in acetonitrile (5 mL) was added 3- chloro-2-fluoro-aniline (42.6 mg, 292 μmol). The mixture was stirred at 25 °C for 2 hr. On completion, the resulting precipitate was filtered, and the filtered cake was concentrated in vacuo to give tert-butyl 7-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] -4,7- diazaspiro[2.5]octane-4-carboxylate (150 mg, crude) as a yellow solid. m/z ES+ [M+1] ⁺ 485.0. Step 2. N-(3-chloro-2-fluorophenyl)-6-(4,7-diazaspiro[2.5]octan-7-yl )pyrido[3,4- d]pyrimidin-4-amine To a solution of tert-butyl 7-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin-6-yl] - 4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 309 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the solution was concentrated in vacuo to give N-(3-chloro-2-fluoro-phenyl)-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,4-d] pyrimidin-4-amine (120 mg, crude) as a yellow oil for next step directly. m/z ES+ [M+1] ⁺ 385.0. Step 3. 1-(7-(4-((3-Chloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimid in-6-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-(4,7-diazaspiro[2.5]octan-7- yl)pyrido[3,4-d]pyrimidin-4-amine (120 mg, 311 μmol) in tetrahydrofuran (3 mL) and water (3 mL) was added sodium bicarbonate (26.2 mg, 311 μmol) until pH = 7~8. Then prop-2-enoyl chloride (28.2 mg, 312 μmol) was added. The mixture was stirred at 0 °C for 5 min. On completion, the mixture was quenched by water (0.5 mL) and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];B%: 28%-58%,10 min) to give 1-[7-[4-(3-chloro-2-fluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octa n-4-yl]prop-2-en-1-one (65.7 mg, 0.15 mmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 - 9.74 (m, 1H), 8.87 (s, 1H), 8.34 (s, 1H), 7.54 (d, J = 6.4 Hz, 2H), 7.44 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.03 - 6.83 (m, 1H), 6.17 (dd, J = 2.0, 16.4 Hz, 1H), 5.82 - 5.65 (m, 1H), 3.86 (s, 2H), 3.68 (d, J = 2.4 Hz, 2H), 3.58 (s, 2H), 1.11 - 1.00 (m, 4H); m/z ES+ [M+1] ⁺ 439.0. Example 362. Preparation of 1-(7-(4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2 -en-1-one Step 1. tert-Butyl 7-(5-bromo-2-methoxy-4-nitrophenyl)-4,7-diazaspiro[2.5]octan e-4- carboxylate To a solution of 1-bromo-5-fluoro-4-methoxy-2-nitro-benzene (600 mg, 2.40 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.35 g, 7.20 mmol). And then tert- butyl 4,7-diazaspir o[2.5]octane-4-carboxylate (509 mg, 2.40 mmol) was added in the mixture. The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was quenched by water 30 mL, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 7-(5-bromo-2-methoxy-4-nitro-phenyl)-4,7-diazaspiro[2.5]octa ne-4- carboxylate (998 mg, 2.26 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H), 3.60 - 3.53 (m, 2H), 3.17 (t, J = 4.4 Hz, 2H), 3.01 (s, 2H), 1.42 (s, 9H), 0.97 - 0.90 (m, 2H), 0.85 - 0.81 (m, 2H); m/z ES+ [M+H] ⁺ 442.1. Step 2. tert-Butyl 7-(4-amino-5-bromo-2-methoxyphenyl)-4,7-diazaspiro[2.5]octan e-4- carboxylate A mixture of tert-butyl 7-(5-bromo-2-methoxy-4-nitro-phenyl)-4,7- diazaspiro[2.5]octane-4- carboxylate (900 mg, 2.03 mmol) and Pt/V/C (90.0 mg, 203 μmol, 3% loading) in ethyl acetate (10.0 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 30 °C for 2 hr under hydrogen atmosphere (15 psi). On completion, the resulting product was dissolved in methanol and filtered to remove the insoluble catalyst. The filtrate was concentrated in vacuo to give tert-butyl 7-(4-amino-5-bromo-2-methoxy-phenyl)-4,7- diazaspiro[2.5]octane-4- carboxylate (830 mg, 1.93 mmol, 94%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 6.77 (s, 1H), 6.46 (s, 1H), 4.92 (s, 2H), 3.69 (s, 3H), 3.50 (s, 2H), 2.80 (d, J = 4.0 Hz, 2H).2.61 (s, 2H), 1.41 (s, 9H), 0.97 - 0.86 (m, 2H), 0.78 (s, 2H); m/z ES+ [M+H] ⁺ 412.0. Step 3. tert-Butyl 7-(4-amino-5-cyano-2-methoxyphenyl)-4,7-diazaspiro[2.5]octan e-4- carboxylate A mixture of tert-butyl 7-(4-amino-5-bromo-2-methoxy-phenyl)-4,7- diazaspiro[2.5]octane-4-carboxylate (700 mg, 1.70 mmol), bis(tri-t-butylphosphine)palladium(0) (86.7 mg, 169 μmol), zinc cyanide (598 mg, 5.09 mmol) in dimethyl acetamide (2.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 130 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by saturated sodium bicarbonate solution (20 mL) at 20 °C, and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, pure ethyl acetate) to give tert-butyl 7-(4-amino-5- cyano-2-methoxy-phenyl)-4,7-diazaspiro[2.5]octane-4-carboxyl ate (600 mg, 1.68 mmol, 78%) as a brown oil. Step 4. tert-Butyl 7-(5-cyano-4-(((dimethylamino)methylene)amino)-2-methoxyphen yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(4-amino-5-cyano-2-methoxy-phenyl)-4,7- diazaspiro[2.5]octane-4-carboxylate (550 mg, 1.53 mmol) in toluene (4.0 mL) was added N,N- dimethylformamide-dimethyl acetamide (548 mg, 4.60 mmol). The mixture was stirred at 110 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl 7-(5- cyano-4-(((dimethylamino)methylene)amino)-2-methoxyphenyl)-4 ,7-diazaspiro[2.5]octane-4- carboxylate (650 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 414.3. Step 5. tert-Butyl 7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(5-cyano-4-(((dimethylamino)methylene)amino)-2- methoxyphenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (600 mg, 1.45 mmol) in acetic acid (3.0 mL) and toluene (3.0 mL) was added 3-chloro-2-fluoro-aniline (232 mg, 1.60 mmol). The mixture was stirred at 110 °C for 16 hr. On completion, the mixture was poured into saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 1:1) to give tert-butyl 7-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 4,7- diazaspiro[2.5]octane-4-carboxylate (350 mg, 0.68 mmol, 44%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.68 (s, 1H), 8.36 (s, 1H), 7.72 (s, 1H), 7.53 - 7.45 (m, 2H), 7.28 (d, J = 0.8 Hz, 1H), 7.17 (s, 1H), 3.95 (s, 3H), 3.64 (s, 2H), 3.11 (s, 2H), 2.93 (s, 2H), 1.43 (s, 9H), 0.99 (s, 2H), 0.89 (s, 2H); m/z ES+ [M+H] ⁺ 514.2. Step 6. N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(4,7-diazaspiro[2.5] octan-7- yl)quinazolin-4-amine To a solution of tert-butyl 7-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]- 4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 194 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro- phenyl)-6-(4,7-diazaspiro[2.5]octan-7-yl)-7-methoxy-quinazol in-4-amine (75.0 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 414.3. Step 7. 1-(7-(4-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin -6-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one To a solution of N-(3-chloro-2-fluoro-phenyl)-6-(4,7-diazaspiro[2.5]octan-7-y l)-7- methoxy-quinazolin-4-amine (75 mg, 181 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (45.6 mg, 543 μmol). And then prop-2-enoyl chloride (19.6 mg, 217 μmol) was added in the mixture. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, ethyl: methanol = 30:1) to give 1-[7-[4-(3- chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]-4,7-diaz aspiro[2.5]octan-4-yl]prop-2-en-1- one (18.8 mg, 40.2 μmol, 20%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.36 (s, 1H), 7.73 (s, 1H), 7.54 - 7.44 (m, 2H), 7.32 - 7.24 (m, 1H), 7.18 (s, 1H), 6.98 - 6.82 (m, 1H), 6.18 (dd, J = 2.0, 16.8 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 3.96 (s, 3H), 3.85 (s, 2H), 3.24 - 3.07 (m, 2H), 3.00 (s, 2H), 1.26 - 0.96 (m, 4H); m/z ES+ [M+H] ⁺ 468.3. Example 363. Preparation of 1-((1S,4S)-5-(4-((4-chloro-5-(cyclopropylmethoxy)pyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one Step 1. 1-((1S,4S)-5-(4-((4-chloro-5-(cyclopropylmethoxy)pyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one To a solution of 4-chloro-5-(cyclopropylmethoxy)pyridin-2-amine (370 mg, 1.86 mmol) in tetrahydrofuran (3.0 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 4.6 mL) and tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane- 2-carboxylate (561 mg, 1.55 mmol). The mixture was stirred at 60 °C for 2 hr. The mixture was then filtered and the filtered cake was concentrated to give tert-butyl (1S,4S)-5-[4-[[4-chloro-5- (cyclopropylmethoxy)-2-pyridyl]amino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, 0.57 mmol, 33%) as a yellow solid. m/z ES+ [M+H] ⁺ 524.1. Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-chloro-5 - (cyclopropylmethoxy)pyridin-2-yl)pyrido[3,2-d]pyrimidin-4-am ine To a solution of tert-butyl (1S,4S)-5-[4-[[4-chloro-5-(cyclopropylmethoxy)-2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (250 mg, 477 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[4-chloro-5-(cyclopropylmethoxy)-2-pyridyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (200 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 423.9. Step 3. 1-((1S,4S)-5-(4-((4-chloro-5-(cyclopropylmethoxy)pyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one To a solution of N-[4-chloro-5-(cyclopropylmethoxy)-2-pyridyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (200 mg, 471 μmol) in tetrahydrofuran (1 mL) was added sodium bicarbonate (118 mg, 1.42 mmol) and prop-2-enoyl chloride (42.7 mg, 471 μmol). The mixture was stirred at 25°C for 0.5 hr. On completion, the mixture was filtered and concentrated to give 1-[(1S,4S)-5-[4-[[4-chloro-5-(cyclopropylmethoxy)- 2-pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicycl o[2.2.1] heptan-2-yl]prop-2-en-1- one (140 mg, 0.29 mmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 - 9.15 (m, 1H), 8.74 (s, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 7.94 (dd, J = 4.0, 9.2 Hz, 1H), 7.54 - 7.08 (m, 1H), 6.87 - 6.36 (m, 1H), 6.14 (m, 1H), 5.73 - 5.58 (m, 1H), 5.33 - 4.77 (m, 2H), 4.02 (d, J = 6.8 Hz, 2H), 3.82 - 3.59 (m, 2H), 3.57 - 3.35 (m, 2H), 2.17 - 1.89 (m, 2H), 1.35 - 1.18 (m, 1H), 0.68 - 0.52 (m, 2H), 0.44 - 0.28 (m, 2H); m/z ES+ [M+H] ⁺ 478.2. Example 364. Preparation of 1-((1S,4S)-5-(4-((4-chloro-5-phenoxypyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one

Step 1. 6-Chloro-N-(4-chloro-5-phenoxypyridin-2-yl)pyrido[3,2-d]pyri midin-4-amine To a solution of 4-chloro-5-phenoxy-pyridin-2-amine (110 mg, 499 μmol) in dimethyl sulfoxide (2 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 1.5 mL) and 4,6- dichloropyrido[3,2-d]pyrimidine (100 mg, 500 μmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-chloro-N- (4-chloro-5-phenoxypyridin-2-yl)pyrido[3,2-d]pyrimidin-4-ami ne (180 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 384.2. Step 2. tert-Butyl (1S,4S)-5-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)pyrido[3 ,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 6-chloro-N-(4-chloro-5-phenoxy-2-pyridyl)pyrido[3,2-d]pyrimi din-4- amine (160 mg, 416 μmol) in 1-methylpyrrolidin-2-one (2 mL) was added diisopropylethylamine (269 mg, 2.08 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (165 mg, 833 μmol). The mixture was stirred at 130 °C for 12 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reversed phase HPLC (water:acetonitrile=20:1 to 1:1) to give tert-butyl (1S,4S)-5-(4-((4-chloro-5-phenoxypyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate (160 mg, 308 μmol, 55%) as a yellow solid; m/z ES+ [M+H] ⁺ 546.2. Step 3. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-chloro-5 -phenoxypyridin-2- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-((4-chloro-5-phenoxypyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate (150 mg, 275 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2.31 g, 20.3 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-chloro-5 -phenoxypyridin-2- yl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 446.2. Step 4. 1-((1S,4S)-5-(4-((4-chloro-5-phenoxypyridin-2-yl)amino)pyrid o[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-chloro-5 - phenoxypyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine (130 mg, 232 μmol) in tetrahydrofuran (2 mL) and water (1 mL) was added potassium carbonate (32.1 mg, 232 μmol) and prop-2-enoyl chloride (21.0 mg, 232 μmol). The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150 * 50mm * 3 um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 45%-75%,10 min) to give 1-((1S,4S)-5-(4-((4-chloro-5-phenoxypyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one (45.3 mg, 89.6 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.63 - 9.45 (m, 1H), 8.94 - 8.80 (m, 1H), 8.62 (s, 1H), 8.33 (s, 1H), 8.00 - 7.85 (m, 1H), 7.40 - 7.25 (m, 3H), 7.19 - 7.10 (m, 1H), 7.01 - 6.90 (m, 2H), 6.89 - 6.35 (m, 1H), 6.21 - 6.07 (m, 1H), 5.59 - 5.40 (m, 1H), 5.41 - 4.91 (m, 2H), 3.82 - 3.70 (m, 2H), 3.65 - 3.50 (m, 2H), 2.13 - 2.00 (m, 2H); m/z ES+ [M+H] ⁺ 500.2. Example 365. Preparation of 1-((1S,4S)-5-(4-((5-(difluoromethoxy)pyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one Step 1. 3-(Difluoromethoxy)-5-nitropyridine To a solution of 5-nitropyridin-3-ol (500 mg, 3.57 mmol) in water (0.7 mL) and N,N- dimethylformamide (4.9 mL) was added potassium carbonate (1.48 g, 10.7 mmol) and (2-chloro- 2,2-difluoro-acetyl)oxysodium (652 mg, 4.28 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 20/1) to give 3-(difluoromethoxy)-5-nitro-pyridine (160 mg, 0.84 mmol, 21%) as a yellow liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (d, J = 2.0 Hz, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.48 (t, J = 2.4 Hz, 1H), 7.70 (s, 1H), 7.78 - 7.26 (m, 1H); m/z ES+ [M+H] ⁺ 191.1. Step 2. 5-(Difluoromethoxy)pyridin-3-amine A mixture of 3-(difluoromethoxy)-5-nitro-pyridine (140 mg, 736 μmol), Pt/V/C (10 mg, 73.6 μmol, 3% loading) in ethyl acetate (3 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 25 °C for 2 hr under hydrogen (15 psi) atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give 5- (difluoromethoxy)pyridin-3-amine (96.0 mg, 539 μmol) as a yellow liquid. m/z ES+ [M+H] ⁺ 161.3. Step 3. tert-Butyl (1S,4S)-5-(4-((5-(difluoromethoxy)pyridin-3-yl)amino)pyrido[ 3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (150 mg, 414 μmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (18.2 mg, 456 μmol, 60% in mineral oil) at 0 °C for 10 min. Then 5- (difluoromethoxy)pyridin-3-amine (73.0 mg, 456 μmol) was added. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 1:2) to give tert-butyl (1S,4S)-5-[4-[[5-(difluoromethoxy)-3-pyridyl]amino]pyrido[3, 2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (30 mg, 61.7 μmol, 13%) as a yellow liquid. m/z ES+ [M+H] ⁺ 486.2. Step 4.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-(diflu oromethoxy)pyridin-3- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[[5-(difluoromethoxy)-3- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (25.0 mg, 51.5 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[5-(difluor omethoxy)-3- pyridyl]pyrido[3,2-d]pyrimidin-4-amine (22.0 mg, crude) as a black solid. m/z ES+ [M+H] ⁺ 386.1. Step 5. 1-((1S,4S)-5-(4-((5-(difluoromethoxy)pyridin-3-yl)amino)pyri do[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[5-(difluor omethoxy)- 3-pyridyl]pyrido[3,2-d]pyrimidin-4-amine (22.0 mg, 57.0 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (11.9 mg, 142 μmol). Then prop-2-enoyl chloride (6.2 mg, 68.5 μmol) was added. The mixture was stirred at 0 °C for 10 mins. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water(10mM NH4HCO3)- acetonitrile];B%: 17%-47%,11min) to give 1-[(1S,4S)-5-[4-[[5-(difluoromethoxy)-3- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptan-2-yl]prop-2-en-1-one (4.94 mg, 11.2 μmol, 19%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77 - 9.39 (m, 1H), 9.33 - 8.97 (m, 1H), 8.49 (s, 2H), 8.22 (d, J = 2.4 Hz, 1H), 8.05 - 7.82 (m, 1H), 7.36 (m, 2H), 6.95 - 6.71 (m, 1H), 6.55 - 6.33 (m, 1H), 6.27 - 6.03 (m, 1H), 5.77 - 5.60 (m, 1H), 5.10 (s, 1H), 4.95 (s, 1H), 3.83 - 3.65 (m, 2H), 3.64 - 3.42 (m, 2H), 3.31 (s, 1H), 3.31 - 3.30 (m, 1H), 2.75 - 2.64 (m, 1H), 2.09 (s, 1H), 2.02 (s, 1H); m/z ES+ [M+H] ⁺ 440.3. Example 366. Preparation of 1-((1S,4S)-5-(4-((5-cyclopropylpyridin-3-yl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one Step 1. 5-Cyclopropylpyridin-3-amine A solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol), cyclopropylboronic acid (1.00 g, 11.6 mmol), tetrakis(triphenylphosphine)palladium(0) (400 mg, 346 μmol) and cesium carbonate (6.00 g, 18.4 mmol) in water (2.0 mL) and dioxane (20.0 mL) was stirred at 100 °C for 12 hr under nitrogen. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/1 to 1/0) to give 5-cyclopropylpyridin-3-amine (400 mg, 2.99 mmol, 46%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.70 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 6.50 (t, J = 2.0 Hz, 1H), 5.15 (s, 2H), 1.84 - 1.72 (m, 1H), 0.95 - 0.86 (m, 2H), 0.62 - 0.55 (m, 2H). Step 2. tert-Butyl (1S,4S)-5-(4-((5-cyclopropylpyridin-3-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 276 μmol), potassium tert-butoxide (1 M in tetrahydrofuran, 829 μL) and 5-cyclopropylpyridin-3-amine (100 mg, 745 μmol) in tetrahydrofuran (2.00 mL) was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purifed by Prep-TLC (petroleum ether : ethyl acetate = 0 : 1) to give tert-butyl (1S,4S)-5-[4-[(5-cyclopropyl-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (100 mg, 0.22 mmol, 76%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.48 - 9.27 (m, 1H), 8.95 (d, J = 8.8 Hz, 1H), 8.42 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.00 (t, J = 2.0 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.38 - 7.04 (m, 1H), 4.55 (d, J = 13.6 Hz, 1H), 3.74 - 3.59 (m, 1H), 3.51 - 3.36 (m, 4H), 2.02 - 1.92 (m, 3H), 1.46 - 1.29 (m, 9H), 1.07 - 1.00 (m, 2H), 0.82 - 0.74 (m, 2H). Step 3. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-cyclopro pylpyridin-3- yl)pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl (1S,4S)-5-[4-[(5-cyclopropyl-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (80.0 mg, 174 μmol) in trifluoroacetic acid (410 mg, 3.60 mmol) and dichloromethane (1.0 mL) was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-(5-cyclopropyl- 3-pyridyl)-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyr ido[3,2-d]pyrimidin-4-amine (65.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 360.2. Step 4.1-((1S,4S)-5-(4-((5-cyclopropylpyridin-3-yl)amino)pyrido[3 ,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of N-(5-cyclopropyl-3-pyridyl)-6-[(1S,4S)-2,5-diazabicyclo[2.2. 1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (65.0 mg, 180 μmol) in tetrahydrofuran (0.50 mL) and water (0.50 mL) was added sodium bicarbonate (45.5 mg, 54 μmol) at 0 °C until pH ~ 8. After that, prop-2-enoyl chloride (24.3 mg, 269 μmol) was added one portion. The mixture was stirred at 20 °C for 0.25 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];B%: 5%-35%,10.5min) and re-purified by Prep-TLC (petroleum ether : ethyl acetate = 0 : 1) to give 1-[(1S,4S)-5-[4-[(5-cyclopropyl-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (5.53 mg, 13.4 μmol, 7%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.52 - 9.32 (m, 1H), 9.07 - 8.95 (m, 1H), 8.48 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.10 - 8.04 (m, 1H), 7.98 (dd, J = 2.8, 9.2 Hz, 1H), 7.46 - 7.14 (m, 1H), 6.95 - 6.42 (m, 1H), 6.21 (ddd, J = 2.4, 7.2, 16.8 Hz, 1H), 5.83 - 5.65 (m, 1H), 11.50 - 5.45 (m, 1H), 5.20 - 4.94 (m, 1H), 3.86 - 3.46 (m, 5H), 2.14 (br s, 1H), 2.08 - 2.05 (m, 2H), 1.12 - 1.07 (m, 2H), 0.86 - 0.82 (m, 2H); m/z ES+ [M+H] ⁺ 414.2. Example 367. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (1.50 g, 3.08 mmol) in N,N-dimethylformamide (20.0 mL) was added 2,2- difluoroethyl trifluoromethanesulfonate (1.32 g, 6.16 mmol) and potassium carbonate (1.70 g, 12.3 mmol). The reaction was stirred at 60 °C for 2 hr. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (1.50 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.29 (br s, 1H), 8.31 (s, 1H), 7.97 - 7.80 (m, 2H), 7.45 - 7.05 (m, 2H), 6.64 - 6.27 (m, 1H), 5.48 - 4.96 (m, 1H), 4.61 - 4.41 (m, 3H), 3.68 - 3.36 (m, 3H), 3.25 (br d, J = 8.8 Hz, 1H), 2.00 - 1.89 (m, 2H), 1.45 - 1.32 (m, 9H). Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(2,2- difluoroethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e A solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (1.30 g, 2.36 mmol) in trifluoroacetic acid (3.08 g, 27.0 mmol) and dichloromethane (12.0 mL) was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated to give N-[3-chloro-4-(2,2- difluoroethoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5-diazabicyclo [2.2.1]heptan-2-yl]pyrido[3,2- d]pyrimidin-4-amine (1.10 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 451.1. Step 3. 1-((1S,4S)-5-(4-((3-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of N-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (1.10 g, 2.44 mmol) in tetrahydrofuran (5.00 mL) and water (5.00 mL) was added sodium bicarbonate (717 mg, 8.54 mmol) at 0 °C until pH ~ 8. After that, prop-2-enoyl chloride (275 mg, 3.04 mmol) was added in one portion. The mixture was stirred at 20 °C for 0.25 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The reaction was purified by Prep-HPLC (column: Welch Xtimate C18 250*50mm*10um;mobile phase: [water(formic acid)-acetonitrile];B%: 15%- 45%,20min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one (505 mg, 1.00 mmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 - 9.18 (m, 1H), 8.31 (d, J = 3.2 Hz, 1H), 7.98 - 7.77 (m, 2H), 7.42 - 7.10 (m, 2H), 6.88 - 6.29 (m, 2H), 6.14 (m, 1H), 5.67 (m, 1H), 5.54 - 5.14 (m, 1H), 5.00 (m, 1H), 4.49 (m, 2H), 3.77 - 3.39 (m, 4H), 2.10 - 1.96 (m, 2H); m/z ES+ [M+H] ⁺ 505.2. Example 368. Preparation of 1-((1S,4S)-5-(4-((5-chloro-4-fluoropyridin-3- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one Step 1. N-(5-chloro-4-fluoropyridin-3-yl)-1,1-diphenylmethanimine To a solution of 3,5-dichloro-4-fluoro-pyridine (2.5 g, 15.1 mmol) and diphenylmethanimine (3.28 g, 18.1 mmol) in dioxane (25 mL) was added tris(dibenzylideneacetone)dipalladium (1.38 g, 1.51 mmol), (5-diphenylphosphanyl-9,9- dimethylxanthen-4-yl)-diphenylphosphane (1.74 g, 3.01 mmol) and cesium carbonate (9.82 g, 30.1 mmol). The mixture was stirred at 90 °C for 12 hr under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 5/1) to give a crude product, which was further triturated with petroleum ether/ethyl acetate (5/1, 10 mL), filtered and concentrated under reduced pressure to give N-(5-chloro-4-fluoro-3-pyridyl)-1,1-diphenyl-methanimine (1.8 g, 4.63 mmol, 31%) as an off-white solid. m/z ES+ [M+H] ⁺ 311.0. Step 2. 5-Chloro-4-fluoropyridin-3-amine To a solution of N-(5-chloro-4-fluoro-3-pyridyl)-1,1-diphenyl-methanimine (500 mg, 1.61 mmol) in methanol (5 mL) was added hydroxyamine hydrochloride (223 mg, 3.22 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give 5- chloro-4-fluoro-pyridin-3-amine (150 mg, 1.02 mmol, 64%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 9.8 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 5.78 (br s, 2H). Step 3. tert-Butyl (1S,4S)-5-(4-((5-chloro-4-fluoropyridin-3-yl)amino)pyrido[3, 2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (400 mg, 1.11 mmol) and potassium tert-butoxide (248 mg, 2.21 mmol) in dimethyl sulfoxide (5 mL) was added 5-chloro-4-fluoro-pyridin-3-amine (162 mg, 1.11 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give tert-butyl (1S,4S)-5-[4-[(5-chloro-4-fluoro-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (68 mg, 144 μmol, 13%) as a brown oil solid. m/z ES+ [M+H] ⁺ 472.2. Step 4. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-4 -fluoropyridin-3- yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[(5-chloro-4-fluoro-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (68 mg, 144 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give N-(5-chloro-4- fluoro-3-pyridyl)-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2 -yl]pyrido[3,2-d]pyrimidin-4-amine (69 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 372.0. Step 5.1-((1S,4S)-5-(4-((5-chloro-4-fluoropyridin-3-yl)amino)pyri do[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of N-(5-chloro-4-fluoro-3-pyridyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (69 mg, crude) in tetrahydrofuran (5 mL) and water (2 mL) was added sodium bicarbonate (59.7 mg, 710 μmol) and prop-2-enoyl chloride (12.9 mg, 142 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(formic acid)- acetonitrile];B%: 17%-47%,10 min) and then re-purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)-acetonitrile];B%: 18%-48%, 7 min) to afford 1-[(1S,4S)-5-[4-[(5-chloro-4-fluoro-3-pyridyl)amino]pyrido[3 ,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (15.5 mg, 36.3 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 - 9.43 (m, 1H), 9.14 - 8.99 (m, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 3.2 Hz, 1H), 7.95 (m, 1H), 7.47 - 7.16 (m, 1H), 6.89 - 6.35 (m, 1H), 6.15 (m, 1H), 5.77 - 5.59 (m, 1H), 5.52 - 4.88 (m, 2H), 3.80 - 3.65 (m, 2H), 3.62 - 3.51 (m, 2H), 2.13 - 2.01 (m, 2H); m/z ES+ [M+H] ⁺ 426.0. Example 369. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(oxetan-3- yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-(oxetan-3- yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido [3,2- d] pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (400 mg, 821 μmol) in N,N- dimethylformamide (8 mL) was added cesium carbonate (535 mg, 1.64 mmol) and oxetan-3-yl 4- methylbenzenesulfonate (281 mg, 1.23 mmol). The mixture was stirred at 100 °C for 12 hr. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/1 to 0/1). to give tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(oxetan-3-yloxy)anilino]py rido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg, 460 μmol, 56%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.30 (s, 1H), 8.02 - 7.87 (m, 1H), 7.84 - 7.72 (m, 1H), 7.60 - 7.01 (m, 1H), 6.84 - 6.68 (m, 1H), 5.46 - 5.40 (m, 1H), 5.02 - 4.96 (m, 2H), 4.65 - 4.60 (m, 2H), 4.58 - 4.52 (m, 1H), 3.70 - 3.58 (m, 1H), 3.47 - 3.40 (m, 2H), 3.30 - 3.22 (m, 2H), 1.43 - 1.35 (m, 11H); m/z ES+ [M+H] ⁺ 543.3. Step 2.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -2-fluoro-4-(oxetan-3- yloxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(oxetan-3- yloxy)anilino]pyrido [3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carb oxylate (200 mg, 368 μmol) in dichloromethane (10 mL) was added zinc bromide (829 mg, 3.68 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2-fluoro-4-(oxetan-3-yloxy)phenyl]-6-[(1S,4S)-2, 5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (150 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 443.3. Step 3. 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(oxetan-3-yloxy)phenyl )amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[3-chloro-2-fluoro-4-(oxetan-3-yloxy)phenyl]-6-[(1S,4S)-2, 5- diazabicyclo [2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (70 mg, 158 μmol) in tetrahydrofuran (1.5 mL), water (0.5 mL) was added prop-2-enoyl chloride (14.3 mg, 158 μmol) and sodium bicarbonate (13.3 mg, 158 μmol). The mixture was stirred at 25 °C for 15 min. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%:18%-48%, 7 min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-(oxetan-3- yloxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptan-2-yl]prop-2-en-1-one (68.4 mg, 138 μmol, 87%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 - 9.15 (m, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.86 - 7.74 (m, 1H), 7.47 - 7.07 (m, 1H), 6.88 - 6.35 (m, 2H), 6.21 - 6.08 (m, 1H), 5.79 - 5.56 (m, 1H), 5.55 - 5.12 (m, 2H), 4.94 (br s, 3H), 4.69 - 4.53 (m, 2H), 3.80 - 3.44 (m, 4H), 2.11 - 1.97 (m, 2H); m/z ES+ [M+H] ⁺ 497.0. Example 370. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((3-methyloxetan-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. 3-(2,3-Dichloro-4-nitrophenoxy)-3-methyloxetane To a solution of 3-methyloxetan-3-ol (629 mg, 7.14 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (285 mg, 7.14 mmol, 60% in mineral oil) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 hr. 2,3-Dichloro-1-fluoro-4-nitro-benzene (1.00 g, 4.76 mmol) was added into the mixture. The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched by saturated ammonium chloride solution (20 mL) at 0 °C, and then extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether : ethyl acetate = 1:1) to give 3-(2,3-dichloro-4-nitro-phenoxy)-3-methyl-oxetane (1 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 9.6 Hz, 1H), 6.86 (d, J = 9.6 Hz, 1H), 4.81 (d, J = 7.2 Hz, 2H), 4.69 (d, J = 7.6 Hz, 2H), 1.74 (s, 3H). Step 2. 3-(2-Chloro-3-fluoro-4-nitrophenoxy)-3-methyloxetane To a solution of 3-(2,3-dichloro-4-nitro-phenoxy)-3-methyl-oxetane (300 mg, 1.08 mmol) in dimethyl sulfoxide (6 mL) was added cesium fluoride (327 mg, 2.16 mmol). The mixture was stirred at 140 °C for 16 hr. On completion, the reaction mixture was quenched by water (50 mL) at 0 °C, and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-(2-chloro-3-fluoro-4-nitro-phenoxy)-3-methyl-oxetane (260 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (t, J = 9.2 Hz, 1H), 6.73 (dd, J = 1.6, 9.6 Hz, 1H), 4.82 - 4.79 (m, 2H), 4.70 (d, J = 7.6 Hz, 2H), 1.76 (s, 3H). Step 3. 3-Chloro-2-fluoro-4-((3-methyloxetan-3-yl)oxy)aniline To a solution of 3-(2-chloro-3-fluoro-4-nitro-phenoxy)-3-methyl-oxetane (260 mg, 993 μmol) in tetrahydrofuran (10 mL) was added Pt/V/C (342 mg, 39.3 μmol, 3% loading). The mixture was stirred at 25 °C for 2 hr under hydrogen (15 psi). On completion, the mixture was filtered and the organic phase was concentrated in vacuo to give 3-chloro-2-fluoro-4-(3- methyloxetan-3-yl)oxy-aniline (350 mg, crude) as a yellow solid for next step directly. m/z ES+ [M+H]+ 232.1. Step 4. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-((3-methyloxetan-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (468 mg, 1.30 mmol) in acetonitrile (20 mL) was added 3-chloro-2-fluoro-4-(3-methyloxetan-3-yl)oxy-aniline (300 mg, 1.30 mmol). The mixture was stirred at 25 °C for 6 hr. On completion, the reaction mixture was quenched by addition of saturated sodium bicarbonate solution (50 mL) to pH = 7~8 at 0 °C, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (silicon dioxide, pure ethyl acetate) to give tert-butyl (1S,4S)-5-[4- [3-chloro-2-fluoro-4-(3-methyloxetan-3-yl)oxy-anilino]pyrido [3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 557.1. Step 5. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-((3- methyloxetan-3-yl)oxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(3-methyloxetan-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (250 mg, 448 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.85 g, 33.7 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the solution was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(3-methyloxetan-3-yl)oxy-phenyl]-6-[( 1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (200 mg, crude) as a yellow oil for next step directly. m/z ES+ [M+H] ⁺ 456.9. Step 6. 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((3-methyloxetan-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[3-chloro-2-fluoro-4-(3-methyloxetan-3-yl)oxy-phenyl]-6-[( 1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- amine (200 mg, 437 μmol) in tetrahydrofuran (5 mL) and water (5 mL) was added sodium bicarbonate (36.7 mg, 437 μmol) to pH = 7~8. Then prop-2-enoyl chloride (39.6 mg, 437 μmol) was added. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)- acetonitrile];B%: 38%-68%,10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-(3- methyloxetan-3-yl)oxy-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2 ,5-diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one (44.2 mg, 86.5 μmol, 18%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 - 9.19 (m, 1H), 8.32 (d, J = 3.2 Hz, 1H), 7.92 (dd, J = 4.0, 9.2 Hz, 1H), 7.88 - 7.75 (m, 1H), 7.51 - 7.06 (m, 1H), 6.82 (dd, J = 10.0, 16.8 Hz, 1H), 6.68 - 6.64 (m, 1H), 6.43 (dd, J = 10.0, 16.4 Hz, 1H), 6.18-6.12 (m, 1H), 5.74 - 5.62 (m, 1H), 5.50 - 5.21 (m, 1H), 5.10 - 4.92 (m, 1H), 4.82 (d, J = 7.2 Hz, 2H), 4.65 (d, J = 7.2 Hz, 2H), 3.80 - 3.46 (m, 4H), 2.13 - 1.97 (m, 2H), 1.73 (s, 3H). m/z ES+ [M+H] ⁺ 510.9. Example 371. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-7-fluoroquinazolin-6-yl)-2,5-diazabicycl o[2.2.1]heptan-2-yl)prop-2- en-1-one

Step 1. tert-Butyl (1S,4S)-5-(5-bromo-2-fluoro-4-nitrophenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate A solution of 1-bromo-4,5-difluoro-2-nitro-benzene (2 g, 8.40 mmol), tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.67 g, 8.40 mmol), potassium carbonate (2.32 g, 16.81 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80 °C for 12 hr. On completion, the reaction mixture was quenched by water 20 mL at 25 °C, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (1S,4S)-tert-butyl 5-(5-bromo-2- fluoro-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbo xylate (3 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 416.0. Step 2. tert-Butyl (1S,4S)-5-(4-amino-5-bromo-2-fluorophenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of (1S,4S)-tert-butyl 5-(5-bromo-2-fluoro-4-nitrophenyl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate (3 g, 7.21 mmol) in ethyl acetate (40 mL) was added Pt/V/C (940 mg, 3.60 mmol, 3% loading). The mixture was stirred at 25 °C for 12 hr under hydrogen (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give (1S,4S)- tert-butyl 5-(4-amino-5-bromo-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]he ptane-2-carboxylate (2.5 g, crude) as a gray solid. m/z ES+[M+H] ⁺ 386.1. Step 3. tert-Butyl (1S,4S)-5-(4-amino-5-cyano-2-fluorophenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-amino-5-bromo-2-fluoro-phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1 g, 2.59 mmol), zinc cyanide (456 mg, 3.88 mmol), tris(dibenzylideneacetone)dipalladium (237 mg, 258 μmol), 2-(2-ditert-butylphosphanylphenyl)- N,N-dimethylaniline (100 mg, 258 μmol) in dimethyl acetamide (10 mL) was stirred at 110 °C for 12 hr under nitrogen. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried by sodium sulfite, filtered and concentrated in vacuo to give tert- butyl (1S,4S)-5-(4-amino-5-cyano-2-fluorophenyl)-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (0.8 g, crude) as a brown solid. m/z ES+[M+H] ⁺ 333.0. Step 4. tert-Butyl (1S,4S)-5-(5-cyano-4-(((E)-(dimethylamino)methylene)amino)-2 - fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-amino-5-cyano-2-fluoro-phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.8 g, 2.41 mmol), N,N-dimethylformamide-dimethyl acetamide (860 mg, 7.22 mmol) in toluene (10 mL) was stirred at 115 °C for 4 hr. On completion, the mixture was concentrated in vacuo to give tert-butyl (1S,4S)-5-(5-cyano-4-(((E)- (dimethylamino)methylene)amino)-2-fluorophenyl)-2,5-diazabic yclo[2.2.1] heptane-2- carboxylate (1 g, crude) as a brown solid. Step 5. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)- 7-fluoroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-ca rboxylate A solution of tert-butyl (1S,4S)-5-[5-cyano-4-[(E)-dimethylaminomethyleneamino]-2- fluoro-phenyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.2 g, 516 μmol), 3-chloro-4- (difluoromethoxy)-2-fluoroaniline (109 mg, 516 μmol), acetic acid (2.10 g, 34.9 mmol) in toluene (3 mL) was stirred at 90 °C for 16 hr. On completion, the mixture was filtered and concentrated in vacuo to give tert-butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)-7- fluoroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carb oxylate (0.15 g, crude) as a yellow oil. m/z ES+[M+H] ⁺ 554.1. Step 6.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -4-(difluoromethoxy)- 2-fluorophenyl)-7-fluoroquinazolin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] - 7-fluoro-quinazolin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-c arboxylate (0.1 g, 180 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give 6-((1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4-(difluorom ethoxy)-2-fluorophenyl)-7- fluoroquinazolin-4-amine (0.1 g, crude) as a yellow oil. m/z ES+[M+H] ⁺ 454.2. Step 7. 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluoropheny l)amino)-7- fluoroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pr op-2-en-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-quinazolin-4-amine (0.1 g, 176 μmol), sodium bicarbonate (44.3 mg, 528 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2- enoyl chloride (15.9 mg, 176 μmol). The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH ₄ HCO ₃ )-acetonitrile];B%: 38%-68%,9 min.) to give 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluoropheny l)amino)-7- fluoroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pr op-2-en-1-one (7.0 mg, 13.8 μmol, 8%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 2.05 - 2.24 (m, 2 H) 3.46 (m, 1 H) 3.61 - 3.88 (m, 2 H) 3.91 - 4.04 (m, 1 H) 4.79 (s, 1 H) 5.01 (d, J=14.4 Hz, 1 H) 5.76 (m, 1 H) 6.23 - 6.35 (m, 1 H) 6.43 - 6.79 (m, 1 H) 6.80 - 7.19 (m, 1 H) 7.26 (dd, J=8.80, 0.80 Hz, 1 H) 7.43 - 7.60 (m, 3 H) 8.42 (d, J=3.60 Hz, 1 H); m/z ES+[M+H] ⁺ 508.0. Example 372. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate To a solution of 6-bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7-f luoro- pyrido[3,2-d]pyrimidin-4-amine (130 mg, 297 μmol) in 1-methylpyrrolidin-2-one (2 mL) was added diisopropylethylamine (230 mg, 1.78 mmo) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (88.4 mg, 446 μmol). The mixture was stirred at 130 °C for 12 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (acetonitrile:water=20:1 to 1:1) to give tert- butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)-7-fluoropyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (50 mg, 90.1 μmol, 30%) as a yellow solid. m/z ES+ [M+H] ⁺ 555.2. Step 2.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -4-(difluoromethoxy)- 2-fluorophenyl)-7-fluoropyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate (50 mg, 90.1 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)-7-fluoropyrido[3,2-d]pyrim idin-4-amine (50 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 455.2. Step 3. 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluoropheny l)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]he ptan-2-yl)prop-2-en-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine (50 mg, 87.9 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (12.2 mg, 87.9 μmol) and prop-2-enoyl chloride (7.96 mg, 87.9 μmol). The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 * 50 mm * 3 um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 26%-56%,10 min) to give 1-((1S,4S)-5-(4-((3- chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-7-fluoropyr ido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (22.9 mg, 44.6 μmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.38 - 8.20 (m, 1H), 8.02 - 7.93 (m, 1H), 7.84 - 7.65 (m, 1H), 7.58 - 7.15 (m, 2H), 6.88 - 6.35 (m, 1H), 6.15 - 6.00 (m, 1H), 5.67 - 5.55 (m, 1H), 5.45 - 5.27 (m, 1H), 5.06 - 4.88 (m, 1H), 3.95 (s, 1H), 3.80 - 3.71 (m, 2H), 3.63 - 3.54 (m, 1H), 2.09 - 1.98 (m, 2H); m/z ES+ [M+H] ⁺ 509.2. Example 373. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (230 mg, 0.64 mmol) in acetonitrile (5 mL) was added 3-chloro-4-(difluoromethoxy)-2-fluoroaniline (134 mg, 0.64 mmol) and the mixture was stirred at 80 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 42%-72%, 7 min) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)pyrido[3,4- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (73 mg, 0.14 mmol, 20%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.01 (s, 1H), 8.60 - 8.50 (m, 1H), 8.48 - 8.34 (m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.80 - 6.29 (m, 1H), 5.17 - 5.02 (m, 1H), 4.63 (s, 1H), 3.76 - 3.33 (m, 4H), 2.02 (d, J = 10.0 Hz, 2H), 1.51 - 1.37 (m, 9H); m/z ES+ [M+H] ⁺ = 536.9. Step 2.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -4-(difluoromethoxy)- 2-fluorophenyl)pyrido[3,4-d]pyrimidin-4-amine A mixture of tert-butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (73 mg, 0.136 mmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (1 mL) was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(difluoromethoxy)-2- fluorophenyl)pyrido[3,4-d]pyrimidin-4-amine (65 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ = 437.0. Step 3. 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)pyrido[3,4-d]pyrimidin-4-am ine (65 mg, 0.15 mmol) and sodium bicarbonate (49.6 mg, 0.59 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (10.7 mg, 0.12 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 mins. On completion, the mixture was concentrated in vacuo to give a residue, and the residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um;mobile phase: [water( NH ₄ HCO ₃ )-acetonitrile];B%: 34%-64%,9 min) to give 1-((1S,4S)-5-(4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (24.3 mg, 47.4 μmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.91 - 8.78 (m, 1H), 8.35 - 8.23 (m, 1H), 7.71 - 7.56 (m, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.16 - 6.41 (m, 3H), 6.35 - 6.23 (m, 1H), 5.83 - 5.66 (m, 1H), 5.10 - 5.01 (m, 2H), 3.81 - 3.48 (m, 4H), 2.20 - 2.05 (m, 2H); m/z ES+ [M+H] ⁺ 513.1. Example 374. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2- en-1-one Step 1. 6-Chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri do[3,2- d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.3 g, 1.50 mmol) in acetonitrile (3 mL) was added 3-chloro-4-(difluoromethoxy)-2-fluoroaniline (349 mg, 1.65 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri do[3,2- d]pyrimidin-4-amine (0.2 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 375.2. Step 2. tert-Butyl 5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate To a solution of 6-chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri do[3,2- d]pyrimidin-4-amine (200 mg, 533 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (413 mg, 3.20 mmol) and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2- carboxylate (170 mg, 800 μmol). The mixture was stirred at 130 °C for 12 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Unisil 3-100 C18 Ultra 150 * 50 mm * 3 um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 60%-90%,10 min) to give tert-butyl 5-(4-((3-chloro- 4-(difluoromethoxy)-2-fluorophenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (0.25 g, 449 μmol, 84%) as a yellow solid. m/z ES+ [M+H] ⁺ 551.2. Step 3. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate and tert-butyl (1R,4R)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e tert-Butyl 5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)pyr ido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (0.25 g, 454 μmol) was separated by SFC (column: Daicel ChiralPak IG (250 * 30 mm, 10 um);mobile phase: [0.1%NH ₃ water ETOH];B%: 45%-45%,3.6;70 min) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (110 mg, 200 μmol, 44%) as a white solid and tert-butyl (1R,4R)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (110 mg, 200 μmol, 44%) as a white solid. Step 4. 6-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)- 2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate (0.1 g, 182 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (770 ug, 6.75 μmol). The mixture was stirred at 25 °C for 1 hr. On completion the mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-am ine (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 451.2. Step 5. 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2-en- 1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-am ine (100 mg, 177 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (24.5 mg, 177 μmol) and prop-2-enoyl chloride (16.0 mg, 177 μmol). The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 * 50 mm * 3 um;mobile phase: [water(formic acid)-acetonitrile];B%: 30%-60%,10 min) in vacuo to give 1-((1S,4S)-5-(4-((3- chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one (17.2 mg, 34.1 μmol, 19%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.58 - 9.26 (m, 1H), 8.49 - 8.31 (m, 1H), 7.96 (d, J = 9.2 Hz, 2H), 7.59 - 7.12 (m, 3H), 6.62 - 6.50 (m, 1H), 6.19 (s, 1H), 5.72 - 5.60 (m, 1H), 4.82 - 4.70 (m, 1H), 3.95 - 3.59 (m, 4H), 3.31 - 3.18 (m, 1H), 2.06 - 1.89 (m, 4H); m/z ES+ [M+H] ⁺ 505.2. Example 375. Preparation of 1-((1R,4R)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2- en-1-one Step 1. 6-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)- 2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1R,4R)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (100 mg, 182 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-am ine (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 451.2. Step 2. 1-((1R,4R)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2-en- 1-one To a solution of 6-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-am ine (100 mg, 177 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (24.5 mg, 177 μmol) and prop-2-enoyl chloride (16.0 mg, 177 μmol, 14.4 μL). The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 * 50 mm * 3 um;mobile phase: [water(formic acid)-acetonitrile];B%: 30%-60%,10 min) to give 1-((1R,4R)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluoropheny l)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-e n-1-one (21.4 mg, 42.0 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 - 9.31 (m, 1H), 8.51 - 8.33 (m, 1H), 8.14 - 7.88 (m, 2H), 7.57 - 7.14 (m, 3H), 6.96 - 6.53 (m, 1H), 6.19 - 6.00 (m, 1H), 5.72 - 5.60 (m, 1H), 4.88 - 4.53 (m, 1H), 3.94 - 3.60 (m, 4H), 3.31 - 3.20 (m, 1H), 2.03 - 1.86 (m, 4H); m/z ES+ [M+H] ⁺ 505.2. Example 376. Preparation of 1-((1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. 6-Chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri mido[5,4- d]pyrimidin-4-amine The mixture of 2,8-dichloropyrimido[5,4-d]pyrimidine (200 mg, 1 mmol) and 3-chloro- 4-(cyclopropylmethoxy)-2-fluoroaniline (214 mg, 1 mmol) in acetonitrile (2 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)-acetonitrile];B%: 48%-78%, 7 min) to give 6-chloro-N-(3-chloro-4- (difluoromethoxy)-2-fluorophenyl)pyrimido[5,4-d]pyrimidin-4- amine (100 mg, 0.26 mmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.39 (s, 1H), 9.04 - 8.84 (m, 2H), 8.65 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 6.79 - 6.39 (m, 1H); m/z ES+ [M+H] ⁺ 379.9. Step 2. tert-Butyl (1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri mido[5,4- d]pyrimidin-4-amine (100 mg, 0.27 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (52.7 mg, 0.27 mmol) in 1-methylpyrrolidin-2-one (2 mL) was added diisopropylethylamine (101 mg, 0.81 mmol) and the mixture was stirred at 100 °C for 2 hr. On completion, the mixture was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH ₄ HCO ₃ )-acetonitrile];B%: 62%-92%,10 min) to give tert-butyl (1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)pyrimido[5,4-d]pyrimidin-2- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (90 mg, 0.17 mmol, 62%) as a yellow solid. m/z ES+ [M+H] ⁺ 542.2. Step 3.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -4-(difluoromethoxy)- 2-fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine A mixture of tert-butyl (1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (90 mg, 0.167 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.33 mL) was stirred at 25 °C for 30 min. On completion, the mixture was concentrated in vacuo to give 6- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4-( difluoromethoxy)-2- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (100 mg, crude) as a yellow oil. m/z ES+ [ ⁺ 442.0. Step 4. 1-((1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)pyrimido[5,4-d]pyrimidin-4- amine (90 mg, 0.21 mmol, trifluoroacetic acid) and sodium bicarbonate (68.0 mg, 1.03 mmol) in anhydrous tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (13.2 mg, 0.9 eq) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-acetonitrile];B%: 47%-77%,10 min) to give 1- ((1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl) amino)pyrimido[5,4-d]pyrimidin- 2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (41.0 mg, 82.7 μmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 - 9.29 (m, 1H), 9.13 (s, 1H), 8.37 (s, 1H), 8.04 - 7.78 (m, 1H), 7.60 - 7.10 (m, 2H), 6.89 - 6.05 (m, 2H), 5.81 - 5.60 (m, 1H), 5.49 - 4.80 (m, 2H), 3.85 - 3.64 (m, 2H), 3.64 - 3.38 (m, 2H), 2.18 - 1.95 (m, 2H); m/z ES+ [M+H] ⁺ 496.0. Example 377. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. 6-Bromo-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)-7 - fluoropyrido[3,2-d]pyrimidin-4-amine To a solution of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (300 mg, 1.14 mmol) in acetonitrile (5 mL) was added 3-chloro-4-(cyclopropylmethoxy)-2-fluoro-aniline (246 mg, 1.14 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered and the filtered cake was concentrated under reduced pressure to give 6-bromo-N-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]-7-fluoro-pyrido[3,2-d] pyrimidin-4-amine (480 mg, 1.09 mmol, 95%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.53 - 8.45 (m, 1H), 8.30 - 8.13 (m, 1H), 7.47 - 7.32 (m, 1H), 7.02 - 6.93 (m, 1H), 3.93 (d, J = 6.8 Hz, 2H), 1.28 - 1.19 (m, 1H), 0.60 - 0.51 (m, 2H), 0.36 - 0.28 (m, 2H); m/z ES+ [M+H] ⁺ 443.1. Step 2. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate To a solution of 6-bromo-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]- 7- fluoro-pyrido[3,2-d]pyrimidin-4-amine (300 mg, 679 μmol) in 1-methylpyrrolidin-2-one (5 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (135 mg, 680 μmol) and diisopropylethylamine (439 mg, 3.40 mmol). The mixture was stirred at 130 °C for 4 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL x 3).The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=3/1 to 2/3) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anili no]-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (150 mg, 268 μmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.30 (s, 1H), 7.80 (d, J = 13.6 Hz, 1H), 7.70 - 7.58 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.27 (d, J = 16.4 Hz, 1H), 4.51 (d, J = 18.8 Hz, 1H), 3.99 (d, J = 7.2 Hz, 2H), 3.89 - 3.80 (m, 1H), 3.75 - 3.59 (m, 1H), 3.42 (s, 2H), 1.98 - 1.89 (m, 2H), 1.43 - 1.36 (m, 9H), 1.32 - 1.26 (m, 1H), 0.65 - 0.58 (m, 2H), 0.42 - 0.34 (m, 2H); m/z ES+ [M+H] ⁺ 559.4. Step 3. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)-7-fluoropyrido[3,2-d]py rimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (130 mg, 232 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1.50 g, 13.2 mmol). The mixture was stirred at 25 °C for 10 min. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine (100 mg, 174 μmol, 75%) as a yellow oil and used into the next step without further purification. m/z ES+ [M+H] ⁺ 459.3. Step 4. 1-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2-fluoroph enyl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]he ptan-2-yl)prop-2-en-1-one To a solution a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido [3,2-d]pyrimidin-4-amine (100 mg, 218 μmol) in water (1 mL), tetrahydrofuran (3 mL) was added sodium bicarbonate (18.3 mg, 218 μmol) and prop-2-enoyl chloride (19.7 mg, 218 μmol). The mixture was stirred at 0 °C for 10 min. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 38%-68%, 7 min) to give 1-[(1S,4S)-5-[4-[3-chloro- 4-(cyclopropylmethoxy)-2-fluoro-anilino]-7-fluoro-pyrido[3,2 -d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (50 mg, 97.5 μmol, 45%) as a yellow solid. NMR (400 MHz, DMSO-d6) δ 7.84 - 7.75 (m, 1H), 7.72 - 7.62 (m, 1H), 7.12 - 7.00 (m, 1H), 6.87 - 6.34 (m, 1H), 6.20 - 6.08 (m, 1H), 5.75 - 5.60 (m, 1H), 5.46 - 5.27 (m, 1H), 5.05 - 4.85 (m, 1H), 4.00 (d, J = 7.2 Hz, 2H), 3.94 - 3.83 (m, 1H), 3.78 - 3.68 (m, 2H), 3.62 - 3.49 (m, 1H), 2.08 - 1.92 (m, 2H), 1.34 - 1.25 (m, 1H), 0.66 - 0.57 (m, 2H), 0.43 - 0.35 (m, 2H); ES+ [M+H] ⁺ 513.0. Example 378. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate A mixture of tert-butyl (1S,4S)-5-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 0.55 mmol), 3-chloro-4- (cyclopropylmethoxy)-2-fluoroaniline (131 mg, 0.55 mmol) in acetonitrile (4 mL) was stirred at 80 °C for 1 hr under nitrogen atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (73 mg, 0.13 mmol, 20%) as a white solid. m/z ES+ [M+H] ⁺ 541.3. Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)pyrido[3,4-d]pyrimidin-4 -amine A mixture of tert-butyl (1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (130 mg, 0.24 mmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (1 mL) was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(cyclopropylmethoxy)-2- fluorophenyl)pyrido[3,4-d]pyrimidin-4-amine (120 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 440.9. Step 3. 1-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)pyrido[3,4-d]pyrimidin-4 -amine (100 mg, 0.23 mmol) and sodium bicarbonate (75.5 mg, 1.15 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (14.7 mg, 0.23 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue, the residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um;mobile phase: [water( NH ₄ HCO ₃ )- acetonitrile];B%: 37%-67%, 8 min) to give 11-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)- 2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (46.6 mg, 94.1 μmol, 52%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.83 - 9.59 (m, 1H), 8.82 (s, 1H), 8.25 (s, 1H), 7.50 - 7.35 (m, 1H), 7.19 (d, J = 4.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.85 - 6.35 (m, 1H), 6.18 - 6.09 (m, 1H), 5.73 - 5.59 (m, 1H), 5.04 (d, J = 15.2 Hz, 1H), 4.92 (s, 1H), 4.00 (d, J = 7.2 Hz, 2H), 3.82 - 3.37 (m, 4H), 2.20 - 1.95 (m, 2H), 1.36 - 1.19 (m, 1H), 0.72 - 0.55 (m, 2H), 0.45 - 0.30 (m, 2H); m/z ES+ [M+H] ⁺ 495.0. Example 379. Preparation of 1-((1S,4S)-5-(8-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. 6-Chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)p yrimido[5,4- d]pyrimidin-4-amine The mixture of 2,8-dichloropyrimido[5,4-d]pyrimidine (200 mg, 1.07 mmol) and 3- chloro-4-(cyclopropylmethoxy)-2-fluoroaniline (214 mg, 1.07 mmol) in acetonitrile (2 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(formic acid)-acetonitrile];B%: 48%-78%, 7 min) to give 6-chloro-N-(3-chloro-4- (cyclopropylmethoxy)-2-fluorophenyl)pyrimido[5,4-d]pyrimidin -4-amine (100 mg, 0.26 mmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.45 (s, 1H), 8.94 (s, 1H), 8.85 (s, 1H), 8.32 (t, J = 8.8 Hz, 1H), 6.86 - 6.79 (m, 1H), 3.96 (d, J = 6.8 Hz, 2H), 1.41 - 1.28 (m, 1H), 0.76 - 0.66 (m, 2H), 0.45 - 0.40 (m, 2H); m/z ES+ [M+H] ⁺ 379.9. Step 2. tert-Butyl (1S,4S)-5-(8-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of 6-chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (100 mg, 0.139 mmol) and tert-butyl (1S,4S)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (52.7 mg, 0.139 mmol) in 1-methylpyrrolidin-2-one (2 mL) was added diisopropylethylamine (101 mg, 0.417 mmol) and the mixture was stirred at 100 °C for 2 hr. On completion, the mixture was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um;mobile phase: [water( NH ₄ HCO ₃ )-acetonitrile];B%: 62%-92%,10 min) to give tert-butyl (1S,4S)-5-(8-((3-chloro-4-(cyclopropylmethoxy)-2-fluoropheny l)amino)pyrimido[5,4- d]pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (90 mg, 0.17 mmol, 62%) as a yellow solid. m/z ES+ [M+H] ⁺ 542.2. Step 3. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)pyrimido[5,4-d]pyrimidin -4-amine The mixture of tert-butyl (1S,4S)-5-(8-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (90 mg, 0.166 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.33 mL) was stirred at 25 °C for 30 min. On completion, the mixture was concentrated in vacuo to give 6- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4-( cyclopropylmethoxy)-2- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (100 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 442.0. Step 4. 1-((1S,4S)-5-(8-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)pyrimido[5,4-d]pyrimidin -4-amine (90 mg, 0.204 mmol) and sodium bicarbonate (68.0 mg, 1.02 mmol) in anhydrous tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (13.2 mg,0.183 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-acetonitrile];B%: 47%-77%,10 min) to give 1-((1S,4S)-5-(8-((3-chloro- 4-(cyclopropylmethoxy)-2-fluorophenyl)amino)pyrimido[5,4-d]p yrimidin-2-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (41.0 mg, 82.7 μmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 - 9.38 (m, 1H), 9.10 (s, 1H), 8.42 - 8.19 (m, 1H), 7.75 - 7.50 (m, 1H), 7.06 (J = 7.6 Hz, 1H), 6.88 - 6.31 (m, 1H), 6.20 – 6.10 (m, 1H), 5.73 - 5.62 (m, 1H), 5.49 - 4.81 (m, 2H), 3.99 (d, J = 6.8 Hz, 2H), 3.80 - 3.40 (m, 4H), 2.19 - 1.89 (m, 2H), 1.37 - 1.16 (m, 1H), 0.67 - 0.56 (m, 2H), 0.43 - 0.33 (m, 2H); m/z ES+ [M+H] ⁺ 496.0. Example 380. Preparation of 1-(8-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-3,8-diazabic yclo[3.2.1]octan-3-yl)prop-2- en-1-one Step 1. 6-Chloro-N-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)p yrido[3,2- d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 1.00 mmol) in acetonitrile (2.0 mL) was added 3-chloro-4-(cyclopropylmethoxy)-2-fluoro-aniline (323 mg, 1.50 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture filtered and the filtered cake was washed with sat. ammonium chloride (15.0 mL), dried in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 5:1 to 3:1) to give 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl] pyrido[3,2- d]pyrimidin-4-amine (160 mg, 422 μmol, 42%) as a yellow solid. m/z ES+ [M+H] ⁺ 379.0. Step 2. tert-Butyl 8-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-3,8-diazabic yclo[3.2.1]octane-3-carboxylate To a solution of 6-chloro-N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (58.0 mg, 153 μmol) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-3-carboxylate (97.4 mg, 459 μmol) in 1-methylpyrrolidin-2-one (1.5 mL) was added diisopropylethylamine (98.8 mg, 765 μmol). The mixture was stirred at 130 °C for 12 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 8-[4-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin -6-yl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (148 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 555.1. Step 3. 6-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-N-(3-chloro-4-(cyclopr opylmethoxy)-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 8-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-3,8-diazabicyclo[3.2.1] octane-3-carboxylate (144 mg, 259 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (4.05 mmol, 0.3 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-(3,8-d iazabicyclo [3.2.1]octan-8-yl)pyrido[3,2-d]pyrimidin-4- amine (72 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 455.0. Step 4. 1-(8-(4-((3-Chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)ami no)pyrido[3,2- d]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)prop-2-e n-1-one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-(3,8- diazabicyclo [3.2.1]octan-8-yl)pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, 132 μmol) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (88.6 mg, 1.06 mmol) in water (0.5 mL), and then a solution of prop-2-enoyl chloride (10.7 mg, 119 μmol) in tetrahydrofuran (1.5 mL) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 34%-64%,10 min) to give 1-[8-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]py rido[3,2-d]pyrimidin- 6-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]prop-2-en-1-one (29.1 mg, 57 μmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.38 - 8.27 (m, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.76 - 7.66 (m, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 6.78 (dd, J = 11.6, 16.0 Hz, 1H), 6.11 (d, J = 16.8 Hz, 1H), 5.68 (d, J = 10.0 Hz, 1H), 4.98 (s, 2H), 4.24 (d, J = 12.8 Hz, 1H), 3.99 (d, J = 6.4 Hz, 2H), 3.86 (d, J = 12.8 Hz, 1H), 3.43 (d, J = 12.4 Hz, 1H), 3.00 (d, J = 12.8 Hz, 1H), 2.07 - 1.87 (m, 2H), 1.82 - 1.62 (m, 2H), 1.36 - 1.18 (m, 1H), 0.61 (d, J = 7.2 Hz, 2H), 0.39 (s, 2H); m/z ES+ [M+H] ⁺ 509.0. Example 381. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)-7-fluoroquinazolin-6-yl)-2,5-diazabicycl o[2.2.1]heptan-2-yl)prop-2- en-1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)-7-fluoroquinazolin-6-yl)-2,5-diazabicycl o[2.2.1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-[5-cyano-4-[(E)-dimethylaminomethyleneamino]-2- fluoro-phenyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.30 g, 774 μmol), 3-chloro-4- (cyclopropylmethoxy)-2-fluoro-aniline (166 mg, 774 μmol) and acetic acid (3.15 g, 52.4 mmol) in toluene (3 mL) was stirred at 90 °C for 13 hr. On completion, the mixture was concentrated in vacuo to give tert-butyl (1S,4S)-5-(4-((3-chloro-4-(cyclopropylmethoxy)-2-fluoropheny l)amino)- 7-fluoroquinazolin-6-yl)-2,5diazabicyclo[2.2.1]heptane-2-car boxylate (0.15 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 558.2. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)-7-fluoroquinazolin-4-am ine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]-7-fluoro-quinazolin-6-yl]-2,5-diazabicyclo[2.2.1]he ptane-2-carboxylate (0.1 g, 179 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6- ((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4-( cyclopropylmethoxy)-2- fluorophenyl)-7-fluoroquinazolin-4-amine (0.1 g, crude, TFA salt) as a yellow solid. m/z ES+[M+H] ⁺ 458.0. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-4-(cyclopropylmethoxy)-2-fluoroph enyl)amino)-7- fluoroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pr op-2-en-1-one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-quinazolin-4-amine (0.1 g, 174 μmol, TFA) and sodium bicarbonate (44.0 mg, 524 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2- enoyl chloride (15.8 mg, 174 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm 5um; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; B%: 40% - 70%, 8 min) to give 1-((1S,4S)-5-(4-((3-chloro-4- (cyclopropylmethoxy)-2-fluorophenyl)amino)-7-fluoroquinazoli n-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (0.017 g, 33 μmol, 18%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (d, J = 2.0 Hz, 1 H), 7.49 - 7.33 (m, 3 H), 6.94 (d, J = 9.2 Hz, 1 H), 6.80 - 6.41 (m, 1 H), 6.33 - 6.23 (m, 1 H), 5.79 - 5.71 (m, 1 H), 4.98 (d, J = 16.4 Hz, 1 H), 4.85 - 4.71 (m, 1 H), 3.98 (d, J = 6.8 Hz, 3 H), 3.89 (d, J = 9.2 Hz, 1 H), 3.84 - 3.76 (m, 1 H), 3.65 - 3.58 (m, 1 H), 3.46 - 3.37 (m, 1 H), 2.23 - 2.02 (m, 2 H), 1.37 - 1.28 (m, 1 H), 0.70 - 0.64 (m, 2 H), 0.47 - 0.39 (m, 2 H); m/z ES+[M+H] ⁺ 512.1. Example 382. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-ethoxy-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. 6-Chloro-N-(3-chloro-4-ethoxy-2-fluorophenyl)pyrido[3,2-d]py rimidin-4-amine To a solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fl uoro- phenol (300 mg, 922 μmol) in acetonitrile (3 mL) was added potassium carbonate (140 mg, 1.01 mmol) and iodoethane (158 mg, 1.01 mmol). The mixture was stirred at 60 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (10 mL) and extracted with ethyl acetate (5 mL ൈ 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/35) to give 6-chloro-N-(3-chloro-4-ethoxy-2-fluoro- phenyl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 0.43 mmol , 42%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (s, 1H), 8.62 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.58 (t, J = 8.8 Hz, 1H), 7.13 (dd, J = 1.6, 9.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). Step 2. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-ethoxy-2-fluorophenyl)amino)pyrido [3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 6-chloro-N-(3-chloro-4-ethoxy-2-fluoro-phenyl)pyrido[3,2-d]p yrimidin- 4-amine (120 mg, 339 μmol) in 1-methyl-2-pyrrolidinone (2 mL) was added diisopropylethylamine (131 mg, 1.02 mmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (101 mg, 509.66 μmol). The mixture was stirred at 80 °C for 2 hr. On completion, water was added into the mixture until no more solid precipitated out. Then the mixture was filtered and the solid was collected to give tert-butyl (1S,4S)-5-[4-(3- chloro-4-ethoxy-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl ]-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (100 mg, 194 μmol, 42%) as an off-white solid. m/z ES+ [M+H] ⁺ 515.3. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -ethoxy-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-(3-chloro-4-ethoxy-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (80.0 mg, 155 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1.23 g, 10.8 mmol). The mixture was stirred at 20 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give N-(3-chloro-4-ethoxy-2-fluoro-phenyl)-6-[(1S,4S)-2,5-diazabi cyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (70 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 415.3. Step 4. 1-((1S,4S)-5-(4-((3-Chloro-4-ethoxy-2-fluorophenyl)amino)pyr ido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-(3-chloro-4-ethoxy-2-fluoro-phenyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2.1] heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, 144 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (12.1 mg, 144 μmol) to adjust pH ~ 7. Then prop-2-enoyl chloride (10.4 mg, 115 μmol) was added dropwise. The mixture was stirred at 0 °C for 15 min. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (5 mL) and extracted with ethyl acetate (5 mL ൈ 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate at 20 ^o C for 5 min to give 1-[(1S,4S)-5-[4-(3-chloro-4-ethoxy-2-fluoro-anilino)pyrido[3 ,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (30.0 mg, 64 μmol, 43%) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 - 9.08 (m, 1H), 8.30 (d, J = 3.2 Hz, 1H), 7.91 (dd, J = 4.0, 9.2 Hz, 1H), 7.86 - 7.73 (m, 1H), 7.43 - 7.14 (m, 1H), 7.08 (d, J = 10.8 Hz, 1H), 6.89 - 6.33 (m, 1H), 6.18 - 6.13 (m, 1H), 5.78 - 5.56 (m, 1H), 5.09 - 4.92 (m, 1H), 4.22 - 4.17 (m, 2H), 3.78 - 3.42 (m, 5H), 2.08 (s, 1H), 2.01 (s, 1H), 1.40 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 469.3. Example 383. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran- 2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. (S)-(Tetrahydrofuran-2-yl)methyl methanesulfonate To a mixture of [(2S)-tetrahydrofuran-2-yl]methanol (200 mg, 1.96 mmol) in dichloromethane (3.0 mL) was added trimethylamine (396 mg, 3.92 mmol), and then methanesulfonyl chloride (336 mg, 2.94 mmol) was added at 0 °C. The reaction mxiture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched by water (5.0 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give [(2S)-tetrahydrofuran-2-yl]methyl methanesulfonate (400 mg, crude) as a yellow oil without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.29 - 4.23 (m, 1H), 4.23 - 4.14 (m, 2H), 3.94 - 3.86 (m, 1H), 3.85 - 3.78 (m, 1H), 3.07 (s, 3H), 2.13 - 1.98 (m, 2H), 1.98 - 1.87 (m, 2H). Step 2. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a mixture of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (120 mg, 246 μmol) and [(2S)-tetrahydrofuran-2-yl]methyl methanesulfonate (53.3 mg, 295 μmol) in N,N-dimethylformamide (2.0 mL) was added potassium carbonate (68.1 mg, 492 μmol), the reaction mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was quchened by water (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl(1S,4S)-5-[4-[3-chloro-2-fluoro-4- [[(2S)-tetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyr imidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (140 mg, crude) as a black oil without purification. m/z ES+[M+H] ⁺ 571.1. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-(((S)- tetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2S)-tetrahydrofuran-2-y l] methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicycl o[2.2.1]heptane-2-carboxylate (120 mg, 210 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (924 mg, 8.10 mmol), the reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[[(2S)-tetrahydrofuran-2- yl]methoxy]phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl]pyrido[3,2-d]pyrimidin-4- amine (80.0 mg, crude) as a yellow oil without purification. m/z ES+[M+H] ⁺ 471.0. Step 4. 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran- 2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]p henyl]-6 - [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (80.0 mg, 169 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added sodium bicarbonate (14.2 mg, 169 μmol) at 0 °C to pH 7~8, and then prop-2-enoyl chloride (15.3 mg, 169 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was quenched by water (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150x25mm 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 16% - 49%,11min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2S)-tetrahydrofuran- 2- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabic yclo[2.2.1]heptan-2-yl]prop-2-en- 1-one (50.5 mg, 96.2 μmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 - 9.18 (m, 1H), 8.29 (d, J = 3.2 Hz, 1H), 7.95-7.87 (m, 1H), 7.86 - 7.72 (m, 1H), 7.39 - 7.17 (m, 1H), 7.14 - 7.04 (m, 1H), 6.87 - 6.36 (m, 1H), 6.21-6.06 (m, 1H), 5.78 - 5.55 (m, 1H), 5.52 - 5.14 (m, 1H), 5.11 - 4.86 (m, 1H), 4.27 - 4.18 (m, 1H), 4.18 - 4.04 (m, 2H), 3.86 - 3.78 (m, 1H), 3.76 - 3.49 (m, 4H), 3.43 - 3.38 (m, 1H), 2.11 - 1.90 (m, 4H), 1.89 - 1.70 (m, 2H); m/z ES+[M+H] ⁺ 525.0. Example 384. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran- 2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. (R)-(Tetrahydrofuran-2-yl)methyl methanesulfonate To a mixture of [(2S)-tetrahydrofuran-2-yl]methanol (200 mg, 1.96 mmol) in dichloromethane (2.0 mL) was added trimethylamine (595 mg, 5.87 mmol), and then methanesulfonyl chloride (449 mg, 3.92 mmol) was added at 0 °C. The reaction mxiture was stirred at 25 °C for 1.5 hr. On completion, the reaction mixture was quenched by water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (397 mg, crude) as a yellow oil without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.29 - 4.23 (m, 1H), 4.22 - 4.14 (m, 2H), 3.94 - 3.78 (m, 2H), 3.07 (s, 3H), 2.10 - 1.99 (m, 1H), 1.99 - 1.89 (m, 2H), 1.75 – 1.64 (m, 1H). Step 2. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a mixture of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (120 mg, 246 μmol) and [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (66.6 mg, 390 μmol) in N,N-dimethylformamide (2.0 mL) was added potassium carbonate (102 mg, 739 μmol), the reaction mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was added water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2R)- tetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (116 mg, 203 μmol, 82%) as a yellow solid without purification. m/z ES+[M+H] ⁺ 571.1. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-(((R)- tetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2R)-tetrahydrofuran-2-y l] methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicycl o[2.2.1]heptane-2-carboxylate (100 mg, 175 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[[(2R)-tetrahydrofuran-2-yl]meth oxy]phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]py rido[3,2-d]pyrimidin-4-amine (96 mg, crude) as a yellow oil without purification. m/z ES+[M+H] ⁺ 471.0. Step 4. 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran- 2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]p henyl]-6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (82.0 mg, 174 μmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was added sodium bicarbonate (117 mg, 1.39 mmol) at 0 °C, and then prop-2-enoyl chloride (14.2 mg, 157 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150x25mm 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 20% - 50%, 10 min) to give 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran- 2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (31.8 mg, 60.5 μmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 4.0, 9.2 Hz, 1H), 7.85 - 7.73 (m, 1H), 7.43 - 7.14 (m, 1H), 7.09 (dd, J = 1.2, 9.2 Hz, 1H), 6.85 - 6.35 (m, 1H), 6.17 – 6.11 (m, 1H), 5.75 - 5.59 (m, 1H), 5.56 - 5.10 (m, 1H), 5.08 - 4.91 (m, 1H), 4.26 - 4.18 (m, 1H), 4.16 - 4.05 (m, 2H), 3.87 - 3.78 (m, 1H), 3.76 - 3.68 (m, 2H), 3.66 - 3.49 (m, 2H), 3.42 (d, J = 11.6 Hz, 1H), 2.08 - 1.89 (m, 4H), 1.88 - 1.72 (m, 2H); m/z ES+[M+H] ⁺ 525.0. Example 385. Preparation of 1-((1S,4S)-5-(4-((2-fluoro-3- (trifluoromethyl)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5-diazabicyclo[2.2.1]heptan- Step 1. 6-Chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)pyrido[3,2-d] pyrimidin-4-amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 999 μmol) and 2-fluoro-3- (trifluoromethyl)aniline (214 mg, 1.20 mmol) in acetonitrile (3.0 mL) was stirred at 40 °C for 1.5 hr. On completion, the reaction mixture was filtered and the filtered cake was concentrated in vacuo to give 6-chloro-N-[2-fluoro-3-(trifluoromethyl)phenyl]p yrido[3,2-d]pyrimidin-4-amine (320 mg, 933 μmol, 93%) as a yellow solid without purification. m/z ES+[M+H] ⁺ 343.0. Step 2. tert-Butyl (1S,4S)-5-(4-((2-fluoro-3-(trifluoromethyl)phenyl)amino)pyri do[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a mixture of 6-chloro-N-[2-fluoro-3-(trifluoromethyl)phenyl]pyrido[3,2-d] pyrimidin- 4-amine (300 mg, 875 μmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carb oxylate (260 mg, 1.31 mmol) in 1-methyl-2-pyrrolidinone (6.0 mL) was added diisopropylethylamine (226 mg, 1.75 mmol), the reaction mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was quenched by water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-[2-fluoro- 3-(tr ifluoromethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diaza bicyclo[2.2.1]heptane-2- carboxylate (300 mg, 594 μmol, 67%) as a yellow solid without purification. m/z ES+[M+H] ⁺ 505.3. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(2-fluoro-3 - (trifluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-[2-fluoro-3-(trifluoromethyl)anilino]pyrido[3,2 -d] pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, 594 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2-fluoro-3 - (trifluoromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-amine (200 mg, 494 μmol, 83%) as a yellow oil without purification. m/z ES+[M+H] ⁺ 405.0. Step 4. 1-((1S,4S)-5-(4-((2-Fluoro-3-(trifluoromethyl)phenyl)amino)p yrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a mixture of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2-fluoro-3 -(trifleoro methyl)phenyl]pyrido[3,2-d]pyrimidin-4-amine (200 mg, 494 μmol) in tetrahydrofuran (3.0 mL) and water (3.0 mL) was added sodium bicarbonate (41.5 mg, 494 μmol) at 0 °C to pH ~ 7, and then prop-2-enoyl chloride (44.7 mg, 494 μmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 30% - 60%, 10 min) to give 1-[(1S,4S)-5-[4-[2-fluoro-3-(trifluoromethyl)anilino]pyrido[ 3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (154 mg, 330 μmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 - 9.29 (m, 1H), 8.67 - 8.47 (m, 1H), 8.41 (d, J = 3.2 Hz, 1H), 7.98-7.92 (m, 1H), 7.61 - 7.53 (m, 1H), 7.51 - 7.46 (m, 1H), 6.91 - 6.35 (m, 1H), 6.21-6.08 (m, 1H), 5.75 - 5.58 (m, 1H), 5.09 - 4.92 (m, 1H), 3.79 - 3.63 (m, 2H), 3.59 - 3.51 (m, 1H), 3.47 - 3.37 (m, 1H), 3.30 (br s, 2H), 2.10 - 1.99 (m, 2H); m/z ES+[M+H] ⁺ 459.0; m/z ES+[M+H] ⁺ 459.0. Example 386. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(2,2-difluoropropyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. 1-Bromo-2-chloro-3-fluoro-4-nitrobenzene To a solution of 4-bromo-3-chloro-2-fluoroaniline (4 g, 17.9 mmol) in trifluoroacetic acid (120 mL) was added hydrogen peroxide (10.1 g, 30% purity) at 0 °C and the mixture was stirred at 70 °C for 1 hr. On completion, the reaction mixture was quenched by saturated sodium sulphite solution (100 mL), then diluted with water 100 mL and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with sat. sodium sulphite (60 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The resiue was purified by flash column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~0% ethyl acetate/Petroleum ethergradient @ 50 mL/min) to give 1-bromo- 2-chloro-3-fluoro-4-nitrobenzene (3 g, 11.8 mmol, 62%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 - 7.86 (m, 1H), 7.66 - 7.60 (m, 1H). Step 2. 2-Chloro-3-fluoro-4-nitro-1-(prop-1-en-2-yl)benzene A mixture of 1-bromo-2-chloro-3-fluoro-4-nitrobenzene (1.5 g, 5.9 mmol), potassium;trifluoro(isopropenyl)boranuide (1.31 g, 8.8 mmol), triethylamine (1.79 g, 17.6 mmol), cyclopenta-2,4-dien-1-yl(diphenyl)phosphane;dichloropalladiu m;iron(2+) (86.3 mg, 0.12 mmol) in dioxane (15 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 0~0% ethyl acetate/Petroleum ethergradient @ 40 mL/min) to give 2-chloro-3-fluoro-4-nitro-1-(prop-1-en-2-yl)benzene (1 g, 4.63 mmol, 79%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 - 7.81 (m, 1H), 7.14 - 6.99 (m, 1H), 5.35 - 5.28 (m, 1H), 5.00 (s, 1H), 2.05 (s, 3H). Step 3. 2-Chloro-1-(2,2-difluoropropyl)-3-fluoro-4-nitrobenzene To a solution of 2-chloro-3-fluoro-4-nitro-1-(prop-1-en-2-yl)benzene (0.4 g, 1.85 mmol) and 1-iodo-4-methylbenzene (40.4 mg, 0.19 mmol) in chloroform (10 mL) and pyridine;hydrofluoride (10.7 g, 70% purity) was added 3-chloroperoxybenzoic acid (565 mg, 85% purity) and the mixture was stirred and reacted in a PTFE sealed tube at 25 °C for 16 hr. On completion, the mixture was quenched by saturated sodium sulphite (10 mL), diluted with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~0% ethyl acetate/Petroleum ethergradient @ 100 mL/min) to give 2-chloro-1-(2,2-difluoropropyl)-3-fluoro- 4-nitrobenzene (170 mg, 0.66 mmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 - 7.90 (m, 1H), 7.40 - 7.33 (m, 1H), 3.56 - 3.37 (m, 2H), 1.76 - 1.62 (m, 3H). Step 4. 3-Chloro-4-(2,2-difluoropropyl)-2-fluoroaniline To a solution of 2-chloro-1-(2,2-difluoropropyl)-3-fluoro-4-nitrobenzene (170 mg, 0.67 mmol) in ethyl acetate (3 mL) was added Pt/V/C (100 mg, 3% loading) and the mixture was stirred at 25 °C for 1 hr under hydrogen atmosphere (15 psi). On completion, the mixture was filtered and the layer was concentrated in vacuo to give 3-chloro-4-(2,2-difluoropropyl)-2-fluoroaniline (150 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 223.9. Step 5. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(2,2-difluoropropyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6yl)-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate A mixture of 3-chloro-4-(2,2-difluoropropyl)-2-fluoro-aniline (150 mg, 0.67 mmol) and tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2- carboxylate (242 mg, 0.67 mmol) in acetonitrile (4 mL) was stirred at 25 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% Formic acid condition) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4- (2,2-difluoropropyl)-2-fluorophenyl)amino)pyrido[3,2-d]pyrim idin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (183 mg, 0.33 mmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 - 9.88 (m, 1H), 8.81 - 8.53 (m, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 12.4 Hz, 1H), 3.72 - 3.62 (m, 3H), 3.49 - 3.37 (m, 4H), 3.24 (s, 1H), 2.11 - 1.87 (m, 2H), 1.73 - 1.58 (m, 3H), 1.44 - 1.33 (m, 9H); m/z ES+ [M+H] ⁺ 549.1. Step 6. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(2,2- difluoropropyl)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e A mixture of tert-butyl (1S,4S)-5-(4-((3-chloro-4-(2,2-difluoropropyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (80 mg, 0.145 mmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (1 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4-(2,2-difluorop ropyl)-2-fluorophenyl)pyrido[3,2-d] pyrimidin-4-amine (70 mg, TFA salt, crude) as a yellow oil. Step 7. 1-((1S,4S)-5-(4-((3-chloro-4-(2,2-difluoropropyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 -(2,2- difluoropropyl)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e (78 mg, 0.17 mmol, TFA salt) and sodium bicarbonate (58.2 mg, 0.85 mmol) in anhydrous tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (12.5 mg, 0.17 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50mm x 3 um;mobile phase: [water(formic acid) - acetonitrile]; B%: 32% -52%, 10 min) to give 1-((1S,4S)-5-(4-((3- chloro-4-(2,2-difluoropropyl)-2-fluorophenyl)amino)pyrido[3, 2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (35.4 mg, 0.083 mmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 - 9.21 (m, 1H), 8.51 - 8.33 (m, 1H), 8.26 - 8.04 (m, 1H), 7.99 - 7.87 (m, 1H), 7.34 (d, J = 8.8 Hz, 2H), 6.91 - 6.31 (m, 1H), 6.22 - 6.06 (m, 1H), 5.75 - 5.54 (m, 1H), 5.53 - 5.11 (m, 1H), 5.11 - 4.87 (m, 1H), 3.81 - 3.64 (m, 2H), 3.62 - 3.45 (m, 4H), 2.12 - 1.95 (m, 2H), 1.75 - 1.57 (m, 3H); m/z ES+ [M+H] ⁺ 424.9. Example 387. Preparation of 1-((1S,4S)-5-(4-((5-chloro-4-ethoxy-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((5-chloro-4-ethoxy-2-fluorophenyl)amino)pyrido [3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A solution of tert-butyl (1S,4S)-5-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.35 g, 718 μmol), iodoethane (89.6 mg, 575 μmol) and potassium carbonate (198.68 mg) in N,N-dimethylformamide (5 mL) was stirred at 100 °C for 16 hr. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-((5-chloro-4-ethoxy-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (0.3 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 515.2. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-4 -ethoxy-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-(5-chloro-4-ethoxy-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.2 g, 388 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give 6- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-4-e thoxy-2-fluorophenyl)pyrido[3,2- d]pyrimidin-4-amine (0.2 g, crude, TFA) as a yellow solid. m/z ES+[M+H] ⁺ 415.0. Step 3. 1-((1S,4S)-5-(4-((5-Chloro-4-ethoxy-2-fluorophenyl)amino)pyr ido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-(5-chloro-4-ethoxy-2-fluoro-phenyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (0.2 g, 378 μmol) and sodium bicarbonate (95.3 mg, 1.13 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop- 2-enoyl chloride (34.2 mg, 378 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm 5um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 41% - 71%, 9 min) to give 1-((1S,4S)-5-(4-((5-chloro-4-ethoxy- 2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (88.0 mg, 0.188 mmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1 H), 8.34 (d, J = 1.6 Hz, 1 H), 8.09 (s, 1 H), 7.90 (dd, J = 9.2, 3.6 Hz, 1 H), 7.26 (d, J = 12.4 Hz, 2 H), 6.80 (dd, J = 16.8, 10.4 Hz, 0.5 H), 6.42 (dd, J = 16.8, 10.4 Hz, 0.5 H), 6.17 - 6.12 (m, 1 H), 5.88 - 5.57 (m, 1 H), 5.51 - 4.86 (m, 2 H), 4.15 (q, J=7.2 Hz, 2 H), 3.81 – 3.39 (m, 4 H), 2.14 - 1.95 (m, 2 H), 1.37 (t, J=6.8 Hz, 3 H); m/z ES+[M+H] ⁺ 469.0. Example 388. Preparation of 1-((1S,4S)-5-(4-((5-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((5-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.3 g, 616 μmol), 2,2- difluoroethyl trifluoromethanesulfonate (92.3 mg, 431 μmol) and potassium carbonate (170 mg, 1.23 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80 °C for 16 hr. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert- butyl (1S,4S)-5-(4-((5-chloro-4-(2,2-difluoroethoxy)-2-fluoropheny l)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.3 g, crude) as a brown solid, m/z ES+[M+H] ⁺ 551.2. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-4 -(2,2- difluoroethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amin e To a solution of tert-butyl (1S,4S)-5-[4-[5-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (0.3 g, 544 μmol) in dichloromethane (6 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- N-(5-chloro-4-(2,2-difluoroethoxy)-2-fluorophenyl) pyrido[3,2-d]pyrimidin-4-amine (0.3 g, crude, TFA) as a yellow solid. m/z ES+[M+H] ⁺ 451.0. Step 3. 1-((1S,4S)-5-(4-((5-Chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of N-[5-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-[(1S,4 S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (0.3 g, 531 umo, TFA) and sodium bicarbonate (133 mg, 1.59 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added prop-2-enoyl chloride (48.0 mg, 531 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm 5um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 40% - 70%, 9 min) to give 1-((1S,4S)-5-(4-((5- chloro-4-(2,2-difluoroethoxy)-2-fluorophenyl)amino)pyrido[3, 2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (0.058 g, 0.115 mmol, 21%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (br, s, 1 H), 8.35 (s, 1 H), 8.15 (br, s, 1 H), 7.93 – 7.89 (m, 1 H), 7.55 – 7.20 (m, 2 H), 6.87 – 6.38 (m, 2 H), 6.17 - 6.13 (m, 1 H), 5.71 - 5.63 (m, 1 H), 5.48 - 4.93 (m, 2 H), 4.52 - 4.43 (m, 2 H), 3.76 - 3.43 (m, 4 H), 2.08 – 2.01 (m, 2 H); m/z ES+[M+H] ⁺ 505.1. Example 389. Preparation of 1-((1S,4S)-5-(4-((5-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((5-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.5 g, 1.03 mmol), (2-chloro- 2,2-difluoro-acetyl)oxysodium (782 mg, 5.13 mmol) and cesium carbonate (1.67 g, 5.13 mmol) in N,N-dimethylformamide (6 mL) was stirred at 100 °C for 16 hr. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 1/1) to give tert-butyl (1S,4S)-5-(4-((5-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (0.15 g, 0.28 mmol, 27%) as a yellow solid. m/z ES+[M+H] ⁺ 537.3. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-4 - (difluoromethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-am ine To a solution of tert-butyl (1S,4S)-5-[4-[5-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (0.15 g, 279 μmol) in dichloromethane (6 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-4 -(difluoromethoxy)-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (0.15 g, crude, TFA) as a yellow solid. Step 3.1-((1S,4S)-5-(4-((5-Chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of N-[5-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (0.15 g, 272 μmol, TFA) and sodium bicarbonate (68.6 mg, 816 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (24.6 mg, 272 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm 5um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 44% - 74%, 9 min) to give 1-((1S,4S)-5-(4-((5- chloro-4-(difluoromethoxy)-2-fluorophenyl)amino) pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (24.0 mg, 55 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (d, J = 1.2 Hz, 1 H), 8.57 - 8.35 (m, 2 H), 7.93 (dd, J = 9.2, 3.6 Hz, 1 H), 7.56 (d, J = 11.2 Hz, 1 H), 7.51 – 7.15 (m, 2 H), 6.85 - 6.38 (m, 1 H), 6.17 - 6.12 (m, 1 H), 5.75 - 5.58 (m, 1 H), 5.29 – 4.94 (m, 2 H), 3.80 - 3.39 (m, 4 H), 2.17 – 1.91 (m, 2 H); m/z ES+[M+H] ⁺ 491.0. Example 390. Preparation of 1-((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy) - 3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3- chloro- 2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate A solution of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (0.08 g, 164 μmol), 2-oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate (44.0 mg, 164 μmol) and potassium carbonate (45.4 mg, 328 μmol) in N,N-dimethylformamide (2 mL) was stirred at 60 °C for 16 hr. On completion, the reaction mixture was quenched by addition water (10 mL) at 25 °C, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-((4-((2- oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-chloro-2-fluorophenyl )amino)pyrido[3,2-d] pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.09 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 583.2. Step 2. N-(4-((2-Oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-chloro-2-flu orophenyl)-6- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2-d]pyr imidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan- 4-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabi cyclo[2.2.1]heptane-2-carboxylate (0.09 g, 154 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give N-(4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-chloro-2-flu orophenyl)-6- ((1S,4S)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrido[3,2-d]pyrimidin-4-amine (0.09 g, crude, TFA) as a yellow solid. m/z ES+[M+H] ⁺ 483.1. Step 3. 1-((1S,4S)-5-(4-((4-((2-Oxabicyclo[2.1.1]hexan-4-yl)methoxy) -3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of N-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2 -yl]pyrido[3,2-d]pyrimidin-4- amine (0.09 g, 150 μmol, TFA), sodium bicarbonate (38.0 mg, 452 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (13.6 mg, 150 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm 5um; mobile phase: [water (ammonium bicarbonate) - ACN]; B%: 36%-66%, 9 min) to give 1- ((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3 -chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one (0.028 g, 52 μmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (d, J = 1.2 Hz, 1 H), 8.30 (d, J = 3.2 Hz, 1 H), 7.98 - 7.71 (m, 2 H), 7.46 - 7.00 (m, 2 H), 6.89 - 6.34 (m, 1 H), 6.17 - 6.11 (m, 1 H), 5.71 - 5.63 (m, 1 H), 5.50 – 4.85 (m, 1 H), 4.54 (s, 1 H), 4.45 (s, 2 H), 3.80 - 3.38 (m, 6 H), 2.13 – 1.97 (m, 2 H), 1.88 (d, J = 4.8 Hz, 2 H), 1.52 (dd, J =4.8, 1.6 Hz, 2 H); m/z ES+[M+H] ⁺ 537.0. Example 391. Preparation of 1-((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy) - 3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-3- chloro- 2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (120 mg, 246 μmol) and 1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane (66.3 mg, 296 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (102 mg, 739 μmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was diluted water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-3- chloro- 2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1] heptane-2-carboxylate (156 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.39 - 9.18 (m, 1H), 8.29 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.79 (t, J = 8.4 Hz, 1H), 7.53 - 7.10 (m, 2H), 4.54 (d, J = 16.4 Hz, 1H), 4.38 (s, 2H), 3.73 (s, 2H), 3.45 - 3.39 (m, 1H), 3.29 - 3.20 (m, 1H), 2.97 - 2.72 (m, 3H), 2.05 - 1.93 (m, 2H), 1.92 - 1.86 (m, 2H), 1.79 - 1.69 (m, 1H), 1.51 - 1.44 (m, 2H), 1.42 - 1.33 (m, 9H); m/z ES+ [M+H] ⁺ 583.1. Step 2. N-(4-((2-Oxabicyclo[2.1.1]hexan-1-yl)methoxy)-3-chloro-2-flu orophenyl)-6- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2-d]pyr imidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan- 1-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabi cyclo[2.2.1]heptane-2-carboxylate (140 mg, 240 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)phenyl] -6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d] pyrimidin-4- amine (126 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 483.1. Step 3. 1-((1S,4S)-5-(4-((4-((2-Oxabicyclo[2.1.1]hexan-1-yl)methoxy) -3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one To a solution of N-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy )phenyl] -6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d] pyrimidin-4-amine (116 mg, 240 μmol) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (161 mg, 1.92 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (19.6 mg, 216 μmol) was added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by addition water (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm 5um; mobile phase: [water(ammonium bicarbonate) - acetonitrile];B%: 39% - 69%, 8 min) to give 1-[(1S,4S)-5-[4- [3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)a nilino]pyrido[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (51.3 mg, 95.5 μmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 - 9.08 (m, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 4.0, 9.2 Hz, 1H), 7.87 - 7.73 (m, 1H), 7.42 - 7.17 (m, 1H), 7.14 (dd, J = 1.2, 9.2 Hz, 1H), 6.87 - 6.36 (m, 1H), 6.25 - 6.09 (m, 1H), 5.76 - 5.60 (m, 1H), 5.55 - 5.09 (m, 1H), 5.09 - 4.90 (m, 1H), 4.38 (s, 2H), 3.84 - 3.60 (m, 4H), 3.60 - 3.42 (m, 2H), 2.96 (t, J = 3.2 Hz, 1H), 2.11 - 1.95 (m, 2H), 1.93 - 1.85 (m, 2H), 1.53 - 1.42 (m, 2H); m/z ES+ [M+H] ⁺ 537.1. Example 392. Preparation of 1-(4-((6-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2 - yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-chlorophenyl)cyclopr opane-1-carbonitrile Step 1. Ethyl 2-(2-chloro-4-nitrophenyl)-2-cyanoacetate To a solution of ethyl 2-cyanoacetate (1.68 g, 14.8 mmol) in dimethylsulfoxide (5 mL) was added potassium hydroxide (830 mg, 14.8 mmol). The mixture was stirred at 25 °C for 1 hr. Then 2-chloro-1-fluoro-4-nitro-benzene (2.00 g, 11.3 mmol) was added. The mixture was stirred at 25 °C for another 7 hr. On completion, the reaction mixture was used to the next step directly without any work-up or purification. Step 2.2-(2-Chloro-4-nitrophenyl)acetonitrile To the above crude solution of ethyl 2-(2-chloro-4-nitro-phenyl)-2-cyano-acetate in dimethylsulfoxide (5 mL) was added hydrochloric acid (1.43 g, 14.5 mmol, 37%) and acetic acid (4 mL). The mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 5/1) to give 2-(2-chloro-4-nitro- phenyl)acetonitrile (1.00 g, 4.48 mmol, 40%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J = 2.4 Hz, 1H), 8.22 (dd, J = 2.4, 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 3.96 (s, 2H); m/z ES+ [M-H] ⁺ 195.1. Step 3. 1-(2-Chloro-4-nitrophenyl)cyclopropane-1-carbonitrile To a solution of 2-(2-chloro-4-nitro-phenyl)acetonitrile (0.90 g, 4.58 mmol) in acetonitrile (10 mL) was added tetrabutylammonium bromide (1.48 g, 4.58 mmol) and 1,2- dibromoethane (2.58 g, 13.7 mmol), followed by the addition of a solution of sodium hydroxide (732 mg, 18.3 mmol) in water (1 mL). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was partitioned between water (20 mL) and ethyl acetate (60 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 1-(2-chloro-4-nitro-phenyl)cyclopropanecarbonitrile (0.40 g, 1.65 mmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J = 2.4 Hz, 1H), 8.14 (dd, J = 2.4, 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 1.90 - 1.86 (m, 2H), 1.44 - 1.40 (m, 2H). Step 4. 1-(4-Amino-2-chlorophenyl)cyclopropane-1-carbonitrile To a solution of 1-(2-chloro-4-nitro-phenyl)cyclopropanecarbonitrile (400 mg, 1.80 mmol) in ethanol (6 mL) and water (3 mL) was added iron power (501 mg, 8.98 mmol) and ammonium chloride (480 mg, 8.98 mmol). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 1- (4-amino-2-chloro-phenyl)cyclopropanecarbonitrile (346 mg, 1.74 mmol, 96%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.09 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 2.4, 8.4 Hz, 1H), 1.70 - 1.65 (m, 2H), 1.29 - 1.25 (m, 2H); m/z ES+ [M+H] ⁺ 193.0. Step 5. 1-(2-Chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4- yl)amino)phenyl)cyclopropane-1-carbonitrile To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 749 μmol) in acetonitrile (1.5 mL) was added 1-(4-amino-2-chloro-phenyl)cyclopropanecarbonitrile (144 mg, 749 μmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was filtered and the filtered cake was collected to give a residue. The crude product was triturated with acetonitrile (1 mL) at 25 °C for 10 min, filtered and dried to give 1-[2-chloro-4-(pyrido[3,2- d]pyrimidin-4-ylamino)phenyl]cyclopropanecarbonitrile (240 mg, 723 μmol, 96%) as a yellow solid. m/z ES+ [M+H] ⁺ 355.7. Step 6. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(1- cyanocyclopropyl)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5-diazabicyclo[2.2.1]heptane-2- carboxylate To a solution of 1-[2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4- yl)amino]phenyl]cyclopropanecarbonitrile (220 mg, 617 μmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (367 mg, 1.85 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added diisopropylethylamine (399 mg, 3.09 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (50 mL), filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1- cyanocyclopropyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-di azabicyclo[2.2.1]heptane-2- carboxylate (319 mg, 603 μmol, 97%) as a yellow solid. m/z ES+ [M+H] ⁺ 518.2. Step 7. 1-(4-((6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyrido[ 3,2-d]pyrimidin-4- yl)amino)-2-chlorophenyl)cyclopropane-1-carbonitrile To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1- cyanocyclopropyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-di azabicyclo[2.2.1]heptane-2- carboxylate (150 mg, 289 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 1-[2-chloro-4-[[6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-yl]a mino]phenyl] cyclopropanecarbonitrile (121 mg, 277 μmol, 95%) as a brown solid. m/z ES+ [M+H] ⁺ 418.1. Step 8. 1-(4-((6-((1S,4S)-5-Acryloyl-2,5-diazabicyclo[2.2.1]heptan-2 -yl)pyrido[3,2- d]pyrimidin-4-yl)amino)-2-chlorophenyl)cyclopropane-1-carbon itrile To a solution of 1-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-yl]amino]phenyl]cyclopropanecarb onitrile (120 mg, 287 μmol) in tetrahydrofuran (0.8 mL) and water (0.8 mL) was added sodium bicarbonate (72.3 mg, 861 μmol) and prop-2-enoyl chloride (25.9 mg, 287 μmol). The mixture was stirred at 0 °C for 0.1 hr. On completion, the reaction mixture was partitioned between dichloromethane (60 mL) and water (20 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (column: Waters Xbridge 150 x 25mm 5um; mobile phase: [water (ammonium bicarbonate) - acetonitrile];B%: 39% - 69%, 10 min) to give 1- [2-chloro-4-[[6-[(1S,4S)-5-prop-2-enoyl-2,5-diazabicyclo[2.2 .1]heptan-2-yl]pyrido[3,2- d]pyrimidin-4-yl]amino]phenyl]cyclopropanecarbonitrile (80.5 mg, 167 μmol, 58%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 - 9.31 (m, 1H), 8.59 - 8.43 (m, 1H), 8.40 - 8.28 (m, 1H), 8.17 - 7.99 (m, 1H), 7.96 - 7.83 (m, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.40 (m, 1H), 6.93 - 6.34 (m, 1H), 6.18 - 6.16 (m, 1H), 5.78 - 5.56 (m, 1H), 5.17 - 4.86 (m, 1H), 3.86 - 3.65 (m, 2H), 3.62 - 3.48 (m, 1H), 3.42 (d, J = 2.0 Hz, 2H), 2.16 - 1.93 (m, 2H), 1.82 - 1.66 (m, 2H), 1.50 - 1.35 (m, 2H); m/z ES+ [M+H] ⁺ 472.1. Example 393. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((R)-2- methyltetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one Step 1. 2-((2,3-dichloro-4-nitrophenoxy)methyl)-2-methyltetrahydrofu ran To a mixture of (2-methyltetrahydrofuran-2-yl)methanol (608 mg, 5.24 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (419 mg, 10.4 mmol, 60% in mineral oil) portionwise at 0 °C, the mixture was stirred at 0 °C for 10 min. Then 2,3-dichloro-1-fluoro-4- nitro-benzene (1.10 g, 5.24 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 2/3) to give 2-[(2,3-dichloro-4-nitro-phenoxy)methyl]-2-methyl- tetrahydrofuran (1.30 g, 4.25 mmol, 81%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 4.02 - 3.90 (m, 4H), 2.19 - 2.05 (m, 2H), 2.05 - 1.98 (m, 1H), 1.85 - 1.78 (m, 1H), 1.38 (s, 3H). Step 2. 2-((2-Chloro-3-fluoro-4-nitrophenoxy)methyl)-2-methyltetrahy drofuran To a mixture of 2-[(2,3-dichloro-4-nitro-phenoxy)methyl]-2-methyl-tetrahydro furan (400 mg, 1.31 mmol) and cesium fluoride (396 mg, 2.61 mmol) in dimethylsulfoxide (10 mL) was stirred at 140 °C for 12 hr. On completion, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]-2-methyl-tetra hydrofuran (360 mg, 1.24 mmol, 95%) as a yellow oil without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 - 8.02 (m, 1H), 6.88 - 6.80 (m, 1H), 4.05 - 3.98 (m, 2H), 3.96 - 3.90 (m, 2H), 2.19 - 2.12 (m, 1H), 2.10 - 2.01 (m, 2H), 1.86 - 1.79 (m, 1H), 1.38 (s, 3H). Step 3. 3-Chloro-2-fluoro-4-((2-methyltetrahydrofuran-2-yl)methoxy)a niline To a mixture of 2-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]-2-methyl- tetrahydrofuran (340 mg, 1.17 mmol) in ethanol (5.0 mL) and water (5.0 mL) was added iron powder (327 mg, 5.87 mmol) and ammonium chloride (627 mg, 11.7 mmol), the reaction mixture was stirred at 80 °C for 12 hr. On completion, the mixture was filtered and the filtrate was partitioned between water (30 mL) and ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-2-fluoro-4-[(2-methyltetrahydrofuran-2- yl)methoxy]aniline (320 mg, crude) as a red oil without further purification. m/z ES+[M+H] ⁺ 260.1. Step 4. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((R)-2-methyltetrahydrof uran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate & tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((S)-2-methyltetrahydrof uran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate A mixture of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (350 mg, 967 μmol) and 3-chloro-2-fluoro-4-[(2- methyltetrahydrofuran-2-yl)methoxy]aniline (301 mg, 1.16 mmol) in acetonitrile (7 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 0/100), which was further separated by SFC (column: Phenomenex-Cellulose-2 (250mm x 30mm, 10um); mobile phase: [methanol - acetonitrile]; B%: 70% - 70%, 5.8; 200min) to give tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2R)-2- methyltetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg, 291 μmol, 30%) as a red oil and tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2S)-2-methyltetrahydrof uran-2- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (190 mg, 324 μmol, 33%) as a red solid. m/z ES+[M+H] ⁺ 585.2. Step 5. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-(((R)-2- methyltetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrim idin-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2R)-2- methyltetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg, 290 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the reaction mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2- fluoro-4-[[(2R)-2-methyltetrahydrofuran-2-yl]methoxy]phenyl] -6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (130 mg, 268 μmol, 92%) as a yellow oil. m/z ES+[M+H] ⁺ 485.0. Step 6. 1-((1S,4S)-5-(4-((3-Chloro-2-fluoro-4-(((R)-2-methyltetrahyd rofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-[[(2R)-2-methyltetrahydrofuran-2- yl]methoxy]phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl]pyrido[3,2-d]pyrimidin-4- amine (130 mg, 268 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (22.5 mg, 268 μmol) at 0 °C to pH 7~8, and then prop-2-enoyl chloride (24.2 mg, 268 μmol) was added. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25mm 10um; mobile phase: [water(formic acid) - acetonitrile]; B%: 21% - 51%, 11min) to give 1-[(1S,4S)-5-[4-[3-chloro-2- fluoro-4-[[(2R)-2-methyltetrahydrofuran-2-yl]methoxy]anilino ]pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (101 mg, 188 μmol, 70%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.36 - 9.22 (m, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.97 – 7.92 (m, 1H), 7.85 - 7.71 (m, 1H), 7.39 - 7.15 (m, 1H), 7.13 – 7.05 (m, 1H), 6.90 - 6.34 (m, 1H), 6.20 – 6.12 (m, 1H), 5.76 - 5.56 (m, 1H), 5.49 - 5.14 (m, 1H), 5.10 - 4.88 (m, 1H), 3.97 (s, 2H), 3.80 (t, J = 6.4 Hz, 2H), 3.76 - 3.47 (m, 4H), 2.09 - 1.97 (m, 4H), 1.96 - 1.87 (m, 1H), 1.75 - 1.67 (m, 1H), 1.29 (s, 3H); m/z ES+[M+H] ⁺ 539.0. Example 394. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-(((S)-2- methyltetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one Step 1. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-(((S)-2- methyltetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrim idin-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2S)-2- methyltetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (190 mg, 324 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the reaction mixture was stirred at 25 °C for 30 min. On completion, the reaction mixtue was concentrated in vacuo to give N-[3-chloro-2-fluoro- 4-[[(2S)-2-methyltetrahydrofuran-2-yl]methoxy]phenyl]-6-[(1S ,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (140 mg, 288 μmol, 88%) as a yellow oil without further purification. m/z ES+[M+H] ⁺ 485.0. Step 2. 1-((1S,4S)-5-(4-((3-Chloro-2-fluoro-4-(((S)-2-methyltetrahyd rofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-[[(2S)-2-methyltetrahydrofuran-2-yl]m ethoxy]ph enyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3 ,2-d]pyrimidin-4-amine (140 mg, 288 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (24.2 mg, 288 μmol) at 0 °C to pH = 7~8, and then prop-2-enoyl chloride (26.1 mg, 288 μmol) was added. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25mm 10um; mobile phase: [water(formic acid) - acetonitrile]; B%: 21% - 51%, 11min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[[(2S)-2- methyltetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (91.8 mg, 170 μmol, 59%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 - 9.19 (m, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.85 - 7.70 (m, 1H), 7.40 - 7.16 (m, 1H), 7.12 - 7.04 (m, 1H), 6.89 - 6.34 (m, 1H), 6.20 - 6.09 (m, 1H), 5.75 - 5.59 (m, 1H), 5.52 - 5.11 (m, 1H), 5.09 - 4.87 (m, 1H), 3.97 (s, 2H), 3.84 - 3.78 (m, 2H), 3.77 - 3.44 (m, 4H), 2.11 - 1.97 (m, 4H), 1.95 - 1.85 (m, 1H), 1.75 - 1.65 (m, 1H), 1.29 (s, 3H); m/z ES+[M+H] ⁺ 539.0. Example 395. Preparation of 1-((1S,4S)-5-(4-((4-(difluoromethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-butyl (1S,4S)-5-(4-((4-(difluoromethoxy)-2,3-difluorophenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A mixture of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-hydroxyphenyl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (200 mg, 0.426 mmol), sodium 2-chloro-2,2-difluoroacetate (648 mg, 4.26 mmol) and cesium carbonate (1.39 g, 4.26 mmol) in N,N-dimethylformamide (7 mL) and water (1 mL) was stirred at 100 °C for 2 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-((4- (difluoromethoxy)-2,3-difluorophenyl)amino)pyrido[3,2-d]pyri midin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, crude) as a gray solid. m/z ES+ [M+H] ⁺ 521.1. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(difluor omethoxy)-2,3- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl (1S,4S)-5-(4-((4-(difluoromethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (300 mg, 0.577 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% Formic acid condition) to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(difluor omethoxy)-2,3- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (70 mg, 0.166 mmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.29 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.72 - 7.61 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.46 - 7.35 (m, 1H), 7.31 - 6.92 (m, 1H), 5.61 - 5.32 (m, 1H), 4.65 (s, 1H), 4.01 - 3.72 (m, 2H), 3.49 (s, 2H), 2.34 (d, J = 11.6 Hz, 1H), 2.16 (d, J = 10.8 Hz, 1H); m/z ES+ [M+H] ⁺ 421.9. Step 3. 1-((1S,4S)-5-(4-((4-(Difluoromethoxy)-2,3-difluorophenyl)ami no)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(difluor omethoxy)- 2,3-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (50 mg, 0.118 mmol) and sodium bicarbonate (45.0 mg, 0.355 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop- 2-enoyl chloride (8.73 mg, 0.106 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um;mobile phase: [water(ammonium bicarbonate) - acetonitrile]; B%: 30% - 60%, 9 min) to give 1-((1S,4S)-5-(4- ((2,3-difluoro-4-hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (41.0 mg, 86 μmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.78 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.37 - 7.30 (m, 1H), 7.22 - 6.82 (m, 2H), 6.81 - 6.39 (m, 1H), 6.31 – 6.25 (m, 1H), 5.84 - 5.68 (m, 1H), 5.27 - 5.11 (m, 1H), 5.03 (br d, J = 16.0 Hz, 1H), 3.83 - 3.49 (m, 4H), 2.19 - 2.03 (m, 2H); m/z ES+ [M+H] ⁺ 475.1. Example 396. Preparation of 1-((1S,4S)-5-(4-((4-(difluoromethoxy)-2-fluoro-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (2 g, 5.5 mmol) in acetonitrile (20 mL) was added 3- chloro-4-(difluoromethoxy)-2-fluoroaniline (1.3 g, 6.1 mmol). The mixture was stirred at 40 °C for 2 hr. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1 g, 1.86 mmol, 30%) as a yellow solid. m/z ES+ [M+H] ⁺ 537.2. Step 2. tert-Butyl (1S,4S)-5-(4-((4-(difluoromethoxy)-2-fluoro-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (60.0 mg, 111 μmol), methylboronic acid (133 mg, 2.23 mmol) and sodium carbonate (35.5 mg, 335 μmol) in dioxane (2.0 mL) and water (0.4 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palla dium(II) (8.79 mg, 11.1 μmol) under nitrogen atmosphere. The reaction mixture was stirred at 110 °C under nitrogen atmosphere for 2 hr. On completion, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic phase was separated, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4- [4-(difluoromethoxy)-2-fluoro-3-methyl-anilino]pyrido[3,2-d] pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (50.0 mg, crude) as a yellow oil without purification. m/z ES+[M+H] ⁺ 517.3. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(difluor omethoxy)-2- fluoro-3-methylphenyl)pyrido[3,2-d]pyrimidin-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-[4-(difluoromethoxy)-2-fluoro-3-methyl- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (50.0 mg, 96.8 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[4- (difluoromethoxy)-2-fluoro-3-methyl-phenyl]pyrido[3,2-d]pyri midin-4-amine (30.0 mg, crude) as a yellow oil without purification. m/z ES+[M+H] ⁺ 417.2. Step 4. 1-((1S,4S)-5-(4-((4-(Difluoromethoxy)-2-fluoro-3- methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a mixture of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[4-(difluor omethoxy)- 2-fluoro-3-methyl-phenyl]pyrido[3,2-d]pyrimidin-4-amine (30.0 mg, 72.0 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (6.05 mg, 72.0 μmol) at 0 °C to pH ~ 7, and then prop-2-enoyl chloride (6.52 mg, 72.0 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic phase was separated, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25mm 10um; mobile phase: [water(formic acid)- acetonitrile]; B%: 20% - 50%, 10 min) to give 1-[(1S,4S)-5-[4-[4-(difluoromethoxy)-2-fluoro-3- methyl-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo [2.2.1]heptan-2-yl]prop-2-en-1-one (25.2 mg, 52.5 μmol, 72%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 - 9.05 (m, 1H), 8.43 - 8.29 (m, 1H), 8.22 - 8.01 (m, 1H), 7.92 (dd, J = 3.2, 9.2 Hz, 1H), 7.51 - 6.99 (m, 2H), 6.93 - 6.29 (m, 1H), 6.21 - 6.06 (m, 1H), 5.77 - 5.54 (m, 1H), 5.50 - 4.87 (m, 2H), 3.82 - 3.63 (m, 2H), 3.62 - 3.49 (m, 2H), 2.21 (d, J = 1.6 Hz, 3H), 2.11 - 1.99 (m, 2H); m/z ES+[M+H] ⁺ 471.0. Example 397. Preparation of 1-((1S,4S)-5-(4-((4-(2,2-difluoroethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-hydroxyphenyl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.9 g, 2.5 mmol) in acetonitrile (9 mL) was added 4- amino-2,3-difluoro-phenol (0.54 g, 3.7 mmol). The mixture was stirred at 40 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-((2,3- difluoro-4-hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (0.3 g, 0.64 mmol, 22%) as a yellow solid. m/z ES+ [M+H] ⁺ 471.2. Step 2. tert-Butyl (1S,4S)-5-(4-((4-(2,2-difluoroethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.15 g, 0.32 mmol) in N,N- dimethylformamide (1.5 mL) was added potassium carbonate (88 mg, 0.64 mmol) and 2,2- difluoroethyl trifluoromethanesulfonate (0.14 g, 0.64 mmol). The mixture was stirred at 40 °C for 12 hr. The mixture was filtered to remove potassium carbonate. The filtrate was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm 3 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 32% - 62%, 7 min) to give tert-butyl (1S,4S)-5-(4-((4-(2,2-difluoroethoxy)- 2,3-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-di azabicyclo[2.2.1]heptane-2- carboxylate (60 mg, 0.11 mmol, 35%) as a yellow solid. m/z ES+ [M+H] ⁺ 535.3. Step 3. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(2,2-dif luoroethoxy)-2,3- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-(2,2-difluoroethoxy)-2,3-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (60 mg, 0.11 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.31 g, 2.7 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(2,2-dif luoroethoxy)-2,3- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (70 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 435.1. Step 4. 1-((1S,4S)-5-(4-((4-(2,2-Difluoroethoxy)-2,3-difluorophenyl) amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[4-(2,2- difluoroethoxy)-2,3-difluoro-phenyl]pyrido[3,2-d]pyrimidin-4 -amine (60 mg, 0.11 mmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (37 mg, 0.44 mmol) and prop-2-enoyl chloride (9.9 mg, 0.11 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 35%-65%, 8 min) to give 1-((1S,4S)-5-(4-((4-(2,2- difluoroethoxy)-2,3-difluorophenyl)amino)pyrido[3,2-d]pyrimi din-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (17.75 mg, 36 μmol, 33%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (d, J = 2.0 Hz, 1H), 8.07 - 7.93 (m, 1H), 7.87 (dd, J = 2.8, 9.2 Hz, 1H), 7.31 - 7.15 (m, 1H), 7.02 (br t, J = 8.8 Hz, 1H), 6.79 (dd, J = 10.4, 16.8 Hz, 1H), 6.52 - 6.41 (m, 1H), 6.40 - 6.18 (m, 2H), 5.86 - 5.67 (m, 1H), 5.40 - 5.13 (m, 1H), 5.07 (d, J = 14.4 Hz, 1H), 4.36 (dt, J = 3.6, 13.6 Hz, 2H), 3.87 - 3.73 (m, 2H), 3.72 - 3.51 (m, 2H), 2.22 - 2.07 (m, 2H); m/z ES+ [M+H] ⁺ 489.0. Example 398. Preparation of 1-((1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.15 g, 0.32 mmol) in N,N- dimethylformamide (1.5 mL) was added potassium carbonate (88 mg, 0.64 mmol) and bromomethylcyclopropane (86 mg, 0.64 mmol). The mixture was stirred at 40 °C for 12 hr. On completion, the mixture was filtered to remove potassium carbonate. The filtrate was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm 3 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 35% - 65%, 7 min) to give tert-butyl (1S,4S)-5-(4-((4-(cyclopropylmethoxy)- 2,3-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-di azabicyclo[2.2.1]heptane-2- carboxylate (55 mg, 104 μmol, 33%) as a yellow oil. m/z ES+ [M+H] ⁺ 525.4. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(cyclopr opylmethoxy)-2,3- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2,3-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (55 mg, 0.1 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.31 g, 2.7 mmol). On completion, the mixture was concentrated in vacuo to give 6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(cyclopropylmethoxy)-2, 3-difluorophenyl)pyrido[3,2- d]pyrimidin-4-amine (65 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 425.2. Step 3. 1-((1S,4S)-5-(4-((4-(Cyclopropylmethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[4-(cyclopropylmethoxy)-2,3-difluoro-phenyl]-6-[(1S,4S)-2, 5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (55 mg, 0.1 mmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (34 mg, 0.41 mmol) and prop-2-enoyl chloride (9.2 mg, 0.10 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 41% - 71%, 8 min) to give 1-((1S,4S)-5-(4-((4- (cyclopropylmethoxy)-2,3-difluorophenyl)amino)pyrido[3,2-d]p yrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (9.33 mg, 19.5 μmol, 18%) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ 8.30 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 1.6, 9.2 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H), 6.78 (dd, J = 10.4, 16.8 Hz, 1H), 6.50 - 6.40 (m, 1H), 6.36 - 6.24 (m, 1H), 5.84 - 5.66 (m, 1H), 5.41 - 5.13 (m, 1H), 5.06 (br d, J = 14.8 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 3.87 - 3.71 (m, 2H), 3.71 - 3.49 (m, 2H), 2.26 - 2.03 (m, 2H), 1.34 - 1.27 (m, 1H), 0.69 - 0.62 (m, 2H), 0.39 (q, J = 5.2 Hz, 2H); m/z ES+ [M+H] ⁺ 479.1. Example 399. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4-(oxetan-3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaz abicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. 4-((6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2 -d]pyrimidin-4- yl)amino)-2,3-difluorophenol A mixture of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-hydroxyphenyl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (120 mg, 0.255 mmol) in trifluoroacetic acid (0.33 mL) and dichloromethane (1 mL) was stirred at 25 °C for 30 min. On completion, the mixture was concentrated in vacuo to give 4-((6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2-d]pyrimidin-4-yl)a mino)-2,3-difluorophenol (120 mg, TFA, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 370.9. Step 2. 1-((1S,4S)-5-(4-((2,3-Difluoro-4-hydroxyphenyl)amino)pyrido[ 3,2-d]pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of 4-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2 - d]pyrimidin-4-yl)amino)-2,3-difluorophenol (100 mg, 0.27 mmol) and sodium bicarbonate (68.0 mg, 0.81 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (22.0 mg, 0.26 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 1-((1S,4S)-5-(4-((2,3-difluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5diazabic yclo[2.2.1]heptan-2-yl)prop-2- en-1-one (41.0 mg, 96.5 μmol, 51%) as a yellow solid. m/z ES+ [M+H] ⁺ 424.9. Step 3. 1-((1S,4S)-5-(4-((2,3-Difluoro-4-(oxetan-3-ylmethoxy)phenyl) amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one A mixture of 1-((1S,4S)-5-(4-((2,3-difluoro-4-hydroxyphenyl)amino)pyrido[ 3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (70 mg, 0.165 mmol), oxetan-3-ylmethyl methanesulfonate (32.9 mg, 1.2 eq) and potassium carbonate (45.59 mg, 0.33 mmol) in N,N-dimethylformamide (1 mL) was stirred at 40 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was directly purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 30% - 60%, 8 min) to give 1-((1S,4S)-5-(4-((2,3-difluoro-4-(oxetan-3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaz abicyclo[2.2.1]heptan-2-yl)prop- 2-en-1-one (41.0 mg, 83 μmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.94 (s, 1H), 8.60 (s, 1H), 8.43 (t, J = 8.8 Hz, 1H), 8.12 - 8.03 (m, 1H), 7.05 - 6.95 (m, 1H), 6.93 - 6.82 (m, 1H), 6.59 - 6.42 (m, 1H), 6.41 - 6.22 (m, 1H), 5.82 - 5.66 (m, 1H), 5.25 - 4.80 (m, 1H), 5.23 - 4.80 (m, 1H), 4.60 (t, J = 6.0 Hz, 2H), 4.33 (d, J = 6.8 Hz, 2H), 4.00 - 3.96 (m, 1H), 3.85 - 3.70 (m, 3H), 3.65 (d, J = 8.0 Hz, 1H), 3.54 - 3.41 (m, 1H), 2.24 - 2.10 (m, 2H); m/z ES+ [M+H] ⁺ 495.1. Example 400. Preparation of N-(1-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl )acrylamide Step 1. 6-Chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri do[3,2- d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (100 mg, 500 μmol) in acetonitrile (1 mL) was added 3-chloro-4-(difluoromethoxy)-2-fluoroaniline (106 mg, 500 μmol). The mixture was stirred at 40 °C for 1 hr. On completion, the reaction mixture was filtered and the cake was concentrated in vacuo to give a residue. The residue was triturated with acetonitrile (3 mL) at 25 ^o C for 5 min and then filtered. The filtered cake was concentrated in vacuo to give 6- chloro-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]pyrid o[3,2-d]pyrimidin-4-amine (170 mg, 424 μmol, 85%) as a yellow solid. m/z ES+ [M+H] ⁺ 374.9. Step 2. tert-Butyl (1-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl )carbamate To a solution of 6-chloro-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]pyr ido[3,2- d]pyrimidin-4-amine (150 mg, 400 μmol) in 1-methyl-2-pyrrolidinone (1.5 mL) was added diisopropylethylamine (155 mg, 1.20 mmol) and tert-butyl N-(azetidin-3- yl)carbamate;hydrochloride (91.8 mg, 440 μmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was pour into water (3 mL) and filtered. The cake was concentrated in vacuo to give tert-butyl (1-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl )carbamate (150 mg, crude) as a brown solid. m/z ES+ [M+H] ⁺ 511.3. Step 3. 6-(3-Aminoazetidin-1-yl)-N-(3-chloro-4-(difluoromethoxy)-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)azetidin-3-yl )carbamate (125 mg, 245 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give 6-(3- aminoazetidin-1-yl)-N-(3-chloro-4-(difluoromethoxy) -2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (125 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 411.1. Step 4. N-(1-(4-((3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)acrylamide To a solution of 6-(3-aminoazetidin-1-yl)-N-(3-chloro-4-(difluoromethoxy)-2- fluorophenyl)pyrido [3,2-d]pyrimidin-4-amine (125 mg, 238 μmol, TFA) in tetrahydrofuran (1 mL) was added sodium bicarbonate (100 mg, 1.19 mmol) in water (1 mL). Then prop-2-enoyl chloride (21.6 mg, 238 μmol) was added. The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm 10um; mobile phase: [water (formic acid)- acetonitrile]; B%: 26% - 56%, 10 min) to give N-(1-(4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)azetidin-3-yl)acrylamide (18.0 mg, 38.7 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.85 (br d, J = 6.8 Hz, 1H), 8.41 (s, 1H), 8.19 (t, J = 8.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.51 - 7.11 (m, 3H), 6.28 - 6.10 (m, 2H), 5.70 - 5.61 (m, 1H), 4.80 - 4.69 (m, 1H), 4.47 (t, J = 8.4 Hz, 2H), 4.07 - 3.99 (m, 2H); m/z ES+ [M+H] ⁺ 465.0. Example 401. Preparation of 1-((1S,4S)-5-(4-((5-(cyclopropylmethoxy)-3-fluoropyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one

Step 1. 5-Bromo-3-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine To a solution of 5-bromo-3-fluoro-pyridin-2-amine (5.00 g, 26.1 mmol) in dimethyl acetamide (75 mL) was added sodium hydride (3.14 g, 78.5 mmol, 60% in mineral oil) portionwise at 0 °C, then the mixture was stirred at 0 °C for 0.5 hr. Then 1-(chloromethyl)-4- methoxybenzene (8.20 g, 52.3 mmol) was added dropwise into the mixture. The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 4/1) to give 5-bromo-3- fluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (6.5 g, 13.3 mmol, 51%) as a yellow liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.90 - 7.64 (m, 1H), 7.15 (d, J = 8.4 Hz, 4H), 6.87 (d, J = 8.4 Hz, 4H), 4.57 (s, 4H), 3.72 (s, 6H), 1.99 (s, 1H), 1.18 (t, J = 7.2 Hz, 1H); m/z ES+ [M+H] ⁺ 432.7. Step 2. 5-Bromo-3-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine A mixture of 5-bromo-3-fluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-a mine (2.47 g, 5.73 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (1.75 g, 6.87 mmol), potassium acetate (1.69 g, 17.2 mmol) in dioxane (10 mL) was degassed and purged with nitrogen for 3 times, then the mixture was added cyclopenta-2,4- dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) (419 mg, 572 μmol). The mixture was stirred at 80 °C for 2 hr under nitrogen atmosphere. On completion, the mixture was diluted with ethyl acetate (200 mL) and washed with brine (20 mL). The organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 3-fluoro-N,N-bis[(4- methoxyphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)pyridin-2-amine (0.5 g, 1.35 mmol, 13%) as a yellow solid. m/z ES+ [M+H] ⁺ 479.0. Step 3. 6-(Bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-ol To a solution of 3-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-(4,4,5,5-tetrame thyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine (4.5 g, 9.41 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was added hydrogen peroxide (5.33 g, 47.0 mmol, 30%) at -10 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was diluted with ethyl acetate (100 mL) and washed with brine (20 mL). The organic layers were dried over sodium sulfate, filtered and carefully concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane/ethyl acetate=1/0 to 10/1) to give 6-[bis[(4- methoxyphenyl)methyl]amino]-5-fluoro-pyridin-3-ol (1.76 g, 4.6 mmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.1 (d, J = 8.4 Hz, 3H), 7.07 – 6.98 (m, 1H), 6.84 (d, J = 8.4 Hz, 5H), 4.31 (s, 4H), 3.71 (s, 5H), 3.83 - 3.62 (m, 1H); m/z ES+ [M+H] ⁺ 369.0. Step 4. 5-(Cyclopropylmethoxy)-3-fluoro-N,N-bis(4-methoxybenzyl)pyri din-2-amine To a solution of 6-[bis[(4-methoxyphenyl)methyl]amino]-5-fluoro-pyridin-3-ol (600 mg, 1.63 mmol) and bromomethylcyclopropane (879 mg, 6.51 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (675 mg, 4.89 mmol). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was diluted with ethyl acetate (200 mL) and washed with brine (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 5-(cyclopropylmethoxy)-3-fluoro-N,N-bis[(4-methoxyphenyl)met hyl]pyridin-2-amine (600 mg, 1.37 mmol, 84%) as a yellow liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (d, J = 2.4 Hz, 1H), 7.38 - 7.25 (m, 1H), 7.14 (d, J = 8.4 Hz, 4H), 6.76 - 6.97 (m, 1H), 6.85 (d, J = 8.4 Hz, 3H), 4.38 (s, 4H), 3.80 (d, J = 7.2 Hz, 2H), 3.71 (s, 6H), 2.66 - 2.32 (m, 11H), 1.41 - 1.01 (m, 1H), 0.72 - 0.44 (m, 2H), 0.41 -0.09 (m, 2H); m/z ES+ [M+H] ⁺ 423.1. Step 5. 5-(Cyclopropylmethoxy)-3-fluoropyridin-2-amine To a solution of 5-(cyclopropylmethoxy)-3-fluoro-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine (580 mg, 1.37 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (7.70 mg, 67.5 μmol,). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was diluted with ethyl acetate (50 mL) and washed with brine (15 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 5-(cyclopropylmethoxy)-3-fluoro-pyridin-2-amine (70 mg, 0.38 mmol, 27%) as a yellow solid. m/z ES+ [M+H] ⁺ 183.1. Step 6. tert-Butyl (1S,4S)-5-(4-((5-(cyclopropylmethoxy)-3-fluoropyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (30.5 mg, 84.4 μmol) and potassium tert-butoxide (37.9 mg, 337 μmol) in dimethylsulfoxide (2 mL) was stirred at 25 °C for 0.5 hr. Then 5- (cyclopropylmethoxy)-3-fluoro-pyridin-2-amine (20.0 mg, 109 μmol) was added. The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was diluted with ethyl acetate (15 mL) and washed with brine (5 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-[4-[[5-(cyclopropylmethoxy)-3-fluoro-2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (5.00 mg, 9.84 μmol, 10%) as a yellow solid. m/z ES+ [M+H] ⁺ 508.2. Step 7. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-(cyclopr opylmethoxy)-3- fluoropyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[[5-(cyclopropylmethoxy)-3-fluoro-2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (15.0 mg, 29.5 μmol) in dichloromethane (1.6 mL) was added trifluoroacetic acid (246 mg, 2.16 mmol). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[5-(cyclopropylmethoxy)-3-fluoro-2-pyridyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (15.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 408.0. Step 8. 1-((1S,4S)-5-(4-((5-(Cyclopropylmethoxy)-3-fluoropyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one To a solution of N-[5-(cyclopropylmethoxy)-3-fluoro-2-pyridyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (15.0 mg, 36.81 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (9.28 mg, 110 μmol) to adjust pH = 7. Then prop-2-enoyl chloride (888 ug, 9.82 μmol) was added. The mixture was stirred at 0 °C for 10 mins. On completion, the reaction mixture was filtered, concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 x 30mm 5um; mobile phase: [water(formic acid) - acetonitrile]; B%: 15% - 45%, 8 min) to give 1-[(1S,4S)-5-[4-[[5-(cyclopropylmethoxy)-3-fluoro-2-pyridyl] amino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one (4.02 mg, 8.7 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 - 9.46 (m, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.94- 7.84 (m, 1H), 7.71-7.51 (m, 1H), 6.93 - 6.32 (m, 1H), 6.22 - 6.08 (m, 1H), 5.79 - 5.56 (m, 1H), 5.10 - 4.90 (m, 1H), 3.98 (d, J = 7.2 Hz, 2H), 3.81 - 3.47 (m, 5H), 2.09 - 1.96 (m, 2H), 1.43 - 1.21 (m, 1H), 0.72 - 0.55 (m, 2H), 0.43 - 0.27 (m, 2H); m/z ES+ [M+H] ⁺ 462.6. Example 402. Preparation of 1-((1S,4S)-5-(4-((5-(difluoromethoxy)-3-fluoropyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one Step 1. 5-(Difluoromethoxy)-3-fluoro-N,N-bis(4-methoxybenzyl)pyridin -2-amine To a solution of 6-[bis[(4-methoxyphenyl)methyl]amino]-5-fluoro-pyridin-3-ol (2.00 g, 5.43 mmol) in N,N-dimethylformamide (35 mL) and water (7 mL) was added potassium carbonate (2.25 g, 16.2 mmol) and (2-chloro-2,2-difluoro-acetyl)oxysodium (1.66 g, 10.8 mmol). The mixture was stirred at 80 °C for 16 hr. On completion, the mixture was poured into water (80 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 5-(difluoromethoxy)-3-fluoro-N,N- bis[(4-methoxyphenyl)methyl]pyridin-2-amine (650 mg, 1.55 mmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (d, J = 2.0 Hz, 1H), 7.66-7.48 (m, 1H), 7.32 (s, 1H), 7.22 - 7.06 (m, 5H), 6.89 - 6.84 (m, 4H), 4.55 (s, 4H), 3.72 (s, 6H); m/z ES+ 419.0. Step 2. 5-(Difluoromethoxy)-3-fluoropyridin-2-amine To a solution of 5-(difluoromethoxy)-3-fluoro-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine (600 mg, 1.29 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (6.40 g, 56.1 mmol). The mixture was stirred at 25 °C for 4 hr. On completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 2). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 5-(difluoromethoxy)-3-fluoro-pyridin-2-amine (220 mg, 1.23 mmol, 86%) as a yellow oil. m/z ES+ [M+H] ⁺ 178.9. Step 3. tert-Butyl (1S,4S)-5-(4-((5-(difluoromethoxy)-3-fluoropyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate To a solution of 5-(difluoromethoxy)-3-fluoro-pyridin-2-amine (100 mg, 561 μmol) in dimethylsulfoxide (5 mL) was added potassium tert-butoxide (193 mg, 1.73 mmol) at 25 °C. Then tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane- 2-carboxylate (156 mg, 431 μmol) was added. The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-[4-[[5-(difluoromethoxy)-3-fluoro-2-pyridyl]amino] pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (45.0 mg, 89.3 μmol, 20%) as a red solid. m/z ES+ [M+H] ⁺ 504.2. Step 4. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-(difluor omethoxy)-3- fluoropyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[[5-(difluoromethoxy)-3-fluoro-2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (40.0 mg, 79.45 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (9.06 mg, 79.45 μmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[5- (difluoromethoxy)-3-fluoro-2-pyridyl]pyrido[3,2-d]pyrimidin- 4-amine (40 mg, crude) as a brown solid. m/z ES+ [M+H] ⁺ 403.9. Step 5. 1-((1S,4S)-5-(4-((5-(Difluoromethoxy)-3-fluoropyridin-2-yl)a mino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[5-(difluor omethoxy)- 3-fluoro-2-pyridyl]pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, 99.1 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (8.33 mg, 99.17 μmol) and prop-2-enoyl chloride (5.39 mg, 59.50 μmol). The mixture was stirred at 0 °C for 10 mins. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150 x 25mm 5um; mobile phase: [water(ammonia)- acetonitrile]; B%: 20% - 50%, 8 min) to give 1-[(1S,4S)-5-[4-[[5- (difluoromethoxy)-3-fluoro-2-pyridyl]amino]pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (9.67 mg, 21 μmol, 21%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.91 - 9.82 (m, 1H), 8.32 - 8.27 (m, 2H), 7.95 – 7.90 (m, 2H), 7.58-7.19 (m, 2H), 6.79 - 6.35 (m, 1H), 6.18 - 6.16 (m, 1H), 5.72 – 5.63 (m, 1H), 5.06 – 4.90 (m, 1H), 3.71 - 3.40 (m, 5H), 2.08 - 1.99 (m, 2H); m/z ES+ [M+H]+ 458.1. Example 403. Preparation of 1-((1S,4S)-5-(4-((3,4-dichloro-2- methoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (3,4-dichloro-2-hydroxyphenyl)carbamate To a solution of 6-amino-2,3-dichloro-phenol (950 mg, 5.34 mmol) in dichloromethane (1 mL) was added di-tert-butyl dicarbonate (3.49 g, 16.0 mmol, 3.68 mL) and zinc chloride (727 mg, 5.34 mmol). The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 20:1 to 5:1) to give tert-butyl N-(3,4-dichloro-2-hydroxy-phenyl)carbamate (680 mg, 3.06 mmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (br s, 1H), 8.41 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 1.47 (s, 9H); m/z ES+ [M+H-56] ⁺ 222.0. Step 2. tert-Butyl (3,4-dichloro-2-methoxyphenyl)carbamate To a solution of tert-butyl N-(3,4-dichloro-2-hydroxy-phenyl)carbamate (650 mg, 2.34 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (484 mg, 3.51 mmol) and methyl iodide (497 mg, 3.51 mmol). The mixture was stirred at 25 °C for 6 hr. On completion, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (3,4-dichloro-2-methoxyphenyl)carbamate (650 mg, 3.38 mmol, 91%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H), 1.48 (s, 9H); m/z ES+ [M+H] ⁺ 292.0. Step 3. 3,4-Dichloro-2-methoxyaniline To a solution of tert-butyl N-(3,4-dichloro-2-methoxy-phenyl)carbamate (200 mg, 684 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol, 0.10 mL). The mixture was stirred at 25 °C for 12 hr. On completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 3,4-dichloro-2-methoxy-aniline (120 mg, 0.62 mmol, 65%) as a yellow oil. m/z ES+ [M+H] ⁺ 192.1. Step 4. tert-Butyl (1S,4S)-5-(4-((3,4-dichloro-2-methoxyphenyl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo [2.2.1]heptane-2-carboxylate (70.0 mg, 193 μmol) and 3,4-dichloro-2-methoxy- aniline (74.3 mg, 387 μmol) in acetonitrile (1 mL) was added trifluoroacetic acid (22.0 mg, 193 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, the mixture was filtered and the cake was concentrated in vacuo to give tert-butyl (1S,4S)-5-[4-(3,4-dichloro-2-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (58.0 mg, 0.11 mmol, 54%) as a yellow solid. m/z ES+ [M+H] ⁺ 517.0. Step 5. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3,4-dichlo ro-2- methoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-(3,4-dichloro-2-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (45.0 mg, 86.9 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(3,4-dichloro -2-methoxy-phenyl)pyrido[3,2- d]pyrimidin-4-amine (35.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 417.1. Step 6. 1-((1S,4S)-5-(4-((3,4-Dichloro-2-methoxyphenyl)amino)pyrido[ 3,2-d]pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(3,4-dichlo ro-2- methoxy-phenyl)pyrido[3,2-d]pyrimidin-4-amine (35.0 mg, 83.8 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (7.05 mg, 83.8 μmol) to adjust pH = 7, then prop-2-enoyl chloride (7.59 mg, 83.8 μmol) was added to the mixture. The mixture was stirred at 0 °C for 15 mins. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 x 30mm 5um; mobile phase: [water(formic acid) - acetonitrile]; B%: 32% - 62%, 8 min) to give 1-[(1S,4S)-5-[4-(3,4-dichloro-2-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (22.0 mg, 46.7 μmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.82 (d, J = 9.0 Hz, 1H), 8.53 (s, 1H), 8.03 - 7.94 (m, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.46 - 7.23 (m, 1H), 6.98 - 6.31 (m, 1H), 6.20 - 6.09 (m, 1H), 5.74 - 5.61 (m, 1H), 5.42 - 4.87 (m, 2H), 3.99 (d, J = 1.6 Hz, 3H), 3.87 - 3.48 (m, 4H), 2.18 - 2.02 (m, 2H); m/z ES+ [M+H] ⁺ 471.2. Example 404. Preparation of 1-((1S,4S)-5-(4-((5-chloro-3-fluoro-4-methylpyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)prop-2-en-1-one Step 1. N-(5-Chloro-3-fluoropyridin-2-yl)acetamide To a solution of 5-chloro-3-fluoro-pyridin-2-amine (2.00 g, 13.6 mmol) in acetic acid (2 mL) was added acetic anhydride (2.00 g, 19.6 mmol) and ferric chloride (60.0 mg, 370 μmol). The mixture was stirred at 25 °C for 3 hr. On completed, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 20:1 to 0:1) to give N- (5-chloro-3-fluoro-2-pyridyl)acetamide (2.30 g, 12.1 mmol, 86%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.13 - 8.09 (m, 1H), 2.08 (s, 3H); m/z ES+ [M+H] ⁺ 189.0 Step 2. N-(5-Chloro-3-fluoro-4-methylpyridin-2-yl)acetamide To a stirred solution of N-(5-chloro-3-fluoro-2-pyridyl)acetamide (500 mg, 2.65 mmol) and diisopropylamine (670 mg, 6.63 mmol) in tetrahydrofuran (8 mL) was added n-butyllithium (2.5 M in tetrahydrofuran, 2.65 mL) dropwise at -70 °C, keeping the internal temperature below - 60 °C. Then the mixture was stirred at -70 °C for 2 hr. Then methyl iodide (752 mg, 5.30 mmol) was added to the mixture. The mixture was stirred at -70 °C to -60 °C for 2 hrs under nitrogen atmosphere. On completion, the mixture was quenched by dropwise addition of water (5 mL) in the ice bath, and then stirred in the ice bath for 0.5 hs. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give N-(5-chloro-3-fluoro-4-methyl-2- pyridyl)acetamide (250 mg, 1.23 mmol, 45%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (br s, 1H), 8.30 (s, 1H), 2.07 (s, 6H); m/z ES+ [M+H] ⁺ 202.8. Step 3. 5-Chloro-3-fluoro-4-methylpyridin-2-amine To a solution of N-(5-chloro-3-fluoro-4-methyl-2-pyridyl)acetamide (250 mg, 1.23 mmol) in methanol (3 mL) was added concentrated hydrochloric acid (12 M, 2 mL). The mixture was refluxed at 60 °C for 4 hr. On completion, the mixture was quenched by saturated sodium hydroxide (2 mL) to adjust pH > 7. Then the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 5-chloro-3-fluoro-4-methyl-pyridin-2-amine (198 mg, 1.23 mmol, 99%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 6.29 (s, 2H), 2.20 (d, J = 2.4 Hz, 3H); m/z ES+ [M+H] ⁺ 161.1. Step 4. tert-Butyl (1S,4S)-5-(4-((5-chloro-3-fluoro-4-methylpyridin-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate To a solution of 5-chloro-3-fluoro-4-methyl-pyridin-2-amine (150 mg, 939 μmol) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (131 mg, 1.17 mmol), the mixture was stirred at 25 °C for 0.5 hr. Then tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg, 469 μmol) was added to the mixture. The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The crude product was purified by reversed- phase HPLC (0.1% formic acid condition) to gave tert-butyl (1S,4S)-5-[4-[(5-chloro-3-fluoro-4- methyl-2-pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diaz abicyclo[2.2.1]heptane-2- carboxylate (80.0 mg, 165 μmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.99 - 9.63 (m, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.55 - 6.97 (m, 1H), 4.59 - 4.50 (m, 1H), 3.71 - 3.56 (m, 1H), 3.45 - 3.37 (m, 2H), 3.31 - 3.21 (m, 2H), 2.39 (d, J = 1.6 Hz, 3H), 2.03 - 1.86 (m, 2H), 1.50 - 1.29 (m, 9H); m/z ES+ [M+H] ⁺ 486.0. Step 5. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(5-chloro-3 -fluoro-4- methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[(5-chloro-3-fluoro-4-me thyl-2-pyridyl)am ino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept ane-2-carboxylate (60.0 mg, 123 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give N-(5-chloro-3-fluoro-4-methyl-2-pyridyl)-6-[(1S,4S)-2,5-diaz abicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (45.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 386.0. Step 6. 1-((1S,4S)-5-(4-((5-Cloro-3-fluoro-4-methylpyridin-2-yl)amin o)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-(5-chloro-3-fluoro-4-methyl-2-pyridyl)-6-[(1S,4S)-2,5-di azabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (45.0 mg, 116 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (9.80 mg, 116 μmol) to adjust pH = 7, then prop-2-enoyl chloride (10.5 mg, 116.6 μmol) was added. The mixture was stirred at 0 °C for 15 mins. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25mm 10um; mobile phase: [water(ammonium bicarbonate) - acetonitrile]; B%: 20% - 50%, 11min) to give 1-[(1S,4S)-5-[4-[(5-chloro-3-fluoro-4-methyl-2- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptan-2-yl]prop-2-en-1-one (34.1 mg, 77 μmol, 65%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 - 9.69 (m, 1H), 8.42 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.04 - 7.82 (m, 1H), 7.50 - 7.10 (m, 1H), 6.89 - 6.33 (m, 1H), 6.30 - 5.99 (m, 1H), 5.88 - 5.49 (m, 1H), 5.15 - 4.86 (m, 1H), 3.76 - 3.49 (m, 4H), 3.44 - 3.39 (m, 1H), 2.39 (s, 3H), 2.09 - 1.98 (m, 2H); m/z ES+ [M+H] ⁺ 440.2. Example 405. Preparation of 1-(7-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspi ro[2.5]octan-4-yl)prop-2-en- 1-one Step 1. tert-Butyl 7-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspi ro[2.5]octane-4-carboxylate A solution of tert-butyl 7-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (120 mg, 319 μmol) and 3-chloro-4-(difluoromethoxy)-2- fluoroaniline (135 mg, 638 μmol) in acetonitrile (3.0 mL) was stirred at 80 °C for 12 hr. On completion, the reaction mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 20/80) to give tert-butyl 7-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]pyrido[3 ,4-d]pyri midin-6-yl]-4,7- diazaspiro[2.5]octane-4-carboxylate (70.0 mg, 127 μmol, 39%) as a yellow solid. m/z ES+[M+H] ⁺ 551.0. Step 2. N-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-6-(4,7-diaza spiro[2.5]octan- 7-yl)pyrido[3,4-d]pyrimidin-4-amine To a mixture of tert-butyl 7-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octa ne-4-carboxylate (70.0 mg, 127 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (50.0 mg, 110 μmol, 87%) as a yellow solid without further purification. m/z ES+[M+H] ⁺ 450.9. Step 3. 1-(7-(4-((3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)amino) pyrido[3,4- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one To a mixture of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (50.0 mg, 110 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (9.32 mg, 110 μmol) at 0 °C to pH = 7~8, and then prop-2-enoyl chloride (10.0 mg, 110 μmol) was added. The reaction mixture was stirred at 0 °C for 30 mins. On completion, the reaction mixture was quenched by water (10.0 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25mm 10um; mobile phase: [water(formic acid) - acetonitrile]; B%: 34% - 67%, 11min) to give 1-[7-[4-[3-chloro-4-(difluoromethoxy)-2- fluoro-anilino]pyrido[3,4-d]pyr imidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1-one (46.6 mg, 90.5 μmol, 81%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 - 9.83 (m, 1H), 8.92 - 8.80 (m, 1H), 8.41 - 8.26 (m, 1H), 7.66 - 7.57 (m, 1H), 7.57 - 7.18 (m, 3H), 7.03 - 6.82 (m, 1H), 6.17 (br d, J = 16.8 Hz, 1H), 5.74 (br d, J = 10.4 Hz, 1H), 3.90 - 3.64 (m, 4H), 3.57 (br s, 2H), 1.18 - 0.95 (m, 4H); m/z ES+[M+H] ⁺ 504.9. Example 406. Preparation of 1-(7-(4-((3-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspi ro[2.5]octan-4-yl)prop-2-en- 1-one

Step 1. tert-Butyl 7-(4-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)pyrido[3,4- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate A solution of tert-butyl 7-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (0.5 g, 1.33 mmol), 4-amino-2-chloro-3-fluoro-phenol (214 mg, 1.33 mmol) in acetonitrile (6 mL) was stirred at 25 °C for 16 hr. On completion, the mixture was filtered and the filtered cake was collected to give tert-butyl 7-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4,7-diazasp iro[2.5]octane-4-carboxylate (0.7 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 501.0. Step 2. tert-Butyl 7-(4-((3-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspi ro[2.5]octane-4-carboxylate A solution of tert-butyl 7-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,4- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate (0.2 g, 399 μmol), 2,2-difluoroethyl trifluoromethanesulfonate (170 mg, 798 μmol) and potassium carbonate (110 mg, 798 μmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 16 hr. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 7- (4-((3-chloro-4-(2,2-difluoroethoxy)-2-fluorophenyl)amino)py rido[3,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (0.15 g, crude) as a brown oil. m/z ES+[M+H] ⁺ 565.3. Step 3. N-(3-Chloro-4-(2,2-difluoroethoxy)-2-fluorophenyl)-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4-amine To a solution of tert-butyl 7-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octa ne-4-carboxylate (0.15 g, 265 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.15 g, 10.1 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give N-(3- chloro-4-(2,2-difluoroethoxy)-2-fluorophenyl)-6-(4,7-diazasp iro[2.5]octan-7-yl)pyrido[3,4- d]pyrimidin-4-amine (0.15 g, crude, TFA) as a yellow solid. Step 4. 1-(7-(4-((3-Chloro-4-(2,2-difluoroethoxy)-2-fluorophenyl)ami no)pyrido[3,4- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan-4-yl)prop-2-en-1- one To a solution of N-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (0.15 g, 259 μmol, TFA) and sodium bicarbonate (65.3 mg, 777 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2- enoyl chloride (23.4 mg, 259 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 38% - 68%, 7 min) to give 1-(7-(4-((3-chloro-4-(2,2-difluoroethoxy)-2- fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-4,7-diazaspi ro[2.5]octan-4-yl)prop-2-en-1-one (85 mg, 164 μmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1 H), 8.84 (s, 1 H), 8.32 (s, 1 H), 7.59 - 7.35 (m, 2 H), 7.25 - 7.11 (m, 1 H), 7.00 – 6.82 (m, 1 H), 6.66 - 6.29 (m, 1 H), 6.17 (dd, J = 2.4, 16.8 Hz, 1 H), 5.83 - 5.65 (m, 1 H), 4.52 (td, J=3.2, 14.4 Hz, 2 H), 3.86 (s, 2 H), 3.72 - 3.54 (m, 4 H), 1.03 (s, 4 H); m/z ES+[M+H] ⁺ 518.9. Example 407. Preparation of (S)-1-(6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptan-1- yl)prop-2-en-1-one

Step 1. (S)-(tetrahydrofuran-3-yl)methyl methanesulfonate To a solution of [(3R)-tetrahydrofuran-3-yl]methanol (500 mg, 4.90 mmol) in dichloromethane (8 mL) was added triethylamine (1.49 g, 14.7 mmol). Then methylsulfonyl methanesulfonate (2.56 g, 14.7 mmol) was added into the mixture at 0 °C. The mixture was stirred at 25 °C for 2 hs. On completion, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried by sodium sulfate, filtered and concentrated in vacuo to give [(3S)-tetrahydrofuran-3-yl]methyl methanesulfonate (760 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.24 - 4.06 (m, 2H), 3.80 - 3.69 (m, 2H), 3.66 - 3.45 (m, 2H), 3.19 (s, 3H), 2.64 - 2.54 (m, 1H), 1.18 (t, J = 7.2 Hz, 2H). Step 2. tert-Butyl (S)-6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)quinazolin-6-yl)-1,6-diazaspiro[3.3] heptane-1-carboxylate To a solution of tert-butyl 6-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (300 mg, 616 μmol) and [(3S)- tetrahyd rofuran-3-yl]methyl methanesulfonate (444 mg, 2.46 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (255 mg, 1.85 mmol). The mixture was stirred at 80 °C for 4 hs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (S)-6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptane-1- carboxylate (200 mg, 350 μmol, 45%) as a black solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 - 9.10 (m, 1H), 8.36 (s, 1H), 8.03 - 7.88 (m, 4H), 4.60 - 4.52 (m, 2H), 4.28 - 4.24 (m, 1H), 4.17 - 4.00 (m, 4H), 3.88 - 3.77 (m, 4H), 3.75 - 3.65 (m, 4H), 2.11 - 1.98 (m, 2H), 1.14 (br s, 9H); m/z ES+ [M+H] ⁺ 571.2. Step 3. (S)-N-(3-chloro-2-fluoro-4-((tetrahydrofuran-3-yl)methoxy)ph enyl)-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[3-chloro-2-fluoro-4-[[(3S)-tetrahydrofuran-3-yl]metho xy]anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]h eptane-1-carboxylate (100 mg, 175 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]p henyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 471.2. Step 4. (S)-1-(6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptan-1-yl)prop-2- en-1-one To a solution of N-[3-chloro-2-fluoro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]p henyl]-6- (1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-ami ne (80.0 mg, 169 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (14.2 mg, 169 μmol) to adjust pH = 7. Then prop-2-enoyl chloride (15.3 mg, 169 μmol) was added. The mixture was stirred at 0 °C for 15 min. On completion, the mixture was filtered, concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- acetonitrile];B%: 24%-54%, 8 min) to give 1-[6- [4-[3-chloro-2-fluoro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy] anilino]pyrido[3,2-d]pyrimidin-6- yl]-1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (33.2 mg, 63.2 μmol, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.37 (s, 1H), 8.06 - 7.89 (m, 1H), 8.00 - 7.87 (m, 1H), 7.21 - 7.06 (m, 2H), 6.34 - 6.25 (m, 1H), 6.17 - 6.07 (m, 1H), 5.77 - 5.68 (m, 1H), 4.79 (br d, J = 9.6 Hz, 2H), 4.54 - 4.46 (m, 1H), 4.28 (d, J = 9.2 Hz, 2H), 4.20 - 4.01 (m, 4H), 3.86 - 3.76 (m, 3H), 3.74 - 3.53 (m, 2H), 2.78 - 2.69 (m, 1H), 2.11 - 1.99 (m, 1H), 1.77 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 525.2. Example 408. Preparation of (R)-1-(6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptan-1- yl)prop-2-en-1-one

Step 1. tert-Butyl (R)-6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptane-1- carboxylate To a solution of tert-butyl 6-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (360 mg, 739 μmol) in N, N- dimethyl formamide (3 mL) was added potassium carbonate (204 mg, 1.48 mmol) and [(3R)- tetrahydrofuran-3-yl]methyl methanesulfonate (200 mg, 1.11 mmol). The mixture was stirred at 60 °C for 16 hs. On completion, water was added into the mixture until there was no more solid precipitated out. Then the mixture was filtered and the filtered cake was collected to give tert- butyl 6-[4-[3-chloro-2-fluoro-4-[[(3R)-tetrahydrofuran-3-yl]methox y]anilino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (280 mg, 490 μmol, 49%) as a gray solid. m/z ES+ [M+1] ⁺ 571.0. Step 2. (R)-N-(3-chloro-2-fluoro-4-((tetrahydrofuran-3-yl)methoxy)ph enyl)-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[3-chloro-2-fluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspi ro[3.3]heptane-1-carboxylate (280 mg, 490 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]phenyl]-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyrido[ 3,2-d]pyrimidin-4-amine (280 mg, crude, TFA) as a brown oil. m/z ES+ [M+1] ⁺ 471.1. Step 3. (R)-1-(6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptan-1-yl)prop-2- en-1-one To a solution of N-[3-chloro-2-fluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]p henyl]-6- (1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-ami ne (280 mg, 594 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (149 mg, 1.78 mmol) to adjust pH ~ 7. Then prop-2-enoyl chloride (37.6 mg, 416 μmol) was added dropwise. The mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was filtered and the filtrate was purified by prep-HPLC (0.1% Formic acid condition. column: Phenomenex Luna C18100*30mm*5um;mobile phase: [water(FA)-ACN];B%: 20%-50%, 8 min) to give 1-[6-[4- [3-chloro-2-fluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]ani lino]pyrido[3,2-d]pyrimidin-6-yl]- 1,6-diazaspiro[3.3]heptan-1-yl]prop-2-en-1-one (52.0 mg, 99.0 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 - 9.00 (m, 1H), 8.37 (s, 1H), 8.11 - 7.79 (m, 2H), 7.32 - 6.90 (m, 2H), 6.64 - 6.25 (m, 1H), 6.21 - 6.03 (m, 1H), 5.83 - 5.59 (m, 1H), 4.83 - 4.26 (m, 4H), 4.18 - 4.10 (m, 2H), 4.09 - 4.02 (m, 1H), 3.85 - 3.77 (m, 2H), 3.72 - 3.57 (m, 2H), 2.77 - 2.70 (m, 1H), 2.64 - 2.57 (m, 3H), 2.18 - 1.97 (m, 1H), 1.85 - 1.60 (m, 1H); m/z ES+ [M+1] ⁺ 525.5. Example 409. Preparation of (R)-1-(6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptan-1- yl)prop-2-en-1-one Step 1. (R)-(tetrahydrofuran-2-yl)methyl methanesulfonate To a solution of [(2R)-tetrahydrofuran-2-yl]methanol (400 mg, 3.92 mmol) in dichloromethane (8 mL) was added triethylamine (1.19 g, 11.7 mmol), the mixture was stirred at 0 °C for 10 min. Then methylsulfonyl methanesulfonate (2.05 g, 11.7 mmol) was added in the mixture. The mixture was stirred at 25 °C for 2 hs. On completion, the mixture was poured into 20 mL water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (850 mg, 4.72 mmol, 96%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.23 - 4.15 (m, 1H), 4.14 - 4.03 (m, 2H), 3.75 (td, J = 6.8, 8.0 Hz, 1H), 3.66 (dt, J = 6.0, 7.6 Hz, 1H), 3.17 (s, 3H), 2.00 - 1.89 (m, 1H), 1.88 - 1.74 (m, 2H), 1.65 - 1.51 (m, 1H). Step 2. tert-Butyl (R)-6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptane-1- carboxylate To a solution of tert-butyl 6-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (200 mg, 410 μmol) in N,N- dimethylformamide (3.0 mL) was added potassium carbonate (113 mg, 821 μmol). And then [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (111 mg, 616 μmol) was added in the mixture. The mixture was stirred at 100 °C for 2 hs. On completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL). The organic layers were dried by anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 1/1 to 0/1) to give tert- butyl 6-[4-[3-chloro-2-fluoro-4-[[(2R)-tetrahydrofuran-2-yl]methox y]anilino]pyrido[3,2- d]pyrimidin-6-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (105 mg, 184 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.35 (s, 1H), 8.04 - 7.83 (m, 2H), 7.15 - 7.05 (m, 2H), 4.67 - 4.50 (m, 2H), 4.32 - 4.17 (m, 3H), 4.15 - 3.99 (m, 4H), 3.81 (t, J = 6.8 Hz, 2H), 3.71 (d, J = 6.8 Hz, 2H), 1.97 - 1.63 (m, 4H), 1.21 - 1.10 (m, 9H); m/z ES+ [M+H] ⁺ 571.3. Step 3. (R)-N-(3-chloro-2-fluoro-4-((tetrahydrofuran-2-yl)methoxy)ph enyl)-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 6-[4-[3-chloro-2-fluoro-4-[[(2R)-tetrahydrofuran-2- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]-1,6-diazaspi ro[3.3]heptane-1-carboxylate (85 mg, 148 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]p henyl]-6-(1,6- diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-amine (70 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 471.1. Step 4. (R)-1-(6-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1,6-dia zaspiro[3.3]heptan-1-yl)prop-2- en-1-one To a solution of N-[3-chloro-2-fluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]p henyl]-6- (1,6-diazaspiro[3.3]heptan-6-yl)pyrido[3,2-d]pyrimidin-4-ami ne (70 mg, 148 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (12.4 mg, 148 μmol) to adjust pH ~ 7. Then prop-2-enoyl chloride (18.8 mg, 208 μmol) was added in the mixture. The mixture was stirred at 0 °C for 15 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (neutral condition:column: Waters xbridge 150*25mm 10um;mobile phase: [water(ammonium bicarbonate)- acetonitrile];B%: 33%-63%,11min) to give 1-[6-[4-[3-chloro-2-fluoro-4-[[(2R)- tetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyrimidin- 6-yl]-1,6-diazaspiro[3.3]heptan-1- yl]prop-2-en-1-one (25.8 mg, 49.1 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- δ 9.22 - 9.09 (m, 1H), 8.37 (s, 1H), 8.05 - 7.98 (m, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.11 (dd, J = 2.4, 9.2 Hz, 2H), 6.64 - 6.26 (m, 1H), 6.18 - 6.05 (m, 1H), 5.78 - 5.67 (m, 1H), 4.82 - 4.26 (m, 4H), 4.26 - 4.20 (m, 1H), 4.20 - 4.01 (m, 4H), 3.86 - 3.80 (m, 1H), 3.75 - 3.67 (m, 1H), 2.66 - 2.55 (m, 2H), 2.08 - 1.92 (m, 2H), 1.89 - 1.73 (m, 2H); m/z ES+ [M+H] ⁺ 525.2. Example 410. 1-((1S,4S)-5-(4-((2,3-difluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5-diazabicyclo [2.2.1]heptan-2-yl)prop-2-en-1-one

Step 1. (1-Fluorocyclopropyl)methanol To a solution of 1-fluorocyclopropanecarboxylic acid (5 g, 48.0 mmol) in anhydrous tetrahydrofuran (40 mL) was added lithium aluminum hydride (2.01 g, 52.8 mmol) portionwise at 0 °C under nitrogen atmosphere. Then the mixtrue was stirred at 30 °C for 2 hs. On completion, the mixture was quenched with hydrochloric acid (1 N, 200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (40 mL), dried and concentarted in vacuo to give (1-fluorocyclopropyl)methanol (2 g, crude) as a colourless oil. ¹ H NMR (400 MHz, CDCl3) δ 3.84 - 3.71 (m, 2H), 1.12 - 0.96 (m, 2H), 0.73 - 0.56 (m, 2H). Step 2. (1-Fluorocyclopropyl)methyl methanesulfonate To a solution of (1-fluorocyclopropyl)methanol (2 g, 22.2 mmol) in dichloromethane (30 mL) was added triethylamine (8.99 g, 88.7 mmol) and methylsulfonyl methanesulfonate (7.73 g, 44.4 mmol) at 0 °C, the mixture was stirred at 25 °C for 2 hs. On completion, the reaction mixtrue was diluted with dichloromethane (200 mL), and the organic layers were washed with water (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (1-fluorocyclopropyl)methyl methanesulfonate (3.3 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 4.56 - 4.39 (m, 2H), 3.11 (s, 3H), 1.30 - 1.20 (m, 2H), 0.87 (q, J = 7.6 Hz, 2H). Step 3. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5-diazabicyclo[2.2.1] -heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (3 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.7 mmol) in N,N-dimethylformamide (50 mL) was added (1- fluorocyclopropyl)methyl methanesulfonate (1.61 g, 9.56 mmol), the mixture was stirred at 80 °C for 16 hs. On completion, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (125 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:2 to 1:3) to give tert-butyl (1S,4S)- 5-[4-[2,3-difluoro-4-[(1-fluorocyclopropyl)methoxy]anilino]p yrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (2.6 g, 4.72 mmol, 74%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 - 9.44 (m, 1H), 8.80 - 8.53 (m, 2H), 8.03 (s, 1H), 7.14 - 6.83 (m, 2H), 5.33 - 4.58 (m, 2H), 4.57 - 4.43 (m, 2H), 3.55 - 3.42 (m, 2H), 2.99 - 2.86 (m, 2H), 2.04 - 1.96 (m, 2H), 1.51 - 1.41 (m, 9H), 1.14 (d, J = 18.0 Hz, 2H), 0.85 - 0.66 (m, 2H); m/z ES+ [M+H] ⁺ 543.6. Step 4. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-((1- fluorocyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-am ine A solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (2.3 g, 4.24 mmol) in trifluoroacetic acid (4 mL) and dichloromethane (20 mL) was stirred at 25 °C for 4 hs. On completion, the mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4- [(1-fluorocyclopropyl)methoxy]phenyl]pyrido [3,2-d]pyrimidin-4-amine (2.3 g, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 443.1. Step 5. 1-((1S,4S)-5-(4-((2,3-difluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (2.3 g, 4.13 mmol) and sodium bicarbonate (347 mg, 4.13 mmol) in anhydrous tetrahydrofuran (10 mL) and water (1 mL) was added prop-2-enoyl chloride (374 mg, 4.13 mmol) at 0 °C, the mixture was stirred at 0 °C for 5 min. On completion, the mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*15um;mobile phase: [water(FA)- acetonitrile];B%: 25%-45%,20min) to give 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.1]heptan- 2-yl]prop-2-en-1-one (890 mg, 1.75 mmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.48 - 9.27 (m, 1H), 8.67 - 8.54 (m, 1H), 8.47 (d, J = 1.2 Hz, 1H), 7.94 (dd, J = 2.8, 9.2 Hz, 1H), 7.59 - 7.11 (m, 2H), 6.89 - 6.29 (m, 1H), 6.21 - 6.05 (m, 1H), 5.76 - 5.59 (m, 1H), 5.37 - 4.84 (m, 2H), 4.68 - 4.46 (m, 2H), 3.78 - 3.39 (m, 4H), 2.16 - 1.96 (m, 2H), 1.15 - 0.97 (m, 2H), 0.90 - 0.73 (m, 2H); m/z ES+ [M+H] ⁺ 497.3. Example 411. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.2 g, 425 μmol) in N,N- dimethylformamide (2 mL) was added potassium carbonate (117 mg, 850 μmol) and [(2S)- tetrahydrofuran-2-yl]methyl methanesulfonate (115 mg, 638 μmol). The mixture was stirred at 60 °C for 12 h. On completion, the reaction mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (1S,4S)-5-(4-((2,3-difluoro- 4-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2 -d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.1 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 555.2. Step 2.6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difl uoro-4-(((S)- tetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (0.1 g, 180 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- (2,3-difluoro-4-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl)py rido[3,2-d]pyrimidin-4-amine (100 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 455.2. Step 3.1-((1S,4S)-5-(4-((2,3-Difluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(((S)- tetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine (0.1 g, 176 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (24.3 mg, 175 μmol) and prop-2-enoyl chloride (15.9 mg, 175 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)- acetonitrile];B%: 15%-45%,10 min) to give 1-((1S,4S)-5-(4-((2,3-difluoro-4-(((S)- tetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrim idin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (28.3 mg, 55.0 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 - 9.18 (m, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.67 - 7.54 (m, 1H), 7.40 - 7.17 (m, 1H), 7.10 – 7.00 (m, 1H), 6.89 - 6.36 (m, 1H), 6.15 – 6.10 (m, 1H), 5.76 - 5.60 (m, 1H), 5.54 - 5.16 (m, 1H), 5.09 - 4.89 (m, 1H), 4.26 - 4.04 (m, 3H), 3.90 - 3.52 (m, 6H), 2.04 - 1.97 (m, 3H), 1.93 - 1.80 (m, 2H), 1.75 - 1.67 (m, 1H); m/z ES+ [M+H] ⁺ 509.0. Example 412. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.2 g, 425 μmol) in N,N- dimethylformamide (2 mL) was added potassium carbonate (117 mg, 850 μmol) and [(2R)- tetrahydrofuran-2-yl]methyl methanesulfonate (115 mg, 638 μmol). The mixture was stirred at 60 °C for 12 h. On completion, the reaction mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under in vacuo to give tert-butyl (1S,4S)-5-(4-((2,3- difluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)amino)p yrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.1 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 555.2. Step 2.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difl uoro-4-(((R)- tetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (0.1 g, 180 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- (2,3-difluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)py rido[3,2-d]pyrimidin-4-amine (100 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 455.2. Step 3.1-((1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(((R)- tetrahydrofuran-2-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine (0.1 g, 175 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (24.3 mg, 175 μmol) and prop-2-enoyl chloride (15.9 mg, 175 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)- acetonitrile];B%: 13%-43%,10 min) to give 1-((1S,4S)-5-(4-((2,3-difluoro-4-(((R)- tetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrim idin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (32.9 mg, 64.0 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 - 9.18 (m, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.67 - 7.54 (m, 1H), 7.40 - 7.17 (m, 1H), 7.10 – 7.00 (m, 1H), 6.89 - 6.36 (m, 1H), 6.15 – 6.10 (m, 1H), 5.76 - 5.60 (m, 1H), 5.54 - 5.16 (m, 1H), 5.09 - 4.89 (m, 1H), 4.26 - 4.04 (m, 3H), 3.90 - 3.52 (m, 6H), 2.04 - 1.97 (m, 3H), 1.93 - 1.80 (m, 2H), 1.75 - 1.67 (m, 1H); m/z ES+ [M+H] ⁺ 509.0. Example 413. Preparation of 1-((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy) - 2,3-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-di azabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2, 3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.13 g, 0.28 mmol) in N,N- dimethylformamide (1.3 mL) was added 1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane (68 mg, 0.3 mmol) and potassium carbonate (76 mg, 0.55 mmol). The mixture was stirred at 40 °C for 12 hs. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed- phase HPLC (0.1% Formic acid condition) to give tert-butyl (1S,4S)-5-(4-((4-((2- oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2,3-difluorophenyl)amin o)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.1 g, 176 μmol, 64%) as a yellow oil. m/z ES+ [M+H] ⁺ 567.3. Step 2. N-(4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2,3-difluoroph enyl)-6-((1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2-d]pyrimidin-4- amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (98 mg, 0.17 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.31 g, 2.7 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give N-(4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2,3-difluoroph enyl)-6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2-d]pyrimidin-4-amin e (100 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 467.1. Step 3.1-((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methox y)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-(2- oxabicyclo[2.1.1]hexan-1-ylmethoxy)phenyl]pyrido[3,2-d]pyrim idin-4-amine (0.1 g, 0.17 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (58 mg, 0.69 mmol) and prop-2-enoyl chloride (14 mg, 0.16 mmol). The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30 mm*3 um; mobile phase: [water (FA)- acetonitrile]; B%: 20%-50%, 7 min) to give 1-((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy) -2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (25.6 mg, 49.1 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (d, J = 1.6 Hz, 1H), 7.94 - 7.78 (m, 2H), 7.29 - 7.12 (m, 1H), 6.99 (t, J = 8.8 Hz, 1H), 6.84 - 6.39 (m, 1H), 6.29 (ddd, J = 1.6, 7.6, 16.8 Hz, 1H), 5.85 - 5.66 (m, 1H), 5.39 - 5.13 (m, 1H), 5.06 (d, J = 14.8 Hz, 1H), 4.34 (s, 2H), 3.85 (s, 2H), 3.83 - 3.72 (m, 2H), 3.71 - 3.52 (m, 2H), 3.00 (t, J = 3.2 Hz, 1H), 2.28 - 2.04 (m, 2H), 2.01 - 1.91 (m, 2H), 1.58 (dd, J = 1.6, 4.8 Hz, 2H); m/z ES+ [M+H] ⁺ 521.0. Example 414. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (130 mg, 276 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (76.7 mg, 552 μmol) and (S)-(tetrahydrofuran-3-yl)methyl methanesulfonate (50 mg, 276 μmol). The mixture was stirred at 60 °C for 16 h. On completion, the mixture was directly purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4- ((2,3-difluoro-4-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)a mino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 180 μmol, 65%) as a yellow solid. m/z ES+ [M+H] ⁺ 555.1. Step 2.6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difl uoro-4-(((S)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine A mixture of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (90 mg, 162 μmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (1 mL) was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(((S)- tetrahydrofuran-3-yl)methoxy) phenyl)pyrido[3,2-d]pyrimidin-4-amine (92 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 455.2. Step 3.1-((1S,4S)-5-(4-((2,3-difluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(((S)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine (90 mg, crude, TFA) and sodium bicarbonate (66.5 mg, 792 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (14.3 mg, 158 μmol) at 0 °C and the mixture was then stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um;mobile phase: [water(ammonium bicarbonate)- acetonitrile];B%: 34%-64%, 9 min) to give 1-((1S,4S)-5-(4- ((2,3-difluoro-4-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)a mino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (33.0 mg, 64.9 μmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 - 9.14 (m, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.96 - 7.81 (m, 1H), 7.71 - 7.50 (m, 1H), 7.45 - 7.19 (m, 1H), 7.13 – 7.03 (m, 1H), 6.83 - 6.39 (m, 1H), 6.17 - 6.13 (m, 1H), 5.76 - 5.56 (m, 1H), 5.53 - 5.13 (m, 1H), 5.11 - 4.89 (m, 1H), 4.11 - 4.00 (m, 2H), 3.84 - 3.63 (m, 5H), 3.62 - 3.47 (m, 3H), 2.73 - 2.64 (m, 1H), 2.09 - 1.98 (m, 3H), 1.75 - 1.62 (m, 1H); m/z ES+ [M+H] ⁺ 509.2. Example 415. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (130 mg, 276 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (76.7 mg, 552 μmol) and (R)-(tetrahydrofuran-3-yl)methyl methanesulfonate (50 mg, 276 μmol). The mixture was stirred at 60 °C for 16 h. On completion, the mixture was directly purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4- ((2,3-difluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)a mino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 180 μmol, 65%) as a yellow solid. m/z ES+ [M+H] ⁺ 555.0. Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(((R)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine A mixture of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (100 mg, 180 μmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (1 mL) was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(((R)- tetrahydrofuran-3-yl)methoxy) phenyl)pyrido[3,2-d]pyrimidin-4-amine (102 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 455.2. Step 3. 1-((1S,4S)-5-(4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(((R)- tetrahydrofuran-3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4 -amine (100 mg, crude, TFA) and sodium bicarbonate (73.9 mg, 880 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (15.9 mg, 176 μmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um;mobile phase: [water(ammonium bicarbonate)- acetonitrile];B%: 34%-64%, 9 min) to give 1-((1S,4S)-5-(4- ((2,3-difluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)a mino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (33.0 mg, 64.9 μmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 - 9.28 (m, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.92 - 7.88 (m, 1H), 7.61 - 7.58 (m, 1H), 7.41 - 7.16 (m, 1H), 7.12 - 7.08 (m, 1H), 6.84 - 6.41 (m, 1H), 6.17 - 6.11 (m, 1H), 5.71 - 5.63 (m, 1H), 5.41 - 5.19 (m, 1H), 5.07 - 4.93 (m, 1H), 4.09 – 4.03 (m, 2H), 3.81 - 3.66 (m, 5H), 3.59 - 3.50 (m, 3H), 2.74 - 2.69 (m, 1H), 2.07 – 2.00 (m, 3H), 1.73 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 509.1. Example 416. Preparation of 1-((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy) - 2,3-difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-di azabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2, 3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (150 mg, 320 μmol) in N,N- dimethylformamide (1.5 mL) was added sodium carbonate (140 mg, 1.30 mmol) and 2- oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate (100 mg, 380 μmol). The mixture was stirred at 60 °C for 12 h. On completion, the mixture was concentrated in vacuo to give a crude product. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2, 3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (95.0 mg, 168 μmol, 52%) as a yellow soild. m/z ES+ [M+H] ⁺ 567.3. Step 2. N-(4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2,3-difluoroph enyl)-6-((1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2-d]pyrimidin-4- amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (95.0 mg, 170 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (310 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo to give N-(4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2,3-difluoroph enyl)-6-((1S,4S)- 2,5diazabicyclo[2.2.1] heptan-2-yl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 467.1. Step 3. 1-((1S,4S)-5-(4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy) -2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-(2- oxabicyclo[2.1.1]hexan-4-ylmethoxy)phenyl]pyrido[3,2-d]pyrim idin-4-amine (97.0 mg, 170 μmol) in water (1 mL) and tetrahydrofuran (1 mL) was added sodium bicarbonate (560 mg, 670 μmol) and prop-2-enoyl chloride (14 mg, 150 μmol), the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18150*25mm*5um;mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 33%-63%, min) to give 1-((1S,4S)-5-(4-((4- ((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2,3-difluorophenyl) amino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (10.1 mg, 19.4 μmol, 11%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 - 9.17 (m, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 3.6, 9.2 Hz, 1H), 7.70 - 7.52 (m, 1H), 7.36 - 7.17 (m, 1H), 7.12 (t, J = 8.8 Hz, 1H), 6.84 - 6.37 (m, 1H), 6.14 (dd, J = 3.6, 16.4 Hz, 1H), 5.72 - 5.61 (m, 1H), 5.57 - 5.10 (m, 1H), 5.07 - 4.91 (m, 1H), 4.53 (s, 1H), 4.45 (s, 2H), 3.76 - 3.53 (m, 6H), 2.08 - 1.98 (m, 2H), 1.86 (d, J = 4.4 Hz, 2H), 1.54 - 1.48 (m, 2H); m/z ES+ [M+H] ⁺ 521.0. Example 417. Preparation of 1-((1S,4S)-5-(4-((4-(difluoromethoxy)-2,5- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((4-(difluoromethoxy)-2,5- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,5-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.13 g, 0.28 mmol) in N,N- dimethylformamide (0.4 mL) was added (2-chloro-2,2-difluoro-acetyl)oxysodium (63 mg, 0.41 mmol) and sodium carbonate (59 mg, 0.55 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was then filtered to remove the solid. The filtrate was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-((4-(difluoromethoxy)-2,5- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (33 mg, 63.4 μmol, 22%) as a white solid. m/z ES+ [M+H] ⁺ 521.1. Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(difluor omethoxy)-2,5- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-(difluoromethoxy)-2,5-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (33 mg, 63 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.31 g, 2.7 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give 6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(difluoromethoxy)-2,5-d ifluorophenyl)pyrido[3,2- d]pyrimidin-4-amine (33 mg, crude, TFA salt) as a white solid. m/z ES+ [M+H] ⁺ 421.1. Step 3. 1-((1S,4S)-5-(4-((4-(difluoromethoxy)-2,5-difluorophenyl)ami no)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[4-(difluor omethoxy)- 2,5-difluoro-phenyl]pyrido[3,2-d]pyrimidin-4-amine (33 mg, 62 μmol) in water (0.5 mL) and tetrahydrofuran (0.5 mL) was added sodium bicarbonate (21 mg, 0.25 mmol) and prop-2-enoyl chloride (3.9 mg, 43 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 29%-59%, 9 min) and then re-purified by prep-HPLC (column: Phenomenex C1875*30 mm*3 um; mobile phase: [water(FA)- acetonitrile]; B%: 8%-38%, 7 min) to give 1- ((1S,4S)-5-(4-((4-(difluoromethoxy)-2,5-difluorophenyl)amino )pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (4.29 mg, 9.04 μmol, 15%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.50 (br. s, 1H), 7.89 (d, J = 4.4 Hz, 1H), 7.81 (dd, J = 2.8, 9.2 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.54 - 7.47 (m, 1H), 7.23 - 6.85 (m, 2H), 6.81 - 6.38 (m, 1H), 6.29 (ddd, J = 2.0, 6.0, 16.8 Hz, 1H), 5.83 - 5.69 (m, 1H), 5.28 - 5.18 (m, 1H), 5.04 (d, J = 13.2 Hz, 1H), 3.86 - 3.50 (m, 4H), 2.20 - 2.03 (m, 2H); m/z ES+ [M+H] ⁺ 474.9. Example 418. Preparation of 1-((1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,5- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2- yl)prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,5- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,5-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (0.15 g, 0.32 mmol) in N,N- dimethylformamide (1.5 mL) was added bromomethylcyclopropane (52 mg, 0.38 mmol) and potassium carbonate (88 mg, 0.64 mmol). The mixture was stirred at 40 °C for 12 h. The mixture was filtered to remove potassium carbonate. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,5- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (83 mg, 158 μmol, 50%) as a yellow oil. Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(cyclopr opylmethoxy)-2,5- difluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2,5-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (83 mg, 0.16 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.31 g, 2.7 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give 6-((1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(cyclopropylmethoxy )-2,5-difluorophenyl)pyrido[3,2- d]pyrimidin-4-amine (100 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 425.1. Step 3. 1-((1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,5-difluorophenyl) amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of N-[4-(cyclopropylmethoxy)-2,5-difluoro-phenyl]-6-[(1S,4S)-2, 5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (85 mg, 0.16 mmol, TFA salt) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (53 mg, 0.63 mmol) and prop-2-enoyl chloride (13 mg, 0.14 mmol). The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 43%-73%, 9 min) to give 1-((1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,5- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (18.2 mg, 38.0 μmol, 24%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (dd, J = 2.4, 3.6 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.10 - 7.95 (m, 1H), 7.91 (dd, J = 3.2, 9.2 Hz, 1H), 7.25 (dd, J = 8.0, 12.0 Hz, 2H), 6.94 - 6.31 (m, 1H), 6.14 (ddd, J = 2.4, 5.6, 16.8 Hz, 1H), 5.77 - 5.52 (m, 1H), 5.50 - 5.12 (m, 1H), 5.10 - 4.90 (m, 1H), 3.93 (d, J = 7.2 Hz, 2H), 3.83 - 3.62 (m, 2H), 3.62 - 3.46 (m, 2H), 2.16 - 1.95 (m, 2H), 1.30 - 1.21 (m, 1H), 0.63 - 0.57 (m, 2H), 0.38 - 0.31 (m, 2H); m/z ES+ [M+H] ⁺ 479.1. Example 419. Preparation of 1-((1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,3- difluorophenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)-2 ,5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,3-difluorophenyl)ami no)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]he ptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (250 mg, 512 μmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (141 mg, 1.02mmol) and bromomethylcyclopropane (82.9 mg, 614 μmol, 58.8 μL). The mixture was stirred at 40 °C for 2 h. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate 20 mL. The organic layers were washed with brine 10 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-[4- (cyclopropylmethoxy)-2,3-difluoro-anilino]-7-fluoro-pyrido[3 ,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 543.3. Step 2. 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-(cyclopr opylmethoxy)-2,3- difluorophenyl)-7-fluoropyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2,3-difluoro-anilino]- 7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate (250 mg, 461 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (52.5 mg, 461 μmol). The mixture was stirred at 25 °C for 6 h. The reaction mixture was concentrated under reduced pressure to give N-[4-(cyclopropylmethoxy)-2,3-difluoro-phenyl]-6-[(1S,4S)-2, 5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine (250 mg, crude, TFA salt) as a brown oil. m/z ES+ [M+H] ⁺ 443.2. Step 3. 1-((1S,4S)-5-(4-((4-(cyclopropylmethoxy)-2,3-difluorophenyl) amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]he ptan-2-yl)prop-2-en-1-one To a solution of N-[4-(cyclopropylmethoxy)-2,3-difluoro-phenyl]-6-[(1S,4S)-2, 5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine (250 mg, crude, TFA salt) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was added sodium bicarbonate (37.7 mg, 449 μmol) and prop-2-enoyl chloride (42.7 mg, 472 μmol). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine 15 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3um;mobile phase: [water(FA)- acetonitrile];B%: 35%-65%, 7 min) to give 1-[(1S,4S)-5-[4-[4- (cyclopropylmethoxy)-2,3-difluoro-anilino]-7-fluoro-pyrido[3 ,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (91.6 mg, 184 μmol, 41%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.79 (m, 1H), 7.55 - 7.40 (m, 1H), 7.05 (t, J = 8.4 Hz, 1H), 6.88 - 6.32 (m, 1H), 6.16 - 6.12 (m, 1H), 5.75 - 5.61 (m, 1H), 5.43 - 5.24 (m, 1H), 5.06 - 4.84 (m, 1H), 3.97 (d, J = 7.2 Hz, 2H), 3.88 (br t, J=11.2 Hz, 1H), 3.76 - 3.69 (m, 2H), 3.61 - 3.50 (m, 1H), 2.07 - 1.94 (m, 2H), 1.31 - 1.23 (m, 1H), 0.63 - 0.58 (m, 2H), 0.38 - 0.34 (m, 2H); m/z ES+ [M+H] ⁺ 497.0. Example 420. Preparation of 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (150 mg, 307 μmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (84.8 mg, 614 μmol) and [(2S)-tetrahydrofuran-2-yl]methyl methanesulfonate (83.0 mg, 460 μmol). The mixture was stirred at 80 °C for 6 hr. On completion, the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert- butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2-yl]met hoxy]anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (150 mg, 264 μmol, 85%) as a yellow oil. m/z ES+ [M+H] ⁺ 573.3. Step 2. 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-[[(2S)- tetrahydrofuran-2-yl]methoxy]phenyl]-7-fluoro-pyrido[3,2-d]p yrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate (150 mg, 261 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol), the mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4- [[(2S)-tetrahydrofuran-2-yl]methoxy]phenyl]-7-fluoro-pyrido[ 3,2-d]pyrimidin-4-amine (120 mg, 78%, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 473.2. Step 3. 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2-yl] methoxy]anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptan-2-yl]prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4- [[(2S)-tetrahydrofuran-2-yl]methoxy]phenyl]-7-fluoro-pyrido[ 3,2-d]pyrimidin-4-amine (120 mg, 253 μmol) in tetrahydrofuran (5 mL) and water (1 mL) was added sodium bicarbonate (21.3 mg, 253 μmol) to pH 7~8, then prop-2-enoyl chloride (22.9 mg, 253 μmol) was added into the mixture. The mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was quenched by addition of water (0.5 mL) at 0 °C, and then diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(NH4HCO3)-ACN];B%: 37%-70%,10 min) to give 1-[(1S,4S)-5-[4- [2,3-difluoro-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]anilino] -7-fluoro-pyrido[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (53.4 mg, 102 μmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 3.6, 13.6 Hz, 1H), 7.55 - 7.40 (m, 1H), 7.17 - 7.05 (m, 1H), 6.85 - 6.36 (m, 1H), 6.17-6.11(m, 1H), 5.75 - 5.60 (m, 1H), 5.44 - 5.28 (m, 1H), 5.07 - 4.83 (m, 1H), 4.24 - 4.17 (m, 1H), 4.16 - 4.03 (m, 2H), 3.93 - 3.84 (m, 1H), 3.83 - 3.77 (m, 1H), 3.76 - 3.67 (m, 3H), 2.09 - 1.96 (m, 3H), 1.95 - 1.79 (m, 2H), 1.75 - 1.65 (m, 1H); m/z ES+ [M+H] ⁺ 527.0. Example 421. Preparation of 1-[(3S)-3-[4-[(5-fluoro-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate To a mixture of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (150 mg, 307 μmol) and [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (66.4 mg, 368 μmol) in N,N- dimethylformamide (3.0 mL) was added potassium carbonate (84.8 mg, 614 μmol), the reaction mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 2/3) to give tert-butyl (1S,4S)-5-[4-[2,3- difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]anilino]-7-fl uoro-pyrido[3,2-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 227 μmol, 73%) as a yellow solid. m/z ES+[M+H] ⁺ 573.3. Step 2. 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-[[(2R)- tetrahydrofuran-2-yl]methoxy]phenyl]-7-fluoro-pyrido[3,2-d]p yrimidin-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate (130 mg, 227 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (25.8 mg, 227 μmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N- [2,3-difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]phenyl]- 7-fluoro-pyrido[3,2-d]pyrimidin-4- amine (100 mg, 211 μmol, 93%) as a yellow solid without further purification. m/z ES+[M+H] ⁺ 473.1. Step 3. 1-[(3S)-3-[4-[(5-fluoro-3-pyridyl)amino]pyrido[3,2-d]pyrimid in-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one To a mixture of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4- [[(2R)-tet rahydrofuran-2-yl]methoxy]phenyl]-7-fluoro-pyrido[3,2-d]pyri midin-4-amine (100 mg, 211 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (17.7 mg, 211 μmol) at 0 °C to pH = 7~8, and then prop-2-enoyl chloride (19.1 mg, 211 μmol) was added. The reaction mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was quenched by addition of water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*15um;mobile phase: [water(FA)-ACN];B%: 32%-62%,10 min) to give 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(2R)- tetrahydrofuran-2-yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d] pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (75.0 mg, 139 μmol, 66%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 - 9.28 (m, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 3.6, 13.6 Hz, 1H), 7.53 - 7.41 (m, 1H), 7.40 - 7.23 (m, 1H), 7.16 - 7.04 (m, 1H), 6.85 - 6.35 (m, 1H), 6.20 - 6.11 (m, 1H), 5.71 - 5.61 (m, 1H), 5.45 - 5.26 (m, 1H), 5.05 - 4.88 (m, 1H), 4.26 - 4.17 (m, 1H), 4.15 - 4.03 (m, 2H), 3.82 (s, 2H), 3.75 - 3.70 (m, 2H), 3.58 - 3.56 (m, 1H), 2.05 - 1.98 (m, 2H), 1.95 - 1.64 (m, 4H); m/z ES+[M+H] ⁺ 527.0. Example 422. Preparation of 1-[(1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (150 mg, 307 μmol) and 1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane (82.6 mg, 368 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (127 mg, 921 μmol). The mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (1S,4S)-5-[4- [2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)anilin o]-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (185 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 585.2. Step 2. 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-(2- oxabicyclo[2.1.1]hexan-1-ylmethoxy)phenyl]-7-fluoro-pyrido[3 ,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate (185 mg, 316 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N- [2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)phenyl ]-7-fluoro-pyrido[3,2- d]pyrimidin-4-amine (229 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 485.0. Step 3. 1-[(1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-(2- oxabicyclo[2.1.1]hexan-1-ylmethoxy)phenyl]-7-fluoro-pyrido[3 ,2-d]pyrimidin-4-amine (229 mg, 383 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (257 mg, 3.06 mmol, 119 μL) in water (0.5 mL), and then prop-2-enoyl chloride (31.2 mg, 344 μmol, 28.1 μL) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by addition of water (50 mL) at 0 °C and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 38%-68%, 9 min) to give 1- [(1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1-yl methoxy)anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2 -yl]prop-2-en-1-one (75.5 mg, 140 μmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 3.6, 13.6 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.18 - 7.07 (m, 1H), 6.84 - 6.36 (m, 1H), 6.18 - 6.10 (m, 1H), 5.72 - 5.60 (m, 1H), 5.44 - 5.27 (m, 1H), 5.04 - 4.87 (m, 1H), 4.38 (s, 2H), 3.93 - 3.64 (m, 5H), 3.62 - 3.48 (m, 1H), 2.95 (t, J = 3.2 Hz, 1H), 2.08 - 1.94 (m, 2H), 1.91 - 1.83 (m, 2H), 1.47 (dd, J = 1.6, 4.4 Hz, 2H); m/z ES+ [M+H] ⁺ 539.0. Example 423. Preparation of 1-[(1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]-7 - fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptan-2-yl]prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]-7-fl uoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (250 mg, 511 μmol) in N,N-dimethyl formamide (4 mL) was added sodium carbonate (108 mg, 1.02 mmol) and (2- chloro-2,2-difluoro-acetyl)oxysodium (117 mg, 768 μmol). The mixture was stirred at 100 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=0/1 to 1/1) to give tert-butyl (1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]-7-fl uoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (52.0 mg, 96.6 μmol, 19%) as a red solid. m/z ES+ [M+H] ⁺ 539.2. Step 2. 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[4-(difluor omethoxy)-2,3- difluoro-phenyl]-7-fluoro-pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptane-2-carboxylate (52.0 mg, 96.6 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 6 hr. The reaction mixture was concentrated under reduced pressure to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[4-(difluor omethoxy)-2,3- difluoro-phenyl]-7-fluoro-pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, crude, TFA) as a brown oil which was used for next step without further purification. m/z ES+ [M+H] ⁺ 439.1. Step 3. 1-[(1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]-7 -fluoro-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[4-(difluor omethoxy)- 2,3-difluoro-phenyl]-7-fluoro-pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, 90.5 μmol) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was added sodium bicarbonate (7.60 mg, 90.5 μmol) and prop-2-enoyl chloride (8.19 mg, 90.5 μmol). The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 35%-65%, 7 min) to give 1-[(1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptan-2-yl]prop-2-en-1- one (6.31 mg, 12.8 μmol, 15%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 - 9.39 (m, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.91 - 7.68 (m, 2H), 7.55 - 7.08 (m, 2 H), 6.87 - 6.21 (m, 1H), 6.22 - 6.09 (m, 1H), 5.76 - 5.59 (m, 1H), 5.46 - 5.26 (m, 1H), 5.06 - 4.86 (m, 1H), 3.93 - 3.85 (m, 1H), 3.77 - 3.71 (m, 2H), 3.61 - 3.52 (m, 1H), 2.08 - 1.96 (m, 2 H); m/z ES+ [M+H] ⁺ 492.9. Example 424. Preparation of 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate A solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (0.15 g, 307.09 μmol), [(3S)-tetrahydrofuran-3-yl]methyl methanesulfonate (166 mg, 921 μmol), potassium carbonate (127 mg, 921 μmol) in N,N-dimethyl formamide (5 mL) was stirred at 80 °C for 16 hr. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate (60.0 mg, 105 μmol, 34%) as a yellow oil. m/z ES+ [M+H] ⁺ 573.3. Step 2. 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-[[(3S)- tetrahydrofuran-3-yl]methoxy]phenyl]-7-fluoro-pyrido[3,2-d]p yrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate (0.050 g, 87.3 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4- [[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl]-7-fluoro-pyrido[ 3,2-d]pyrimidin-4-amine (50.0 mg, crude, TFA salt) as a yellow oil. Step 3. 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3-yl] methoxy]anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptan-2-yl]prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4- [[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl]-7-fluoro-pyrido[ 3,2-d]pyrimidin-4-amine (0.050 g, 85.3 μmol, TFA), sodium bicarbonate (7.16 mg, 85.3 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (7.72 mg, 85.3 μmol) at 0 °C, the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was directly purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 36%-66%, 9 min) to give 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3-yl] methoxy]anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptan-2-yl]prop-2-en-1-one (0.013 g, 24.7 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 3.2 Hz, 1H), 7.88 - 7.78 (m, 1H), 7.55 - 7.48 (m, 1H), 6.95 - 6.85 (m, 1H), 6.85 - 6.36 (m, 1H), 6.35 - 6.25 (m, 1H), 5.82- 5.70 (m, 1H), 5.28 - 5.18 (m, 1H), 5.07 - 4.97 (m, 1H), 4.07 - 3.65 (m, 10H), 2.85 - 2.72 (m, 1H), 2.20 - 2.02 (m, 3H), 1.85 - 1.75 (m, 1H); m/z ES+ [M+H] ⁺ 527.1. Example 425. Preparation of 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (150 mg, 307 μmol) and [(3R)-tetrahydrofuran-3-yl]methyl methanesulfonate (92.2 mg, 307 μmol) in N,N- dimethylformamide (2 mL) was added potassium carbonate (127 mg, 921 μmol). The mixture was stirred at 60 °C for 12 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]met hoxy]anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (187 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 573.2. Step 2. 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-[[(3R)- tetrahydrofuran-3-yl]methoxy]phenyl]-7-fluoro-pyrido[3,2-d]p yrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2, 5-diazabicyclo[2.2.1]heptane-2- carboxylate (187 mg, 327 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3- difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]-7-flu oro-pyrido[3,2-d]pyrimidin-4- amine (231 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 473.0. Step 3. 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3-yl] methoxy]anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptan-2-yl]prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4- [[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]-7-fluoro-pyrido[ 3,2-d]pyrimidin-4-amine (231 mg, 394 μmol, trifluoroacetic acid salt.) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (265 mg, 3.15 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (32.1 mg, 354 μmol) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by addition of water (50 mL) at 0 °C and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 36%-66%, 9 min) to give 1-[(1S,4S)-5-[4-[2,3- difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]anilino]-7-fl uoro-pyrido[3,2-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (47.7 mg, 90.6 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.79 (dd, J = 3.6, 13.6 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.16 - 7.06 (m, 1H), 6.85 - 6.36 (m, 1H), 6.18 - 6.07 (m, 1H), 5.75 - 5.58 (m, 1H), 5.43 - 5.25 (m, 1H), 5.04 - 4.87 (m, 1H), 4.15 - 3.97 (m, 2H), 3.93 - 3.62 (m, 6H), 3.61 - 3.47 (m, 2H), 2.76 - 2.64 (m, 1H), 2.11 - 1.89 (m, 3H), 1.74 - 1.62 (m, 1H); m/z ES+ [M+H] ⁺ 527.0. Example 426. Preparation of 1-[(1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (50.0 mg, 102 μmol) and 2-oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate (32.0 mg, 119 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (41.2 mg, 298 μmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4-ylm ethoxy)anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptane-2-carboxylate (101 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 585.2. Step 2. 6-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-(2- oxabicyclo[2.1.1]hexan-4-ylmethoxy)phenyl]-7-fluoro-pyrido[3 ,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate (101 mg, 173 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol, 0.3 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl]-N-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4-ylmethoxy) phenyl]-7-fluoro-pyrido[3,2- d]pyrimidin-4-amine (125 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 485.0. Step 3. 1-[(1S,4S)-5-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[2,3-difluo ro-4-(2- oxabicyclo[2.1.1]hexan-4-ylmethoxy)phenyl]-7-fluoro-pyrido[3 ,2-d]pyrimidin-4-amine (125 mg, 209 μmol, trifluoroacetic acid Salt.) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (140 mg, 1.67 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (17.0 mg, 188 μmol) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by addition of water (50 mL) at 0 °C and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 38%-68%,10 min) to give 1-[(1S,4S)-5-[4-[2,3- difluoro-4-(2-oxabicyclo[2.1.1]hexan-4-ylmethoxy)anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (43.5 mg, 80.7 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.32 (d, J = 2.8 Hz, 1H), 7.80 (dd, J = 3.6, 13.6 Hz, 1H), 7.58 - 7.45 (m, 1H), 7.18 - 7.07 (m, 1H), 6.84 - 6.37 (m, 1H), 6.19 - 6.08 (m, 1H), 5.73 - 5.61 (m, 1H), 5.47 - 5.25 (m, 1H), 5.06 - 4.87 (m, 1H), 4.54 (s, 1H), 4.47 (s, 2H), 3.94 - 3.82 (m, 1H), 3.79 - 3.67 (m, 2H), 3.65 - 3.47 (m, 3H), 2.12 - 1.92 (m, 2H), 1.91 - 1.82 (m, 2H), 1.52 (dd, J = 1.6, 4.4 Hz, 2H); m/z ES+ [M+H] ⁺ 539.0. Example 427. Preparation of 1-[(1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2,3-difluoro-anilino ]- 7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1 ]heptan-2-yl]prop-2-en-1-one Step 1. tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyanomethoxy)-2-fluoro-anilino]pyr ido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (150 mg, 308 μmol) in N,N-dimethyl formamide (3 mL) was added potassium carbonate (85.2 mg, 616 μmol) and 2-bromoacetonitrile (40.7 mg, 339 μmol). The mixture was stirred at 40 °C for 6 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert- butyl (1S,4S)-5-[4-[3-chloro-4-(cyanomethoxy)-2-fluoro-anilino]pyr ido[3,2-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (160 mg, 304 μmol, 99%) as a brown solid which was used for next step without purification. m/z ES+ [M+H] ⁺ 526.3. Step 2. 2-[2-Chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-y l]pyrido[3,2- d]pyrimidin-4-yl]amino]-3-fluoro-phenoxy]acetonitrile To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyanomethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (160 mg, 304 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 8 hr. The reaction mixture was concentrated under reduced pressure to give 2-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-y l]pyrido[3,2- d]pyrimidin-4-yl]amino]-3-fluoro-phenoxy]acetonitrile (130 mg, crude, TFA) as a brown oil which was used for the next step without further purification. m/z ES+ [M+H] ⁺ 426.2. Step 3. 1-[(1S,4S)-5-[4-[4-(Cyclopropylmethoxy)-2,3-difluoro-anilino ]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2 -yl]prop-2-en-1-one To a solution of N-[4-(cyclopropylmethoxy)-2,3-difluoro-phenyl]-6-[(1S,4S)-2, 5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine (250 mg, 449 μmol, TFA) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was added sodium bicarbonate (37.7 mg, 449 μmol) and prop-2-enoyl chloride (42.7 mg, 472 μmol). The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 35%-65%, 7 min) to give 1-[(1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2,3- difluoro-anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop- 2-en-1-one (91.6 mg, 184 μmol, 41%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 - 9.17 (m, 1H), 8.33 (d, J = 2.8 Hz, 1H), 8.04 - 7.84 (m, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.90 - 6.34 (m, 1H), 6.24 - 6.15 (m, 1H), 5.75 - 5.58 (m, 1H), 5.37 (s, 3H), 5.11 - 4.92 (m, 1H), 3.83 - 3.50 (m, 4H), 2.14 - 1.98 (m, 2H); m/z ES+ [M+H] ⁺ 479.9. Example 428. Preparation of 1-(4-((6-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2 - yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-chloro-3-fluoropheny l)cyclopropane-1- carbonitrile Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate A solution of 1-(4-amino-2-chloro-3-fluoro-phenyl)cyclopropanecarbonitrile (31.4 mg, 149 μmol) and tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (45.0 mg, 124 μmol) in acetonitrile (0.8 mL) was stirred at 60 °C for 12 hr. The reaction mixture was filtered and the filtered cake was washed with acetonitrile (10 mL × 3) and then concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro-anili no]pyrido[3,2-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (80.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 536.1. Step 2. 1-[2-Chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-y l]pyrido[3,2- d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cyclopropanecarbonit rile A solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (70.0 mg, 130 μmol) in dichloromethane (0.9 mL) was added hydrochloric acid /dioxane (4 M, 0.3 mL) .The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 1-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cyclop ropanecarbonitrile (80.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 435.9. Step 3. 1-[2-Chloro-3-fluoro-4-[[6-[(1S,4S)-5-prop-2-enoyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile To a solution of 1-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cyclop ropanecarbonitrile (60 mg, 127 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (21.3 mg, 254 μmol), and then prop-2-enoyl chloride (5.75 mg, 63.5 μmol) was added. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex luna C18 150×25mm× 10um;mobile phase: [water(formic acid)- acetonitrile];B%: 26%-56%, 10 min) to give desired compound 1-[2-chloro-3-fluoro-4-[[6-[(1S,4S)-5-prop-2-enoyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile (10.2 mg, 20.0 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 - 9.27 (m, 1H), 8.51 - 8.37 (m, 2H), 7.94 (dd, J = 4.0, 9.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 6.88 - 6.34 (m, 1H), 6.18 - 6.10 (m, 1H), 5.77 - 5.61 (m, 1H), 5.40 - 4.90 (m, 2H), 3.79 - 3.67 (m, 2H), 3.53 (d, J = 10.4 Hz, 1H), 3.62 - 3.50 (m, 1H), 2.11 - 2.00 (m, 2H), 1.81 - 1.77 (m, 2H), 1.50 - 1.46 (m, 2H); m/z ES+[M+H] ⁺ 490.0. Example 429. Preparation of 1-(4-((6-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2 - yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-chloro-3-fluoropheny l)cyclobutane-1-carbonitrile

Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(1-cyanocyclobutyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 276 μmol) in acetonitrile (1 mL) was added 1-(4-amino-2-chloro-3-fluoro-phenyl)cyclobutanecarbonitrile (68.3 mg, 304 μmol). The mixture was stirred at 60 °C for 2 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4-(1-cyanocyclobutyl)-2-fluorophenyl )amino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (75.0 mg, 134 μmol, 48%) as a brown oil. m/z ES+ [M+H] ⁺ 550.3. Step 2. 1-(4-((6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyrido[ 3,2-d]pyrimidin-4- yl)amino)-2-chloro-3-fluorophenyl)cyclobutane-1-carbonitrile To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclobutyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (70.0 mg, 127 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was cocentrated in vacuo to give 1-(4-((6- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,2-d]pyr imidin-4-yl)amino)-2-chloro-3- fluorophenyl)cyclobutane-1-carbonitrile (75.0 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 450.2. Step 3. 1-(4-((6-((1S,4S)-5-Acryloyl-2,5-diazabicyclo[2.2.1]heptan-2 -yl)pyrido[3,2- d]pyrimidin-4-yl)amino)-2-chloro-3-fluorophenyl)cyclobutane- 1-carbonitrile To a solution of 1-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cyclob utanecarbonitrile (70.0 mg, 124 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (1 mL) addded sodium bicarbonate (41.7 mg, 497 μmol) and prop-2-enoyl chloride (10.1 mg, 112 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The mixture was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 30%-60%, 10 min) to give 1-(4-((6- ((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrid o[3,2-d]pyrimidin-4-yl)amino)-2- chloro-3-fluorophenyl)cyclobutane-1-carbonitrile (15.2 mg, 30.2 μmol, 24%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) 9.58 - 9.15 (m, 1H), 8.42 (d, J = 3.6 Hz, 1H), 8.37 - 8.15 (m, 1H), 7.95 (dd, J = 4.0, 9.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 6.94 - 6.29 (m, 1H), 6.14 (ddd, J = 2.2, 6.0, 16.8 Hz, 1H), 5.76 - 5.59 (m, 1H), 5.55 - 5.12 (m, 1H), 5.11 - 4.85 (m, 1H), 3.88 - 3.64 (m, 2H), 3.63 - 3.48 (m, 2H), 2.89 - 2.81 (m, 2H), 2.78 - 2.68 (m, 2H), 2.39 - 2.32 (m, 1H), 2.15 - 2.01 (m, 2H), 1.99 - 1.90 (m, 1H); m/z ES+ [M+H] ⁺ 503.9. Example 430. Preparation of (E)-1-[(1S,4S)-5-[4-(3-chloro-4-ethoxy-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]-4- (dimethylamino)but-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-(3-chloro-4-ethoxy-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (90.0 mg, 185 μmol), potassium carbonate (51.1 mg, 369 μmol) in N,N- dimethylformamide (1.5 mL) was added iodoethane (39.0 mg, 250 μmol). The mixrure was stirred at 60 °C for 1 h. On completion, the reaction mixture was diluted with brine (40 mL) and water (40 mL) and then extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether : ethyl acetate = 1:2) to give tert-butyl (1S,4S)-5-[4-(3-chloro-4-ethoxy-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (58.0 mg, 108 μmol, 58%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.30 (s, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.83 - 7.75 (m, 1H), 7.48 - 7.13 (m, 1H), 7.07 (d, J = 9.2 Hz, 1H), 5.57 - 4.86 (m, 1H), 4.54 (d, J = 16.4 Hz, 1H), 4.19 (q, J = 6.8 Hz, 2H), 3.67 - 3.60 (m, 1H), 3.42 (m, J = 11.2 Hz, 2H), 3.25 (d, J = 10.0 Hz, 1H), 1.94 - 2.01 (m, 2H), 1.42 - 1.35 (m, 12H); m/z ES+ [M+H] ⁺ 515.0. Step 2. N-(3-Chloro-4-ethoxy-2-fluoro-phenyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e To a solution of tert-butyl (1S,4S)-5-[4-(3-chloro-4-ethoxy-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (58.0 mg, 112 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-chloro-4-ethoxy-2-fluoro-phenyl)-6-[(1S,4S)-2,5-diazabi cyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 415.0. Step 3. (E)-1-[(1S,4S)-5-[4-(3-Chloro-4-ethoxy-2-fluoro-anilino)pyri do[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-(dim ethylamino)but-2-en-1-one To a solution of N-(3-chloro-4-ethoxy-2-fluoro-phenyl)-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (40.0 mg, 75.6 μmol, TFA) in N,N-dimethylformamide (1 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (28.7 mg, 75.6 μmol), (E)-4- (dimethylamino)but-2-enoic acid;hydrochloride (18.8 mg, 113 μmol) and diisopropylethylamine (48.9 mg, 378 μmol), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (Phenomenex C18150*25mm*10um;mobile phase: [water (FA)- ACN];B%: 7%-37%, 8 min) to give (E)-1-[(1S,4S)-5-[4-(3-chloro-4-ethoxy-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]-4-(dimethylamino)but- 2-en-1-one (38.1 mg, 72.5 μmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 - 9.10 (m, 1H), 8.37 - 8.25 (m, 1H), 8.15 (s, 1H), 7.96 - 7.72 (m, 2H), 7.46 - 7.14 (m, 1H), 7.11 - 7.01 (m, 1H), 6.73 - 6.26 (m, 2H), 5.53 - 5.21 (m, 1H), 5.04 - 4.91 (m, 1H), 4.18 (m, J = 6.8 Hz, 2H), 3.78 - 3.41 (m, 4H), 3.36 - 3.22 (m, 2H), 2.34 (d, J = 19.6 Hz, 6H), 2.12 - 1.94 (m, 2H), 1.39 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H] ⁺ 526.4. Example 431. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-5-fluoroquinazolin-6-yl)-2,5-diazabicycl o[2.2.1]heptan-2-yl)prop-2- en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)- 5-fluoroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-ca rboxylate To a solution of 6-bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-5-f luoro- quinazolin-4-amine (250 mg, 572 μmol) in toluene (3 mL) was added tris(dibenzylideneacetone)dipalladium (26.2 mg, 28.6 μmol), (R)-(+)-2,2'- Bis(diphenylphosphino)-1,1'-binaphthyl (35.6 mg, 57.2 μmol), sodium tert-butoxide (82.6 mg, 858 μmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (148 mg, 744 μmol). The mixture was stirred at 110 °C for 16 h under nitrogen. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 um; mobile phase: [water (FA)-ACN]; B%: 37%-67%, 10 min) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-5-fluoroquinazolin-6-yl)-2,5-diazabicycl o[2.2.1]heptane-2-carboxylate (200 mg, 181 μmol, 32%) as a white solid. m/z ES+ [M+H] ⁺ 554.1. Step 2. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)-5-fluoroquinazolin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-5-fluoroquinazolin-6-yl)-2,5-diazabicycl o[2.2.1]heptane-2-carboxylate (200 mg, 361 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 20 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)-5-fluoroquinazolin-4-amine (200 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 454.1. Step 3. 1-((1S,4S)-5-(4-((3-Chloro-4-(difluoromethoxy)-2-fluoropheny l)amino)-5- fluoroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pr op-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)-5-fluoroquinazolin-4-amine (40 mg, 88 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (12.1 mg, 88.1 μmol) and prop-2-enoyl chloride (7.98 mg, 88.1 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 * 50mm * 3 um; mobile phase: [water (FA)-ACN];B%: 25%-55%, 10 min) to give 1-((1S,4S)-5-(4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)-5-fluoroquinazolin-6 -yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (9.89 mg, 19.3 μmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 1H), 8.34 - 8.20 (m, 1H), 8.10 - 8.04 (m, 1H), 7.59 - 7.50 (m, 2H), 7.23 -6.45 (m, 3H), 6.32 - 6.27 (m, 1H), 5.77 - 5.73 (m, 1H), 5.00 - 4.98 (m, 2H), 3.97 - 3.95 (m, 1H), 3.85 - 3.67 (m, 2H), 3.47 - 3.45 (m, 1H), 2.23 - 2.12 (m, 2H); m/z ES+ [M+H] ⁺ 507.9. Example 432. Preparation of 1-((1S,4S)-5-(8-((3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2 ,5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one Step 1. 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4-(2,2,2- trifluoroethyl)phenyl)pyrimido[5,4-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.100 g, 275 μmol) in isopropanol (1 mL) was added hydrochloric acid (1 M, 275 μL) and 3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline (125 mg, 551 μmol). The mixture was stirred at 80 °C for 12 h. On completion, the reaction mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 * 25mm * 10 um; mobile phase: [water (FA)-ACN]; B%: 50%- 80%, 10 min) to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4- (2,2,2-trifluoroethyl)phenyl)pyrimido[5,4-d]pyrimidin-4-amin e (20.0 mg, 44.1 μmol, 16%) as a yellow solid. m/z ES+ [M+H] ⁺ 454.2. Step 2. 1-((1S,4S)-5-(8-((3-Chloro-2-fluoro-4-(2,2,2- trifluoroethyl)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2 ,5-diazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-2 -fluoro-4- (2,2,2-trifluoroethyl)phenyl)pyrimido[5,4-d]pyrimidin-4-amin e (20.0 mg, 44.1 μmol) in tetrahydrofuran (0.5 mL) and water (0.25 mL) was added potassium phosphate (6.09 mg, 44.0 μmol) and prop-2-enoyl chloride (3.99 mg, 44.1 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 * 25 mm * 10 um; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min) to give 1-((1S,4S)-5-(8-((3-chloro-2-fluoro- 4-(2,2,2-trifluoroethyl)phenyl)amino)pyrimido[5,4-d]pyrimidi n-2-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (1.99 mg, 3.88 μmol, 8.8%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.58 - 8.45 (m, 2H), 7.43 - 7.32 (m, 1H), 6.88 - 6.43 (m, 1H), 6.39 - 6.24 (m, 1H), 5.86 - 5.73 (m, 1H), 5.35 - 5.30 (m, 1H), 5.12 - 5.04 (m, 1H), 3.93 - 3.63 (m, 6H), 2.26 - 2.08 (m, 2H); m/z ES+ [M+H] ⁺ 507.9. Example 433. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl ]-2,5-diazabicyclo[2.2.1]heptan- 2-yl]prop-2-en-1-one Step 1. 6-Bromo-N-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)phenyl] -7-fluoro- pyrido[3,2-d]pyrimidin-4-amine To a mixture of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (150 mg, 571 μmol) in acetonitrile (4 mL) was added 3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline (260 mg, 1.14 mmol), the mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=9:1) to give 6-bromo-N-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)phenyl]-7-fluoro-pyrido[3,2-d]pyrimidin-4-ami ne (264 mg, 494 μmol, 86%) as a yellow solid. m/z ES+ [M+H] ⁺ 452.9. Step 2. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)anil ino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptane-2-carboxylate To a mixture of 6-bromo-N-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)phenyl] -7-fluoro- pyrido[3,2-d]pyrimidin-4-amine (150 mg, 330 μmol), tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (98.3 mg, 496 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (85.4 mg, 661 μmol), the mixture was stirred at 130 °C for 1.5 hr. On completion, the reaction mixture was diluted with brine (40 mL) and extracted with ethyl acetate (25 mL × 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=6/1 to 3/1) to give tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl ]-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (204 mg, 307 μmol, 93%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.42 - 8.32 (m, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 13.6 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 5.25 - 5.13 (m, 1H), 4.50 (d, J = 19.2 Hz, 1H), 3.89 - 3.82 (m, 2H), 3.40 (s, 2H), 2.68 - 2.63 (m, 2H), 1.96 (s, 2H), 1.36 (d, J = 18.4 Hz, 9H), 1.15 (t, J = 7.2 Hz, 1H), 0.87 - 0.75 (m, 1H); m/z ES+ [M+H] ⁺ 571.1. Step 3. N-[3-Chloro-2-fluoro-4-(2,2,2-trifluoroethyl)phenyl]-6-[(1S, 4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl ]-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (100 mg, 175 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dichloromethane (30 mL) and then concentrated under reduced pressure to give N-[3-chloro-2- fluoro-4-(2,2,2-trifluoroethyl)phenyl]-6-[(1S,4S)-2,5-diazab icyclo[2.2.1]heptan-2-yl]-7-fluoro- pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 471.0. Step 4. 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-(2,2,2-trifluoroethyl)a nilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2 -yl]prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)phenyl]-6-[(1S, 4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine (100 mg, 171 μmol, trifluoroacetic acid) in tetrahydrofuran (2 mL) and water (0.7 mL) was added sodium bicarbonate (28.7 mg, 341.9 μmol), then the mixture was added prop-2-enoyl chloride (15.5 mg, 171 μmol) at 0 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex luna C18150*25mm* 10um;mobile phase: [water (FA)- ACN]; B%: 39%-69%, 10.5 min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)a nilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2 -yl]prop-2-en-1-one. ¹ H NMR (400 MHz, m/z ES+ [M+H] ⁺ 471.0.) δ 9.36 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.08 (q, J = 7.6 Hz, 1H), 7.83 (m, J = 3.6, 13.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.83 - 6.37 (m, 1H), 6.18 - 6.09 (m, 1H), 5.66 (m, J = 2.4, 10.4, 16.0 Hz, 1H), 5.36 - 5.21 (m, 1H), 5.05 - 4.86 (m, 1H), 3.93 - 3.83 (m, 3H), 3.80 - 3.67 (m, 2H), 3.63 - 3.51 (m, 1H), 2.10 - 1.95 (m, 2H); m/z ES+ [M+H] ⁺ 525.3. Example 434. Preparation of 1-[(1S,4S)-5-[4-[4-(cyclopropylmethoxy)-3-ethynyl-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-bromo-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate To a mixture of tert-butyl (1S,4S)-5-[4-(3-bromo-2-fluoro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (180 mg, 338 μmol) and cesium carbonate (220 mg, 677 μmol) in N,N-dimethylformamide (5 mL) was added bromomethylcyclopropane (45.7 mg, 338 μmol). The mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was diluted with brine (40 mL) and water (20 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, ethyl acetate) to give tert-butyl (1S,4S)-5-[4-[3-bromo-4-(cyclopropylmethoxy)-2-fluoro-anilin o]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (170 mg, 278 μmol, 82%) as a yellow oil. m/z ES+ [M+H] ⁺ 587.1. Step 2. tert-Butyl (1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2-fluoro-3-(2- trimethylsilylethynyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2 ,5-diazabicyclo[2.2.1]heptane-2- carboxylate To a mixture of tert-butyl (1S,4S)-5-[4-[3-bromo-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (46.0 mg, 78.5 μmol), ethynyl(trimethyl)silane (44.1 mg, 449 μmol) and N-cyclohexyl-N-methyl- cyclohexanamine (65.8 mg, 336 μmol) in N,N-dimethylformamide (0.2 mL) was added [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phos phane;methanesulfonate (8.17 mg, 11.2 μmol) under nitrogen, the mixture was stirred at 90 °C for 16 hr under nitrogen. On completion, the reaction mixture was diluted with brine (25 mL) and extracted with ethyl acetate (25 mL × 2). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/2 to 0/1) to give tert-butyl (1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2-fluoro-3-(2- trimethylsilylethynyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2 ,5-diazabicyclo[2.2.1]heptane-2- carboxylate (59.0 mg, 97.8 μmol, 87%) as a yellow oil. m/z ES+ [M+H] ⁺ 603.2. Step 3. N-[4-(cyclopropylmethoxy)-3-ethynyl-2-fluoro-phenyl]-6-[(1S, 4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e To a mixture of tert-butyl (1S,4S)-5-[4-[4-(cyclopropylmethoxy)-2-fluoro-3-(2- trimethylsilylethynyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2 ,5-diazabicyclo[2.2.1]heptane-2- carboxylate (59.0 mg, 97.9 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[4-(cyclopropylmethoxy)-3-ethynyl-2-fluoro- phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido [3,2-d]pyrimidin-4-amine (50.0 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 431.0. Step 4. 1-[(1S,4S)-5-[4-[4-(Cyclopropylmethoxy)-3-ethynyl-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one To a mixture of N-[4-(cyclopropylmethoxy)-3-ethynyl-2-fluoro-phenyl]-6-[(1S, 4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (30.0 mg, 55.1 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (2 mL) and water (0.7 mL) was added sodium bicarbonate (9.26 mg, 110 μmol), then the mixture was added prop-2-enoyl chloride (3.49 mg, 38.5 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 20%-50%,10.5 min) to give 1-[(1S,4S)-5-[4-[4-(cyclopropylmethoxy)-3-ethynyl-2- fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo [2.2.1]heptan-2-yl]prop-2-en-1-one (6.34 mg, 13.1 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 - 9.06 (m, 1H), 8.32 - 8.24 (m, 1H), 7.98 - 7.76 (m, 2H), 7.40 - 7.12 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.85 - 6.37 (m, 1H), 6.14 (m, J = 2.4, 5.6, 16.8 Hz, 1H), 5.74 - 5.61 (m, 1H), 5.55 - 5.13 (m, 1H), 5.10 - 4.90 (m, 1H), 4.57 (s, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.76 - 3.64 (m, 2H), 3.60 - 3.51 (m, 2H), 2.13 - 1.99 (m, 2H), 1.28 - 1.21 (m, 1H), 0.66 - 0.54 (m, 2H), 0.43 - 0.33 (m, 2H); m/z ES+ [M+H] ⁺ 485.0. Example 435. Preparation of 1-[(1S,4S)-5-[4-[3-ethynyl-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptan-2-yl]prop-2- en-1-one Step 1. Oxetan-3-ylmethyl methanesulfonate To a solution of oxetan-3-ylmethanol (500 mg, 5.68 mmol) and triethylamine (1.72 g, 17.0 mmol) in dichloromethane (8 mL) was added methylsulfonyl methanesulfonate (1.48 g, 8.51 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane: ethyl acetate =3:1 to 2:1) to give oxetan-3-ylmethyl methanesulfonate (940 mg, 5.66 mmol, 99%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.84 (m, 2H), 4.65 - 4.28 (m, 4H), 3.57 - 3.22 (m, 1H), 3.06 (s, 3H). Step 2. tert-Butyl (1S,4S)-5-[4-[3-bromo-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(3-bromo-2-fluoro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (180 mg, 338 μmol) and oxetan-3-ylmethyl methanesulfonate (112 mg, 677 μmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (220 mg, 677 μmol). The mixture was stirred at 60 °C for 6 hr. On completion, the mixture was duilted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane: ethyl acetate = 1:3 to 1:2) to give tert-butyl (1S,4S)-5-[4-[3-bromo-2- fluoro-4-(oxetan-3-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (194 mg, 322 μmol, 95%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (s, 1H), 8.88 - 8.60 (m, 1H), 8.59 (s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 8.05 - 7.84 (m, 1H), 7.01 - 6.92 (m, 1H), 6.85 (m , 1H), 4.92 (m, 2H), 4.66-4.31 (m, 2H), 4.30 (d, J = 6.6 Hz, 2H), 3.85 - 3.40 (m, 6H), 2.12 - 2.06 (m, 1H), 1.50 - 1.42 (m, 9H), 0.90 - 0.85 (m, 2H). Step 3. tert-Butyl (1S,4S)-5-[4-[2-fluoro-4-(oxetan-3-ylmethoxy)-3-(2- trimethylsilylethynyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2 ,5-diazabicyclo[2.2.1]heptane-2- carboxylate A mixture of tert-butyl (1S,4S)-5-[4-[3-bromo-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (120 mg, 199 μmol), ethynyl(trimethyl)silane (111 mg, 1.14 mmol), N-cyclohexyl-N-methyl- cyclohexanamine (167 mg, 855 μmol) and cataCXium® A Pd G3 (20.8 mg, 28.5 μmol) in N,N- dimethylformamide (2 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 3 hr under nitrogen atmosphere. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane: ethyl acetate =15:1 to 9:1) to give tert-butyl (1S,4S)-5-[4-[2-fluoro-4-(oxetan-3-ylmethoxy)-3-(2- trimethylsilylethynyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2 ,5-diazabicyclo[2.2.1]heptane-2- carboxylate (169 mg, 273 μmol, 96%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 - 8.70 (m, 1H), 8.56 (s, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.00 - 6.89 (m, 1H), 6.82 - 6.73 (m, 1H), 4.94 - 4.82 (m, 2H), 4.72 - 4.55 (m, 3H), 4.34 - 4.20 (m, 2H), 4.11 (q, J = 7.2 Hz, 1H), 3.73 - 3.40 (m, 6H), 2.51 (s, 6H), 1.23 (s, 10H), 0.28 (s, 6H). Step 4. 6-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-N-[3-ethynyl- 2-fluoro-4- (oxetan-3-ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl (1S,4S)-5-[4-[2-fluoro-4-(oxetan-3-ylmethoxy)-3-(2- trimethylsilylethynyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2 ,5-diazabicyclo[2.2.1]heptane-2- carboxylate (150 mg, 242 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (2 mL) was stirred at 25 °C for 6 hr. On completion, the mixture was concentrated in vacuo to give 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[3-ethynyl-2- fluoro-4-(oxetan-3- ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (130 mg, 231 μmol, 96%) as a yellow oil. m/z ES+ [M+H] ⁺ 447.3. Step 5. 1-[(1S,4S)-5-[4-[3-Ethynyl-2-fluoro-4-(oxetan-3-ylmethoxy)an ilino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[3-ethynyl- 2-fluoro-4- (oxetan-3-ylmethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-amine (130 mg, 231 μmol) and sodium bicarbonate (19.4 mg, 231 μmol) in anhydrous tetrahydrofuran (3 mL) and water (1 mL) was added prop-2-enoyl chloride (20.9 mg, 231 μmol) at 0 °C, the mixture was stirred at 25 °C for 0.1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex C18150*25 mm*10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 24%-54%, 5 min) to give 1-[(1S,4S)-5-[4-[3-ethynyl-2- fluoro-4-(oxetan-3-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (15.8 mg, 31.2 μmol, 13%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 - 9.12 (m, 1H), 8.30 (d, J = 3.2 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.43 - 7.12 (m, 1H), 7.03 (m, 1H), 6.85 - 6.35 (m, 1H), 6.14 (m, 1H), 5.74 - 5.57 (m, 1H), 5.48 - 5.14 (m, 1H), 5.10 - 4.89 (m, 1H), 4.72 (m, 2H), 4.58 (s, 1H), 4.48 (t, J = 6.0 Hz, 2H), 4.32 (d, J = 6.8 Hz, 2H), 3.76 - 3.71 (m, 1H), 3.68 (d, J = 6.8 Hz, 1H), 3.58 (d, J = 9.2 Hz, 2H), 3.44 (s, 1H), 2.08 (s, 1H), 2.00 (s, 1H); m/z ES+ [M+H] ⁺ 501.1. Example 436. Preparation of 1-[(1S,4S)-5-[4-[3-(difluoromethyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one Step 1. 1-(Difluoromethyl)-2-fluoro-3-nitro-benzene To a solution of 2-fluoro-3-nitro-benzaldehyde (500 mg, 2.96 mmol) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (1.91 g, 11.8 mmol) at 0 °C, and the mixture was stirred at 25 °C for 4 hr under nitrogen atmosphere. On completion, the reaction mixture was adjusted to pH = 9 with aqueous sodium bicarbonate (50 mL) at 0 °C. Then the reaction mixture was extracted with methylene dichloride (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- (difluoromethyl)-2-fluoro-3-nitro-benzene (550 mg, crude) as a brown liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (t, J = 7.6 Hz, 1H), 7.93 (t, J = 6.8 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 6.97 (s, 1H), 6.84 (s, 1H); m/z ES+ [M+H] ⁺ 192.1. Step 2. 3-(Difluoromethyl)-2-fluoro-aniline To a solution of 1-(difluoromethyl)-2-fluoro-3-nitro-benzene (120 mg, 627 μmol) in ethyl acetate (2.5 mL) was added palladium on activated carbon (60.0 mg, 10% loading). The mixture was stirred at 25 °C under hydrogen balloon (15 psi) for 6 hr. On completion, the reaction mixture was filtered with diatomite and the filtrate was concentrated to give 3- (difluoromethyl)-2-fluoro-aniline (100 mg, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.04 - 6.72 (m, 4H), 3.82 (s, 2H); m/z ES+ [M+H] ⁺ 162.1. Step 3. tert-Butyl (1S,4S)-5-[4-[3-(difluoromethyl)-2-fluoro-anilino]pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of 3-(difluoromethyl)-2-fluoro-aniline (67.5 mg, 418 μmol) in acetonitrile (1 mL) was added tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (90.0 mg, 249 μmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, dichloromethane: methanol = 10:1) to give tert-butyl (1S,4S)-5-[4-[3-(difluoromethyl)-2-fluoro-anilino]pyrido[3,2 -d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (120 mg, 234 μmol, 94%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.23 - 9.12 (m, 1H), 9.11 - 9.01 (m, 1H), 8.63 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.12 - 6.78 (m, 2H), 5.20 - 4.89 (m, 1H), 4.79 - 4.71 (m, 2H), 4.68 - 4.66 (m, 1H), 4.68 - 4.61 (m, 1H), 3.70 - 3.62 (m, 1H), 3.59 - 3.52 (m, 2H), 2.04 (s, 2H), 1.49 - 1.40 (m, 9H); m/z ES+ [M+H] ⁺ 487.2. Step 4. 6-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-N-[3-(difluor omethyl)-2-fluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-(difluoromethyl)-2-fluoro-anilino]pyrido[3,2 - d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (80.0 mg, 164 μmol) in dichloromethane (3.20 mL) was added trifluoroacetic acid (410 mg, 3.60 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated to give 6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-N-[3-(difluoromethyl)-2-fluo ro-phenyl]pyrido[3,2-d]pyrimidin- 4-amine (80.0 mg, crude, trifluoroacetic acid) as a brown oil. m/z ES+ [M+H] ⁺ 387.2. Step 5. 1-[(1S,4S)-5-[4-[3-(Difluoromethyl)-2-fluoro-anilino]pyrido[ 3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[3-(difluor omethyl)- 2-fluoro-phenyl]pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 160 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (1.60 mL) and water (0.8 mL) was added sodium bicarbonate (134 mg, 1.60 mmol). Then the mixture was added prop-2-enoyl chloride (13.0 mg, 144 μmol) and then stirred at 0 °C for 10 min. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN];B%: 30%-60%, 8 min) to give 1-[(1S,4S)-5-[4-[3-(difluoromethyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one (26.4 mg, 60.0 μmol, 38%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.56 - 8.33 (m, 2H), 7.99-7.88 (m, 1H), 7.49 - 7.09 (m, 4H), 6.89 - 6.36 (m, 1H), 6.20 - 6.09 (m, 1H), 5.76 - 5.58 (m, 1H), 5.40 (s, 1H), 5.02 (d, J =10.0 Hz,1H), 3.80 - 3.62 (m, 2H), 3.61 - 3.40 (m, 2H), 2.15 - 1.95 (m, 2H); m/z ES+ [M+H] ⁺ 441.2. Example 437. Preparation of 1-[(1S,4S)-5-[4-(3-ethynyl-2-fluoro-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2 -yl]prop-2-en-1-one Step 1. 2-Fluoro-3-(2-trimethylsilylethynyl)aniline To a mixture of 3-bromo-2-fluoro-aniline (2.00 g, 10.5 mmol) in toluene (2 mL) was added copper(I) iodide (200 mg, 1.05 mmol), triphenylphosphine (552 mg, 2.11 mmol) and diisopropylethylamine (2.72 g, 21.0 mmol) under nitrogen atmosphere. Then a solution of ethynyl(trimethyl)silane (1.55 g, 15.8 mmol) and bis(triphenylphosphine)palladium(II) dichloride (738 mg, 1.05 mmol) was added and the mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. On completion, the reaction mixture was filtered and the filtrate was diluted with water (100 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate=100/1 to 1/0) and repurified by reversed-phase HPLC (0.1% NH3•H2O conditions) to give 2-fluoro-3-(2-trimethylsilylethynyl)aniline (1.25 g, 5.91 mmol, 56%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.77 - 6.67 (m, 2H), 6.64 - 6.58 (m, 1H), 3.64 (s, 2H), 0.15 (s, 9H). m/z ES+ [M+H] ⁺ 207.9. Step 2. 3-Ethynyl-2-fluoro-aniline To a mixture of 2-fluoro-3-(2-trimethylsilylethynyl)aniline (800 mg, 3.86 mmol) in methanol (9 mL) was added potassium hydroxide (433 mg, 77.3 μmol) at 0 °C, then the mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was diluted with water (80 mL), and then extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-ethynyl-2- fluoro-aniline (446 mg, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.96 - 6.83 (m, 2H), 6.82 - 6.73 (m, 1H), 3.67 - 3.33 (m, 2H), 3.28 (s, 1H). m/z ES+ [M+H] ⁺ 136.0. Step 3. 6-Bromo-N-(3-ethynyl-2-fluoro-phenyl)-7-fluoro-pyrido[3,2-d] pyrimidin-4- amine To a mixture of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (306 mg, 1.17 mmol) in acetonitrile (2 mL) was added 3-ethynyl-2-fluoro-aniline (150 mg, 1.11 mmol), then the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was diluted with water 150 mL, and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-bromo-N-(3-ethynyl-2-fluoro-phenyl)-7-fluoro-pyrido[3,2-d] pyrimidin-4-amine (363 mg, 1.01 mmol, 91%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.2 (s, 1H), 8.62 (s, 1H), 8.33 - 8.21 (m, 1H), 7.78 - 7.73 (m, 1H), 7.53 - 7.46 (m, 1H), 7.33 - 7.19 (m, 1H), 4.60 - 4.51 (m, 1H); m/z ES+ [M+H] ⁺ 362.9. Step 4. tert-Butyl-(1S,4S)-5-[4-(3-ethynyl-2-fluoro-anilino)-7-fluor o-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a mixture of 6-bromo-N-(3-ethynyl-2-fluoro-phenyl)-7-fluoro-pyrido[3,2- d]pyrimidin-4-amine (330 mg, 914 μmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (272 mg, 1.37 mmol) in N-methylpyrrolidone (3.5 mL) was added diisopropylethylamine (236 mg, 1.83 mmol), then the mixture was stirred at 130 °C for 1 h. On completion, the reaction mixture was diluted with water (90 mL), and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate=10:1 to 1:1) to give tert-butyl-(1S,4S)-5-[4-(3-ethynyl-2-fluoro-anilino)-7-fluor o-pyrido[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (305 mg, 637 μmol, 70%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.98 (s, 1H), 8.89 (s, 1H), 8.63 (s, 1H), 7.61 (d, J = 13.2 Hz, 1H), 7.23 - 7.16 (m, 2H), 5.10 (d, J = 8.8 Hz, 1H), 4.62 (s, 1H), 3.91 (d, J = 9.6 Hz, 1H), 3.84 - 3.58 (m, 2H), 3.55 (s, 1H), 3.36 (s, 1H), 2.02 (d, J = 10.0 Hz, 2H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 479.1. Step 5. 6-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-N-(3-ethynyl- 2-fluoro-phenyl)- 7-fluoro-pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl-(1S,4S)-5-[4-(3-ethynyl-2-fluoro-anilino)-7-fluor o-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (150 mg, 313 μmol) in dichloromethane (4 mL) and trifluoroacetic acid (0.4 mL) was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give 6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-N-(3-ethynyl-2-fluoro-phenyl )-7-fluoro-pyrido[3,2-d]pyrimidin- 4-amine (150 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 378.9. Step 6. 1-[(1S,4S)-5-[4-(3-Ethynyl-2-fluoro-anilino)-7-fluoro-pyrido [3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one To a mixture of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(3-ethynyl- 2-fluoro- phenyl)-7-fluoro-pyrido[3,2-d]pyrimidin-4-amine (150 mg, 304 μmol) in tetrahydrofuran (2 mL) and water (0.5 mL) was added sodium bicarbonate (51.2 mg, 609 μmol) and prop-2-enoyl chloride (30.3 mg, 335 μmol), then the mixture was stirred at 0 °C for 1 h. On completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 8 min) to give 1-[(1S,4S)- 5-[4-(3-ethynyl-2-fluoro-anilino)-7-fluoro-pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (54.4 mg, 125 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.17 - 8.08 (m, 1H), 7.83 (d, J = 13.6 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.31 - 7.26 (m, 1H), 6.83 - 6.26 (m, 1H), 6.20 - 6.08 (m, 1H), 5.70 - 5.62 (m, 1H), 5.36 - 5.23 (m, 1H), 5.05 - 4.86 (m, 1H), 4.56 (s, 1H), 3.93 - 3.85 (m, 1H), 3.81 - 3.67 (m, 2H), 3.63 - 3.52 (m, 1H), 2.08 - 1.97 (m, 2H); m/z ES+ [M+18] ⁺ 433.0. Example 438. Preparation of 1-[7-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tan-4-yl]prop-2-en-1-one Step 1. tert-Butyl 7-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tane-4-carboxylate A solution of tert-butyl 7-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 265 μmol) and 3-chloro-4-(cyclopropylmethoxy)- 2-fluoro-aniline (68.6 mg, 318 μmol) in acetonitrile (5 mL) was stirred at 40 °C for 2 hr. On completion, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, pure ethyl acetate) to give tert-butyl 7-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]pyrim ido[5,4- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate (133 mg, 239 μmol, 90%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (s, 1H), 8.77 - 8.65 (m, 1H), 8.53 (s, 1H), 6.80 (dd, J = 2.0, 9.2 Hz, 1H), 6.64 - 6.55 (m, 1H), 3.98 (s, 2H), 3.92 (d, J = 7.2 Hz, 2H), 3.83 - 3.79 (m, 2H), 3.72 - 3.66 (m, 2H), 1.50 (s, 9H), 1.31 - 1.25 (m, 1H), 1.07 - 1.00 (m, 2H), 0.92 - 0.84 (m, 2H), 0.71 - 0.64 (m, 2H), 0.43 - 0.36 (m, 2H). Step 2. N-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine A solution of tert-butyl 7-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tane-4-carboxylate (110 mg, 197 μmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (2.5 mL) was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]-6-(4,7-diazaspiro[2.5] octan-7-yl)pyrimido[5,4- d]pyrimidin-4-amine (110 mg, 193 μmol, 98%) as a yellow solid. m/z ES+ [M+H] ⁺ 456.0. Step 3. 1-[7-[4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]py rimido[5,4- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1- one To a solution of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine (110 mg, 193.00 μmol) and sodium bicarbonate (16.2 mg, 193 μmol) in tetrahydrofuran (3 mL) and water (1 mL) was added prop-2- enoyl chloride (17.4 mg, 193 μmol), the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The crude product was purified by prep- HPLC [column: Phenomenex luna C18150*25 mm* 10 um; mobile phase: [water (FA)-ACN]; B%: 58%-88%,10.5 min] to give 1-[7-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tan-4-yl]prop-2-en-1-one (28.9 mg, 56.1 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.68 (s, 1H), 9.10 (s, 1H), 8.31 (s, 1H), 7.55 (t, J = 8.8 Hz, 1H), 7.24 - 6.62 (m, 2H), 6.18 (dd, J = 2.4, 16.8 Hz, 1H), 5.76 (d, J = 12.0 Hz, 1H), 4.01 (d, J = 7.2 Hz, 4H), 3.96 - 3.69 (m, 4H), 1.37 - 1.21 (m, 1H), 1.18 - 0.90 (m, 4H), 0.68 - 0.55 (m, 2H), 0.45 - 0.31 (m, 2H); m/z ES+ [M+H] ⁺ 510.0. Example 439. Preparation of 1-[7-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tan-4-yl]prop-2-en-1-one

Step 1. tert-Butyl 7-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]pyrimido [5,4- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate To a mixture of tert-butyl 7-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 265 μmol) in acetonitrile (1 mL) was added 3- chloro-4-(difluoromethoxy)-2-fluoroaniline (73.0 mg, 345 μmol), then the mixture was stirred at 40 °C for 1 h. On completion, the mixture was concentrated in vacuo to give a residue. The crude product was triturated with ethyl acetate (1 mL) to give tert-butyl 7-[4-[3-chloro-4- (difluoromethoxy)-2-fluoro-anilino]pyrimido[5,4-d]pyrimidin- 6-yl]-4,7-diazaspiro[2.5]octane-4- carboxylate (118 mg, 178 μmol, 67%) as a yellow oil. m/z ES+ [M+H] ⁺ 552.1. Step 2. N-[3-Chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-(4,7-diaz aspiro[2.5]octan- 7-yl)pyrimido[5,4-d]pyrimidin-4-amine To a mixture of tert-butyl 7-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tane-4-carboxylate (98.0 mg, 178 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (385 mg, 3.37 mmol), then the mixture was stirred at 20 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-(4,7-diaz aspiro[2.5]octan-7- yl)pyrimido[5,4-d]pyrimidin-4-amine (80.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 452.0. Step 3. 1-[7-[4-[3-Chloro-4-(difluoromethoxy)-2-fluoro-anilino]pyrim ido[5,4- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1- one To a mixture of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine (80.0 mg, 141 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.1 mL) was added prop-2-enoyl chloride (14.1 mg, 156 μmol) and sodium bicarbonate (23.8 mg, 283 μmol). Then the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25 mm*5 um; mobile phase: [water (FA)-ACN]; B%: 55%-85%, 10 min) to give 1-[7-[4-[3-chloro-4- (difluoromethoxy)-2-fluoro-anilino]pyrimido[5,4-d]pyrimidin- 6-yl]-4,7-diazaspiro[2.5]octan-4- yl]prop-2-en-1-one (24.6 mg, 48.5 μmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.76 - 9.48 (m, 1H), 9.04 (s, 1H), 8.27 (s, 1H), 7.75 - 7.66 (m, 1H), 7.32 - 7.23 (m, 1H), 7.48 (s, 1H), 6.94 - 6.73 (m, 1H), 6.10 (dd, J = 1.6, 16.8 Hz, 1H), 5.67 (d, J = 10.8 Hz, 1H), 4.08 - 3.56 (m, 6H), 1.05 - 0.83 (m, 4H); m/z ES+ [M+H] ⁺ 506.0. Example 440. Preparation of 1-((1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octan-2-yl)prop- 2-en-1-one Step 1. 6-Chloro-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyri mido[5,4- d]pyrimidin-4-amine A mixture of 4,6-dichloropyrimido[5,4-d]pyrimidine (310 mg, 1.54 mmol) and 3-chloro- 4-(difluoromethoxy)-2-fluoroaniline (326 mg, 1.54 mmol) in acetonitrile (5 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was filtered and the cake was collected to give 6-chloro- N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)pyrimido[5,4- d]pyrimidin-4-amine (500 mg, 1.33 mmol, 86%) as a yellow solid. m/z ES+ [M+H] ⁺ 375.9. Step 2. tert-Butyl 5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octane-2- carboxylate To a solution of 6-chloro-N-(3-chloro-4-(difluoromethoxy)-2- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (407 mg, 1.08 mmol) in N-methyl pyrrolidone (5 mL) was added diisopropylethylamine (420 mg, 3.25 mmol) and tert-butyl 2,5- diazabicyclo[2.2.2]octane-2-carboxylate (230 mg, 1.08 mmol). The mixture was stirred at 100 °C for 2 hr. On completion, the mixture was directly purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl 5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octane-2- carboxylate (300 mg, 544 μmol, 49%) as a yellow solid. m/z ES+ [M+H] ⁺ 552.1. Step 3. tert-Butyl (1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octane-2- carboxylate tert-Butyl 5-(8-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)pyr imido[5,4- d]pyrimidin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (300 mg, 544 μmol) was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase:[0.1% NH ₃ H ₂ O MeOH]; B%: 65%-65%, 9.0 min) to give tert-butyl (1S,4S)-5-(8-((3- chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)pyrimido[5,4 -d]pyrimidin-2-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (140 mg, 0.25 mmol, 47%) as a yellow solid and tert- butyl (1R,4R)-5-(8-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)pyrimido[5,4- d]pyrimidin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (140 mg, 0.25 mmol, 45%) as a yellow solid. m/z ES+ [M+H] ⁺ 552.1; m/z ES+ [M+H] ⁺ 552.1. Step 4. 6-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)- 2-fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine A mixture of tert-butyl (1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octane-2- carboxylate (140 mg, 253 μmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.33 mL) was stirred at 25 °C for 30 min. On completion, the mixture was concentrated in vacuo to give 6- ((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4-(d ifluoromethoxy)-2- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (143 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 452.2. Step 5. 1-((1S,4S)-5-(8-((3-Chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octan-2-yl)prop-2- en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)pyrimido[5,4-d]pyrimidin -4-amine (143 mg, 253 μmol, trifluoroacetic acid salt) and sodium bicarbonate (106 mg, 1.26 mmol) in anhydrous tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (22.9 mg, 253 μmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875 * 30mm * 3um; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 7 min) to give 1-((1S,4S)-5-(8-((3-chloro-4-(difluoromethoxy)-2-fluoropheny l)amino)pyrimido[5,4- d]pyrimidin-2-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-e n-1-one (33.1 mg, 65.5 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 - 9.07 (m, 1H), 8.96 - 8.75 (m, 2H), 8.65 - 8.56 (m, 1H), 7.18 (d, J = 9.2 Hz, 1H), 6.76 - 6.54 (m, 1H), 6.46 (d, J = 6.0 Hz, 1H), 6.43 - 6.33 (m, 1H), 5.82 - 5.70 (m, 1H), 5.41 - 4.31 (m, 2H), 4.05 - 3.89 (m, 2H), 3.89 - 3.75 (m, 2H), 2.28 - 2.09 (m, 2H), 2.07 - 1.89 (m, 2H); m/z ES+ [M+H] ⁺ 506.1. Example 441. Preparation of 1-((1R,4R)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octan-2-yl)prop- 2-en-1-one Step 1. 6-((1R,4R)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (difluoromethoxy)- 2-fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine A mixture of tert-butyl (1R,4R)-5-(8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octane-2- carboxylate (140 mg, 253 μmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.33 mL) was stirred at 25 °C for 30 min. On completion, the mixture was concentrated in vacuo to give 6- ((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4-(d ifluoromethoxy)-2- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (143 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 452.2. Step 2. 1-((1R,4R)-5-(8-((3-Chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2,5-diazab icyclo[2.2.2]octan-2-yl)prop-2- en-1-one To a solution of 6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (cyclopropylmethoxy)-2-fluorophenyl)pyrimido[5,4-d]pyrimidin -4-amine (143 mg, 253 μmol, trifluoroacetic acid) and sodium bicarbonate (106 mg, 1.26 mmol) in anhydrous tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (22.9 mg, 253 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875 * 30mm * 3um; mobile phase: [water (FA)-ACN]; B%: 45% - 75%, 7 min) to give 1-((1R,4R)-5-(8-((3- chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)pyrimido[5,4 -d]pyrimidin-2-yl)-2,5- diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one (29.6 mg, 58.5 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 9.20 - 9.06 (m, 1H), 8.98 - 8.75 (m, 2H), 8.65 - 8.58 (m, 1H), 7.18 (d, J = 9.2 Hz, 1H), 6.77 - 6.55 (m, 1H), 6.50 - 6.35 (m, 2H), 5.90 - 5.69 (m, 1H), 5.40 - 4.34 (m, 2H), 4.08 - 3.90 (m, 2H), 3.90 - 3.79 (m, 2H), 2.27 - 2.09 (m, 2H), 2.05 - 1.93 (m, 2H); m/z ES+ [M+H] ⁺ 506.1. Example 442. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.2]octan-2-yl]prop-2-en- 1-one

Step 1. tert-Butyl 5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7-fluor o- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2 -carboxylate To a solution of 6-bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7-f luoro- pyrido[3,2-d]pyrimidin-4-amine (300 mg, 685 μmol) and tert-butyl 2,5- diazabicyclo[2.2.2]octane-2-carboxylate (175 mg, 823 μmol) in 1-methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (177 mg, 1.37 mmol, 239 μL). The mixture was stirred at 130 °C for 1 hr. On completion, the mixture was quenched with brine (30 mL) and extracted with ethyl acetate (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give tert-butyl5-[4-[3-chloro-4- (difluoromethoxy)-2-fluoro-anilino]-7-fluoro-pyrido[3,2-d]py rimidin-6-yl]-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (500 mg, 557 μmol, 81%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 - 8.79 (m, 2H), 8.61 (s, 1H), 7.62 (d, J = 13.6 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.75 - 6.31 (m, 1H), 4.85 (s, 1H), 4.51 - 4.30 (m, 1H), 3.88 - 3.76 (m, 2H), 3.67 - 3.55 (m, 1H), 2.29 - 2.11 (m, 2H), 1.98 - 1.83 (m, 3H), 1.49 (d, J = 6.4 Hz, 9H); m/z ES+ [M+H] ⁺ 569.1. Step 2. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] -7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]o ctane-2-carboxylate Compound tert-butyl 5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7-fluor o- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2 -carboxylate (500 mg, 557 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm,10 um); mobile phase: [0.1%NH ₃ H ₂ O IPA]; B%: 30%-30%, 7.55; 226.5min) to give tert-butyl (1S,4S)-5-[4-[3- chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7-fluoro-pyrido [3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (160 mg, 273 μmol, 31%) as a white solid and and tert- butyl (1R,4R)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] -7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (230 mg, 400 μmol, 45%) as a white solid. m/z ES+ [M+H] ⁺ 569.1; m/z ES+ [M+H] ⁺ 569.1. Step 3. N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.2]octan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimid in-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] - 7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2 ]octane-2-carboxylate (100 mg, 176 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5-diazabicyclo[2.2.2]octan-2-yl]-7-fluoro-pyrido[3,2-d]pyr imidin-4-amine (100 mg, crude, trifluoroacetic acid salt) as yellow oil. m/z ES+ [M+H] ⁺ 469.0. Step 4. 1-[(1S,4S)-5-[4-[3-Chloro-4-(difluoromethoxy)-2-fluoro-anili no]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octan-2- yl]prop-2-en-1-one To a solution of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.2]octan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimid in-4-amine (100 mg, 171 μmol, trifluoroacetic acid salt) in anhydrous tetrahydrofuran (4 mL) and water (0.8 mL) was added sodium bicarbonate (144 mg, 1.72 mmol) at 0 °C. Then prop-2-enoyl chloride (14.0 mg, 154 μmol, 12.6 μL) was added and the mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was quenched with methanol (4 mL) and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 1- [(1S,4S)-5-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino ]-7-fluoro-pyrido[3,2-d]pyrimidin- 6-yl]-2,5-diazabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one (23.6 mg, 44.6 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.37 (s, 1H), 7.94 - 7.81 (m, 2H), 7.55 - 7.18 (m, 2H), 6.86 - 6.57 (m, 1H), 6.22 - 6.12 (m, 1H), 5.75 - 5.66 (m, 1H), 5.14 (s, 1H), 4.73 - 4.49 (m, 1H), 4.07 - 3.55 (m, 4H), 2.14 - 1.87(m, 4H); m/z ES+ [M+H] ⁺ 523.0. Example 443. Preparation of 1-(7-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)-4,7 -diazaspiro[2.5]octan-4- yl)prop-2-en-1-one

Step 1. tert-Butyl 7-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octane -4-carboxylate To a solution of 6-bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7-f luoro- pyrido[3,2-d]pyrimidin-4-amine (0.20 g, 457 μmol) in N-methyl pyrrolidone (2 mL) was added diisopropylethylamine (177 mg, 1.37 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4- carboxylate (97 mg, 457 μmol). The mixture was stirred at 130 °C for 2 h. On completion, the reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (acetonitrile: water=20:1 to 1:1) to give tert- butyl 7-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-7- fluoropyrido[3,2- d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (0.2- g, 352 μmol, 77%) as a yellow solid. m/z ES+ [M+H] ⁺ 569.1; Step 2. N-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-7-fluoro-6-( 4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl 7-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octa ne-4-carboxylate (0.100 g, 175 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under reduced pressure to give N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-7-fluoro-6-( 4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 469.2. Step 3. 1-(7-(4-((3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)amino) -7- fluoropyrido[3,2-d]pyrimidin-6-yl)-4,7-diazaspiro[2.5]octan- 4-yl)prop-2-en-1-one To a solution of N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-7-fluoro-6-( 4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, 172 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (23.7 mg, 171 μmol) and prop-2-enoyl chloride (15.5 mg, 171 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 * 50 mm * 3 um; mobile phase: [water (FA)-ACN]; B%: 43%-73%, 10 min) in vacuo to give 1-(7-(4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)-7-fluoropyrido[3,2-d ]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octan-4-yl)prop-2-en-1-one (15.8 mg, 29.9 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 - 7.40 (m, 1H), 8.45 - 8.38 (m, 1H), 7.99 - 7.83 (m, 2H), 7.60 - 7.14 (m, 2H), 6.17 - 6.10 (m, 1H), 5.75 - 5.70 (m, 1H), 3.91 - 3.60 (m, 7H), 1.19 - 0.95 (m, 5H); m/z ES+ [M+H] ⁺ 522.9. Example 444. Preparation of 1-((1R,4R)-5-(4-((3-chloro-4-(2,2-difluoroethyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2- en-1-one Step 1. tert-Butyl 5-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (300 mg, 1.65 mmol) in N- methylpyrrolidone (5 mL) was added diisopropylethylamine (641 mg, 4.96 mmol) and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (526 mg, 2.48 mmol). The mixture was stirred at 100 °C for 16 hr. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC (mobile phase: [water (0.225% FA)-ACN]; B%: 40%-50%, 10 min) to give tert-butyl 5-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2. 2.2]octane- 2-carboxylate (430 mg, 1.20 mmol, 73%) as a yellow solid. m/z ES+ [M+H] ⁺ 358.1. Step 2. tert-Butyl 5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate To a solution of tert-butyl 5-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (380 mg, 1.06 mmol) and diisopropylethylamine (824 mg, 6.38 mmol) in toluene (3 mL) was added phosphorus oxychloride (326 mg, 2.13 mmol). The mixture was stirred at 110 °C for 2 hr. The reaction mixture was concentrated in vacuo. The obtained residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 3/1 to 1/1) to give tert-butyl 5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (340 mg, 841 μmol, 93%) as a yellow oil. m/z ES+ [M+H] ⁺ 376.1. Step 3. tert-Butyl 5-(4-((3-chloro-4-(2,2-difluoroethyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate To a solution of tert-butyl 5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (280 mg, 745 μmol) in acetonitrile (1 mL) was added 3- chloro-4-(2,2-difluoroethyl)-2-fluoro-aniline (203 mg, 968 μmol). The mixture was stirred at 40 °C for 1 hr. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 3/1 to 0/1) to give tert-butyl 5-(4-((3-chloro-4-(2,2-difluoroethyl)-2-fluorophenyl)amino)p yrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (160 mg, 271 μmol, 93%) as a yellow oil. m/z ES+ [M+H] ⁺ 549.2. Step 4. tert-Butyl (1R,4R)-5-(4-((3-chloro-4-(2,2-difluoroethyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate tert-Butyl 5-(4-((3-chloro-4-(2,2-difluoroethyl)-2-fluorophenyl)amino)p yrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e (160 mg, 271 μmol) was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [0.1% NH ₃ H ₂ O MeOH]; B%: 60%-60%, 4.5 min) to give tert-butyl (1S,4S)-5-(4-((3-chloro-4- (2,2-difluoroethyl)-2-fluorophenyl)amino) pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (80 mg, 143 μmol, 50%) as a yellow solid and tert-butyl (1R,4R)-5-(4-((3-chloro-4-(2,2-difluoroethyl)-2-fluorophenyl )amino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (73.0 mg, 132 μmol, 46%) as a yellow solid. m/z ES+ [M+H] ⁺ 549.2; m/z ES+ [M+H] ⁺ 549.2. Step 5. 6-((1R,4R)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (2,2- difluoroethyl)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1R,4R)-5-(4-((3-chloro-4-(2,2-difluoroethyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octane-2-carboxylate (63.0 mg, 115 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated in vacuo to give 6-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (2,2-difluoroethyl)-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (64.0 mg, 114 μmol, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 448.9. Step 6. 1-((1R,4R)-5-(4-((3-Chloro-4-(2,2-difluoroethyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2-en- 1-one To a solution of 6-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-chloro-4- (2,2- difluoroethyl)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (64.0 mg, 114 μmol, trifluoroacetic acid salt) in anhydrous tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (47.8 mg, 568 μmol) and prop-2-enoyl chloride (9.26 mg, 102 μmol). The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex C1875*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 7 min) and re-purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 47%-77%, 10 min) to give 1-((1R,4R)-5-(4-((3-chloro-4-(2,2-difluoroethyl)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.2]octan-2-yl)prop-2-en- 1-one (3.43 mg, 6.82 μmol, 6.0%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 - 9.25 (m, 1H), 8.38 (s, 1H), 7.96 (d, J = 9.2 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.94 - 6.54 (m, 1H), 6.50 - 6.13 (m, 2H), 5.80 - 4.53 (m, 3H), 3.88 - 3.82 (m, 1H), 3.80 - 3.62 (m, 3H), 3.47 - 3.40 (m, 2H), 2.01 - 1.90 (m, 4H); m/z ES+ [M+H] ⁺ 503.0. Example 445. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6- yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrimido[5 ,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A solution of tert-butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 358 μmol) and 4-amino-2-chloro-3-fluoro- phenol (57.8 mg, 358 μmol) in acetonitrile (2 mL) was stirred at 60 °C for 1 hr. On completion, the mixture was concentrated to give tert-butyl(1S,4S)-5-[4-(3-chloro-2-fluoro-4-hydroxy- anilino)pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate (230 mg, crude) as a yellow solid. m/z ES + [M+H] ⁺ 488.0. Step 2. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6- yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-hydroxy- anilino)pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate (200 mg, 409 μmol) and (1-fluorocyclobutyl)methyl methanesulfonate (112 mg, 614 μmol) in N,N- dimethylformamide (3 mL) was added potassium carbonate (169 mg, 1.23 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was partitioned between ethyl acetate (40 mL × 3) and brine (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give tert- butyl(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1-fluorocyclobutyl) methoxy]anilino]pyrimido[5,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (100 mg, 137 μmol, 33%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.06 (s, 1H), 8.76 (s, 1H), 8.65 - 8.49 (m, 2H), 6.88 (d, J = 8.8 Hz, 1H), 5.22 - 5.04 (m, 1H), 4.79 - 4.57 (m, 1H), 4.23 - 4.14 (m, 2H), 3.83 - 3.62 (m, 2H), 3.59 - 3.33 (m, 2H), 2.53 - 2.37 (m, 4H), 2.15 - 1.86 (m, 4H), 1.51 - 1.42 (m, 9H); m/z ES + [M+H] ⁺ 574.2. Step 3. N-[3-Chloro-2-fluoro-4-[(1-fluorocyclobutyl)methoxy]phenyl]- 6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6- yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (80 mg, 139 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol, 400 μL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]phenyl]-6-[(1S,4S)-2,5-diazabicyclo [2.2.1]heptan-2-yl]pyrimido[5,4- d]pyrimidin-4-amine (80 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES + [M+H] ⁺ 474.2. Step 4. 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6- yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-[(1-fluorocyclobutyl)methoxy]phenyl]- 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]p yrimidin-4-amine (80.0 mg, 136 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (2 mL) and water (0.3 mL) was added sodium carbonate (34.2 mg, 408 μmol, 15.8 μL) at 0 °C. Then prop-2-enoyl chloride (9.85 mg, 108 μmol, 8.88 μL) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was quenched with methanol (4 mL) and then concentrated to give a residue. The residue was triturated with dimethylsulfoxide (2 mL) at 25 °C for 10 min to give 1- [(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1-fluorocyclobutyl)meth oxy]anilino]pyrimido[5,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (11.8 mg, 21.2 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 - 9.35 (m, 1H), 9.10 (s, 1H), 8.31 (s, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.90 - 6.37 (m, 1H), 6.21 – 6.08 (m, 1H), 5.76 – 5.60 (m,1H), 5.52 - 4.89 (m, 2H), 4.44 - 4.30 (m, 2H), 3.81 - 3.43 (m, 4H), 2.38 - 2.24 (m, 4H), 2.13 - 1.96 (m, 2H), 1.87 - 1.56 (m, 2H); m/z ES+ [M+H] ⁺ 528.0. Example 446. Preparation of 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate (120 mg, 316 μmol) and 4-amino-2-chloro-3-fluoro- phenol (55.0 mg, 340 μmol) in acetonitrile (1 mL) was stirred at 40 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was triturated with petroleum/ethyl acetate (3:1, 4 mL) to afford compound tert-butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-hydroxy- anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (190 mg, 309 μmol, 98%) as a brown solid. m/z ES+ [M+H] ⁺ 505.2. Step 2. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (170 mg, 337 μmol) and (1-fluorocyclobutyl)methyl methanesulfonate (92.0 mg, 505 μmol) in N,N- dimethylformamide (2 mL) was added potassium carbonate (140 mg, 1.01 mmol). The mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 0/1) to give tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (90.0 mg, 131 μmol, 39%) as a brown solid. ¹ H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.59 (s, 2H), 7.74 - 7.62 (m, 1H), 6.91 - 6.84 (m, 1H), 5.17 - 5.01 (m, 1H), 4.79 - 4.54 (m, 1H), 4.23 - 4.15 (m, 2H), 3.93 - 3.73 (m, 2H), 3.68 - 3.47 (m, 2H), 2.54 - 2.33 (m, 4H), 2.07 - 1.84 (m, 4H), 1.47 (d, J = 18.4 Hz, 9H); m/z ES+ [M+H] ⁺ 591.2. Step 3. N-[3-chloro-2-fluoro-4-[(1-fluorocyclobutyl)methoxy]phenyl]- 6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (60.0 mg, 102 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]phenyl]-6-[(1S,4S)-2,5-diazabicyclo [2.2.1]heptan-2-yl]-7-fluoro- pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, crude, trifluoroacetic acid) as a brown solid. m/z ES+ [M+H] ⁺ 491.2. Step 4. 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1-fluorocyclobutyl)me thoxy]anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptan-2-yl]prop-2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-[(1-fluorocyclobutyl)methoxy]phenyl]- 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido [3,2-d]pyrimidin-4-amine (60.0 mg, 99.2 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (2 mL) and water (1 mL) was added sodium bicarbonate (167 mg, 1.98 mmol). Then prop-2-enoyl chloride (7.18 mg, 79.4 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate=0:1) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (33.0 mg, 55.1 μmol, 56%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.78-7.75 (m, 1H), 7.68 (q, J = 8.8 Hz, 1H), 7.14-7.01 (m, 1H), 6.83 - 6.34 (m, 1H), 6.12 (m, 1H), 5.69 - 5.59 (m, 1H), 5.41 - 5.26 (m, 1H), 5.02 - 4.85 (m, 1H), 4.39 - 4.29 (m, 2H), 3.90 - 3.82 (m, 1H), 3.74 - 3.66 (m, 2H), 3.59 - 3.48 (m, 1H), 2.36 - 2.31 (m, 2H), 2.28 (d, J = 8.8 Hz, 2H), 2.04 - 1.95 (m, 2H), 1.86 - 1.73 (m, 1H), 1.70 - 1.56 (m, 1H); m/z ES+ [M+H] ⁺ 545.1. Example 447. Preparation of 1-[(1S,4S)-5-[4-[[3-fluoro-5-[(1-fluorocyclopropyl)methoxy]- 2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptan-2-yl]prop-2-en- 1-one Step 1. tert-Butyl (1S,4S)-5-(4-((5-bromo-3-fluoropyridin-2-yl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A solution of 5-bromo-3-fluoro-pyridin-2-amine (63.4 mg, 332 μmol) in N,N- dimethylformamide (1 mL) was added sodium hydride (13.3 mg, 332 μmol, 60% in mineral oil). The mixture was stirred at 0 °C for 0.5 hr. Then tert-butyl (1S,4S)-5-(4-chloropyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (100 mg, 276 μmol) was added and the mixture was stirred at 25 °C for 1.5 hr. On completion, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, ethyl acetate: methylene dichloride= 10:1) to give tert-butyl (1S,4S)-5-[4-[(5-bromo-3-fluoro-2- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (200 mg, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.75 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.68 (m, 1H), 7.07 - 6.97 (m, 1H), 5.18 - 4.87 (m, 1H), 4.78 - 4.60 (m, 1H), 3.73 (br d, J = 7.6 Hz, 2H), 3.57 - 3.49 (m, 2H), 1.62 (s, 9H), 1.27 (s, 2H); m/z ES+ [M+H] ⁺ 518.0. Step 2. tert-Butyl (1S,4S)-5-(4-((3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2- yl)pyridin-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diaza bicyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-[4-[(5-bromo-3-fluoro-2-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (180 mg, 349 μmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (133 mg, 523 μmol) in dioxane (2 mL) was added potassium acetate (103 mg, 1.05 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.5 mg, 34.9 μmol). The mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2- yl)-2-pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabi cyclo[2.2.1]heptane-2-carboxylate (290 mg, crude) as a black oil. m/z ES+ [M+H] ⁺ 563.3. Step 3. tert-Butyl (1S,4S)-5-(4-((3-fluoro-5-hydroxypyridin-2-yl)amino)pyrido[3 ,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a solution of tert-butyl (1S,4S)-5-[4-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-pyridyl]amino]pyrido[3,2-d]pyrimidin-6- yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (270 mg, 479 μmol) in water (1 mL) and acetonitrile (3 mL) was added Oxone (589 mg, 958 μmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was poured into saturated sodium sulfite (10 mL) and extracted with ethyl acetate (10 mL x 3).The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, methylene dichloride: methanol = 10:1) to give tert-butyl (1S,4S)-5-[4-[(3-fluoro-5-hydroxy-2-pyridyl)amino]pyrido[3,2 -d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (80.0 mg, crude) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.00 - 8.59 (m, 1H), 8.53 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.89 (s, 1H), 7.06 - 6.95 (m, 2H), 5.18 - 4.85 (m, 1H), 4.75 (s, 1H), 4.63 (s, 1H), 3.68 (d, J = 8.4 Hz, 2H), 3.56 - 3.49 (m, 2H), 2.02 (s, 2H), 1.28 - 1.24 (m, 9H); m/z ES+ [M+H] ⁺ 454.2. Step 4. tert-Butyl (1S,4S)-5-[4-[[3-fluoro-5-[(1-fluorocyclopropyl)methoxy]-2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-[(3-fluoro-5-hydroxy-2- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (50.0 mg, 110 μmol) and (1-fluorocyclopropyl)methyl methanesulfonate (27.8 mg, 165 μmol) in N,N- dimethylformamide (0.5 mL) was added potassium carbonate (45.7 mg, 330 μmol). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was partitioned between ethyl acetate (20 mL × 3) and brine (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep- TLC (silicon dioxide, dichloromethane : methanol=10:1) to give tert-butyl (1S,4S)-5-[4-[[3- fluoro-5-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]amino]pyri do[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (20.0 mg, 38.0 μmol, 34%) as a yellow oil. m/z ES+ [M+H] ⁺ 526.2. Step 5.6-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-N-[3-fluoro -5-[(1- fluorocyclopropyl)methoxy]-2-pyridyl]pyrido[3,2-d]pyrimidin- 4-amine To a solution of tert-butyl (1S,4S)-5-[4-[[3-fluoro-5-[(1-fluorocyclopropyl)methoxy]-2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (20.0 mg, 38.0 μmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (77.0 mg, 675 μmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture reaction was concentrated in vacuo to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[3-fluoro-5 -[(1- fluorocyclopropyl)methoxy]-2-pyridyl]pyrido[3,2-d]pyrimidin- 4-amine (20.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 426.1. Step 6.1-[(1S,4S)-5-[4-[[3-Fluoro-5-[(1-fluorocyclopropyl)methoxy ]-2- pyridyl]amino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[ 2.2.1]heptan-2-yl]prop-2-en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-[3-fluoro-5 -[(1- fluorocyclopropyl)methoxy]-2-pyridyl]pyrido[3,2-d]pyrimidin- 4-amine (20.0 mg, 37.0 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (0.5 mL) and water (0.1 mL) was added sodium bicarbonate (6.23 mg, 74.1 μmol) at 0 °C. Then prop-2-enoyl chloride (1.00 mg, 11.0 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was quenched with methanol (4 mL) and concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)- ACN];B%: 16%-46%,11min) to give 1-[(1S,4S)-5-[4-[[3-fluoro-5-[(1- fluorocyclopropyl)methoxy]-2-pyridyl]amino]pyrido[3,2-d]pyri midin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (3.05 mg, 6.14 μmol, 16%) as yellow gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.85 - 9.52 (m, 1H), 8.26 - 8.06 (m, 2H), 7.93 – 7.84 (m, 1H), 7.73 – 7.56 (m, 1H), 7.49 - 6.98 (m, 1H), 6.84 - 6.34 (m, 1H), 6.19 – 6.06 (m, 1H), 5.72 - 5.61 (m, 1H), 5.60 - 5.10 (m, 1H), 5.08 - 4.87 (m, 1H), 4.53 - 4.40 (m, 2H), 3.75 - 3.40 (m, 4H), 2.07 - 1.94 (m, 2H), 1.23 - 1.13 (m, 2H), 0.94 - 0.87 (m, 2H); m/z ES+ [M+H] ⁺ 480.1. Example 448. Preparation of 1-[(1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chlor o- 2-fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyc lo[2.2.1]heptan-2-yl]prop-2-en- 1-one Step 1.1-Bicyclo[1.1.1]pentanylmethanol To a mixture of bicyclo[1.1.1]pentane-1-carboxylic acid (0.1 g, 892 μmol) in anhydrous tetrahydrofuran (2 mL) was added lithium aluminum hydride (50.77 mg, 1.34 mmol) in portions at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min, then heated to 25 °C and stirred for 16 hr. On completion, the reaction mixture was quenched by sodium sulfate decahydrate 100 mg at 25 °C and stirred for 30 min. Then the mixture was filtered and concentrated under reduced pressure to give 1-bicyclo[1.1.1]pentanylmethanol (85 mg, 779 μmol, 87%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.54 (s, 2H), 2.55 (s, 1H), 1.75 (s, 6H). Step 2.1-Bicyclo[1.1.1]pentanylmethyl methanesulfonate To a mixture of 1-bicyclo[1.1.1]pentanylmethanol (85 mg, 866 μmol) in dichloromethane (2 mL) was added triethylamine (263 mg, 2.60 mmol) and methylsulfonyl methanesulfonate (226 mg, 1.30 mmol) in one portion at 0 °C. The mixture was stirred at 25 °C for 16 hr. On completion, the reaction mixture was quenched by addition water 5 mL at 25 °C, and then diluted with dichloromethane 5 mL and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 1- bicyclo[1.1.1]pentanylmethyl methanesulfonate (0.12 g, 613 μmol, 71%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.14 (s, 2H), 3.00 (s, 3H), 2.57 (s, 1H), 1.84 (s, 6H). Step 3. tert-Butyl (1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2 -fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate To a mixture of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (150 mg, 308 μmol) and 1-bicyclo[1.1.1]pentanylmethyl methanesulfonate (81.4 mg, 462 μmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (128 mg, 924 μmol) in one portion. The mixture was then heated to 60 °C and stirred for 5 hr. On completion, the reaction mixture was quenched by addition water 50 mL at 25 °C, and then diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=1/1) to give tert-butyl (1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2 - fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate (120 mg, 182 μmol, 59%) as a yellow oil. m/z ES+ [M+H] ⁺ 567.3. Step 4. N-[4-(1-Bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fluoro-phe nyl]-6-[(1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- amine A solution of tert-butyl (1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2 - fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate (120 mg, 212 μmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N- [4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fluoro-pheny l]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (90 mg, 150 μmol, 71%) as a yellow oil. m/z ES+ [M+H] ⁺ 467.0. Step 5.1-[(1S,4S)-5-[4-[4-(1-Bicyclo[1.1.1]pentanylmethoxy)-3-chl oro-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one To a mixture of N-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fluoro-phe nyl]-6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (90 mg, 193 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (48.6 mg, 578 μmol) and prop-2-enoyl chloride (15.7 mg, 173 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 35%-65%,10 min) to give 1-[(1S,4S)- 5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (18.45 mg, 35.4 μmol, 18.4%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ):煩 9.43 - 9.17 (m, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.96 - 7.70 (m, 2H), 7.41 - 6.99 (m, 2H), 6.89 - 6.29 (m, 1H), 6.14 (ddd, J = 2.4, 5.7, 16.8 Hz, 1H), 5.76 - 5.33 (m, 1H), 5.10 - 4.89 (m, 1H), 4.11 (s, 2H), 3.79 - 3.48 (m, 4H), 2.56 (s, 1H), 2.11 - 1.93 (m, 3H), 1.83 (s,6H), m/z ES+ [M+H] ⁺ 521.0. Example 449. Preparation of 1-[(1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-2,3- difluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyc lo[2.2.1]heptan-2-yl]prop-2-en- 1-one

Step 1. tert-Butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2-d]py rimidin- 6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate A mixture of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.5 g, 1.38 mmol) and 4-amino-2,3-difluoro-phenol (221 mg, 1.52 mmol) in acetonitrile (5 mL) was stirred at 40 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-(2,3- difluoro-4-hydroxy-anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2- carboxylate (0.6 g, 1.24 mmol, 89%) as a yellow solid. m/z ES+ [M+H] ⁺ 471.2. Step 2. tert-Butyl (1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-2,3-difluo ro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate To a mixture of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (150 mg, 318 μmol) and 1- bicyclo[1.1.1]pentanylmethyl methanesulfonate (84.3 mg, 478 μmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (132 mg, 956 μmol) in one portion .The mixture was then heated to 60 °C and stirred for 16 hr. On completion, the reaction mixture was quenched by addition water 50 mL at 25 °C, and then diluted with ethyl acetate 50 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-2,3-difluo ro-anilino]pyrido[3,2-d]pyrimidin- 6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg, 308 μmol, 97%) as a yellow oil. m/z ES+ [M+H] ⁺ 551.5. Step 3. N-[4-(1-Bicyclo[1.1.1]pentanylmethoxy)-2,3-difluoro-phenyl]- 6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e A mixture of tert-butyl (1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-2,3-difluo ro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (170 mg, 308 μmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[4-(1- bicyclo[1.1.1]pentanylmethoxy)-2,3-difluoro-phenyl]-6-[(1S,4 S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl]pyrido[3,2-d]pyrimidin-4-amine (130 mg, 273 μmol, 88%) as a yellow oil. m/z ES+ [M+H] ⁺ 451.4. Step 4.1-[(1S,4S)-5-[4-[4-(1-Bicyclo[1.1.1]pentanylmethoxy)-2,3-d ifluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one To a mixture of N-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-2,3-difluoro-phenyl]- 6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (130 mg, 288 μmol) in anhydrous tetrahydrofuran (3 mL) and water (3 mL) was added sodium bicarbonate (72.7 mg, 865 μmol) and prop-2-enoyl chloride (23.5 mg, 259 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)-ACN];B%: 32%-62%,10 min) to give 1-[(1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-2,3-dif luoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one (48.69 mg, 91.7 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 - 9.18 (m, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.90 (dd, J = 3.9, 9.2 Hz, 1H), 7.69 - 7.50 (m, 1H), 7.41 - 6.99 (m, 2H), 6.90 - 6.34 (m, 1H), 6.14 (ddd, J = 2.4, 5.6, 16.8 Hz, 1H), 5.77 - 5.27 (m, 2H), 5.10 - 4.86 (m, 1H), 4.10 (s, 2H), 3.78 - 3.48 (m, 4H), 2.55 (s, 1H), 2.12 - 1.94 (m, 2H), 1.82 (s, 6H); m/z ES+ [M+H] ⁺ 505.0. Example 450. Preparation of 1-[(1S,4S)-5-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-2,3- difluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyc lo[2.2.1]heptan-2-yl]prop-2-en- 1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((4-((3,3-difluorocyclobutyl)methoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate To a solution of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (130 mg, 276 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (100 mg, 724 μmol) and (3,3-difluorocyclobutyl)methyl methanesulfonate (72 mg, 360 μmol). The mixture was stirred at 80 ℃ for 12 hr. The mixture was poured into water (8 mL) and stirred at 20 ℃ for 0.3 h. The resulting precipitate was collected by filtration, which was further dried in vacuo to give tert-butyl (1S,4S)-5-(4-((4-((3,3-difluorocyclobutyl)methoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (140 mg, 241 μmol, 87%) as a yellow solid. m/z ES+ [M+H] ⁺ 575.0. Step 2.6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(4-((3,3- difluorocyclobutyl)methoxy)-2,3-difluorophenyl)pyrido[3,2-d] pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-((4-((3,3-difluorocyclobutyl)methoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptane-2- carboxylate (140 mg, 244 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (719 mg, 6.30 mmol, 467 μL). The mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- N-(4-((3,3-difluorocyclobutyl)methoxy)-2,3-difluorophenyl)py rido[3,2-d]pyrimidin-4-amine (100 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 475.2. Step 3.1-((1S,4S)-5-(4-((4-((3,3-Difluorocyclobutyl)methoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazab icyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4-((3,3- difluorocyclobutyl)methoxy)-2,3-difluorophenyl)pyrido[3,2-d] pyrimidin-4-amine (100 mg, 170 μmol, trifluoroacetic acid salt) in anhydrous tetrahydrofuran (1.2 mL) and water (0.2 mL) was added sodium bicarbonate (57.1 mg, 680煱mol) to adjust pH ~ 8. Then prop-2-enoyl chloride (11.6 mg, 129 μmol) was added into the mixture at 0 °C. The mixture was stirred at 25 °C for 10 min. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30 mm*3um; mobile phase: [water(FA)-ACN]; B%: 25%-55%, 7 min) to give 1-((1S,4S)-5-(4-((4-((3,3- difluorocyclobutyl)methoxy)-2,3-difluorophenyl)amino)pyrido[ 3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (50.8 mg, 96.2 μmol, 57%) as a yellow solid. ¹ H NMR (400 MHz DMSO-d ₆ ) δ 9.46 - 9.13 (m, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 4.0, 9.2 Hz, 1H), 7.73 - 7.54 (m, 1H), 7.43 - 7.15 (m, 1H), 7.14 - 7.05 (m, 1H), 6.86 - 6.36 (m, 1H), 6.14 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 5.74 - 5.61 (m, 1H), 5.55 - 5.11 (m, 1H), 5.10 - 4.90 (m, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.76 - 3.42 (m, 4H), 2.82 - 2.52 (m, 5H), 2.12 - 1.95 (m, 2H); m/z ES+ [M+H] ⁺ 529.0. Example 451. Preparation of 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyr imidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyr imidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate (55 mg, 145 μmol) and 3-chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)aniline (33.8 mg, 145 μmol) in acetonitrile (1 mL) was stirred at 40 °C for 2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was triturated with ethyl acetate (3 mL) to give tert-butyl(1S,4S)-5-[4-[3- chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]anilino]-7-f luoro-pyrido[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (50 mg, 72.2 μmol, 50%) as a yellow solid. m/z ES+ [M+H] ⁺ 577.1. Step 2. N-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyr imidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (40 mg, 69.3 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). Then the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4- [(1-fluorocyclopropyl)methoxy]phenyl]-6-[(1S,4S)-2,5-diazabi cyclo[2.2.1]heptan-2-yl]-7-fluoro- pyrido[3,2-d]pyrimidin-4-amine (30 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 477.1. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl )methoxy]anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptan-2-yl]prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido [3,2-d]pyrimidin-4-amine (20 mg, 41.94 μmol) and prop-2-enoyl chloride (4.56 mg, 50.3 μmol) in water (0.1 mL) and tertrahydrofuran (1 mL) was added sodium bicarbonate (7.05 mg, 83.9 μmol), then the mixture was stirred at 0 °C for 1 hr. On completion, the reaction mixture was filter and then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30mm*5um;mobile phase: [water (FA)-ACN];B%: 30%-60%, 8 min) to give 1- [(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)met hoxy]anilino]-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one (10.03 mg, 18.9 μmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.31 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 3.7, 13.7 Hz, 1H), 7.70 (q, J = 8.6 Hz, 1H), 7.08 (br d, J = 2.3 Hz, 1H), 6.83 - 6.38 (m, 1H), 6.14 (td, J = 2.6, 16.6 Hz, 1H), 5.71 - 5.63 (m, 1H), 5.43 - 5.29 (m, 1H), 5.04 - 4.87 (m, 1H), 4.57 - 4.38 (m, 2H), 3.88 (br t, J = 11.9 Hz, 1H), 3.79 - 3.67 (m, 2H), 3.62 - 3.50 (m, 1H), 2.09 - 1.94 (m, 2H), 1.24 - 1.14 (m, 2H), 0.95 - 0.87 (m, 2H); m/z ES+ [M+H] ⁺ 531.3. Example 452. Preparation of 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a mixture of tert-butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (50 mg, 137 μmol) in acetonitrile (1 mL) was added 3- chloro-2-fluoro-4-((1-fluorocyclopropyl)methoxy)aniline (32.2 mg, 137 μmol), the mixture was stirred at 40 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was pAurified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=6/1 to 0:1) to give tert-butyl (1S,4S)-5-[4-[3-chloro-2- fluoro-4-[(1-fluorocyclopropyl)methoxy]anilino]pyrimido[5,4- d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (28 mg, 30.7 μmol, 22%) as a yellow oil. m/z ES+ [M+H] ⁺ 560.1. Step 2. N-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (18 mg, 32.1 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol), the mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2- fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl]-6-[(1S,4S)-2, 5-diazabicyclo[2.2.1]heptan-2- yl]pyrimido[5,4-d]pyrimidin-4-amine (18 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 460.1. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one To a mixture of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]p yrimidin-4-amine (18 mg, 31.3 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (5.27 mg, 62.7 μmol). Then prop-2-enoyl chloride (1.70 mg, 18.8 μmol) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC (Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 35%- 65%,10.5min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (9.04 mg, 17.6 μmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 - 9.35 (m, 1H), 9.10 (s, 1H), 8.31 (s, 1H), 7.66 (d, J = 6.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.88 - 6.30 (m, 1H), 6.14 (m, J = 2.0, 5.6, 16.8 Hz, 1H), 5.77 - 5.58 (m, 1H), 5.53 - 4.83 (m, 2H), 4.61 - 4.34 (m, 2H), 3.86 - 3.47 (m, 4H), 2.11 - 1.89 (m, 2H), 1.22 - 1.11 (m, 2H), 0.98 - 0.86 (m, 2H). m/z ES+ [M+H] ⁺ 513.9. Example 453. Preparation of 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- methylcyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one

Step 1. 2-Chloro-3-fluoro-1-((1-methylcyclopropyl)methoxy)-4-nitrobe nzene To a solution of 2-chloro-3-fluoro-4-nitro-phenol (150 mg, 783 μmol), di-tert-butyl azodicarboxylate (361 mg, 1.57 mmol) and triphenylphosphine (411 mg, 1.57 mmol) in toluene (3 mL) was added (1-methylcyclopropyl)methanol (135 mg, 1.57 mmol) at 0 °C. The mixture was then stirred at 25 °C for 16 h. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate=3:1) and then re-purified by SFC [column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O IPA];B%: 15%-15%,6.8;88 min] to give 2-chloro-3-fluoro-1-[(1-methylcyclopropyl)methoxy]-4-nitro- benzene (50 mg, 193 μmol, 25%) as a white solid. NMR (400 MHz, CDCl ₃ ) δ 6.75 – 6.70 (m, 1H), 6.62 – 6.52 (m, 1H), 3.90 (s, 2H), 1.24 (s, 3H), 0.65 – 0.57 (m, 2H), 0.55 – 0.50 (m, 2H). Step 2. 3-Chloro-2-fluoro-4-((1-methylcyclopropyl)methoxy)aniline To a solution of 2-chloro-3-fluoro-1-[(1-methylcyclopropyl)methoxy]-4-nitro-b enzene (70 mg, 270 μmol) in ethanol (2 mL) and water (0.2 mL) was added iron powder (75.28 mg, 1.35 mmol) and ammonium chloride (72.10 mg, 1.35 mmol). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-chloro-2-fluoro-4-[(1-methylcyclopropyl)methoxy]aniline (50 mg, 0.22 mmol, 81%) as a yellow oil. m/z ES+ [M+H] ⁺ 230.0. Step 3. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- methylcyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (78.7 mg, 217 μmol) in acetonitrile (3 mL) was added 3-chloro-2-fluoro-4-[(1-methylcyclopropyl)methoxy]aniline (50 mg, 217 μmol), the mixture was stirred at 40 °C for 2 hr. On completion, the crude product was triturated with ethyl acetate (2 mL). The mixture was filtered and the filtered cake was collected to give tert-butyl (1S,4S)-5-[4- [3-chloro-2-fluoro-4-[(1-methylcyclopropyl)methoxy]anilino]p yrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (70 mg, 126 μmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.48 (s, 1H), 8.71 - 8.58 (m, 2H), 8.44 - 8.31 (m, 1H), 7.26 - 6.97 (m, 1H), 6.80 ( d, J = 9.2 Hz, 1H), 5.33 - 5.12 (m, 1H), 4.85 - 4.65 (m, 1H), 3.88 (s, 2H), 3.78 - 3.67 (m, 1H), 3.58 (d, J = 1.6 Hz, 1H), 3.53 - 3.35 (m, 1H), 2.17 - 2.00 (m, 3H), 1.51 - 1.41 (m, 9H), 1.31 - 1.28 (m, 3H), 0.65 - 0.58 (m, 2H), 0.53 - 0.48 (m, 2H). Step 4. N-[3-Chloro-2-fluoro-4-[(1-methylcyclopropyl)methoxy]phenyl] -6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e A solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- methylcyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (60 mg, 108 μmol) in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[(1-methylcyclopropyl)methoxy]phenyl] -6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (60 mg, 105 μmol, 98%) as a yellow oil. m/z ES+ [M+H] ⁺ 455.1. Step 5.1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- methylcyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-[(1-methylcyclopropyl)methoxy]phenyl] -6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyr imidin-4-amine (60 mg, 105 μmol) and sodium bicarbonate (8.86 mg, 105 μmol) in anhydrous tetrahydrofuran (3 mL) and water (1 mL) was added prop-2-enoyl chloride (9.54 mg, 105 μmol), the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The crude product was purified by prep-HPLC [column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 35%-65%,10 min to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4- [(1-methylcyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin -6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (24.2 mg, 47.5 μmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (d, J = 1.4 Hz, 1H), 8.29 (d, J = 3.2 Hz, 1H), 7.90 (dd, J = 3.8, 9.2 Hz, 1H), 7.84 - 7.73 (m, 1H), 7.41 - 7.09 (m, 1H), 7.02 (dd, J = 1.6, 9.2 Hz, 1H), 6.86 - 6.37 (m, 1H), 6.35 - 6.09 (m, 1H), 5.72 - 5.61 (m, 1H), 5.53 - 5.12 (m, 1H), 5.10 - 4.90 (m, 1H), 3.91 (s, 2H), 3.79 - 3.38 (m, 4H), 2.10 - 1.97 (m, 2H), 1.23 (s, 3H), 0.61 - 0.53 (m, 2H), 0.47 - 0.40 (m, 2H); m/z ES+ [M+H] ⁺ 509.0. Example 454. Preparation of 1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- methylcyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-cyclobutoxy-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabi cyclo[2.2.1]heptane-2- carboxylate (0.2 g, 410 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (170 mg, 1.23 mmol) and bromocyclobutane (55.5 mg, 410 μmol). The mixture was stirred at 100 °C for 12 hr. On completion, the mixture was filtered and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-((3-chloro-4-cyclobutoxy-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (0.1 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 541.2. Step 2.6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -4-cyclobutoxy-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-((3-chloro-4-cyclobutoxy-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (0.1 g, 184 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (385 mg, 3.38 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - cyclobutoxy-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 441.2. Step 3.1-((1S,4S)-5-(4-((3-Chloro-4-cyclobutoxy-2-fluorophenyl)am ino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - cyclobutoxy-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (0.1 g, 180 μmol) in tertrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (24.9 mg, 180 μmol) and prop-2-enoyl chloride (16.3 mg, 180 μmol). The mixture was stirred at 0 °C for 0.2 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 25%-55%,10 min) to give 1-((1S,4S)-5-(4-((3-chloro-4-cyclobutoxy-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one (20.38 mg, 40.8 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 - 9.18 (m, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.91 – 7.88 (m, 1H), 7.83 - 7.71 (m, 1H), 7.43 - 7.14 (m, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.86 - 6.37 (m, 1H), 6.15 – 6.10 (m, 1H), 5.77 - 5.59 (m, 1H), 5.52 - 4.92 (m, 2H), 4.84 – 4.80 (m, 1H), 3.79 - 3.64 (m, 2H), 3.61 - 3.47 (m, 2H), 2.17 - 1.98 (m, 4H), 1.86 - 1.62 (m, 2H); m/z ES+ [M+H] ⁺ 494.9. Example 455. Preparation of 1-[(1S,4S)-5-[4-[3-Chloro-4-(cyclopropoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro-anilino]pyr ido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te To a mixture of 3-chloro-4-(cyclopropoxy)-2-fluoro-aniline (100 mg, 496 μmol) and tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2- carboxylate (179 mg, 496 μmol) in acetonitrile (3 mL) was stirred at 25 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether : ethyl acetate = 1:1) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro-anilino]pyr ido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (75 mg, 121 μmol, 24%) as a yellow solid. m/z ES+ [M+H] ⁺ 527.2. Step 2. N-[3-Chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e A mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (75 mg, 142 μmol) in dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3- chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5-diaz abicyclo[2.2.1]heptan-2- yl]pyrido[3,2-d]pyrimidin-4-amine (60 mg, 122 μmol, 86%) as a yellow oil. m/z ES+ [M+H] ⁺ 427.2. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-4-(cyclopropoxy)-2-fluoro-anilin o]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a mixture of N-[3-chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (60 mg, 141 μmol) in anhydrous tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (35.4 mg, 421 μmol) and prop-2-enoyl chloride (11.5 mg, 126 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water (FA)-ACN];B%: 25%-55%, 7 min) to give 1-[(1S,4S)-5- [4-[3-chloro-4-(cyclopropoxy)-2-fluoro-anilino]pyrido[3,2-d] pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (16.78 mg, 34.8 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.41 - 9.20 (m, 1H), 8.29 (d, J = 3.1 Hz, 1H), 7.98 - 7.74 (m, 2H), 7.44 - 7.09 (m, 2H), 6.89 - 6.34 (m, 1H), 6.14 (ddd, J = 2.4, 5.6, 16.8 Hz, 1H), 5.78 - 5.19 (m, 2H), 5.14 - 4.86 (m, 1H), 4.03 (tt, J = 3.2, 6.0 Hz, 1H), 3.80 - 3.49 (m, 4H), 2.11 - 1.93 (m, 2H), 0.88 - 0.83 (m, 2H), 0.79 - 0.73 (m, 2H); m/z ES+ [M+H] ⁺ 481.0. Example 456. Preparation of 1-[(1S,4S)-5-[4-[4-(cyclopropoxy)-2,3-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[4-(cyclopropoxy)-2,3-difluoro-anilino]pyrido[3 ,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te A mixture of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (150 mg, 415 μmol) and 4-(cyclopropoxy)-2,3- difluoro-aniline (84.4 mg, 456 μmol) in acetonitrile (3 mL) was stirred at 25 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (ether/ethyl acetate = 1:1) to give tert-butyl (1S,4S)-5-[4-[4- (cyclopropoxy)-2,3-difluoro-anilino]pyrido[3,2-d]pyrimidin-6 -yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.15 g, 249 μmol, 60%) as a yellow oil. m/z ES+ [M+H] ⁺ 511.4. Step 2. N-[4-(Cyclopropoxy)-2,3-difluoro-phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e A mixture of tert-butyl (1S,4S)-5-[4-[4-(cyclopropoxy)-2,3-difluoro-anilino]pyrido[3 ,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (150 mg, 294 μmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[4- (cyclopropoxy)-2,3-difluoro-phenyl]-6-[(1S,4S)-2,5-diazabicy clo[2.2.1]heptan-2-yl]pyrido[3,2- d]pyrimidin-4-amine (120 mg, 263 μmol, 89%) as a yellow oil. m/z ES+ [M+H] ⁺ 411.3. Step 3.1-[(1S,4S)-5-[4-[4-(Cyclopropoxy)-2,3-difluoro-anilino]pyr ido[3,2-d]pyrimidin- 6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one To a mixture of N-[4-(cyclopropoxy)-2,3-difluoro-phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (120 mg, 292 μmol) in anhydrous tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (73.7 mg, 877 μmol) and prop-2-enoyl chloride (23.8 mg, 263 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)-ACN];B%: 21%-51%,10 min) to give 1-[(1S,4S)-5-[4-[4-(cyclopropoxy)-2,3-difluoro-anilino]pyrid o[3,2-d]pyrimidin-6- yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (53.12 mg, 114 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.40 - 9.20 (m, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 4.0, 9.2 Hz, 1H), 7.61 (br d, J = 9.6 Hz, 1H), 7.42 - 7.04 (m, 2H), 6.86 - 6.35 (m, 1H), 6.14 (ddd, J = 2.4, 5.8, 16.8Hz, 1H), 5.77 - 5.29 (m, 2H), 5.08 - 4.88 (m, 1H), 4.12 - 3.96 (m, 1H), 3.78 - 3.49 (m, 4H), 2.12 - 1.93 (m, 2H), 0.89 - 0.71 (m, 4H); m/z ES+ [M+H] ⁺ 465.0. Example 457. Preparation of 1-[(1S,4S)-5-[4-(2,3-difluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]prop-2-en-1-one

Step 1. Spiro[2.3]hexan-5-ol To a solution of spiro[2.3]hexan-5-one (0.75 g, 7.80 mmol) in methanol (8 mL) was added sodium borohydride (443 mg, 11.7 mmol) portionwise at 0 °C, the mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. The reaction mixture was quenched by 20 mL water at 0 °C, and then extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give spiro[2.3]hexan-5-ol (0.35 g, crude) as a yellow oil. Step 2. Spiro[2.3]hexan-5-yl methanesulfonate To a solution of spiro[2.3]hexan-5-ol (0.34 g, 3.46 mmol) in dichloromethane (5 mL) was added triethylamine (876mg, 8.66 mmol) and methanesulfonic anhydride (1.51 g, 8.66 mmol) at 0 °C, the mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by addition water 65 mL at 25 °C, and then extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (45 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give spiro[2.3]hexan-5-yl methanesulfonate (0.55 g, crude) as a yellow oil. Step 3. tert-Butyl (1S,4S)-5-[4-(2,3-difluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (110 mg, 0.23 mmol) in N,N- dimethylformamide (2 mL) was added potassium carbonate (100 mg, 1.07 mmol) and spiro[2.3]hexan-5-yl methanesulfonate (60.0 mg, 0.33 mmol), the mixture was stirred at 80 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 20:1 to 1:1) to give tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-spiro[2.3]hexan-5-yloxy-anilino )pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (50 mg, 0.09 mmol, 40%) as a white solid. m/z ES+ [M+H] ⁺ 551.3. Step 4.6-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-N-(2,3-difl uoro-4- spiro[2.3]hexan-5-yloxy-phenyl)pyrido[3,2-d]pyrimidin-4-amin e To a solution of tert-butyl (1S,4S)-5-[4-(2,3-difluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (50 mg, 0.09 mmol) in dichloromethane(0.5 mL) was added trifluoroacetic acid (385 mg, 3.38 mmol), the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(2,3-difluo ro-4- spiro[2.3]hexan-5-yloxy-phenyl)pyrido[3,2-d]pyrimidin-4-amin e (52 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 451.3. Step 5.1-[(1S,4S)-5-[4-(2,3-Difluoro-4-spiro[2.3]hexan-5-yloxy-an ilino)pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(2,3-difluo ro-4- spiro[2.3]hexan-5-yloxy-phenyl)pyrido[3,2-d]pyrimidin-4-amin e (52 mg, 92.1 μmol, trifluoroacetic acid) in tertrahydrofuran (0.3 mL) and water (0.1 mL) was added potassium carbonate (25.5 mg, 184 μmol) at 0 °C. Then prop-2-enoyl chloride (8.34 mg, 92.1 μmol) was added and the mixture was stirred at 0 °C for 0.2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 34%-64%, 10 min) to give 1- [(1S,4S)-5-[4-(2,3-difluoro-4-spiro[2.3]hexan-5-yloxy-anilin o)pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (22.02 mg, 43.2 μmol, 47%) as a yellow solid. (400 MHz, DMSO-d ₆ ) δ 9.30 (br. s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 9.2, 4.0 Hz, 1H), 7.65 – 7.55 (m, 1H), 7.40 – 7.10 (m, 1H), 7.00 – 6.90 (m, 1H), 6.85 – 6.40 (m, 1H), 6.20 – 6.10 (m, 1H), 5.75 – 5.60 (m, 1H), 5.55 – 5.15 (m, 1H), 5.10 – 4.90 (m, 2H), 3.80 – 3.49 (m, 4H), 2.50 – 2.35 (m, 4H), 2.15 – 1.95 (m, 2H), 0.60 – 0.45 (m, 4H); m/z ES+ [M+H] ⁺ 505.0. Example 458. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4-(1- methylcyclobutoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one

Step 1. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-(1- methylcyclobutoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate To a solution of 2,3-difluoro-4-(1-methylcyclobutoxy)aniline (40 mg, 188 μmol) in acetonitrile (0.4 mL) was added tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (64.0 mg, 177 μmol). The mixture was stirred at 25 ℃ for 6 hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-(1-methylcyclobutoxy)phenyl)am ino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 539.3. Step 2.6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difl uoro-4-(1- methylcyclobutoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-(1- methylcyclobutoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (40 mg, 74.3 μmol) in dichloromethane (1 mL) was added zinc bromide (320 mg, 1.42 mmol). The mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4- (1-methylcyclobutoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (32 mg, crude) as a yellow gum. m/z ES+ [M+H] ⁺ 438.9. Step 3.1-((1S,4S)-5-(4-((2,3-Difluoro-4-(1- methylcyclobutoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(1- methylcyclobutoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (32 mg, 73 μmol) in anhydrous tetrahydrofuran (0.5 mL) and water (0.1 mL) was added sodium bicarbonate (18.4 mg, 219 μmol) to adjust pH ~ 8. Then prop-2-enoyl chloride (3.89 mg, 42.9 μmol) was added into the mixture at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN]; B%: 46%-76%, 8 min) to give 1-((1S,4S)-5-(4-((2,3-difluoro-4-(1- methylcyclobutoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (14.6 mg, 28.7 μmol, 39%) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d6) δ 9.40 - 9.18 (m, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 4.0, 9.2 Hz, 1H), 7.71 - 7.52 (m, 1H), 7.43 - 7.10 (m, 1H), 6.94 - 6.86 (m, 1H), 6.85 - 6.37 (m, 1H), 6.14 (ddd, J = 2.4, 5.6, 16.8 Hz, 1H), 5.73 - 5.61 (m, 1H), 5.57 - 5.10 (m, 1H), 5.08 - 4.91 (m, 1H), 3.78 - 3.46 (m, 4H), 2.40 - 2.34 (m, 2H), 2.18 - 2.11 (m, 2H), 2.08 (br s, 1H), 2.00 (br s, 1H), 1.79 - 1.66 (m, 2H), 1.53 (s, 3H); m/z ES+ [M+H] ⁺ 493.0. Example 459. Preparation of 1-((1S,4S)-5-(4-((2,3-difluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one

Step 1.2-Chloro-3-fluoro-4-(1-methylcyclopropoxy)-1-nitrobenzene To a solution of 1-methylcyclopropanol (280 mg, 3.88 mmol) in anhydrous tetrahydrofuran (10 mL) was added sodium hydride (155 mg, 3.88 mmol, 60% in mineral oil) at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. Then 2-chloro-3,4-difluoro-1-nitrobenzene (500 mg, 2.58 mmol) was added into the mixture and the mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition saturated ammonium chloride solution 10 mL at 0 °C, and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine 30 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 10/1) to give 2-chloro-3-fluoro-4-(1- methylcyclopropoxy)-1-nitrobenzene (420 mg, 1.71 mmol, 66%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, J = 2.0, 9.2 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 1.62 (s, 3H), 1.13 - 1.07 (m, 2H), 0.87 - 0.81 (m, 2H). Step 2.2,3-Difluoro-1-(1-methylcyclopropoxy)-4-nitrobenzene To a solution of 2-chloro-3-fluoro-4-(1-methylcyclopropoxy)-1-nitrobenzene (320 mg, 1.30 mmol) in dimethylsulfoxide (3 mL) was added cesium fluoride (512 mg, 3.37 mmol). The mixture was stirred at 140 °C for 16 hr. The reaction mixture was quenched by addition water 5 mL at 0 °C, and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine 4 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 10/1) to give 2,3-difluoro-1-(1- methylcyclopropoxy)-4-nitrobenzene (260 mg, 908 μmol, 70%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.61 (s, 1H), 8.00 - 7.85 (m, 1H), 7.20 - 6.88 (m, 1H), 1.62 (s, 3H), 1.15 - 1.06 (m, 2H), 0.89 - 0.78 (m, 2H). Step 3.2,3-Difluoro-4-(1-methylcyclopropoxy)aniline A mixture of 2,3-difluoro-1-(1-methylcyclopropoxy)-4-nitro-benzene (260 mg, 1.13 mmol) and Pt/V/C (100 mg, 15.4 μmol, 3% purity) in ethyl acetate (10 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 25 °C for 1 hr under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 1/1) to give 2,3-difluoro-4-(1- methylcyclopropoxy)aniline (170 mg, 850 μmol, 75%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.85 - 6.77 (m, 1H), 6.45 (dt, J = 2.4, 9.2 Hz, 1H), 3.64 - 3.47 (m, 2H), 1.52 (s, 3H), 1.08 - 1.00 (m, 2H), 0.69 - 0.61 (m, 2H); m/z ES+ [M+H] ⁺ 199.8. Step 4. tert-Butyl (1S,4S)-5-(4-((2,3-difluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -2,5- diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 276 μmol) in acetonitrile (1 mL) was added 2,3-difluoro-4-(1-methylcyclopropoxy)aniline (60 mg, 301 μmol). The mixture was stirred at 25 °C for 7 hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(4-((2,3-difluoro-4-(1-methylcyclopropoxy)phenyl)a mino)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (160 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 525.0. Step 5.6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difl uoro-4-(1- methylcyclopropoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-(1- methylcyclopropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2- carboxylate (70 mg, 133 μmol) in dichloromethane (1 mL) was added zinc bromide (601 mg, 2.67 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4- (1-methylcyclopropoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (70 mg, crude) as a yellow gum. m/z ES+ [M+H] ⁺ 425.0. Step 6.1-((1S,4S)-5-(4-((2,3-Difluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -2,5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2,3-difluo ro-4-(1- methylcyclopropoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (60 mg, 141 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (35.6 mg, 424 μmol) to adjust the pH ~ 8. Then prop-2-enoyl chloride (11.1 mg, 123 μmol, 10 μL) was added into the mixture at 0 °C. The mixture was stirred at 0 °C for 10 min. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water( NH4HCO3)- ACN];B%: 42%-72%,10 min) to give 1-((1S,4S)-5-(4-((2,3-difluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) -2,5-diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one (24.1 mg, 50.2 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d6) δ 9.40 - 9.18 (m, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 4.0, 9.2 Hz, 1H), 7.69 - 7.54 (m, 1H), 7.37 - 7.15 (m, 2H), 6.86 - 6.36 (m, 1H), 6.14 (ddd, J = 2.4, 5.6, 16.8 Hz, 1H), 5.74 - 5.59 (m, 1H), 5.58 - 5.12 (m, 1H), 5.11 - 4.89 (m, 1H), 3.76 - 3.39 (m, 4H), 2.13 - 1.96 (m, 2H), 1.55 (s, 3H), 1.03 - 0.96 (m, 2H), 0.85 - 0.77 (m, 2H); m/z ES+ [M+H] ⁺ 479.0. Example 460. Preparation of (E)-1-((1S,4S)-5-(4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)-4- (dimethylamino)but-2-en-1-one Step 1. (E)-1-((1S,4S)-5-(4-((3-Chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)-4- (dimethylamino)but-2-en-1-one To a solution of 6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4 - (difluoromethoxy)-2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-am ine (100 mg, 229 μmol) and (E)- 4-(dimethylamino)but-2-enoic acid (37.91 mg, 229 μmol, HCl) in pyridine (1 mL) was added 3- (((ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminium chloride (87.8 mg, 458 μmol). The mixture was stirred at 15 °C for 1 hr. On completion, the mixture was directly purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5um;mobile phase: [water( NH4HCO3)- ACN];B%: 33%-63%, 9 min) and then re-purified by prep-HPLC (column: Phenomenex C1875 x 30mm x 3um;mobile phase: [water(FA)-ACN];B%: 10%-40%, 7 min) to give (E)-1-((1S,4S)- 5-(4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)pyr ido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4-(dimethylamino)but-2-en-1- one (61.0 mg, 0.11 mmol, 52%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.59 - 9.13 (m, 1H), 8.43 - 8.29 (m, 1H), 8.20 - 8.01 (m, 1H), 7.98 - 7.85 (m, 1H), 7.58 - 7.04 (m, 3H), 6.71 - 6.54 (m, 1H), 6.37 - 5.94 (m, 1H), 5.61 - 5.08 (m, 1H), 5.05 - 4.83 (m, 1H), 3.79 - 3.64 (m, 2H), 3.57 - 3.49 (m, 2H), 3.07 - 2.94 (m, 2H), 2.17 - 2.07 (m, 6H), 2.00 (s, 2H); m/z ES+ [M+H] ⁺ 547.9. Example 461. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-d iazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one Step 1. tert-butyl(1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-d iazabicyclo[2.2.1]heptane-2- carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (50.0 mg, 138 μmol) and 3-chloro-2-fluoro-4- (trifluoromethoxy)aniline (30.0 mg, 130 μmol) in acetonitrile (1 mL) was stirred at 40 °C for 2 hr. Then the mixture was stirred at 60 °C for 3 hr. Then the mixture was further stirred at 40 °C for 12 hr. On completion, the mixture was quenched with methanol (4 mL) and concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate= 1:2) to give a residue. Then the residue was purified by prep-TLC (silicon dioxide, dichloromethane : methanol= 10 : 1) to give tert-butyl(1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-d iazabicyclo[2.2.1]heptane-2- carboxylate (27.0 mg, crude) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 - 9.40 (m, 1H), 8.45 - 8.23 (m, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.61 - 7.51 (m, 1H), 4.57 - 4.55 (m, 1H), 3.68 - 3.59 (m, 2H), 2.10 - 1.88 (m, 6H), 1.42 - 1.34 (m, 9H); m/z ES+ [M+H] ⁺ 555.0. Step 2.6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro -2-fluoro-4- (trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-d iazabicyclo[2.2.1]heptane-2- carboxylate (27.0 mg, 48.6 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N-[3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (27.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 455.0. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-(trifluoromethoxy)ani lino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a solution of N-[3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4-amin e (27.0 mg, 47.4 μmol, trifluoroacetic acid) and prop-2-enoyl chloride (3.01 mg, 33.2 μmol) in anhydrous tetrahydrofuran (0.5 mL) and water (0.1 mL) was added sodium bicarbonate (11.9 mg, 142 μmol). The mixture was stirred at 0 °C for 10 min. On completion, the mixture was quenched with methanol (4 mL) and then concentrated to give a residue. The residue was purified by prep- HPLC (column: Phenomenex C18150*25mm*10um;mobile phase: [water( NH4HCO3)- ACN];B%: 44%-74%, 8 min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-d iazabicyclo[2.2.1]heptan-2-yl]prop- 2-en-1-one (2.77 mg, 5.41 μmol, 11%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 - 9.30 (m, 1H), 8.42 (d, J = 3.2 Hz, 1H), 8.34 - 8.21 (m, 1H), 7.95 (dd, J = 3.6, 9.6 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.48 - 7.05 (m, 1H), 6.85 - 6.38 (m, 1H), 6.17 - 6.11 (m, 1H), 5.74 - 5.55 (m, 1H), 5.52 - 4.91 (m, 2H), 3.77 - 3.64 (m, 2H), 3.61 - 3.52 (m, 2H), 2.11 - 2.01 (m, 2H); m/z ES+ [M+H] ⁺ 508.9. Example 462. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (70.0 mg, 192 μmol) and 3-chloro-2-fluoro-4- (trifluoromethoxy)aniline (44.2 mg, 192 μmol) in acetonitrile (1 mL) was stirred at 60 °C for 1 hr. On completion, the mixture was quenched with methanol (4 mL) and concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate=2:1) to give tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate (80.0 mg, 138 μmol, 71%) as a yellow solid. m/z ES+ [M+H] ⁺ 556.3. Step 2. N-[3-Chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate (80.0 mg, 143 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2-fluoro-4- (trifluoromethoxy)phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1] heptan-2-yl]pyrimido[5,4- d]pyrimidin-4-amine (80.0 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 456.0. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-(trifluoromethoxy)ani lino]pyrimido[5,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a solution of N-[3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-6-[(1S,4S)- 2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine (80.0 mg, 140 μmol, trifluoroacetic acid) and prop-2-enoyl chloride (10.1 mg, 112 μmol) in anhydrous tetrahydrofuran (2 mL) and water (0.4 mL) was added sodium bicarbonate (35.3 mg, 421 μmol). The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was quenched with methanol (4 mL) and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 52%- 82%, 10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4- (trifluoromethoxy)anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5 -diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one (22.72 mg, 44.33 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.89 - 9.49 (m, 1H), 9.22 - 9.08 (m, 1H), 8.49 - 8.33 (m, 1H), 8.19 - 7.93 (m, 1H), 7.59 (s, 1H), 6.91 - 6.32 (m, 1H), 6.23 - 6.06 (m, 1H), 5.78 - 5.59 (m, 1H), 5.45 - 4.88 (m, 2H), 3.79 - 3.49 (m, 4H), 2.15 - 1.97 (m, 2H); m/z ES+ [M+H] ⁺ 510.1. Example 463. Preparation of 1-[(1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octan-2-yl]prop-2-en-1-one

Step 1.6-Chloro-N-[4-(difluoromethoxy)-2,3-difluoro-phenyl]pyrido [3,2-d]pyrimidin-4- amine A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (150 mg, 750 μmol) and 4- (difluoromethoxy)-2,3-difluoro-aniline (161 mg, 825 μmol) in acetonitrile (4 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleumether/ethyl acetate (5:1, 6 mL) to give 6- chloro-N-[4-(difluoromethoxy)-2,3-difluoro-phenyl]pyrido[3,2 -d]pyrimidin-4-amine (280 mg, crude) as a yellow solid. Step 2. tert-Butyl (1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]pyrid o[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylat e To a solution of 6-chloro-N-[4-(difluoromethoxy)-2,3-difluoro-phenyl]pyrido[3 ,2- d]pyrimidin-4-amine (80.0 mg, 223 μmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate (70.0 mg, 330 μmol) in 1-methylpyrrolidin-2-one (1 mL) was added diisopropylethylamine (57.7 mg, 446 μmol). The mixture was stirred at 120 °C for 1 hr. On completion, the reaction mixture was poured into brine (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (silicon dioxide, petroleum ether: ethyl acetate=1:3) to give tert-butyl (1S,4S)-5-[4-[4- (difluoromethoxy)-2,3-difluoro-anilino]pyrido[3,2-d]pyrimidi n-6-yl]-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (110 mg, 196 μmol, 87%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 - 9.28 (m, 1H), 8.63 - 8.51 (m, 1H), 8.49 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.61 - 7.17 (m, 3H), 5.41 - 3.99 (m, 1H), 3.85 - 3.41 (m, 4H), 1.95 - 1.86 (m, 4H), 1.41 (d, J = 8.0 Hz, 9H); m/z ES+ [M+H] ⁺ 535.3. Step 3.6-[(1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl]-N-[4-(difluo romethoxy)-2,3- difluoro-phenyl]pyrido[3,2-d]pyrimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[4-(difluoromethoxy)-2,3-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (90.0 mg, 168 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). Then the mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give 6- [(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl]-N-[4-(difluorome thoxy)-2,3-difluoro- phenyl]pyrido[3,2-d]pyrimidin-4-amine (90.0 mg, crude, trifluoroacetic acid) as a brown oil. m/z ES+ [M+H] ⁺ 435.3. Step 4.1-[(1S,4S)-5-[4-[4-(Difluoromethoxy)-2,3-difluoro-anilino] pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octan-2-yl]prop-2-e n-1-one To a solution of 6-[(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl]-N-[4-(difluoro methoxy)- 2,3-difluoro-phenyl]pyrido[3,2-d]pyrimidin-4-amine (90.0 mg, 164 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (276 mg, 3.28 mmol). Then prop-2-enoyl chloride (11.9 mg, 131 μmol) was added into the mixture and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 26%-56%, 26 min) to give 1-[(1S,4S)-5-[4-[4- (difluoromethoxy)-2,3-difluoro-anilino]pyrido[3,2-d]pyrimidi n-6-yl]-2,5- diazabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one (58.1 mg, 109 μmol, 66%) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.62 - 8.51 (m, 1H), 8.49 (s, 1H), 8.20 (s, 1H), 7.99 (d, J = 9.4 Hz, 1H), 7.63 - 7.19 (m, 3H), 6.91 - 6.55 (m, 1H), 6.18-6.02 (m, 1H), 5.72-5.52(m, 1H), 5.48 - 4.35 (m, 1H), 3.94 - 3.69 (m, 4H), 2.04 - 1.89 (m, 4H); m/z ES+ [M+H] ⁺ 489.1. Example 464. Preparation of 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one

Step 1.6-Chloro-N-[2,3-difluoro-4-[(1-fluorocyclopropyl)methoxy]p henyl]pyrido[3,2- d]pyrimidin-4-amine To a mixture of 4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-2,3-difluoro- phenol (100 mg, 323 μmol) in N,N-dimethylformamide (1 mL) was added (1-fluorocyclopropyl)methyl methanesulfonate (81.7 mg, 485 μmol) and cesium carbonate (211 mg, 647 μmol), the mixture was stirred at 80 °C for 4 hr. On completion, the reaction mixture was diluted with brine (25 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=4/1 to 1/1) to give 6-chloro-N-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (74 mg, 180 μmol, 55%) as a yellow oil. m/z ES+ [M+H] ⁺ 381.1. Step 2. tert-Butyl (1S,4S)-5-[4-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate To a mixture of 6-chloro-N-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (64 mg, 168 μmol), diisopropylethylamine (43.4 mg, 336 μmol) in 1-methylpyrrolidin-2-one (1 mL) was added tert- butyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (53.5 mg, 252 μmol), the mixture was stirred at 130 °C for 2 hr. On completion, the reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, ethyl acetate) to give tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate (70 mg, 122 μmol, 72%) as a yellow solid. m/z ES+ [M+H] ⁺ 557.3. Step 3. 6-[(1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl]-N-[2,3-difluor o-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine To a mixture of tert-butyl (1S,4S)-5-[4-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate (60 mg, 107 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol), then the mixture was stirred at 25 °C for 1 hr. On completion, The reaction mixture was concentrated under reduced pressure to give 6-[(1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl]-N-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (60 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 457.1. Step 4.1-[(1S,4S)-5-[4-[2,3-Difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octan- 2-yl]prop-2-en-1-one To a mixture of 6-[(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl]-N-[2,3-difluor o-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (60 mg, 105 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (1 mL) and water (0.33 mL) was added sodium bicarbonate (17.67 mg, 210 μmol). Then prop-2-enoyl chloride (9.52 mg, 105 μmol) was added at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC (Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 30%- 60%,10 min) to give 1-[(1S,4S)-5-[4-[2,3-difluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octan- 2-yl]prop-2-en-1-one (24.6 mg, 46.9 μmol, 44%) as a yellow gum. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.39 (s, 1H), 8.63 - 8.52 (m, 1H), 8.48 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.38 - 7.18 (m, 2H), 6.90 - 6.51 (m, 1H), 6.18 (m, J = 2.4, 16.7, 18.9 Hz, 1H), 5.72 (m, J = 2.4, 10.5, 13.0 Hz, 1H), 5.49 - 4.47 (m, 4H), 3.93 - 3.54 (m, 4H), 2.09 - 1.86 (m, 4H), 1.12 - 0.96 (m, 2H), 0.88 - 0.73 (m, 2H); m/z ES+ [M+H] ⁺ 511.1. Example 465. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5- diazabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one Step 1.6-Chloro-N-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine A solution of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fl uoro-phenol (100 mg, 307 μmol), (1-fluorocyclopropyl)methyl methanesulfonate (77.5 mg, 461 μmol) and cesium carbonate (200 mg, 615 μmol) in N,N-dimethylformamide (10 mL) was stirred at 80 °C for 2 h. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane: ethyl acetate =8:1) to give 6-chloro-N-[3-chloro-2-fluoro-4- [(1-fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin- 4-amine (91 mg, 163 μmol, 53%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.11 - 8.00 (m, 2H), 7.62 (m, 1H), 7.23 - 7.15 (m, 1H), 4.69 - 4.48 (m, 4H), 1.37 - 1.16 (m, 7H), 1.03 - 0.91 (m, 5H); m/z ES+ [M+H] ⁺ 396.8. Step 2. tert-Butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate To a solution of 6-chloro-N-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (80 mg, 201 μmol) in 1- methylpyrrolidin-2-one (4 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane-2- carboxylate (64.13 mg, 302 μmol) and diisopropylethylamine (52.06 mg, 403 μmol). The mixture was stirred at 120 °C for 1 h. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, ethyl acetate: dichloromethane =3:1) to give tert-butyl (1S,4S)-5- [4-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]anilin o]pyrido[3,2-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (80 mg, 129 μmol, 64%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 - 8.38 (m, 2H), 8.25 - 8.10 (m, 1H), 7.10 - 6.95 (m, 1H), 6.83 (m, 1H), 4.48 - 4.21 (m, 3H), 3.84 - 3.76 (m, 1H), 3.62 - 3.54 (m, 2H), 3.45 - 3.40 (m, 1H), 3.33 (s, 2H), 2.12 - 2.03 (m, 2H), 1.81 (m, 2H), 1.40 (d, J = 3.2 Hz, 9H), 1.20 - 1.15 (m, 2H), 0.82 (m, 2H); m/z ES+ [M+H] ⁺ 573.2. Step 3. N-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-[(1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine A solution of tert-butyl (1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate (60 mg, 104 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (0.5 mL) was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuo to give N- [3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl]-6 -[(1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-amine (60 mg, 102 μmol, 98%) as a yellow oil. m/z ES+ [M+H] ⁺ 473.1. Step 4.1-[(1S,4S)-5-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.2]octan- 2-yl]prop-2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6- [(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyri midin-4-amine (60 mg, 102 μmol) and sodium bicarbonate (8.59 mg, 102 μmol) in anhydrous tetrahydrofuran (2 mL) and water (1 mL) was added prop-2-enoyl chloride (9.25 mg, 102 μmol) at 0 °C. The mixture was stirred at 25 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(FA)-ACN];B%: 22%-52%,10.5min to give compound 1-[(1S,4S)-5-[4-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)m ethoxy]anilino]pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2]octan-2-yl]prop-2-e n-1-one (16.6 mg, 31.5 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 - 9.21 (m, 1H), 8.32 - 8.24 (m, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.83 - 7.66 (m, 1H), 7.33 - 7.06 (m, 2H), 6.89 - 6.54 (m, 1H), 6.15 (m, 1H), 5.69 (m, 1H), 5.64 - 4.51 (m, 2H), 4.49 - 4.37 (m, 2H), 3.89 - 3.56 (m, 4H), 2.00 - 1.85 (m, 4H), 1.16 (m, 2H), 0.95 - 0.84 (m, 2H); m/z ES+ [M+H] ⁺ 527.1. Example 466. Preparation of 1-[7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-4,7- diazaspiro[2.5]octan-4-yl]prop-2-en-1-one Step 1. tert-Butyl 7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-4,7-diazaspiro[2.5]octane-4- carboxylate To a solution of (1-fluorocyclopropyl)methyl methanesulfonate (45.23 mg, 269 μmol) in N,N-dimethylformamide (3 mL) was added tert-Butyl 7-(8-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-4,7-diaza spiro[2.5]octane-4-carboxylate (90.0 mg, 179 μmol) and potassium carbonate (49.56 mg, 358 μmol). Then the mixture was stirred at 80 °C for 12 hr. On completion, the residue was poured into water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=5/1 to 0/1) to give tert-butyl 7- [4-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]anilin o]pyrimido[5,4-d]pyrimidin-6-yl]- 4,7-diazaspiro[2.5]octane-4-carboxylate (70 mg, 122 μmol, 68%) as a yellow solid. m/z ES+ [M+H] ⁺ 574.3. Step 2. N-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine To a solution of tert-butyl 7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-4,7-diazaspiro[2.5]octane-4- carboxylate (50 mg, 87.1 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (56.53 mg, 496 μmol), then the mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]-6-(4,7-diazaspiro[2.5]octa n-7-yl)pyrimido[5,4-d]pyrimidin- 4-amine (35 mg, 73.85 μmol, 85%) as a yellow oil. m/z ES+ [M+H] ⁺ 474.2. Step 3.1-[7-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-4,7-diazaspiro[2.5]octan-4- yl]prop-2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine (35 mg, 73.8 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.1 mL) was added sodium bicarbonate (12.4 mg, 147 μmol) and prop-2-enoyl chloride (7.35 mg, 81.2 μmol), then the mixture was stirred at 0 °C for 15 min. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 48%-78%,10 min) to give 1-[7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrimido[5,4-d]pyrimidin-6 -yl]-4,7-diazaspiro[2.5]octan-4- yl]prop-2-en-1-one (15.10 mg, 28.6 μmol, 39%) as a yellow solid. NMR (400 MHz, DMSO- d ₆ ) δ 9.84 - 9.57 (m, 1H), 9.10 (s, 1H), 8.40 - 8.24 (m, 1H), 7.59 (br t, J = 8.9 Hz, 1H), 7.14 (br d, J = 9.3 Hz, 1H), 7.03 - 6.77 (m, 1H), 6.18 (br d, J = 17.0 Hz, 1H), 5.88 - 5.62 (m, 1H), 4.57 - 4.42 (m, 2H), 4.17 - 3.70 (m, 6H), 1.27 - 1.05 (m, 4H), 1.02 - 0.90 (m, 4H); m/z ES+ [M+H] ⁺ 528.1. Example 467. Preparation of 1-[7-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-4,7-diazaspiro[2.5]octan- 4-yl]prop-2-en-1-one

Step 1.6-Chloro-N-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine A mixture of 2-chloro-4-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-3-fl uoro-phenol (100 mg, 308 μmol), (1-fluorocyclopropyl)methyl methanesulfonate (77.6 mg, 461 μmol) and cesium carbonate (200 mg, 615 μmol) in N,N-dimethylformamide (1 mL) was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL ×3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate = 3:1) to give 6-chloro-N-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (60.0 mg, 116 μmol, 38%) as a yellow solid. m/z ES+ [M+H] ⁺ 397.0. Step 2. tert-Butyl 7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-4,7-diazaspiro[2.5]octane-4- carboxylate To a mixture of 6-chloro-N-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]pyrido[3,2-d]pyrimidin-4-am ine (50.0 mg, 126 μmol) in 1- methylpyrrolidin-2-one (0.5 mL) was added tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (53.5 mg, 252 μmol) and diisopropylethylamine (81.4 mg, 629 μmol), then the mixture was stirred at 130 °C for 1 hr. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate= 1:2) to give tert-butyl 7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-4,7-diazaspiro[2.5]octane-4- carboxylate (50.0 mg, 83.0 μmol, 66%) as a yellow solid. m/z ES+ [M+H] ⁺ 573.2. Step 3. N-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine A mixture of tert-butyl 7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-4,7-diazaspiro[2.5]octane-4- carboxylate (40.0 mg, 69.8 μmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 473.1. Step 4.1-[7-[4-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy ]anilino]pyrido[3,2- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1- one To a mixture of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-(4,7- diazaspiro[2.5]octan-7-yl)pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, 68.2 μmol, trifluoroacetic acid salt) in anhydrous tetrahydrofuran (1 mL) and water (0.1 mL) was added sodium bicarbonate (5.73 mg, 68.2 μmol) and prop-2-enoyl chloride (6.17 mg, 68.2 μmol). The mixture was stirred at 0 °C for 15 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 30%- 60%,10.5min) to give 1-[7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]-4,7-diazaspiro[2.5]octan-4- yl]prop-2-en-1-one (19.7 mg, 37.1 μmol, 54%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.30 (s, 1H), 8.30 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.70 (t, J = 8.8 Hz, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.12 (dd, J = 1.6, 9.2 Hz, 1H), 7.00 - 6.82 (m, 1H), 6.16 (dd, J = 2.4, 16.8 Hz, 1H), 5.74 (d, J = 11.2 Hz, 1H), 4.59 - 4.40 (m, 2H), 3.97 - 3.66 (m, 6H), 1.25 - 1.05 (m, 4H), 1.05 - 0.97 (m, 2H), 0.95 - 0.88 (m, 2H); m/z ES+ [M+H] ⁺ 527.1. Example 468. Preparation of 1-[7-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tan-4-yl]prop-2-en-1-one

Step 1. tert-Butyl 7-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoroanilino]pyrimi do[5,4- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(8-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-4,7-diaza spiro[2.5]octane-4-carboxylate (90.0 mg, 179 μmol) and cesium carbonate (117 mg, 359 μmol) in N,N-dimethylformamide (1.5 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (40.3 mg, 188 μmol). The mixture was stirred at 80 °C for 0.5 hr. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether / ethyl acetate=1/1) to afford compound tert-butyl 7-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoroanilino]pyrimi do[5,4-d]pyrimidin-6-yl]-4,7- diazaspiro[2.5]octane-4-carboxylate (40.0 mg, 70.7 μmol, 39%) as a yellow solid. m/z ES+ [M+H] ⁺ 566.0. Step 2. N-[3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine A mixture of tert-butyl 7-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]oc tane-4-carboxylate (30.0 mg, 53.0 μmol) in trifluoroacetic acid (462 mg, 4.05 mmol) and dichloromethane (1 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to afford compound N-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine (23.0 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 466.0. Step 3. N-[3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine To a mixture of N-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4-amine (23.0 mg, 49.4 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.1 mL) was added sodium bicarbonate (8.30 mg, 98.7 μmol). Then prop-2-enoyl chloride (4.92 mg, 54.3 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 45%-75%,9 min) to afford compound 1-[7-[4-[3- chloro-4-(2,2-difluoroethoxy)-2-fluoro-anilino]pyrimido[5,4- d]pyrimidin-6-yl]-4,7- diazaspiro[2.5]octan-4-yl]prop-2-en-1-one (16.3 mg, 31.3 μmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 9.11 (s, 1H), 8.32 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.21 - 7.19 (m, 1H), 7.04 - 6.84 (m, 1H), 6.63 - 6.32 (m, 1H), 6.21 - 6.16(m, 1H), 5.76 (d, J = 12.0 Hz, 1H), 4.56 - 4.48 (m, 2H), 4.20 - 3.66 (m, 6H), 1.13 - 0.92 (m, 4H); m/z ES+ [M+H] ⁺ 520.1. Example 469. Preparation of 1-[7-[4-[3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-anilino]-7 - fluoro-pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan -4-yl]prop-2-en-1-one Step 1. tert-Butyl 7-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-anilino]-7-fl uoro- pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octane-4-car boxylate A solution of tert-butyl 7-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 254 μmol) and 3-chloro-4-(2,2-difluoroethoxy)-2- fluoro-aniline (74.5 mg, 330 μmol) in acetonitrile (1 mL) was stirred at 40 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep- TLC (silicon dioxide, petroleum ether: ethyl acetate=1:1) to give tert-butyl 7-[4-[3-chloro-4-(2,2- difluoroethoxy)-2-fluoro-anilino]-7-fluoro-pyrido[3,2-d]pyri midin-6-yl]-4,7- diazaspiro[2.5]octane-4-carboxylate (40.0 mg, 61.8 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.35 (s, 1H), 7.88 (d, J = 14.0 Hz, 1H), 7.66 (t, J = 8.8 Hz, 1H), 7.23 - 7.14 (m, 1H), 6.63 - 6.28 (m, 1H), 4.51-4.40 (m, 2H), 3.72 - 3.62 (m, 4H), 3.52 (s, 2H), 1.43 (s, 9H), 0.97 - 0.84 (m, 4H); m/z ES+ [M+H] ⁺ 583.2. Step 2. N-[3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)-7-fluoro-pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl 7-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan e-4-carboxylate (40.0 mg, 68.6 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N- [3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7-dia zaspiro[2.5]octan-7-yl)-7-fluoro- pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, crude, trifluoroacetic acid ) as a yellow oil. m/z ES+ [M+H] ⁺ 483.2. Step 3.1-[7-[4-[3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-anilino] -7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1- one To a solution of N-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-(4,7- diazaspiro[2.5]octan-7-yl)-7-fluoro-pyrido[3,2-d]pyrimidin-4 -amine (40.0 mg, 67.0 μmol, trifluoroacetic acid ) in anhydrous tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (113 mg, 1.34 mmol). Then prop-2-enoyl chloride (4.85 mg, 53.6 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 45%-75%,15min) to give 1-[7-[4- [3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-4,7- diazaspiro[2.5]octan-4-yl]prop-2-en-1-one (17.0 mg, 31.6 μmol, 47%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.36 (s, 1H), 7.89 (d, J = 14.4 Hz, 1H), 7.68 (t, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.01 - 6.81 (m, 1H), 6.61 - 6.32 (m, 1H), 6.16 -6.14 (m, 1H), 5.74 (d, J = 10.8 Hz, 1H), 4.51-4.50 (m, 2H), 3.91 - 3.69 (m, 4H), 3.62 (s, 2H), 1.17 - 0.98 (m, 4H); m/z ES+ [M+H] ⁺ 537.2. Example 470. Preparation of 1-[7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyr imidin-6-yl]-4,7- diazaspiro[2.5]octan-4-yl]prop-2-en-1-one Step 1. tert-Butyl 7-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)-7-fluoro-pyrido[3 ,2- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate A solution of tert-butyl 7-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (130 mg, 330 μmol) and 4-amino-2-chloro-3-fluoro-phenol (58.7 mg, 363 μmol) in acetonitrile (1 mL) was stirred at 40 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate=1:2) to give tert-butyl 7-[4-(3-chloro-2-fluoro-4-hydroxy- anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspir o[2.5]octane-4-carboxylate (100 mg, 154 μmol, 46%) as a brown solid. m/z ES+ [M+H] ⁺ 519.1. Step 2. tert-Butyl 7-[4-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]anil ino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan e-4-carboxylate To a solution of tert-butyl 7-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octane-4-car boxylate (100 mg, 193 μmol) and (1-fluorocyclopropyl)methyl methanesulfonate (32.4 mg, 193 μmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (79.9 mg, 578 μmol). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate=1:3) to give tert-butyl 7-[4- [3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]anilino]- 7-fluoro-pyrido[3,2-d]pyrimidin-6- yl]-4,7-diazaspiro[2.5]octane-4-carboxylate (55.0 mg, 87.5 μmol, 45%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 14.4 Hz, 1H), 7.62 (t, J = 8.8 Hz, 1H), 7.12- 7.10 (m, 1H), 4.56 - 4.41 (m, 2H), 3.73 - 3.61 (m, 4H), 3.52 (s, 2H), 1.43 (s, 9H), 1.21 - 1.14 (m, 2H), 0.97 - 0.85 (m, 6H); m/z ES+ [M+H] ⁺ 591.1. Step 3. N-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-(4,7- diazaspiro[2.5]octan-7-yl)-7-fluoro-pyrido[3,2-d]pyrimidin-4 -amine To a solution of tert-butyl 7-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyr imidin-6-yl]-4,7- diazaspiro[2.5]octane-4-carboxylate (75.0 mg, 127 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]phenyl]-6-(4,7-diazaspiro[2.5]octa n-7-yl)-7-fluoro-pyrido[3,2- d]pyrimidin-4-amine (75.0 mg, crude, trifluoroacetic acid) as a brown oil. m/z ES+ [M+H] ⁺ 491.2. Step 4.1-[7-[4-[3-Chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy ]anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]p rop-2-en-1-one To a solution of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-(4,7- diazaspiro[2.5]octan-7-yl)-7-fluoro-pyrido[3,2-d]pyrimidin-4 -amine (75.0 mg, 124 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (0.4 mL) and water (0.1 mL) was added sodium bicarbonate (208 mg, 2.48 mmol). Then prop-2-enoyl chloride (8.98 mg, 99.2 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-acetonitrile];B%: 48%-78%,15min) to give 1-[7-[4-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]a nilino]-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]-4,7-diazaspiro[2.5]octan-4-yl]prop-2-en-1- one (17.7 mg, 32.2 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.37 (s, 1H), 7.89 (d, J = 14.4 Hz, 1H), 7.64 (t, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 6.4 Hz, 1H), 6.16-6.14 (m, 1H), 5.74 (d, J = 11.2 Hz, 1H), 4.52 - 4.43 (m, 2H), 3.92 - 3.68 (m, 4H), 3.62 (s, 2H), 1.23 - 1.00 (m, 6H), 0.91 (d, J = 7.2 Hz, 2H); m/z ES+ [M+H] ⁺ 545.1. Example 471. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy ]- 2-fluoro-anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabic yclo[2.2.1]heptan-2-yl]prop-2- en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2 -fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (75 mg, 206 μmol) in acetonitrile (1 mL) was added 3- chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-aniline (60.4 mg, 227 μmol), then the mixture was stirred at 40 °C for 1 hr. On completion, the residue was concentrated in vacuo to give a residue. The crude product was triturated with ethyl acetate (2 mL) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2 -fluoro-anilino]pyrimido[5,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (120 mg, crude) as a brown solid. m/z ES+ [M+H] ⁺ 592.1. Step 2. N-[3-Chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-phe nyl]-6-[(1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin- 4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]- 2-fluoro-anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (110 mg, 186 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616. mg, 5.40 mmol). Then the mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro- phenyl]-6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimi do[5,4-d]pyrimidin-4-amine (90 mg, 169 μmol, 91%) as a yellow oil. m/z ES+ [M+H] ⁺ 492.1. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-4-[(3,3-difluorocyclobutyl)metho xy]-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptan-2-yl]prop-2-en-1-one To a solution of N-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-phe nyl]-6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]p yrimidin-4-amine (90 mg, 183 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.1 mL) was added sodium bicarbonate (15.4 mg, 183 μmol) and prop-2-enoyl chloride (18.2 mg, 201 μmol), then the mixture was stirred at 0 °C for 15 min. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(NH3H2O)-ACN];B%: 40%-70%, 8 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4- [(3,3-difluorocyclobutyl)methoxy]-2-fluoro-anilino]pyrimido[ 5,4-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (32.97 mg, 58.1 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 - 9.37 (m, 1H), 9.17 - 9.03 (m, 1H), 8.32 (br s, 1H), 7.75 - 7.59 (m, 1H), 7.18 - 7.05 (m, 1H), 6.90 - 6.34 (m, 1H), 6.23 - 6.06 (m, 1H), 5.68 (ddd, J = 2.2, 10.3, 19.8 Hz, 1H), 5.55 - 4.86 (m, 2H), 4.21 (br d, J = 5.1 Hz, 2H), 3.80 - 3.44 (m, 4H), 2.81 - 2.59 (m, 4H), 2.55 (br s, 1H), 2.12 - 1.97 (m, 2H); m/z ES+ [M+H] ⁺ 546.0. Example 472. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy ]- 2-fluoro-anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2- yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2 -fluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate (80.0 mg, 210 μmol) and 3-chloro-4-[(3,3- difluorocyclobutyl)methoxy]-2-fluoro-aniline (60.0 mg, 225 μmol) in acetonitrile (1 mL) was stirred at 40 °C for 1 hr. On completion, the mixture was quenched with methanol (4 mL) and concentrated to give tert-butyl(1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl) methoxy]-2- fluoro-anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-di azabicyclo[2.2.1]heptane-2- carboxylate (140 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 610.1. Step 2. N-[3-Chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-phe nyl]-6-[(1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]py rimidin-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]- 2-fluoro-anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2- carboxylate (110 mg, 180 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-[(3,3- difluorocyclobutyl)methoxy]-2-fluoro-phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7- fluoro-pyrido[3,2-d]pyrimidin-4-amine (110 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 509.1. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-4-[(3,3-difluorocyclobutyl)metho xy]-2-fluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptan-2-yl]prop-2-en-1- one To a solution of N-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-phe nyl]-6- [(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido [3,2-d]pyrimidin-4-amine (110 mg, 176 μmol, trifluoroacetic acid) and prop-2-enoyl chloride (12.7 mg, 141 μmol, 11.5 μL) in anhydrous tetrahydrofuran (2 mL) and water (0.4 mL) was added sodium bicarbonate (44.5 mg, 529 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was quenched with methanol (4 mL) and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 35%-65%,10 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-[(3,3- difluorocyclobutyl)methoxy]-2-fluoro-anilino]-7-fluoro-pyrid o[3,2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (15.0 mg, 26.7 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.37 – 8.23 (m, 1H), 7.83 - 7.64 (m, 2H), 7.17 - 7.06 (m, 1H), 6.84 - 6.33 (m, 1H), 6.19 - 6.09 (m, 1H), 5.72 - 5.60 (m, 1H), 5.44 - 5.26 (m, 1H), 5.05 - 4.84 (m, 1H), 4.24 - 4.15 (m, 2H), 3.94 - 3.80 (m, 1H), 3.77 - 3.67 (m, 2H), 3.60 - 3.51 (m, 1H), 2.78 - 2.65 (m, 5H), 2.07 - 1.97 (m, 2H); m/z ES+ [M+H] ⁺ 563.2. Example 473. Preparation of 1-[2-Chloro-3-fluoro-4-[[6-[(1S,4S)-5-prop-2-enoyl-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclobutanecarbonitrile Step 1. tert-Butyl (1S,4S)-5-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (200 mg, 1.10 mmol) and tert- butyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (303 mg, 1.43 mmol) in 1- methylpyrrolidin-2-one (3 mL) was added diisopropylethylamine (1.42 g, 11.0 mmol). The mixture was sealed and heated at 170 °C for 6 h under microwave irradiation. On completion, the mixture was concentrated to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (1S,4S)-5-(4-hydroxypyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (40 mg, 110 μmol, 10.1%) as a brown solid. m/z ES+ [M+H] ⁺ 358.0. Step 2. tert-Butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (40 mg, 111 μmol) in toluene. (1 mL) was added diisopropylethylamine (86.7 mg, 671 μmol) and phosphorus oxychloride (34.3 mg, 223 μmol), the mixture was stirred at 110 °C for 5 h. On completion, the reaction mixture was quenched with saturated ammonium chloride solution to pH = 7~8. Then the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was separated and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 9/1) to give tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (20 mg, 50.8 μmol, 45%) as a yellow oil. m/z ES+ [M+H] ⁺ 376.0. Step 3. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclobutyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octane-2-carboxylate A solution of 1-(4-amino-2-chloro-3-fluoro-phenyl)cyclobutanecarbonitrile (14.3 mg, 63.8 μmol) and tert-butyl (1S,4S)-5-(4-chloropyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (20 mg, 53.2 μmol) in acetonitrile (1 mL) was stirred at 80 °C for 16 hr. On completion, the mixture was diluted with ethyl acetate (10 mL) and concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, ethyl acetate: petroleum ether = 5:1) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclobutyl)- 2-fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyc lo[2.2.2]octane-2-carboxylate (16 mg, 26.2 μmol, 49%) as a yellow solid. m/z ES+ [M+H] ⁺ 564.3. Step 4.1-[2-Chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2- yl]pyrido[3,2- d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cyclobutanecarbonitr ile A solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclobutyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.2] octane-2-carboxylate (16 mg, 28.3 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (0.8 mL) was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo to give 1-[2-chloro-4-[[6-[(1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4-yl]am ino]-3-fluoro- phenyl]cyclobutanecarbonitrile (16 mg, 27.6 μmol, 98%) as a yellow oil. m/z ES+ [M+H] ⁺ 464.1. Step 5.1-[2-Chloro-3-fluoro-4-[[6-[(1S,4S)-5-prop-2-enoyl-2,5- diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclobutanecarbonitrile To a solution of 1-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2- yl]pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cyclob utanecarbonitrile (16 mg, 27.6 μmol) and sodium bicarbonate (2.33 mg, 27.6 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.5 mL) was added prop-2-enoyl chloride (2.51 mg, 27.6 μmol), the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated to give a residue. The crude product was purified by prep-HPLC [column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 32%-62%,10 min] to give 1-[2-chloro-3-fluoro-4-[[6-[(1S,4S)-5- prop-2-enoyl-2,5-diazabicyclo[2.2.2]octan-2-yl]pyrido[3,2-d] pyrimidin-4- yl]amino]phenyl]cyclobutanecarbonitrile (12.5 mg, 24.1 μmol, 87%) as a green gum. NMR (400 MHz, DMSO-d ₆ ) δ 10.20 - 9.73 (m, 1H), 9.03 - 8.73 (m, 1H), 8.49 - 8.22 (m, 1H), 7.77 - 7.50 (m, 1H), 7.47 - 7.31 (m, 1H), 7.29 - 7.10 (m, 1H), 6.97 - 6.52 (m, 1H), 6.23 - 6.18 (m, 1H), 5.75 - 5.72 (m, 1H), 5.13 - 4.91 (m, 1H), 4.88 - 4.58 (m, 1H), 3.92 - 3.79 (m, 1H), 3.77 - 3.54 (m, 3H), 2.94 - 2.82 (m, 2H), 2.81 - 2.65 (m, 2H), 2.44 - 2.27 (m, 1H), 2.05 - 1.84 (m, 5H); m/z ES+ [M+H] ⁺ 518.1. Example 474. Preparation of 1-[2-Chloro-3-fluoro-4-[[7-fluoro-6-[(1S,4S)-5-prop-2-enoyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclobutanecarbonitrile Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclobutyl)-2-fluoro-anilin o]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptane-2-carboxylate A solution of 1-(4-amino-2-chloro-3-fluoro-phenyl)cyclobutanecarbonitrile (88.7 mg, 394 μmol) and tert-butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate (150 mg, 394 μmol) in acetonitrile (2 mL) was stirred at 80 °C for 16 hr. On completion, the mixture was filtered and the filtered cake was concentrated in vacuo to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclobutyl)-2-fluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (200 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 568.3. Step 2.1-[2-Chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2 -yl]-7-fluoro- pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cyclobuta necarbonitrile A solution of tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclobutyl)-2-fluoro-anilin o]- 7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate (200 mg, 352 μmol) in trifluoroacetic acid (0.3 mL) and dichloromethane 2.4 mL) was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give 1-[2-chloro-4-[[6-[(1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]py rimidin-4-yl]amino]-3-fluoro- phenyl]cyclobutanecarbonitrile (200 mg, 343 μmol, 98%) as a yellow oil. m/z ES+ [M+H] ⁺ 468.0. Step 3.1-[2-Chloro-3-fluoro-4-[[7-fluoro-6-[(1S,4S)-5-prop-2-enoy l-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclobutanecarbonitrile To a solution of 1-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-y l]-7- fluoro-pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cy clobutanecarbonitrile (200 mg, 343 μmol) and sodium bicarbonate (28.8 mg, 343 μmol) in anhydrous tetrahydrofuran (2 mL) and water (1 mL) was added prop-2-enoyl chloride (31.1 mg, 343 μmol), the mixture was stirred at 0 °C for 10 min. On completion, the mixture was filtered and concentrated in vacuo to give a residue. A small part of crude product was purified by prep-HPLC [column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 39%-69%,9 min] and the other part of crude product was purified by reversed-phase HPLC (0.1% formic acid condition, ACN/H2O: 20%~70%, 15 min) to give 1-[2-chloro-3-fluoro-4-[[7-fluoro-6-[(1S,4S)-5-prop-2- enoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimi din-4- yl]amino]phenyl]cyclobutanecarbonitrile (42.6 mg, 81.3 μmol, 24%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.38 (s, 1H), 8.49 - 8.39 (m, 1H), 8.18 - 8.07 (m, 1H), 7.85 (dd, J = 3.6, 13.6 Hz, 1H), 7.38 (dd, J = 1.2, 8.8 Hz, 1H), 6.90 - 6.35 (m, 1H), 6.23 - 6.08 (m, 1H), 5.71 - 5.67 (m, 1H), 5.40 - 5.18 (m, 1H), 5.11 - 4.83 (m, 1H), 3.96 - 3.83 (m, 1H), 3.82 - 3.66 (m, 2H), 3.65 - 3.51 (m, 1H), 2.96 - 2.81 (m, 2H), 2.80 - 2.64 (m, 2H), 2.43 - 2.27 (m, 1H), 2.14 - 1.92 (m, 3H); m/z ES+ [M+H] ⁺ 522.1. Example 475. Preparation of 1-[2-chloro-3-fluoro-4-[[7-fluoro-6-[(1S,4S)-5-prop-2-enoyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro-anili no]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate (150 mg, 394 μmol) and 1-(4-amino-2-chloro-3- fluoro-phenyl)cyclopropanecarbonitrile (83.1 mg, 394 μmol) in acetonitrile (2 mL) was stirred at 80 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (silicon dioxide, ethyl acetate: petroleum ether =1:0) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro-anili no]-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (120 mg, 186 μmol, 47%) as a yellow solid. m/z ES+ [M+H] ⁺ 554.2. Step 2.1-[2-Chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2 -yl]-7-fluoro- pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cycloprop anecarbonitrile A solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate (120 mg, 216 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL) was stirred at 25 °C for 1.5 hr. On completion, the reaction mixture was concentrated in vacuo to give 1-[2- chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7- fluoro-pyrido[3,2-d]pyrimidin-4- yl]amino]-3-fluoro-phenyl]cyclopropanecarbonitrile (120 mg, 211 μmol, 98%) as a yellow oil. m/z ES+ [M+H] ⁺ 454.0. Step 3.1-[2-Chloro-3-fluoro-4-[[7-fluoro-6-[(1S,4S)-5-prop-2-enoy l-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile To a solution of 1-[2-chloro-4-[[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-y l]-7- fluoro-pyrido[3,2-d]pyrimidin-4-yl]amino]-3-fluoro-phenyl]cy clopropanecarbonitrile (120 mg, 211 μmol) and sodium bicarbonate (17.7 mg, 211 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.5 mL) was added prop-2-enoyl chloride (19.1 mg, 211 μmol) at 0 °C, the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC [column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 36%-66%, 10 min] to give 1-[2-chloro-3-fluoro-4- [[7-fluoro-6-[(1S,4S)-5-prop-2-enoyl-2,5-diazabicyclo[2.2.1] heptan-2-yl]pyrido[3,2- d]pyrimidin-4-yl]amino]phenyl]cyclopropanecarbonitrile (11.2 mg, 22.0 μmol, 10.4%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.43 (d, J = 3.2 Hz, 1H), 8.10 (q, J = 8.4 Hz, 1H), 7.85 (dd, J = 3.6, 13.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.89 - 6.35 (m, 1H), 6.21 - 6.04 (m, 1H), 5.70 - 5.67 (m, 1H), 5.40 - 5.20 (m, 1H), 5.11 - 4.86 (m, 1H), 3.95 - 3.84 (m, 1H), 3.82 - 3.67 (m, 2H), 3.64 - 3.51 (m, 1H), 2.12 - 1.96 (m, 2H), 1.87 - 1.74 (m, 2H), 1.56 - 1.43 (m, 2H); m/z ES+ [M+H] ⁺ 508.3. Example 476. Preparation of 1-[2-Chloro-3-fluoro-4-[[7-fluoro-6-[(1S,4S)-5-prop-2-enoyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrido[3,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile

Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro-anilino]-7- fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl)-2, 5- diazabicyclo[2.2.1]heptane-2-carboxylate (110 mg, 173 μmol) and 3-chloro-4-(cyclopropoxy)-2- fluoro-aniline (35.0 mg, 173 μmol) in acetonitrile (0.5 mL) was stirred at 60 °C for 1 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to dichloromethane/methanol = 10/1) to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2- fluoro-anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-di azabicyclo[2.2.1]heptane-2- carboxylate (150 mg, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.30 (s, 1H), 7.80 (d, J = 13.6 Hz, 1H), 7.70 (t, J = 8.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.36 - 5.19 (m, 1H), 4.51 (d, J = 18.4 Hz, 1H), 4.06 - 4.03 (m, 1H), 3.92 - 3.78 (m, 1H), 3.76 - 3.60 (m, 1H), 3.47 - 3.35 (m, 2H), 3.29 (s, 1H), 1.97 - 1.89 (m, 2H), 1.39 (d, J = 17.6 Hz, 9H), 0.90 - 0.70 (m, 4H); m/z ES+ [M+H] ⁺ 545.2. Step 2. N-[3-Chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro-anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]h eptane-2-carboxylate (130 mg, 239 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N- [3-chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5-d iazabicyclo[2.2.1]heptan-2-yl]-7- fluoro-pyrido[3,2-d]pyrimidin-4-amine (130 mg, crude, trifluoroacetic acid) as a brown solid. m/z ES+ [M+H] ⁺ 445.0. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-4-(cyclopropoxy)-2-fluoro-anilin o]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2 -yl]prop-2-en-1-one To a solution of N-[3-chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-pyrido[3,2-d]pyrimi din-4-amine (130 mg, 292 μmol) in anhydrous tetrahydrofuran (0.5 mL) and water (0.1 mL) was added sodium bicarbonate (491 mg, 5.84 mmol). Then prop-2-enoyl chloride (26.5 mg, 292 μmol, 23.8 μL) was added and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-acetonitrile];B%: 38%-68%,15min) to give 1-[(1S,4S)-5-[4-[3- chloro-4-(cyclopropoxy)-2-fluoro-anilino]-7-fluoro-pyrido[3, 2-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (31.6 mg, 63.4 μmol, 21%) as a yellow solid. NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.80 - 7.77 (m, 1H), 7.71 (q, J = 8.4 Hz, 1H), 7.38 - 7.30 (m, 1H), 6.84 - 6.35 (m, 1H), 6.14 - 6.11 (m, 1H), 5.69-5.66 (m, 1H), 5.43 - 5.25 (m, 1H), 5.05 - 4.84 (m, 1H), 4.04 - 4.02 (m, 1H), 3.94 - 3.81 (m, 1H), 3.78 - 3.66 (m, 2H), 3.63 - 3.47 (m, 1H), 2.10 - 1.92 (m, 2H), 0.92 - 0.69 (m, 4H); m/z ES+ [M+H] ⁺ 498.9. Example 477. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate A solution of tert-butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (50.0 mg, 138 μmol) and 3-chloro-4-(cyclopropoxy)- 2-fluoro-aniline (27.8 mg, 138 μmol) in acetonitrile (0.5 mL) was stirred at 60 °C for 1 hr. On completion, the mixture was concentrated to give tert-butyl (1S,4S)-5-[4-[3-chloro-4- (cyclopropoxy)-2-fluoro-anilino]pyrimido[5,4-d]pyrimidin-6-y l]-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate (130 mg, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 - 9.75 (m, 1H), 9.13 (s, 1H), 8.43 (s, 1H), 7.64 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.75 (s, 1H), 5.44 - 4.98 (m, 1H), 4.63 - 4.42 (m, 1H), 3.50 - 3.41 (m, 2H), 3.38 - 3.15 (m, 2H), 2.04 - 1.96 (m, 2H), 1.42 - 1.35 (m, 9H), 0.92 - 0.84 (m, 2H), 0.80 - 0.74 (m, 2H); m/z ES+ [M+H] ⁺ 527.9. Step 2. N-[3-Chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine To a solution of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate (130 mg, 246 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N- [3-chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5-d iazabicyclo[2.2.1]heptan-2- yl]pyrimido[5,4-d]pyrimidin-4-amine (130 mg, crude, trifluoroacetic acid) as a brown solid. m/z ES+ [M+H] ⁺ 427.9. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-4-(cyclopropoxy)-2-fluoro-anilin o]pyrimido[5,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a solution of N-[3-chloro-4-(cyclopropoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5 - diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine (130 mg, 240 μmol, trifluoroacetic acid) in anhydrous tetrahydrofuran (1 mL) and water (0.2 mL) was added sodium bicarbonate (403 mg, 4.80 mmol). Then prop-2-enoyl chloride (17.4 mg, 192 μmol, 15.7 μL) was added and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)-acetonitrile];B%: 34%-64%, 8 min) to give 1-[(1S,4S)-5-[4-[3-chloro-4-(cyclopropoxy)-2-fluoro-anilino] pyrimido[5,4-d]pyrimidin-6-yl]- 2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (27.5 mg, 57.1 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 - 9.40 (m, 1H), 9.10 (s, 1H), 8.31 (s, 1H), 7.79 - 7.56 (m, 1H), 7.43 - 7.25 (m, 1H), 6.88 - 6.33 (m, 1H), 6.22 - 6.06 (m, 1H), 5.68-5.63 (m, 1H), 5.50 - 4.88 (m, 2H), 4.04 (s, 1H), 3.81 - 3.49 (m, 4H), 2.19 - 1.93 (m, 2H), 0.90 - 0.75 (m, 4H); m/z ES+ [M+H] ⁺ 482.1. Example 478. Preparation of 1-[(1S,4S)-5-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptan-2-yl]prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate A mixture of tert-butyl (1S,4S)-5-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (25 mg, 68.9 μmol) and 3-chloro-4-(cyclobutoxy)-2- fluoro-aniline (14.8 mg, 68.9 μmol) in acetonitrile (0.4 mL) was stirred at 40 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (2 mL) at 25 ℃ for 5 min to give tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro-anilino]pyri mido[5,4-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (20 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 542.0. Step 2. N-[3-Chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine To a mixture of tert-butyl (1S,4S)-5-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2. 1]heptane-2-carboxylate (20 mg, 36.9 μmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine (20 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 442.1. Step 3.1-[(1S,4S)-5-[4-[3-Chloro-4-(cyclobutoxy)-2-fluoro-anilino ]pyrimido[5,4- d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]prop-2- en-1-one To a mixture of N-[3-chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrimido[5,4-d]pyrimidin-4-am ine (20 mg, 35.9 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (6.04 mg, 71.9 μmol) and prop-2-enoyl chloride (3.26 mg, 35.9 μmol) at 0 °C, the mixture was stirred at 0 °C for 0.1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 47%-77%,15min) to give 1- [(1S,4S)-5-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro-anilino]pyr imido[5,4-d]pyrimidin-6-yl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one (12.2 mg, 24.4 μmol, 67%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77 - 9.38 (m, 1H), 9.10 (s, 1H), 8.31 (s, 1H), 7.74 - 7.52 (m, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.86 - 6.33 (m, 1H), 6.21 - 6.02 (m, 1H), 5.67 (m, J = 2.0, 10.4, 19.6 Hz, 1H), 5.52 - 4.89 (m, 2H), 4.88 - 4.75 (m, 1H), 3.80 - 3.40 (m, 4H), 2.49 - 2.42 (m, 2H), 2.17 - 1.97 (m, 4H), 1.90 - 1.76 (m, 1H), 1.73 - 1.60 (m, 1H); m/z ES+ [M+H] ⁺ 495.9. Example 479. Preparation of 1-((1S,4S)-5-(4-(3-chlorophenoxy)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-(3-chlorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1S,4S)-tert-butyl 5-(4-(methylsulfinyl)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (50.0 mg, 128 umol) and 3-Chlorphenol (135 uL, 1.28 mmol) were dissolved in dimethylsulfoxide (1.00 mL), and potassium tert-butoxide (14.7 mg, 128 umol) was added. The mixture was heated to 50 ºC and stirring was continued for 18 hours. The mixture was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo to afford tert-butyl (1S,4S)-5-(4-(3-chlorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)-2 ,5- diazabicyclo[2.2.1]heptane-2-carboxylate as a colorless residue that was carried forward without further purification. m/z ES+[M+H] ⁺ 490.3. Step 2. 1-((1S,4S)-5-(4-(3-chlorophenoxy)pyrido[3,2-d]pyrimidin-6-yl )-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (1S,4S)-tert-butyl 5-(4-(3-chlorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (58.3 mg, 128 umol) was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (1.00 mL, 12.9 mmol) was added to the mixture. Stirring was continued for 1 hour. The mixture was concentrated in vacuo to afford a residue that was redissolved in dichloromethane. The mixture was concentrated in vacuo to afford a residue that was dissolved in tetrahydrofuran (2.00 mL). N,N-Diisopropylethylamine (225 uL, 1.28 mmol) and acrylic anhydride (16.2 uL, 141 umol) were added to the mixture. Stirring was continued for 1 hour. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and lyophilized to afford 1-((1S,4S)-5-(4-(3-chlorophenoxy)pyrido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one as a white solid (7.08 mg, 17.4 umol, 14% over three steps). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 0.6 Hz, 1H), 8.05 (dd, J = 9.3, 3.7 Hz, 1H), 7.58 – 7.40 (m, 3H), 7.40 – 7.35 (m, 1H), 7.28 (dd, J = 8.1, 1.5 Hz, 1H), 6.60 (m, 1H), 6.14 (m, 1H), 5.67 (m, 1H), 5.05 m, 2H), 3.78 – 3.63 (m, 2H), 3.62 – 3.48 (m, 2H), 2.15 – 1.93 (m, 2H); m/z ES+ [M+H]+ 408.1. Example 480. Preparation of 1-((1S,4S)-5-(4-(3-chloro-4- (cyclopropylmethoxy)phenoxy)pyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptan- 2-yl)prop-2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-(3-chloro-4-(cyclopropylmethoxy)phenoxy)pyrido[ 3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (1S,4S)-tert-butyl 5-(4-(methylsulfinyl)pyrido[3,2-d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (50.0 mg, 128 umol) and 3-chloro-4- (cyclopropylmethoxy)phenol (105 uL, 642 umol) were dissolved in dimethylsulfoxide (1.00 mL), and potassium tert-butoxide (14.7 mg, 128 umol) was added. The mixture was heated to 50 ºC and stirring was continued for 2 hours. The mixture was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo to afford tert-butyl (1S,4S)-5-(4-(3-chloro-4- (cyclopropylmethoxy)phenoxy)pyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptane-2- carboxylate as a colorless residue. m/z ES+ [M+H]+ 524.2. Step 2. 1-((1S,4S)-5-(4-(3-Chloro-4-(cyclopropylmethoxy)phenoxy)pyri do[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2- en-1-one (1S,4S)-tert-butyl 5-(4-(3-chloro-4-(cyclopropylmethoxy)phenoxy)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (67.3 mg, 128 umol) was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (1.00 mL, 12.9 mmol) was added to the mixture. Stirring was continued for 1 hour. The mixture was concentrated in vacuo to afford a residue that was redissolved in dichloromethane. The mixture was concentrated in vacuo to afford a residue that was dissolved in tetrahydrofuran (2.00 mL). N,N- Diisopropylethylamine (225 uL, 1.28 mmol) and acrylic anhydride (16.2 uL, 141 umol) were added to the mixture. Stirring was continued for 1 hours. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and lyophilized to afford 1-((1S,4S)-5-(4-(3-chloro-4- (cyclopropylmethoxy)phenoxy)pyrido[3,2-d]pyrimidin-6-yl)-2,5 -diazabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one as a white solid (6.28 mg, 13.1 umol, 10% over three steps). ¹ H NMR (500 MHz, MeOD-d ₄ ) δ 8.41 (s, 1H), 8.02 (dd, J = 9.3, 1.9 Hz, 1H), 7.45 – 7.25 (m, 2H), 7.16 (d, J = 1.3 Hz, 2H), 6.92 – 6.74 (m, 1H), 6.68 – 6.41 (m, 1H), 6.31 (m, 1H), 5.77 (m, 1H), 5.31 (s, 1H), 5.07 (m, 1H), 3.98 (d, J = 6.8 Hz, 2H), 3.88 – 3.78 (m, 2H), 3.75 – 3.60 (m, 2H), 2.29 – 2.01 (m, 2H), 1.32 (m, 1H), 0.70 – 0.58 (m, 2H), 0.45 – 0.35 (m, 2H); m/z ES+ [M+H] ⁺ 478.3. Example 481. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one Step 1. tert-Butyl (3-chloro-2-fluoro-4-hydroxyphenyl)carbamate 4-Amino-2-chloro-3-fluorophenol (3.00 g, 18.6 mmol) was dissolved in tetrahydrofuran (30.0 mL) and di-tert-butyl dicarbonate (4.69 mL, 20.4 mmol) was added. Stirring was continued for 18 hours. The mixture was quenched with methanol (4.00 mL) and concentrated in vacuo. The residue was purified using C18 reverse phase chromatography (60 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and lyophilized to tert-butyl (3-chloro-2-fluoro-4-hydroxyphenyl)carbamate (3.50 g, 13.4 mmol, 72 %) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (s, 1H), 6.70 (dd, J = 9.1, 2.0 Hz, 1H), 6.45 (s, 1H), 5.99 (br. s, 1H), 1.51 (s, 9H). Step 2. tert-Butyl (3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)carbamate Tert-butyl (3-chloro-2-fluoro-4-hydroxyphenyl)carbamate (250 mg, 955 umol) was dissolved in acetonitrile (5.00 mL) and 3-(bromomethyl)tetrahydrofuran (105 uL, 955 umol) was added along with cesium carbonate (311 mg, 955 umol). The mixture was heated to 80 °C and stirring was continued for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and concentrated in vacuo to afford tert-butyl (3-chloro-2-fluoro-4- ((tetrahydrofuran-3-yl)methoxy)phenyl)carbamate as a colorless residue that was carried forward without further purification (330 mg, yield over 100 % due to impurities). Step 3.3-Chloro-2-fluoro-4-((tetrahydrofuran-3-yl)methoxy)aniline Tert-butyl (3-chloro-2-fluoro-4-((tetrahydrofuran-3-yl)methoxy)phenyl)c arbamate was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (73.8 uL, 954 umol) was added to the mixture. Stirring was continued for 1 hour and the mixture was concentrated in vacuo to afford a residue that was redissolved in dichloromethane (10.0 mL). The mixture was concentrated in vacuo to afford 3-chloro-2-fluoro-4-((tetrahydrofuran-3-yl)methoxy)aniline as colorless residue that was carried forward without further purification. ¹ H NMR (500 MHz, MeOD-d ₄ ) δ 7.32 – 7.18 (m, 2H), 6.99 – 6.85 (m, 2H), 4.04 – 3.97 (m, 3H), 3.94 (dd, J = 9.2, 7.8 Hz, 2H), 3.82 (ddd, J = 13.9, 7.9, 4.1 Hz, 4H), 3.72 – 3.65 (m, 2H), 3.62 (dt, J = 10.5, 5.3 Hz, 2H), 2.76 – 2.65 (m, 2H), 2.10 – 1.98 (m, 2H), 1.76 – 1.64 (m, 2H). Step 4. 6-Chloro-N-(3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine 4,6-dichloropyrido[3,2-d]pyrimidine (191 mg, 952 umol) and 3-chloro-2-fluoro-4- ((tetrahydrofuran-3-yl)methoxy)aniline (234 mg, 952 umol) were dissolved in acetonitrile (10.0 mL). Stirring was continued for 18 hours. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (30 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and concentrated in vacuo to afford 6-chloro-N-(3-chloro-2-fluoro-4-((tetrahydrofuran- 3-yl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (190 mg, 464 umol, 49 %) as a light- yellow solid. m/z ES+ [M+H] ⁺ 409.1. Step 5. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate 6-chloro-N-(3-chloro-2-fluoro-4-((tetrahydrofuran-3-yl)metho xy)phenyl)pyrido[3,2- d]pyrimidin-4-amine (140 mg, 342 umol) was dissolved in dimethylsulfoxide (5.00 mL) and (1S,4S)-tertbutyl-2,5-diazabicyclo[2.2.1]heptane -2-carboxylate (67.8 mg, 342 umol) was added. N,N-Diisopropylethylamine (120 uL, 684 umol) was added and the mixture was heated to 80 °C. Stirring was continued for 18 hours. The mixture was cooled to room temperature and concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and lyophilized to afford tert-butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3-yl)me thoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (35 mg, 61.3 umol, 18 %) as a light-yellow solid. m/z ES+ [M+H] ⁺ 571.2. Step 6. 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one (1S,4S)-tert-butyl 5-(4-((3-chloro-2-fluoro-4-((tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-dia zabicyclo[2.2.1]heptane-2- carboxylate (35.0 mg, 61.3 umol) was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (1.00 mL, 12.9 mmol). Stirring was continued for 2 hours before the mixture was concentrated in vacuo. The resulting residue was redissolved in dichloromethane (10.0 mL) and concentrated in vacuo to afford a residue that was dissolved in tetrahydrofuran (5.00 mL). N,N- Diisopropylethylamine (108 uL, 614 umol) and acrylic anhydride (7.74 uL, 67.5 umol) were added to the mixture and stirring was continued for 1 hour. The mixture was concentrated in vacuo to afford a residue that was purified using C18 reverse phase chromatography (12 g cartridge) with ammonium formate and acetonitrile (0-100 % gradient) as eluent. The pure fractions were collected and lyophilized to afford 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4- ((tetrahydrofuran-3-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyr imidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (10 mg, 19.0 umol, 31% over two steps) as a light-yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 8.30 (d, J = 3.8 Hz, 1H), 7.91 (dd, J = 9.2, 4.7 Hz, 1H), 7.80 (s, 1H), 7.11 (m, 2H), 6.62 (m, 1H), 6.15 (m, 1H), 5.71 – 5.60 (m, 1H), 5.01 (m, 2H), 4.16 – 4.02 (m, 2H), 3.86 – 3.42 (m, 8H), 2.78 – 2.67 (m, 1H), 2.05 (m, 3H), 1.72 (m, 1H); m/z ES+ [M+H] ⁺ 525.2. Example 482. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclobutyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one

Step 1. tert-Butyl (3-chloro-2-fluoro-4-((1-fluorocyclobutyl)methoxy)phenyl)car bamate Tert-butyl (3-chloro-2-fluoro-4-((1-methylcyclobutyl)methoxy)phenyl)car bamate (120 mg, 345 umol, 45 %) was prepared and purified according to the procedure outlined above. Step 2.3-Chloro-2-fluoro-4-((1-fluorocyclobutyl)methoxy)aniline 3-chloro-2-fluoro-4-((1-methylcyclobutyl)methoxy)aniline (colorless oil) was prepared according to the procedure outlined above and carried forward without further purification. m/z ES+ [M+H] ⁺ 247.9. Step 3. 6-Chloro-N-(3-chloro-2-fluoro-4-((1- fluorocyclobutyl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-ami ne 6-chloro-N-(3-chloro-2-fluoro-4-((1-methylcyclobutyl)methoxy )phenyl)pyrido[3,2- d]pyrimidin-4-amine (7.0 mg, 17.0 umol, 4.1 % over two steps) was prepared and purified according to the procedure outlined above as a light-yellow solid m/z ES+ [M+H] ⁺ 411.0. Step 4. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclobutyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1S,4S)-tert-butyl 5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclobutyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was prepared and purified according to the procedure outlined above and carried forward. m/z ES+ [M+H] ⁺ 573.1. Step 5. 1-((1S,4S)-5-(4-((3-Chloro-2-fluoro-4-((1- fluorocyclobutyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclobutyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (1.0 mg, 1.90 umol, 9.1 % over final two steps) was prepared and purified according to the procedure outlined above as a light-yellow solid. ¹ H NMR (500 MHz, MeOD-d ₄ ) δ 8.35 (s, 1H), 8.13 (s, 1H), 7.91 (dd, J = 9.2, 1.7 Hz, 1H), 7.26 (s, 1H), 7.06 (dd, J = 9.2, 1.9 Hz, 1H), 6.64 (m, 1H), 6.31 (m, 1H), 5.78 (m, 1H), 5.09 (m, 2H), 4.29 (d, J = 21.5 Hz, 2H), 3.89 – 3.61 (m, 4H), 2.43 (m, 4H), 2.26 – 2.06 (m, 2H), 1.93 (s, 1H), 1.71 (m, 1H); m/z ES+ [M+H] ⁺ 527.2. Example 483. Preparation of 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one Step 1. tert-Butyl (3-chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)carbamate Tert-butyl (3-chloro-2-fluoro-4-((1-fluorocyclopropyl)methoxy)phenyl)ca rbamate was prepared and purified according to the procedure outlined above and obtained as a colorless residue (140 mg, 419 umol, 55 %). Step 2. 3-Chloro-2-fluoro-4-((1-fluorocyclopropyl)methoxy)aniline 3-chloro-2-fluoro-4-((1-fluorocyclopropyl)methoxy)aniline was prepared according to the procedure outlined above and obtained as a colorless residue. m/z ES+ [M+H] ⁺ 233.9. Step 3. 6-Chloro-N-(3-chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-am ine 6-chloro-N-(3-chloro-2-fluoro-4-((1-fluorocyclopropyl)methox y)phenyl)pyrido[3,2- d]pyrimidin-4-amine was prepared and purified according to the procedure outlined above and obtained as a light-yellow solid (60 mg, 151 umol, 42 %). m/z ES+ [M+H] ⁺ 396.8. Step 4. tert-Butyl (1S,4S)-5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1S,4S)-tert-butyl 5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was prepared and purified according to the procedure outlined above and obtained as a light-yellow solid that was carried forward. m/z ES+ [M+H] ⁺ 559.1. Step 5. 1-((1S,4S)-5-(4-((3-Chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one 1-((1S,4S)-5-(4-((3-chloro-2-fluoro-4-((1- fluorocyclopropyl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidi n-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (20.5 mg, 40.0 umol, 26% over three steps) was prepared and purified according to the procedure outlined above and obtained as a light-yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.30 (d, J = 3.7 Hz, 1H), 7.88 (m, 2H), 7.39 – 7.06 (m, 2H), 6.61 (m, 1H), 6.14 (ddd, J = 16.8, 7.1, 2.3 Hz, 1H), 5.67 (ddd, J = 26.7, 10.3, 2.3 Hz, 1H), 5.00 (m, 2H), 4.46 (d, J = 22.4 Hz, 2H), 3.77 – 3.47 (m, 4H), 2.04 (m, 2H), 1.16 (m, 2H), 0.94 – 0.88 (m, 2H); m/z ES+ [M+H] ⁺ 513.2. Example 484. Preparation of 1-((1S,4S)-5-(4-((3-chloro-4-((3,3- difluorocyclobutyl)methoxy)-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one Step 1. tert-Butyl (3-chloro-4-((3,3-difluorocyclobutyl)methoxy)-2- fluorophenyl)carbamate Tert-butyl (3-chloro-4-((3,3-difluorocyclobutyl)methoxy)-2-fluorophenyl )carbamate was prepared according to the procedure outlined above and obtained as a colorless residue. Step 2.3-Chloro-4-((3,3-difluorocyclobutyl)methoxy)-2-fluoroanili ne 3-chloro-4-((3,3-difluorocyclobutyl)methoxy)-2-fluoroaniline was prepared according to the procedure outlined above as a colorless residue. m/z ES+ [M+H] ⁺ 265.8. Step 3. 6-Chloro-N-(3-chloro-4-((3,3-difluorocyclobutyl)methoxy)-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine 6-chloro-N-(3-chloro-4-((3,3-difluorocyclobutyl)methoxy)-2-f luorophenyl)pyrido[3,2- d]pyrimidin-4-amine 340 mg, 792 umol, 83 % over three steps) was prepared and purified according to the procedure outlined above as a light-yellow solid. m/z ES+ [M+H] ⁺ 428.9. Step 4. tert-Butyl (1S,4S)-5-(4-((3-chloro-4-((3,3-difluorocyclobutyl)methoxy)- 2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate (1S,4S)-tert-butyl 5-(4-((3-chloro-4-((3,3-difluorocyclobutyl)methoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptane-2-carboxylate was prepared and purified according to the procedure outlined above and obtained as a colorless residue. m/z ES+ [M+H] ⁺ 591.1. Step 5. 1-((1S,4S)-5-(4-((3-Chloro-4-((3,3-difluorocyclobutyl)methox y)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one 1-((1S,4S)-5-(4-((3-chloro-4-((3,3-difluorocyclobutyl)methox y)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop-2-en- 1-one (15.1 mg, 27.7 umol, 9.6% over three steps) was prepared and purified according to the procedure outlined above and obtained as a light-yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.30 (d, J = 3.8 Hz, 1H), 7.91 (dd, J = 9.2, 4.8 Hz, 1H), 7.81 (s, 1H), 7.11 (d, J = 9.2 Hz, 2H), 6.87 – 6.36 (m, 1H), 6.15 (ddd, J = 16.8, 7.1, 2.2 Hz, 1H), 5.68 (ddd, J = 26.7, 10.3, 2.3 Hz, 1H), 5.01 (m, J = 67.3 Hz, 2H), 4.20 (d, J = 5.9 Hz, 2H), 3.79 – 3.46 (m, 4H), 2.75 (m, 5H), 2.06 (m, 2H); m/z ES+ [M+H] ⁺ 545.0. Example 485. Preparation of 1-((1S,4S)-5-(4-((3-cyclopropyl-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabic yclo[2.2.1]heptan-2-yl)prop- 2-en-1-one Step 1. tert-Butyl (1S,4S)-5-(4-((3-cyclopropyl-2-fluorophenyl)amino)pyrido[3,2 - d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (1S,4S)-tert-butyl 5-(4-((3-cyclopropyl-2-fluorophenyl)amino)pyrido[3,2-d]pyrim idin-6- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (40.0 mg, 84.9 umol), cyclopropylboronic acid (43.8 mg, 510 umol), potassium phosphate tribasic (110 mg, 510 umol), and tricyclohexylphosphine (4.91 mg, 17.0 umol) were suspended in toluene (2.00 mL). The mixture was heated to 120 degrees in a sealed microwave tube, and stirring was continued for 1 hour. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were concentrated in vacuo to afford tert-Butyl (1S,4S)-5-(4- ((3-cyclopropyl-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate as a colorless residue that was carried forward without further purification. m/z ES+ [M+H] ⁺ 477.1. Step 2. 1-((1S,4S)-5-(4-((3-cyclopropyl-2-fluorophenyl)amino)pyrido[ 3,2-d]pyrimidin- 6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one 1-((1S,4S)-5-(4-((3-cyclopropyl-2-fluorophenyl)amino)pyrido[ 3,2-d]pyrimidin-6-yl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was prepared and purified according to the procedure outlined above and obtained as a light-yellow solid (17.0 mg, 39.4 umol, 47 % over final three steps). ¹ H NMR (500 MHz, DMSO) δ 9.50 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 7.94 (dd, J = 9.2, 4.0 Hz, 1H), 7.19 (s, 1H), 7.17 (dd, J = 14.7, 6.8 Hz, 1H), 6.62 (ddd, J = 198.1, 16.7, 10.3 Hz, 2H), 6.15 (ddd, J = 16.8, 7.3, 2.3 Hz, 1H), 5.68 (ddd, J = 28.0, 10.3, 2.3 Hz, 1H), 5.02 (d, J = 67.1 Hz, 2H), 3.79 – 3.52 (m, 4H), 2.16 – 1.99 (m, 3H), 1.02 (dd, J = 8.4, 2.1 Hz, 2H), 0.77 (dd, J = 5.2, 2.0 Hz, 2H); m/z ES+ [M+H] ⁺ 431.1. Example 486. Preparation of 1-((1S,4S)-5-(4-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)- yl)pyrido[3,2-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]hepta n-2-yl)prop-2-en-1-one Step 1. 6-Chloro-N-(3-ethynyl-2-fluorophenyl)pyrido[3,2-d]pyrimidin- 4-amine 6-chloro-N-(3-ethynyl-2-fluorophenyl)pyrido[3,2-d]pyrimidin- 4-amine (123.0 mg, 412 umol, 92%) was prepared according to the procedure outlined above and obtained as a white solid. m/z ES+ [M+H]+ 298.9. Step 2. tert-Butyl (1S,4S)-5-(4-((3-ethynyl-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (1S,4S)-tert-butyl 5-(4-((3-ethynyl-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (91.0 mg, 198 umol, 48%) was prepared according to the procedure outlined above and obtained as a yellow solid. m/z ES+ [M+H]+ 461.2. Step 3. 1-((1S,4S)-5-(4-((3-Ethynyl-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one 1-((1S,4S)-5-(4-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)py rido[3,2-d]pyrimidin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (18.3 mg, 44.2, 22% over 2 steps) was prepared according to the procedure outlined above and obtained as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.40 (d, J = 3.5 Hz, 1H), 8.28 (s, 1H), 7.93 (dd, J = 9.2, 4.0 Hz, 1H), 7.38 – 7.31 (m, 1H), 7.28 (t, J = 7.9 Hz, 1H), 6.62 (ddd, J = 157.6, 16.7, 10.3 Hz, 1H), 6.14 (ddd, J = 16.8, 6.0, 2.3 Hz, 1H), 5.67 (ddd, J = 22.9, 10.3, 2.3 Hz, 1H), 5.32 (s, 1H), 5.00 (d, J = 52.2 Hz, 1H), 4.55 (s, 1H), 3.86 – 3.37 (m, 5H), 2.05 (d, J = 31.2 Hz, 2H); m/z ES+ [M+H]+ 415.1. Example 487. Preparation of 4-((6-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-3-chloro-2-fluorobenzo nitrile Step 1. 3-Chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fl uorobenzonitrile 2-chloro-4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-fl uorobenzonitrile one (46.3 mg, 140 umol, 46%) was prepared according to the procedure outlined above and obtained as a white solid. m/z ES+ [M+H]+ 333.9. Step 2. tert-Butyl (1S,4S)-5-(4-((2-chloro-4-cyano-3-fluorophenyl)amino)pyrido[ 3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (1S,4S)-tert-butyl 5-(4-((2-chloro-4-cyano-3-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyla te (41.1 mg, 82.9 umol, 70%) was prepared according to the procedure outlined above and obtained as a yellow solid. Step 3.4-((6-((1S,4S)-5-Acryloyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyrido[3,2- d]pyrimidin-4-yl)amino)-3-chloro-2-fluorobenzonitrile 4-((6-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl )pyrido[3,2-d]pyrimidin-4- yl)amino)-3-chloro-2-fluorobenzonitrile (18.4 mg, 40.9 umol, 31%) was prepared according to the procedure outlined above and obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 7.95 (ddd, J = 10.1, 9.0, 2.7 Hz, 2H), 7.36 (s, 1H), 6.62 (ddd, J = 165.2, 16.8, 10.5 Hz, 1H), 6.14 (ddd, J = 16.8, 6.3, 2.3 Hz, 1H), 5.67 (ddd, J = 24.6, 10.3, 2.3 Hz, 1H), 5.18 (s, 1H), 5.02 (d, J = 54.0 Hz, 1H), 3.87 – 3.37 (m, 4H), 2.07 (d, J = 30.4 Hz, 2H); m/z ES+ [M+H]+ 450.1. Example 488. Synthesis and Characterization of Additional Exemplary Compounds Additional exemplary compounds were synthesized following the procedures described herein. Characterizations of the compounds are shown in Table A below.

Example 489. Biological Activity of Exemplary Compounds Retroviral Production: EGFR mutants were subcloned into pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs, San Diego, CA). Retroviral expression vector retrovirus was produced by transient transfection of HEK 293T cells with the retroviral EGFR mutant expression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs), pCMV-Gag-Pol vector and pCMV-VSV-G- Envelope vector. Briefly, HEK 293T/17 cells were plated in 100 mm collagen coated plate (354450, Corning Life Sciences, Tewksbury, MA) (4 10 ⁵ per plate) and incubated overnight. The next day, retroviral plasmids (3 Pg of EGFR mutant, 1.0 Pg of pCMV-Gag-Pol and 0.5 Pg pCMV-VSV-G) were mixed in 500 Pl of Optimem (31985, Life Technologies). The mixture was incubated at room temperature for 5 min and then added to Optimem containing transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. Mixture was then added dropwise to HEK 293T cells. The next day the medium was replaced with fresh culture medium and retrovirus was harvested @ 24 and 48 hrs. Generation of EGFR mutant stable cell lines: BaF3 cells (1.5E5 cells) were infected with 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in a 37°C incubator overnight. Cells were then spun for 5 minutes to pellet the cells. Supernatant was removed and cells re-infected a fresh 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in 37°C incubator overnight. Cells were then maintained in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine containing 10 ng/ml IL-3. After 48 hours cells were selected for retroviral infection in 10 Pg/ml Blasticidin for one week. Blasticidin resistant populations were washed twice in phosphate buffered saline before plating in media lacking IL-3 to select for IL-3 independent growth. Assay for cell proliferation: BaF3 cell lines were resuspended at 1.3E5 c/ml in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine and 1% Pen/Strep and dispensed in triplicate (17.5E4 c/well) into 96 well plates. To determine the effect of drug on cell proliferation, cells incubated for 3 days in the presence of vehicle control or test drug at varying concentrations. Inhibition of cell growth was determined by luminescent quantification of intracellular ATP content using CellTiterGlo (Promega), according to the protocol provided by the manufacturer. Comparison of cell number on day 0 versus 72 hours post drug treatment was used to plot dose- response curves. The number of viable cells was determined and normalized to vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls was expressed as a fraction of 1 and graphed using PRISM ^® software (Graphpad Software, San Diego, CA). EC ₅₀ values were determined with the same application. Cellular protein analysis: Cell extracts were prepared by detergent lysis (RIPA, R0278, Sigma, St Louis, MO) containing 10 mM Iodoacetamide (786-228, G-Biosciences, St, Louis, MO), protease inhibitor (P8340, Sigma, St. Louis, MO) and phosphatase inhibitors (P5726, P0044, Sigma, St. Louis, MO) cocktails. The soluble protein concentration was determined by micro-BSA assay (Pierce, Rockford IL). Protein immunodetection was performed by electrophoretic transfer of SDS-PAGE separated proteins to nitrocellulose, incubation with antibody, and chemiluminescent second step detection. Nitrocellulose membranes were blocked with 5% nonfat dry milk in TBS and incubated overnight with primary antibody in 5% bovine serum albumin. The following primary antibodies from Cell Signaling Technology were used at 1:1000 dilution: phospho-EGFR[Y1173] and total EGFR. β-Actin antibody, used as a control for protein loading, was purchased from Sigma Chemicals. Horseradish peroxidase-conjugated secondary antibodies were obtained from Cell Signaling Technology and used at 1:5000 dilution. Horseradish peroxidase-conjugated secondary antibodies were incubated in nonfat dry milk for 1 hour. SuperSignal chemiluminescent reagent (Pierce Biotechnology) was used according to the manufacturer's directions and blots were imaged using the Alpha Innotech image analyzer and AlphaEaseFC software (Alpha Innotech, San Leandro CA). Tables B and C assign each compound a potency code: A, B, C, D, or E. According to the code, A represents an IC50 value <20 nM; B represents an IC50 value ≥20 nM and <50 nM; C represents an IC ₅₀ value ≥50 nM and <100 nM; and D represents an IC ₅₀ value ≥100 nM and <500 nM; and E represents an IC ₅₀ value ≥500 nM. Table B

Table C

EQUIVALENTS The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.