6-(HETEROCYCLOALKYL-OXY)-QUINAZOLINE DERIVATIVES AND USES THEREOF RELATED APPLICATION [001] This application claims priority to, and the benefit of, U.S. Application No. 63/211,909, filed June 17, 2021, the entire content of each of which is incorporated herein by reference. BACKGROUND [002] 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 [003] 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, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); Y is a C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently 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 ; each R ^Y1 independently is oxo, halogen, OH, CN, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 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 R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [004] 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 1-6. [005] In some aspects, the present disclosure provides an isotopic derivative of a compound described. [006] In some aspects, the present disclosure provides a method of preparing a compound described herein. [007] 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 1-92). [008] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. [009] 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. [010] 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. [011] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. [012] In some aspects, the present disclosure provides a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor. [013] 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. [014] 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. [015] 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. [016] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION [017] 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 [018] 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, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); Y is a C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently 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 ; each R ^Y1 independently is oxo, halogen, OH, CN, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 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 R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [019] 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, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); Y is a C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently 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-(C3-C8 cycloalkyl), -O-(C6-C10 aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, OH, -CN, 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, 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 ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [020] 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, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); Y is a C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [021] It is understood that, for a compound of Formula (I), W ¹ , R ^W1 , W ² , R ^W2 , Y, R ^Y , R ^Y1 , and R ^Y1a 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 , Y, R ^Y , R ^Y1 , and R ^Y1a 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 , Y, R ^Y , R ^Y1 , and R ^Y1a . Variables W ¹ , W ² , R ^W1 , and R ^W2 [022] In some embodiments, W ¹ is =CR ^W1 –. In some embodiments, W ¹ is =CH–. [023] In some embodiments, W ¹ is =N–. [024] In some embodiments, R ^W1 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). [025] In some embodiments, R ^W1 is H. [026] In some embodiments, W ² is =CR ^W2 –. In some embodiments, W ² is =CH–. In some embodiments, W ² is =CF–. [027] In some embodiments, R ^W2 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). [028] In some embodiments, R ^W2 is H or halogen. [029] In some embodiments, R ^W2 is H. [030] In some embodiments, R ^W2 is halogen. In some embodiments, R ^W2 is fluorine. [031] In some embodiments, W ¹ is =CR ^W1 - and W ² is =CR ^W2 -. [032] In some embodiments, W ¹ is N and W ² is =CR ^W2 -. [033] In some embodiments, W ¹ is =CR ^W1 - and W ² is N. [034] In some embodiments, W ¹ is CH and W ² is CH. [035] In some embodiments, W ¹ is N and W ² is CH. [036] In some embodiments, W ¹ is CH and W ² is N. Variables Y, R ^Y , R ^Y1 , R ^Y1a [037] In some embodiments, Y is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ - C ₁₀ aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y . [038] In some embodiments, Y is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl. [039] In some embodiments, Y is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ - C ₁₀ aryl or 5- to 9-membered heteroaryl is substituted with one or more R ^Y . [040] In some embodiments, Y is C ₆ -C ₁₀ aryl, wherein the C ₆ -C ₁₀ aryl is optionally substituted with one or more R ^Y . [041] In some embodiments, Y is phenyl optionally substituted with one or more R ^Y . [042] In some embodiments, Y is phenyl. [043] In some embodiments, Y is phenyl substituted with one or more R ^Y . [044] In some embodiments, Y is 5- to 9-membered heteroaryl optionally substituted with one or more R ^Y . [045] In some embodiments, Y is pyridyl optionally substituted with one or more R ^Y . [046] In some embodiments, Y is pyridyl. [047] In some embodiments, Y is pyridyl substituted with one or more R ^Y . [048] In some embodiments, Y is indazole optionally substituted with one or more R ^Y . [049] In some embodiments, Y is indazole. [050] In some embodiments, Y is indazole substituted with one or more R ^Y . [051] In some embodiments, at least one 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 - C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 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 . [052] In some embodiments, at least one R ^Y is halogen, alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ - C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl) is optionally substituted with one or more R ^Y1 . [053] In some embodiments, at least one R ^Y is halogen. In some embodiments, at least one R ^Y is F. In some embodiments, at least one R ^Y is Cl. In some embodiments, at least one R ^Y is Br. In some embodiments, at least one R ^Y is I. [054] In some embodiments, at least one R ^Y is C ₁ -C ₆ alkyl optionally substituted with one or more R ^Y1 . [055] In some embodiments, at least one R ^Y is C ₁ -C ₆ alkyl substituted with one or more R ^Y1 . [056] In some embodiments, at least one R ^Y is C ₁ alkyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₂ alkyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₃ alkyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₄ alkyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₅ alkyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₆ alkyl optionally substituted with one or more R ^Y1 . [057] In some embodiments, at least one R ^Y is C ₁ alkyl. In some embodiments, at least one R ^Y is C ₂ alkyl. In some embodiments, at least one R ^Y is C ₃ alkyl. In some embodiments, at least one R ^Y is C ₄ alkyl. In some embodiments, at least one R ^Y is C ₅ alkyl. In some embodiments, at least one R ^Y is C6 alkyl. [058] In some embodiments, at least one R ^Y is C ₁ -C ₆ alkoxyl, wherein the C ₁ -C ₆ alkoxyl is optionally substituted with one or more R ^Y1 . [059] In some embodiments, at least one R ^Y is C ₁ -C ₆ alkoxyl substituted with one or more R ^Y1 . [060] In some embodiments, at least one R ^Y is C ₁ alkoxyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₂ alkoxyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₃ alkoxyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₄ alkoxyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C5 alkoxyl optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is C ₆ alkoxyl optionally substituted with one or more R ^Y1 . [061] In some embodiments, at least one R ^Y is C ₁ -C ₆ alkoxyl. In some embodiments, at least one R ^Y is C ₁ alkoxyl. In some embodiments, at least one R ^Y is C ₂ alkoxyl. In some embodiments, at least one R ^Y is C ₃ alkoxyl. In some embodiments, at least one R ^Y is C ₄ alkoxyl. In some embodiments, at least one R ^Y is C ₅ alkoxyl. In some embodiments, at least one R ^Y is C ₆ alkoxyl. [062] In some embodiments, at least one R ^Y is -O-(C ₃ -C ₈ cycloalkyl) optionally substituted with one or more R ^Y1 . [063] In some embodiments, at least one R ^Y is -O-(C ₃ -C ₈ cycloalkyl) substituted with one or more R ^Y1 . [064] In some embodiments, at least one R ^Y is -O-(C ₃ cycloalkyl) optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is -O-(C ₄ cycloalkyl) optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is -O-(C ₅ cycloalkyl) optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is -O-(C ₆ cycloalkyl) optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is -O-(C ₇ cycloalkyl) optionally substituted with one or more R ^Y1 . In some embodiments, at least one R ^Y is -O-(C ₈ cycloalkyl) optionally substituted with one or more R ^Y1 . [065] In some embodiments, at least one R ^Y is -O-(C ₃ cycloalkyl). In some embodiments, at least one R ^Y is -O-(C ₄ cycloalkyl). In some embodiments, at least one R ^Y is -O-(C ₅ cycloalkyl). In some embodiments, at least one R ^Y is -O-(C ₆ cycloalkyl). In some embodiments, at least one R ^Y is -O-(C ₇ cycloalkyl). In some embodiments, at least one R ^Y is -O-(C ₈ cycloalkyl). [066] In some embodiments, at least one R ^Y is -O-(cyclopropyl). In some embodiments, at least one R ^Y is -O-(cyclobutyl). In some embodiments, at least one R ^Y is -O-(bicyclo[3.2.0]hexyl). [067] In some embodiments, at least one R ^Y1 is oxo, halogen, OH, -CN, 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, 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 ^Y1a . [068] In some embodiments, at least one R ^Y1 is oxo. [069] In some embodiments, at least one R ^Y1 is halogen, OH, -CN, 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, wherein the C3-C8 cycloalkyl, 3- to 9-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y1a . [070] In some embodiments, at least one R ^Y1 is halogen, -CN, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a . [071] In some embodiments, at least one R ^Y1 is halogen. In some embodiments, at least one R ^Y1 is F. In some embodiments, at least one R ^Y1 is Cl. In some embodiments, at least one R ^Y1 is Br. In some embodiments, at least one R ^Y1 is I. [072] In some embodiments, at least one R ^Y1 is CN. [073] In some embodiments, at least one R ^Y1 is C ₃ -C ₈ cycloalkyl. In some embodiments, at least one R ^Y1 is C ₃ cycloalkyl. In some embodiments, at least one R ^Y1 is C ₄ cycloalkyl. In some embodiments, at least one R ^Y1 is C ₅ cycloalkyl. In some embodiments, at least one R ^Y1 is C ₆ cycloalkyl. In some embodiments, at least one R ^Y1 is C ₇ cycloalkyl. In some embodiments, at least one R ^Y1 is C ₈ cycloalkyl. [074] In some embodiments, at least one R ^Y1 is C ₃ -C ₈ cycloalkyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is C ₃ cycloalkyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is C ₄ cycloalkyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is C ₅ cycloalkyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is C ₆ cycloalkyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is C ₇ cycloalkyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is C ₈ cycloalkyl optionally substituted with one or more R ^Y1a . [075] In some embodiments, at least one R ^Y1 is cyclopropyl. In some embodiments, at least one R ^Y1 is cyclobutyl. In some embodiments, at least one R ^Y1 is bicyclo[1.1.1]pentyl. In some embodiments, at least one R ^Y1 is bicyclo[3.2.0]hexyl. [076] In some embodiments, at least one R ^Y1 is cyclopropyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is cyclobutyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is bicyclo[1.1.1]pentyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is bicyclo[3.2.0]hexyl optionally substituted with one or more R ^Y1a . [077] In some embodiments, at least one R ^Y1 is 3- to 9-membered heterocycloalkyl optionally substituted with one or more R ^Y1a . [078] In some embodiments, at least one R ^Y1 is 3- to 9-membered heterocycloalkyl. In some embodiments, at least one R ^Y1 is 3-membered heterocycloalkyl. In some embodiments, at least one R ^Y1 is 4-membered heterocycloalkyl. In some embodiments, at least one R ^Y1 is 5-membered heterocycloalkyl. In some embodiments, at least one R ^Y1 is 6-membered heterocycloalkyl. In some embodiments, at least one R ^Y1 is 7-membered heterocycloalkyl. In some embodiments, at least one R ^Y1 is 8-membered heterocycloalkyl. In some embodiments, at least one R ^Y1 is 9-membered heterocycloalkyl. [079] In some embodiments, at least one R ^Y1 is oxetanyl. In some embodiments, at least one R ^Y1 is tetrahydrofuranyl. In some embodiments, at least one R ^Y1 is tetrahydropyranyl. In some embodiments, at least one R ^Y1 is 2-oxabicyclo[2.1.1]hexyl. [080] In some embodiments, at least one R ^Y1 is oxetanyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is tetrahydrofuranyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is tetrahydropyranyl optionally substituted with one or more R ^Y1a . In some embodiments, at least one R ^Y1 is 2-oxabicyclo[2.1.1]hexyl optionally substituted with one or more R ^Y1a . [081] In some embodiments, at least one R ^Y1a is halogen or C ₁ -C ₆ alkyl. [082] In some embodiments, at least one R ^Y1a is halogen. In some embodiments, at least one R ^Y1a is F. In some embodiments, at least one R ^Y1a is Cl. In some embodiments, at least one R ^Y1a is Br. In some embodiments, at least one R ^Y1a is I. [083] In some embodiments, at least one R ^Y1a is C ₁ -C ₆ alkyl. In some embodiments, at least one R ^Y1a is C ₁ alkyl. In some embodiments, at least one R ^Y1a is C ₂ alkyl. In some embodiments, at least one R ^Y1a is C ₃ alkyl. In some embodiments, at least one R ^Y1a is C ₄ alkyl. In some embodiments, at least one R ^Y1a is C5 alkyl. In some embodiments, at least one R ^Y1a is C6 alkyl. [084] In some embodiments, Y is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ - C ₁₀ aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [085] In some embodiments, Y is C6-C10 aryl optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [086] In some embodiments, Y is 5- to 9-membered heteroaryl optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [087] In some embodiments, the compound is of formula (I-a) or (I-b):

(I-b) or a pharmaceutically acceptable salt or stereoisomer thereof. [088] In some embodiments, the compound is of formula (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I- i):

(I-i) or a pharmaceutically acceptable salt or stereoisomer thereof. [089] In some embodiments, the compound is of formula (I-j), (I-k), (I-l), or (I-m):

(I-m) 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. [090] In some embodiments, the compound is selected from a compound described in Table I, or a pharmaceutically acceptable salt or stereoisomer thereof. [091] In some embodiments, the compound is selected from a compound described in Table I, or a pharmaceutically acceptable salt thereof. [092] In some embodiments, the compound is selected from a compound described in Table I. Table I.

[093] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of a compound disclosed herein. [094] In some embodiments, the compound is an isotopic derivative of a compound described in Table I, or a pharmaceutically acceptable salt thereof. [095] In some embodiments, the compound is an isotopic derivative of a compound described in Table I. [096] 0It 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. [097] In some embodiments, the isotopic derivative is a deuterium labeled compound. [098] In some embodiments, the isotopic derivative is a deuterium labeled compound of a compound of the Formulae disclosed herein. [099] In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I, or a pharmaceutically acceptable salt thereof. [0100] In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I. [0101] 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%. [0102] 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. [0103] 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. [0104] 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. [0105] 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. [0106] 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. [0107] 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. [0108] 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.” [0109] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents. [0110] 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). [0111] 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. [0112] 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. [0113] 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. [0114] 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. [0115] 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. [0116] 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. [0117] 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”. [0118] 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. [0119] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions. [0120] 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). [0121] 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. [0122] 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. [0123] 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. [0124] 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. [0125] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. [0126] 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. [0127] 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. [0128] 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. [0129] 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. keto enol enolate [0130] 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. [0131] 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. [0132] 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. [0133] 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. [0134] 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 phosforamidic 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, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 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. [0135] 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 C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0136] 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 C1-C10 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-(C1-C4 alkyl)piperazin-1-ylmethyl. [0137] 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 [0138] In some aspects, the present disclosure provides a method of preparing a compound disclosed herein. [0139] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein. [0140] 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. [0141] In some aspects, the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein. [0142] 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. [0143] 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. [0144] 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. [0145] 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. [0146] 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. [0147] 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. [0148] 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. [0149] 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. [0150] The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art. [0151] 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. [0152] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. [0153] 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. [0154] 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. [0155] 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). [0156] General routes for the preparation of a compound of the application are described in Schemes 1-6. Scheme 1

Scheme 3

Scheme 5

Scheme 6 Biological Assays [0157] 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. [0158] 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. [0159] 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. [0160] In some embodiments, the biological assay is described in the Examples herein. [0161] In some embodiments, the biological assay is an assay measuring cell proliferation. [0162] 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. [0163] 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). [0164] 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 [0165] 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 [0166] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. [0167] 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. [0168] 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. [0169] 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. [0170] 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. [0171] 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. [0172] 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. [0173] 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. [0174] 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. [0175] 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. [0176] 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. [0177] 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. [0178] 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. [0179] 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. [0180] 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. [0181] 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). [0182] 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. [0183] 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 [0184] 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. [0185] 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. [0186] 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. [0187] 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. [0188] 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. [0189] 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. [0190] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a compound described herein. [0191] 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. [0192] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a composition described herein. [0193] 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. [0194] 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. [0195] 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. [0196] 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. [0197] 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. [0198] 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. [0199] 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. [0200] 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. [0201] 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. [0202] 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. [0203] 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. [0204] 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. [0205] 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. [0206] 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. [0207] 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. [0208] 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. [0209] 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. [0210] 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. [0211] 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. [0212] 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. [0213] 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. [0214] 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. [0215] 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). [0216] 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). [0217] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. [0218] In some aspects, the present disclosure provides a compound described herein for use in the treatment of cancer. [0219] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer. [0220] In some aspects, the present disclosure provides a composition described herein for use in the treatment of cancer. [0221] 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. [0222] 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. [0223] 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. [0224] 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. [0225] 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. [0226] 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. [0227] 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. [0228] 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. [0229] 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). [0230] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer. [0231] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for treating cancer. [0232] 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. [0233] 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. [0234] 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. [0235] 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. [0236] 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. [0237] 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. [0238] 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. [0239] 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. [0240] 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). [0241] In some aspects, the present disclosure provides use of a compound described herein for preventing or treating cancer. [0242] In some aspects, the present disclosure provides use of a compound described herein in for treating cancer. [0243] 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. [0244] 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. [0245] 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. [0246] 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. [0247] 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. [0248] 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. [0249] 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. [0250] 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. [0251] [0252] In some embodiments, cancer is a solid tumor. [0253] 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. [0254] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof. [0255] In some embodiments, the cancer is glioblastoma. [0256] In some embodiments, the cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR). [0257] In some embodiments, the oncogenic variant is an oncogenic variant in an ErbB receptor. [0258] In some embodiments, the oncogenic variant in the ErbB receptor is an allosteric variant. [0259] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor. [0260] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR). [0261] In some embodiments, the ErbB receptor is a HER2 receptor. [0262] In some embodiments, the oncogenic variant is an oncogenic variant in an epidermal growth factor receptor (EGFR). [0263] In some embodiments, the oncogenic variant in the EGFR is an allosteric variant. [0264] In some embodiments, the oncogenic variant is an oncogenic variant of a HER2 receptor. [0265] In some embodiments, the oncogenic variant in the HER2 receptor is an allosteric variant. [0266] In some embodiments, the oncogenic variant in the EGFR is an EGFR variant III (EGFR- Viii) variant. [0267] 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. [0268] 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. [0269] 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. [0270] 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. [0271] 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. [0272] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor. [0273] 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. [0274] 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. [0275] 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. [0276] 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. [0277] 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. [0278] 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. [0279] 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. [0280] 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. [0281] 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. [0282] 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. [0283] 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. [0284] 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. [0285] 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). [0286] 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. [0287] 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. [0288] 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. [0289] 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. [0290] 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. [0291] 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. [0292] 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. [0293] 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. [0294] 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. [0295] 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. [0296] 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. [0297] 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. [0298] In some embodiments, the therapeutically effective amount induces a period of remission. [0299] In some embodiments, the compound induces a period of remission. [0300] In some embodiments, the therapeutically effective amount improves a prognosis of the subject. [0301] In some embodiments, the compound improves a prognosis of the subject. [0302] 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. [0303] In some embodiments, the use comprises treating the subject with a Non-Type I inhibitor. [0304] In some embodiments, the composition comprises a Non-Type I inhibitor. [0305] 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 [0306] Exemplary Embodiment No. 1. A compound of Formula (I), a steroisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W ¹ is =CR ^W1 – or =N–; R ^W1 is H, halogen, C ₁ - C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ - C ₆ alkyl); Y is a C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently 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-(C6-C10 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 ; each R ^Y1 independently is halogen, OH, -CN, 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, 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 ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [0307] Exemplary Embodiment No.2. The compound of claim 1, wherein: W ¹ is =CR ^W1 – or ; R ^W1 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); W ² is =CR ^W2 – or =N–; R ^W2 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl); Y is a C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [0308] Exemplary Embodiment No. 3. The compound of any one of the preceding claims, wherein W ¹ is =CR ^W1 –. [0309] Exemplary Embodiment No. 4. The compound of any one of the preceding claims, wherein R ^W1 is halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). [0310] Exemplary Embodiment No. 5. The compound of any one of the preceding claims, wherein W ¹ is =CH– or =N–. [0311] Exemplary Embodiment No. 6. The compound of any one of the preceding claims, wherein W ² is =CR ^W2 –. [0312] Exemplary Embodiment No. 7. The compound of any one of the preceding claims, wherein R ^W2 is halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl). [0313] Exemplary Embodiment No. 8. The compound of any one of the preceding claims, wherein W ² is =CH– or =N–. [0314] Exemplary Embodiment No. 9. The compound of any one of the preceding claims, wherein W ¹ is =CH– and W ² is CH–. [0315] Exemplary Embodiment No. 10. The compound of any one of the preceding claims, wherein W ¹ is =N– and W ² is =CH–. [0316] Exemplary Embodiment No. 11. The compound of any one of the preceding claims, wherein . [0317] Exemplary Embodiment No. 12. The compound of any one of the preceding claims, wherein ² are . [0318] Exemplary Embodiment No. 13. The compound of any one of the preceding claims, wherein Y is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9- membered heteroaryl is substituted with one or more R ^Y . [0319] Exemplary Embodiment No. 14. The compound of any one of the preceding claims, wherein Y is C ₆ -C ₁₀ aryl optionally substituted with one or more R ^Y . [0320] Exemplary Embodiment No. 15. The compound of any one of the preceding claims, wherein Y is 5- to 9-membered heteroaryl optionally substituted with one or more R ^Y . [0321] Exemplary Embodiment No. 16. The compound of any one of the preceding claims, wherein Y is phenyl optionally substituted with one or more R ^Y . [0322] Exemplary Embodiment No. 17. The compound of any one of the preceding claims, wherein Y is phenyl. [0323] Exemplary Embodiment No. 18. The compound of any one of the preceding claims, wherein Y is pyridyl optionally substituted with one or more R ^Y . [0324] Exemplary Embodiment No. 19. The compound of any one of the preceding claims, wherein Y is pyridyl. [0325] Exemplary Embodiment No. 20. The compound of any one of the preceding claims, wherein Y is indazole optionally substituted with one or more R ^Y . [0326] Exemplary Embodiment No. 21. The compound of any one of the preceding claims, wherein Y is indazole. [0327] Exemplary Embodiment No. 22. The compound of any one of the preceding claims, 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, C6-C10 aryl, 5- to 9-membered heteroaryl, -O-(C3-C8 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 . [0328] Exemplary Embodiment No. 23. The compound of any one of the preceding claims, 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, or 5- to 9-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, alkynyl, 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 is optionally substituted with one or more R ^Y1 . [0329] Exemplary Embodiment No. 24. The compound of any one of the preceding claims, wherein 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 . [0330] Exemplary Embodiment No. 25. The compound of any one of the preceding claims, wherein R ^Y is CN, oxo, halogen, OH, [0331] Exemplary Embodiment No. 26. The compound of any one of the preceding claims, wherein R ^Y is C ₁ -C ₆ alkyl optionally substituted with one or more R ^Y1 . [0332] Exemplary Embodiment No. 27. The compound of any one of the preceding claims, wherein R ^Y is -O-(C ₃ -C ₈ cycloalkyl) optionally substituted with one or more R ^Y1 . [0333] Exemplary Embodiment No. 28. The compound of any one of the preceding claims, wherein R ^Y is C ₁ -C ₆ alkoxyl optionally substituted with one or more R ^Y1 . [0334] Exemplary Embodiment No. 29. The compound of any one of the preceding claims, wherein R ^Y is -O-(cyclopropyl), -O-(cyclobutyl), or -O-(bicyclo[3.2.0]hexyl), wherein the -O- (cyclopropyl), -O-(cyclobutyl), or -O-(bicyclo[3.2.0]hexyl) is optionally substituted with one or more R ^Y1 . [0335] Exemplary Embodiment No. 30. The compound of any one of the preceding claims, wherein R ^Y1 is 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, 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 ^Y1a . [0336] Exemplary Embodiment No. 31. The compound of any one of the preceding claims, wherein R ^Y1 is halogen, OH or -CN. [0337] Exemplary Embodiment No. 32. The compound of any one of the preceding claims, wherein R ^Y1 is cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, or bicyclo[3.2.0]hexyl, wherein the cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, or bicyclo[3.2.0]hexyl is optionally substituted with one or more R ^Y1a . [0338] Exemplary Embodiment No. 33. The compound of any one of the preceding claims, wherein R ^Y1 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 2-oxabicyclo[2.1.1]hexyl, wherein the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 2-oxabicyclo[2.1.1]hexyl is optionally substituted with one or more R ^Y1a . [0339] Exemplary Embodiment No. 34. The compound of any one of the preceding claims, wherein R ^Y1a is halogen. [0340] Exemplary Embodiment No. 35. The compound of any one of the preceding claims, wherein R ^Y1a is C ₁ -C ₆ alkyl. [0341] Exemplary Embodiment No. 36. The compound of any one of the preceding claims, wherein Y is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [0342] Exemplary Embodiment No. 37. The compound of any one of the preceding claims, wherein Y is C6-C10 aryl optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [0343] Exemplary Embodiment No. 38. Y is 5- to 9-membered heteroaryl optionally substituted with one or more R ^Y ; each R ^Y independently is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, or -O-(C ₃ -C ₈ cycloalkyl), wherein the C1-C6 alkyl, C1-C6 alkoxyl, or -O-(C3-C8 cycloalkyl) is optionally substituted with one or more R ^Y1 ; each R ^Y1 independently is halogen, -CN, C ₃ -C ₈ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R ^Y1a ; and each R ^Y1a independently is halogen or C ₁ -C ₆ alkyl. [0344] Exemplary Embodiment No.39. The compound of any one of the preceding claims, being of formula (I-a) or (I-b), or a pharmaceutically acceptable salt or stereoisomer thereof. [0345] Exemplary Embodiment No.40. The compound of any one of the preceding claims, being of formula (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), or a pharmaceutically acceptable salt or stereoisomer thereof. [0346] Exemplary Embodiment No.41. The compound of any one of the preceding claims, being of formula (I-j), (I-k), (I-l), or (I-m), 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. [0347] Exemplary Embodiment No.42. The compound of any one of the preceding claims, being selected from the compounds described in Table I and pharmaceutically acceptable salt or stereoisomer thereof. [0348] Exemplary Embodiment No.43. An isotopic derivative of the compound of any one of the preceding claims. [0349] Exemplary Embodiment No. 44. A method of preparing the compound of any one of the preceding claims. [0350] Exemplary Embodiment No.45. A pharmaceutical composition comprising the compound of any one of the preceding [0351] claims and one or more pharmaceutically acceptable carriers or excipients. [0352] Exemplary Embodiment No.46. A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a compound of any one of the preceding claims. [0353] Exemplary Embodiment No. 47. A method of preventing or treating cancer, comprising administering the subject in need thereof a compound of any one of the preceding claims. [0354] Exemplary Embodiment No. 48. The compound of any one of the preceding claims for use in the prevention or treatment of cancer. [0355] Exemplary Embodiment No. 49. The compound of any one of the preceding claims for use in the inhibition of an oncogenic variant of an ErbB receptor. [0356] Exemplary Embodiment No.50. The method or the compound of any one of the preceding claims, wherein the cancer is a solid tumor. [0357] Exemplary Embodiment No.51. The method or the compound of any one of the preceding claims, 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. [0358] Exemplary Embodiment No.52. The method or the compound of any one of the preceding claims, wherein the cancer is glioblastoma (GBM) or any subtype thereof. [0359] Exemplary Embodiment No.53. The method or the compound of any one of the preceding claims, wherein the cancer is glioblastoma. [0360] Exemplary Embodiment No.54. The method or the compound of any one of the preceding claims, wherein the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an ErbB receptor. [0361] Exemplary Embodiment No.55. The method or the compound of any one of the preceding claims, wherein the oncogenic variant of the ErbB receptor comprises an allosteric mutation. [0362] Exemplary Embodiment No.56. The method or the compound of any one of the preceding claims, wherein the oncogenic variant of an ErbB receptor is an allosteric variant of the ErbB receptor. [0363] Exemplary Embodiment No.57. The method or the compound of any one of the preceding claims, wherein the oncogenic variant or the oncogenic mutation is detected by a Food and Drug Administration (FDA)-approved diagnosis. Definitions [0364] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [0365] 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. [0366] 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. [0367] 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. [0368] 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. [0369] 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 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. [0370] 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. [0371] 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., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “ ” 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. [0372] 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. [0373] 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. [0374] 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. [0375] 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). [0376] 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. [0377] 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). [0378] 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, indolizine. [0379] 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). [0380] 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. [0381] 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. [0382] 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. [0383] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-. [0384] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. [0385] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. [0386] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl 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, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0387] 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. [0388] 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. [0389] 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. [0390] 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. [0391] 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. [0392] 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 [0393] 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. [0394] 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. [0395] 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. [0396] 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. [0397] 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. [0398] 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. [0399] 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. [0400] 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. [0401] 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. [0402] [0403] 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. [0404] 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. [0405] 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. [0406] 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. [0407] 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. [0408] 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. [0409] 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. [0410] 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. [0411] 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. [0412] 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. [0413] 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. [0414] 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. [0415] 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. [0416] 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. [0417] 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. [0418] 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. [0419] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. [0420] 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. [0421] 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. [0422] 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. [0423] 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. [0424] 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. [0425] 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. [0426] 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. [0427] 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. [0428] 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. [0429] 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 [0430] 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). [0431] 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). [0432] 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). [0433] 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). [0434] 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). [0435] 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 [0436] For exemplary purposes, 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 DCM Dichloromethane DMSO Dimethylsulfoxide EA ethyl acetate ES / ESI electrospray ionisation HPLC high-performance liquid chromatography IPA Isopropylalcohol LC liquid chromatography MS mass spectrometry NMR nuclear magnetic resonance Py Pyridine RT retention time SFC supercritical fluid chromatography TFA trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography Synthesis of Intermediates and Anilines Preparation of Intermediate-A: tert-Butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (Int-A) [0437] Step 1. Synthesis of 3-Amino-6-chloro-pyridine-2-carboxamide [0438] 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 × 3). The combined organic layers were washed with brine (2 L × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-amino-6-chloro-pyridine-2-carboxamide (21 g, 0.12 mol, 89%) as a pink solid. m/z ES + [M+H] ⁺ 172.1. [0439] Step 2. Synthesis of 6-Chloropyrido[3,2-d]pyrimidin-4-ol [0440] 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 the filter cake was dried in vacuo to give 6-chloropyrido[3,2-d]pyrimidin-4-ol (18 g, 99.1 mmol, 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). [0441] Step 3. Synthesis of tert-Butyl (3S)-3-(4-hydroxypyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate [0442] To a mixture of 6-chloropyrido[3,2-d]pyrimidin-4-ol (13 g, 71.6 mmol) and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (26.8 g, 143 mmol) in dimethylsulfoxide (200 mL) was added potassium tertbutoxide (16.1 g, 143 mmol), the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by formic acid to adjust pH = 7, and then added water (500 mL). The mixture was filtered and the filter cake was dried in vacuo to give tert-butyl (3S)-3-(4- hydroxypyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxyl ate (14.3 g, 43.1 mmol, 60%) as a yellow solid. m/z ES + [M-100+1] ⁺ 233.0. [0443] Step 4. Synthesis of tert-Butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate [0444] To a mixture of tert-butyl (3S)-3-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (14.3 g, 43.0 mmol) in toluene (300 mL) was added diisopropylethyl amine (27.8 g, 215 mmol), and then phosphorus oxychloride (8.58 g, 55.9 mmol) was added. The reaction mixture was stirred at 110 °C for 1 h. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (12 g, 34.3 mmol, 79%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.35 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 5.71 (d, J = 13.6 Hz, 1H), 3.81 - 3.49 (m, 2H), 3.48 - 3.41(m, 1H), 2.52 - 2.20 (m, 2H), 1.39 (d, J = 6.4 Hz, 9H); m/z ES + [M+H] ⁺ 351.1. Preparation of Intermediate-B: tert-Butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6yl]oxypyrrolidine-1-carboxyl ate (Int-B) [0445] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate, Int-A (1 g, 2.85 mmol) in acetonitrile (10 mL) was added 4-amino-2-chloro-3-fluoro- phenol (553 mg, 3.42 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give tert-butyl (3S)-3-[4- (3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2-d]pyrimidin- 6yl]oxypyrrolidine-1-carboxylate (1.4 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.87 (s, 1H), 10.05 (d, J = 10.8 Hz, 1H), 8.59 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.48 - 7.40 (m, 2H), 6.94 (d, J = 9.2 Hz, 1H), 6.04 - 5.99 (m, 1H), 3.79 - 3.70 (m, 3H), 2.34 - 2.21 (m, 1H), 2.16 - 2.05 (m, 1H); m/z ES+ [M+H] ⁺ 476.3. Preparation of Intermediate-C: tert-Butyl (3S)-3-[4-(5-chloro-2-fluoro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (Int-C) [0446] Step 1. Synthesis of 2-Chloro-5-fluoro-4-nitro-phenol [0447] 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, 70% purity) at 0 °C. The mixture was stirred at 25 °C for 0.25 h. 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 (silica gel, 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). [0448] Step 2. Synthesis of 4-Amino-2-chloro-5-fluoro-phenol [0449] To a solution of 2-chloro-5-fluoro-4-nitro-phenol (1 g, 5.22 mmol) in methanol (5 mL) and water (5 mL) was added iron (2.54 g, 45.4 mmol) and ammonium chloride (3.07 g, 57.4 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the reaction 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 4-amino-2-chloro-5- fluoro-phenol (800 mg, 4.97 mmol, 95%) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 6.75 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 12.4 Hz, 1H), 4.68 (s, 2H). [0450] Step 3. Synthesis of tert-Butyl (3S)-3-[4-(5-chloro-2-fluoro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0451] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (100 mg, 285 μmol) in acetonitrile (1 mL) was added 4-amino-2-chloro-5-fluoro- phenol (55.3 mg, 342 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)-3-[4-(5-chloro-2-fluoro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (130 mg, 0.27 mmol, 93%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 10.65 (s, 1H), 8.81 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.03 (d, J = 11.2 Hz, 1H), 6.05 (d, J = 17.6 Hz, 1H), 3.79 - 3.69 (m, 4H), 2.31 - 2.23 (m, 1H), 2.14 (dd, J = 2.8, 4.8 Hz, 1H), 1.40 (br. d, J = 4.8 Hz, 9H); m/z ES+ [M+H] ⁺ 476.1. Preparation of Intermediate-D: 6-Bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine (Int-D) [0452] Step 1. Synthesis of 6-Bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine [0453] To a solution of 6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (2.00 g, 8.20 mmol) in toluene (20 mL) was added phosphorus oxychloride (1.49 g, 9.68 mmol) and diisopropylethyl amine (2.97 g, 22.9 mmol). The reaction was stirred at 110 °C for 2 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 5/1) to give 6-bromo-4-chloro-7-fluoro-pyrido[3,2- d]pyrimidine (1.60 g, 6.13 mmol, 63%) as a yellow solid. m/z ES+ [M+H] ⁺ 260.2. Preparation of Intermediate-E: 2-Chloro-3-fluoro-4-nitrophenol (Int-E) [0454] Step 1. Synthesis of 1-Benzyloxy-2-chloro-3-fluoro-4-nitro-benzene [0455] To a solution of 2-chloro-1,3-difluoro-4-nitro-benzene (10.0 g, 51.6 mmol) in N,N- dimethylformamide (60 mL) was added benzyl alcohol (6.71 g, 62.00 mmol) and potassium carbonate (17.8 g, 129 mmol). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL × 4). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give 1-benzyloxy-2-chloro-3-fluoro-4-nitro-benzene (2.50 g, 8.90 mmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (t, J = 9.2 Hz, 1H), 7.52 - 7.36 (m, 5H), 7.33 (m, 1H), 5.41 (s, 2H). [0456] Step 2. Synthesis of 2-Chloro-3-fluoro-4-nitro-phenol [0457] To a solution of 1-benzyloxy-2-chloro-3-fluoro-4-nitro-benzene (2.30 g, 8.17 mmol) in dichloromethane (5.0 mL) was added boron tribromide (4.09 g, 16.3 mmol, 1.57 mL). The mixture was stirred at 0 °C for 2 h. The mixture was quenched by saturated sodium bicarbonate solution to adjust pH > 7 and then extracted with ethyl acetate (100 mL × 3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give 2- chloro-3-fluoro-4-nitro-phenol (800 mg, 4.19 mmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.36 (s, 1H), 8.05 (t, J = 9.1 Hz, 1H), 6.95 (m, 1H). Preparation of Intermediate F: tert-Butyl (S)-3-((4-((2,3-difluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolid ine-1-carboxylate (Int-F) [0458] Step 1. tert-Butyl (S)-3-((4-((2,3-difluoro-4-hydroxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0459] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (2.00 g, 5.70 mmol) in acetonitrile (20 mL) was added 4-amino-2,3-difluoro-phenol (910 mg, 6.27 mmol). The mixture was stirred at 40 °C for 4 hours. On completion, the reaction mixture was filtered and the filtered cake was washed with acetonitrile (80 mL), dried in vacuo to give tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2-d]pyrim idin-6- yl]oxypyrrolidine-1-carboxylate (3.02 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 459.9. Preparation of Intermediate G: (2-Oxabicyclo[2.1.1]hexan-4-yl)methyl 4- methylbenzenesulfonate (Int-G)

[0460] Step 1. (3,3-Dimethoxycyclobutane-1,1-diyl)dimethanol [0461] 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-d6) δ 4.47 (t, J = 5.4 Hz, 2H), 3.35 (d, J = 5.5 Hz, 4H), 3 (s, 6H), 1.77 (s, 4H). [0462] Step 2. (3,3-Dimethoxycyclobutane-1,1-diyl)bis(methylene) bis(4- methylbenzenesulfonate) [0463] 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. ¹ H NMR (400 MHz, DMSO-d6) 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). [0464] Step 3. (3-Oxocyclobutane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) [0465] 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-d6) 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). [0466] Step 4. (3-Hydroxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylben zenesulfonate) [0467] 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-d6) 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). [0468] Step 5. 2-Oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate [0469] 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). Preparation of Intermediate H: 6-Chloropyrido[3,2-d]pyrimidin-4-ol (Int-H) [0470] Step 1. 3-Amino-6-chloro-pyridine-2-carboxamide [0471] 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. [0472] Step 2. 6-Chloropyrido[3,2-d]pyrimidin-4-ol [0473] 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). Preparation of Intermediate I: 1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexane (Int-I) [0474] 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 (SiO2, 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). Preparation of Intermediate J: tert-Butyl (S)-3-((6-cyano-5-(((dimethylamino)methylene)- amino)-3-fluoropyridin-2-yl)oxy)pyrrolidine-1-carboxylate (Int-J) [0475] Step 1. tert-Butyl (S)-3-((3-fluoro-5-nitropyridin-2-yl)oxy)pyrrolidine-1-carbo xylate. To a mixture of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (5 g, 26.7 mmol) in anhydrous tetrahydrofuran (100 mL) was added sodium hydride (2.14 g, 53.4 mmol, 60 wt%). The mixture was stirred at 25 °C for 1 hour. Then a soultion of 2-chloro-3-fluoro-5-nitro-pyridine (5.19 g, 29.4 mmol) in anhydrous tetrahydrofuran (20 mL) was added and the mixtuer was stirred at 25 °C for 2 hours. On completion, the reaction mixture was poured into ammonium chloride solution (200 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried with anhydrous anhydrous sodium sulfate, filtered and concented in vacuo to give tert-butyl (3S)-3-[(3- fluoro-5-nitro-2-pyridyl)oxy]pyrrolidine-1-carboxylate (4 g, 14.7 mmol, 46%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 3.70 - 3.48 (m, 4H), 2.18 ( s, 2H), 1.40 (s, 9H); m/z ES+ [M+H] ⁺ 272.1. [0476] Step 2. tert-Butyl (S)-3-((5-amino-3-fluoropyridin-2-yl)oxy)pyrrolidine-1-carbo xylate ^. To a mixture of tert-butyl (3S)-3-[(3-fluoro-5-nitro-2-pyridyl)oxy]pyrrolidine-1-carbox ylate (4 g, 12.2 mmol) in methanol (40 mL) and water (7 mL) was added ammonium chloride (3.27 g, 61.1 mmol) and iron powder (3.41 g, 61.1 mmol). The mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered and the filtrate was diluted with water (30 mL), which was then extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[(5- amino-3-fluoro-2-pyridyl)oxy]pyrrolidine-1-carboxylate (4 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 241.9; [0477] Step 3. tert-Butyl (S)-3-((5-amino-6-bromo-3-fluoropyridin-2-yl)oxy)pyrrolidine -1- carboxylate. A mixture of tert-butyl (3S)-3-[(5-amino-3-fluoro-2-pyridyl)oxy]pyrrolidine-1- carboxylate (4 g, 13.5 mmol) in N,N-dimethylformamide (40 mL) was added N-bromosuccinimide (2.39 g, 13.5 mmol) portionwise. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 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=20/1 to 3:1) to give tert-butyl (3S)-3-[(5-amino-6-bromo-3-fluoro-2- pyridyl)oxy]pyrrolidine-1-carboxylate (4 g, 12.5 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3): δ 6.89 (d, J = 10.4 Hz, 1H), 5.47 ( s, 1H), 3.87 - 3.52 (m, 6H), 2.18 (s, 2H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 320.0. [0478] Step 4. tert-Butyl (S)-3-((5-amino-6-cyano-3-fluoropyridin-2-yl)oxy)pyrrolidine -1- carboxylate. A mixture of tert-butyl (3S)-3-[(5-amino-6-bromo-3-fluoro-2- pyridyl)oxy]pyrrolidine-1-carboxylate (4 g, 10.6 mmol) in 1-methylpyrrolidin-2-one (40 mL) was added cuprous cyanide (1.90 g, 21.3 mmol). Then the mixture was stirred at 130 °C for 2 hours under nitrogen. On completion, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried with anhydrous anhydrous sodium sulfate, filtered and concented in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 2/1) to give tert-butyl (3S)-3-[(5-amino-6-cyano-3-fluoro-2-pyridyl)oxy]pyrrolidine- 1-carboxylate (1.3 g, 3.77 mmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.89-6.87 (m, 1H), 5.47 (s, 1H), 4.25 (s, 1H), 3.70 - 3.59 (m, 2H), 2.17 (s, 2H), 1.59 (s, 3H), 1.48 (s, 9H); m/z ES+ [M+Na] ⁺ 345.1. [0479] Step 5. tert-Butyl (S)-3-((6-cyano-5-(((dimethylamino)methylene)amino)-3- fluoropyridin-2-yl)oxy)pyrrolidine-1-carboxylate. To a mixture of tert-butyl (3S)-3-[(5-amino-6- cyano-3-fluoro-2-pyridyl)oxy]pyrrolidine-1-carboxylate (1.2 g, 3.72 mmol) in toluene (12 mL) was added N,N-Dimethylformamide dimethyl acetal (1.33 g, 11.2 mmol). Then the mixture was stirred at 110 °C for 2 hours. On completion, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure to give tert-butyl (3S)-3-[[6-cyano- 5-(dimethylaminomethyleneamino)-3-fluoro-2-pyridyl]oxy]pyrro lidine-1-carboxylate (1.58 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 377.9. Preparation of Intermediate K: tert-Butyl (S)-3-((8-chloropyrimido[5,4-d]pyrimidin-2- yl)oxy)pyrrolidine-1-carboxylate (Int-K) [0480] Step 1. 6-(Methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-ol. To a solution of 6- methylsulfanylpyrimido[5,4-d]pyrimidin-4-ol (2.00 g, 10.3 mmol) in methanol (25 mL) and water (25 mL) was added Oxone (8.23 g, 13.4 mmol). The mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 6-methylsulfonylpyrimido[5,4-d]pyrimidin-4-ol (2.70 g, crude) as an off-white solid. m/z ES+ [M+H] ⁺ 226.9. [0481] Step 2. tert-Butyl (S)-3-((8-hydroxypyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrrolidi ne-1- carboxylate. To a mixture of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (331 mg, 1.77 mmol) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 1.06 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. Then 6- methylsulfonylpyrimido[5,4-d]pyrimidin-4-ol (200 mg, 884 μmol) was added and the mixture was stirred at 0 °C for 1.5 hr. On completion, the reaction mixture was poured into saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (15 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=10/1 to 1/2) to afford tert-butyl (3S)-3-(4-hydroxypyrimido [5,4-d]pyrimidin- 6-yl)oxypyrrolidine-1-carboxylate (133 mg, 386 μmol, 44%) as a yellow solid. m/z ES+ [M+H] ⁺ 334.0. [0482] Step 3. tert-Butyl (S)-3-((8-chloropyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrrolidin e-1- carboxylate. To a mixture of tert-butyl (3S)-3-(4-hydroxypyrimido [5,4-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (133 mg, 399 μmol) in toluene (10 mL) was added diisopropylethylamine (309 mg, 2.39 mmol) and phosphorus oxychloride (122 mg, 798 μmol), then the mixture was stirred at 110 °C for 1 hr. On completion, the reaction mixture was 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 afford compound tert-butyl (3S)-3-(4-chloropyrimido [5,4-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate (74 mg, 207 μmol, 52%) as a yellow solid. m/z ES+ [M+Na] ⁺ 373.8. Preparation of Intermediate L & Intermediate M: tert-Butyl (S)-3-((4-chloro-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxyl ate (Int-L) and tert-butyl (S)-3-((4- ((2,3-difluoro-4-hydroxyphenyl)amino)-7-fluoropyrido[3,2-d]p yrimidin-6-yl)oxy)pyrrolidine-1- carboxylate (Int-M) [0483] Step 1. Methyl (S)-3-amino-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)- 5- fluoropicolinate. To a solution of tert-butyl (3S)-3-[(5-amino-6-bromo-3-fluoro-2- pyridyl)oxy]pyrrolidine-1-carboxylate (6.00 g, 16.0 mmol) and triethylamine (19.4 g, 191 mmol) in methanol (100 mL) was added cyclopenta-2,4-dien-1- yl(diphenyl)phosphane;dichloropalladium;iron(2+) (2.33 g, 3.19 mmol) under nitrogen atmosphere. Then the mixture was stirred at 80 °C for 16 hours under carbon monoxide (50 psi). On completion, the solvent was carefully removed under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 4/1) to give methyl 3-amino-6-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxy-5- fluoro-pyridine-2-carboxylate (4.00 g, 11.1 mmol, 69%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.17 (d, J = 12.0 Hz, 1H), 6.62 (s, 2H), 5.40 (d, J = 2.80 Hz, 1H), 3.79 (s, 3H), 3.67 - 3.51 (m, 1H), 3.46 - 3.35 (m, 2H), 2.28 - 1.98 (m, 2H), 1.41 (s, 9H);m/z ES+ [M+Na] ⁺ 378.0 [0484] Step 2. tert-Butyl (S)-3-((7-fluoro-4-hydroxypyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate. To a mixture of methyl 3-amino-6-[(3S)-1-tert- butoxycarbonylpyrrolidin-3-yl]oxy-5-fluoro-pyridine-2-carbox ylate (4.00 g, 11.3 mmol) in ethanol (40 mL) was added acetic acid methanimidamide (5.86 g, 56.3 mmol. Then the mixture was stirred at 120 °C for 16 hour. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/1 to 1/8) to give tert-butyl (3S)-3-(7-fluoro-4-hydroxy- pyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate (2.80 g, 7.93 mmol, 71%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.64 - 11.07 (m, 1H), 7.25 (d, J = 14.0 Hz, 1H), 6.71 (d, J = 9.5 Hz, 1H), 4.97 (d, J = 10.8 Hz, 1H), 2.89 - 2.60 (m, 3H), 2.59 - 2.53 (m, 1H), 1.28 (s, 2H), 0.49 (d, J = 2.0 Hz, 9H); m/z ES+ [M+Na] ⁺ 373.2 [0485] Step 3. tert-Butyl (S)-3-((4-chloro-7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyr rolidine- 1-carboxylate. To a mixture of tert-butyl (3S)-3-(7-fluoro-4-hydroxy-pyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (2.50 g, 7.14 mmol) and diisopropylethylamine (5.53 g, 42.8 mmol) in toluene (50 mL) was added phosphorus oxychloride (2.19 g, 14.3 mmol) portionwise, the mixture was stirred at 110 °C for 2 hours. On completion, the solvent was carefully removed in vacuo to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=10/1 to 3/1) to give tert-butyl (3S)-3-(4-chloro-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate (1.72 g, 4.46 mmol, 63%) as a pink solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.57 (d, J = 10.0 Hz, 1H), 4.97 (s, 1H), 3.05 - 2.86 (m, 1H), 2.83 - 2.63 (m, 2H), 2.62 - 2.53 (m, 1H), 1.60 - 1.36 (m, 2H), 0.59 (s, 9H); m/z ES+ [M+Na] ⁺ 391.0 [0486] Step 4. tert-Butyl (S)-3-((4-((2,3-difluoro-4-hydroxyphenyl)amino)-7-fluoropyri do[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate. To a mixture of tert-butyl (3S)-3-(4-chloro-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxyl ate (160 mg, 434 μmol) in acetonitrile (1.5 mL) was added 4-amino-2,3-difluoro-phenol (94.4 mg, 651 μmol). Then the mixture was stirred at 40 °C for 3 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (10 mL) at 25 °C for 30 min to give tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (220 mg, crude) as a yellow soild. m/z ES+ [M+H] ⁺ 478.2. Preparation of Intermediate-N: 6-Bromo-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-5- fluoroquinazolin-4-amine (Int-N)

[0487] 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; [0488] 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-fluoro-aniline (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. Preparation of Intermediate-O: 6-Bromo-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-7- fluoropyrido[3,2-d]pyrimidin-4-amine (Int-O) [0489] Step 1. 6-Bromo-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-7-fl uoropyrido[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-fluoro-aniline (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-f luoro- 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. Preparation of Aniline-1: 3-Chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)an iline (A-1) [0490] Step 1. Synthesis of 1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexane [0491] To a solution of (3-methylenecyclobutyl)methanol (500 mg, 5.09 mmol) in methyl tert- butyl ether (10 mL) and water (5 mL) was added iodine (2.60 g, 10.2 mmol) and sodium bicarbonate (850 mg, 10.1 mmol). The reaction was stirred at 20 °C for 12 h. On completion, the reaction mixture was quenched with aqueous sodium thiosulfate (100 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=10/1 to 4/1) to afford 1- (iodomethyl)-2-oxabicyclo[2.1.1]hexane (830 mg, 3.71 mmol, 69%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.83 (s, 2H), 3.47 (s, 2H), 2.85 (t, J = 3.2 Hz, 1H), 1.77 (br. t, J = 4.4 Hz, 2H), 1.54 (dd, J = 1.6, 4.4 Hz, 2H). [0492] Step 2. Synthesis of 1-[(2-Chloro-3-fluoro-4-nitro-phenoxy)methyl]-2- oxabicyclo[2.1.1]hexane [0493] A solution of 2-chloro-3-fluoro-4-nitro-phenol (300 mg, 1.57 mmol), 1-(iodomethyl)-2- oxabicyclo[2.1.1]hexane (400 mg, 1.79 mmol) and potassium carbonate (600 mg, 4.34 mmol) in N,N-dimethylformamide (10.0 mL) was stirred at 80 °C for 12 h. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to afford 1-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]-2- oxabicyclo[2.1.1]hexane (200 mg, 0.70 mmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 - 7.98 (m, 1H), 7.33 - 7.19 (m, 1H), 4.58 - 4.44 (m, 2H), 3.72 (s, 2H), 2.96 (t, J = 3.2 Hz, 1H), 1.88 (t, J = 4.4 Hz, 2H), 1.47 (dd, J = 1.6, 4.4 Hz, 2H). [0494] Step 3. Synthesis of 3-Chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)an iline [0495] To a solution of 1-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]-2- oxabicyclo[2.1.1]hexane (200 mg, 695 μmol) in methanol (1.0 mL) and water (1.0 mL) was added iron powder (320 mg, 5.73 mmol) and ammonium chloride (400 mg, 7.48 mmol). The reaction mixture was stirred at 80 °C for 1 h. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% FA condition) to afford 3-chloro-2- fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)aniline (107 mg, 0.42 mmol, 59%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.78 (dd, J = 1.6, 8.8 Hz, 1H), 6.71 - 6.63 (m, 1H), 4.94 (s, 2H), 4.15 (s, 2H), 3.69 (s, 2H), 2.92 (t, J = 3.2 Hz, 1H), 1.83 (br. t, J = 4.4 Hz, 2H), 1.41 (dd, J = 1.6, 4.4 Hz, 2H); m/z ES+ [M+H] ⁺ 258.1. Preparation of Aniline-2: 3-Chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline (A-2) [0496] Step 1. Synthesis of Tetrahydrofuran-3-ylmethyl methanesulfonate [0497] To a solution of tetrahydrofuran-3-ylmethanol (2.00 g, 19.5 mmol) and triethylamine (3.57 g, 35.2 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (4.04 g, 35.2 mmol) at 0 °C dropwise. The mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was quenched with aq. sodium hydrogen carbonate solution (100 mL) at 0 °C and extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give tetrahydrofuran-3-ylmethyl methanesulfonate (3.80 g, 21.1 mmol, 86%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.23 - 4.08 (m, 2H), 3.78 - 3.69 (m, 2H), 3.66 - 3.59 (m, 1H), 3.47 (dd, J = 5.6, 8.8 Hz, 1H), 3.19 (s, 3H), 2.65 - 2.53 (m, 1H), 2.07 - 1.89 (m, 1H), 1.67 - 1.51 (m, 1H). [0498] Step 2. Synthesis of 3-[(2-Chloro-3-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran [0499] To a solution of tetrahydrofuran-3-ylmethyl methanesulfonate (400 mg, 2.22 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (613 mg, 4.44 mmol) and 2- chloro-3-fluoro-4-nitro-phenol (467 mg, 2.44 mmol). The mixture was stirred at 100 °C for 2 h. On completion, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (30 mL). The organic phase was washed by brine and 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 3-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran (0.10 g, 0.36 mmol, 14%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (t, J = 9.2 Hz, 1H), 7.25 (dd, J = 1.6, 9.6 Hz, 1H), 4.28 - 4.15 (m, 2H), 3.85 - 3.75 (m, 2H), 3.72 - 3.64 (m, 1H), 3.57 (dd, J = 5.6, 8.8 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.10 - 1.99 (m, 1H), 1.77 - 1.66 (m, 1H). [0500] Step 3. Synthesis of 3-Chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline [0501] To a solution of 3-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran (90.0 mg, 326 μmol) in methanol (0.5 mL) and water (0.5 mL) was added iron powder (158 mg, 2.84 mmol) and ammonium chloride (192 mg, 3.59 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the resulting product was dissolved in methanol (0.5 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (silica gel, dichloromethane: methanol = 30:1) to give 3-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline (40 mg, 0.16 mmol, 27%) as a gray oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.80 - 6.74 (m, 1H), 6.72 - 6.65 (m, 1H), 4.96 (s, 2H), 3.78 - 3.75 (m, 2H), 3.65 (q, J = 7.6 Hz, 2H), 3.55 (dd, J = 5.6, 8.4 Hz, 2H), 2.64 - 2.60 (m, 1H), 1.66 (qd, J = 6.8, 12.8 Hz, 2H); m/z ES+ [M+H] ⁺ 246.3. Preparation of Aniline-3: 5-Chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline (A-3) [0502] Step 1. Synthesis of 2-Chloro-5-fluoro-4-nitro-phenol [0503] 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, 70% purity) at 0 °C. The mixture was stirred at 25 °C for 0.25 h. 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 (silica gel, 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). [0504] Step 2. Synthesis of 3-[(2-Chloro-5-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran [0505] 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 μL) in tetrahydrofuran (9.00 mL) was added triphenylphosphine (822 mg, 3.13 mmol) and diisopropyl azodicarboxylate (581 mg, 2.87 mmol) under nitrogen gas. The mixture was stirred at 60 °C for 2 h. On completion, the mixture was concentrated. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=5:1 to 1:1) to give 3-[(2-chloro-5-fluoro-4-nitro- phenoxy)methyl]tetrahydrofuran (1.13 g, 4.11 mmol, 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). [0506] Step 3. Synthesis of 5-Chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline [0507] 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 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. Preparation of Aniline-4: 5-Chloro-2-fluoro-4-(oxetan-3-ylmeth oxy)aniline (A-4) [0508] Step 1. Synthesis of Oxetan-3-ylmethyl methanesulfonate [0509] To a mixture of oxetan-3-ylmethanol (1 g, 11.3 mmol) in dichloromethane (20 mL) was added in triethylamine (2.30 g, 22.7 mmol). Then methanesulfonyl chloride (2.60 g, 22.7 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum : ethyl acetate = 1 : 1) to give oxetan-3-ylmethyl methanesulfonate (1.3 g, 7.83 mmol, 69%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.68 - 4.62 (m, 2H), 4.45 - 4.32 (m, 4H), 3.36 - 3.33 (m, 1H), 3.21 (s, 3H). [0510] Step 2. Synthesis of 3-[(2-Chloro-5-fluoro-4-nitro-phenoxy)methyl]oxetane [0511] To a solution of 2-chloro-5-fluoro-4-nitro-phenol (400 mg, 2.09 mmol) in N,N- dimethylformamide (8 mL) was added potassium carbonate (577 mg, 4.18 mmol). Oxetan-3- ylmethyl methanesulfonate (451 mg, 2.71 mmol) was then added to the mixture. The mixture was stirred at 100 °C for 2 h. On completion, the reaction mixture was quenched by addition water 10 mL and extracted with ethyl acetate (5 mL × 4). The combined organic layers were washed with brine (5 mL × 4), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to afford 3-[(2-chloro- 5-fluoro-4-nitro-phenoxy)methyl]oxetane (200 mg, 0.77 mmol, 34%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 13.2 Hz, 1H), 4.73 (t, J = 6.8 Hz, 2H), 4.49 - 4.42 (m, 4H), 3.52 - 3.42 (m, 1H). [0512] Step 3. Synthesis of 5-Chloro-2-fluoro-4-(oxetan-3-ylmeth oxy)aniline [0513] To a solution of 3-[(2-chloro-5-fluoro-4-nitro-phenoxy)methyl]oxetane (180 mg, 687 μmol) in methanol (1.0 mL) and water (1.0 mL) was added iron powder (334 mg, 5.99 mmol) and ammonium chloride (404 mg, 7.57 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was filtered, concentrated in vacuo, then poured into water (10 mL) and extracted with ethyl acetate (5.0 mL × 3). The organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give 5-chloro-2-fluoro-4-(oxetan-3-ylmeth oxy)aniline (168 mg, 0.73 mmol, 95%) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.03 (d, J = 12.4 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 4.96 (s, 2H), 4.68 (dd, J = 6.4, 8.0 Hz, 2H), 4.45 - 4.39 (m, 2H), 4.13 (d, J = 6.4 Hz, 2H), 3.30 (s, 1H); m/z ES+ [M+H] ⁺ 246.1. Preparation of Aniline-5. 3-Chloro-5-(cyclopropylmethoxy)aniline (A-5) [0514] Step 1. Synthesis of 1-Chloro-3-(cyclopropylmethoxy)-5-nitro-benzene [0515] To a solution of 3-chloro-5-nitro-phenol (200 mg, 1.15 mmol) in acetonitrile (2.0 mL) was added potassium carbonate (478 mg, 3.46 mmol) and bromomethylcyclopropane (622 mg, 4.61 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was concentrated in vacuo to give 1-chloro-3-(cyclopropylmethoxy)-5-nitro-benzene (250 mg, 1.10 mmol, 84%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (t, J = 2.0 Hz, 1H), 7.67 (t, J = 2.0 Hz, 1H), 7.53 (t, J = 2.0 Hz, 1H), 3.98 (d, J = 7.2 Hz, 2H), 1.34 - 1.11 (m, 1H), 0.66 - 0.53 (m, 2H), 0.43 - 0.27 (m, 2H). [0516] Step 2. Synthesis of 3-Chloro-5-(cyclopropylmethoxy)aniline [0517] To a solution of 1-chloro-3-(cyclopropylmethoxy)-5-nitro-benzene (250 mg, 1.10 mmol) in methanol (2.0 mL) and water (2.0 mL) was added iron powder (534 mg, 9.55 mmol) and ammonium chloride (646 mg, 12.1 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the 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 in vacuo to give 3-chloro-5-(cyclopropylmethoxy)aniline (210 mg, 1.07 mmol, 77%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.16 (t, J = 2.0 Hz, 1H), 6.09 - 6.06 (m, 1H), 6.05 - 6.03 (m, 1H), 5.35 (s, 2H), 3.70 (d, J = 7.2 Hz, 2H), 1.22 - 1.10 (m, 1H), 0.57 - 0.51 (m, 2H), 0.31 - 0.25 (m, 2H); m/z ES+ [M+H] ⁺ 198.1. Preparation of Aniline-6: 4-Chloro-3-(cyclopropylmethoxy) aniline (A-6) [0518] Step 1. Synthesis of 1-Chloro-2-(cyclopropylmethoxy)-4-nitro-benzene [0519] 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 h. On completion, the mixture was quenched with water (3.0 mL) and filtered. The filtered cake was collected and triturated with water (30 mL) to afford 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 - 7.69 (m, 1H), 4.07 (d, J = 7.2 Hz, 2H), 1.34 - 1.20 (m, 1H), 0.66 - 0.56 (m, 2H), 0.44 - 0.33 (m, 2H). [0520] Step 2. Synthesis of 4-Chloro-3-(cyclopropylmethoxy) aniline [0521] To a solution of 1-chloro-2-(cyclopropylmethoxy)-4-nitro-benzene (4.00 g, 17.5 mmol) in methanol (120 mL) was added platinum on carbon (2.00 g, 3% loading, 20.2 mmol) in one portion at 25 °C under hydrogen gas. The mixture was stirred at 25 °C under hydrogen gas balloon (15 psi) for 2 h. On completion, the mixture was filtered and concentrated to give 4-chloro-3- (cyclopropylmethoxy) aniline (3.40 g, 17.3 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); m/z ES+ [M+H] ⁺ 198.1. Preparation of [0522] Step 1. Synthesis of 4-(Cyclopropylmethoxy)-1-fluoro-2-nitro-benzene [0523] To a solution of 4-fluoro-3-nitro-phenol (300 mg, 1.91 mmol) in N,N-dimethylformamide (2.0 mL) was added potassium carbonate (791 mg, 5.73 mmol) and bromomethylcyclopropane (1.03 g, 7.64 mmol). The mixture was stirred at 80 °C for 2 h. The 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 4-(cyclopropylmethoxy)-1- fluoro-2-nitro-benzene (300 mg, 1.42 mmol, 74%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.59 (dd, J = 3.2, 6.0 Hz, 1H), 7.51 (dd, J = 9.2, 10.8 Hz, 1H), 7.38 (td, J = 3.6, 9.2 Hz, 1H), 3.90 (d, J = 7.2 Hz, 2H), 1.31 - 1.14 (m, 1H), 0.57 (dd, J = 1.6, 8.0 Hz, 2H), 0.38 - 0.27 (m, 2H). [0524] Step 2. Synthesis of 5-(Cyclopropylmethoxy)-2-fluoro-aniline [0525] To a solution of 4-(cyclopropylmethoxy)-1-fluoro-2-nitro-benzene (300 mg, 1.42 mmol) in ethyl acetate (2.0 mL) was added platinum on carbon (185 mg, 3% loading, 710 μmol) under hydrogen gas balloon (15 psi). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 5-(cyclopropylmethoxy)-2- fluoro-aniline (200 mg, 1.10 mmol, 77%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.82 (dd, J = 8.8, 11.2 Hz, 1H), 6.29 (dd, J = 3.2, 7.6 Hz, 1H), 6.00 (td, J = 3.2, 8.8 Hz, 1H), 5.05 (s, 2H), 3.65 (d, J = 6.8 Hz, 2H), 1.24 - 1.04 (m, 1H), 0.57 - 0.45 (m, 2H), 0.32 - 0.19 (m, 2H); m/z ES+ [M+H] ⁺ 181.0. Preparation of Aniline-8: 4-Chloro-2-fluoro-5-methoxy-aniline (A-8) [0526] Step 1. Synthesis of 4-Chloro-2-fluoro-5-methoxy-aniline [0527] To a solution of 1-chloro-5-fluoro-2-methoxy-4-nitro-benzene (300 mg, 1.46 mmol) in methanol (3.0 mL) and water (3 mL) was added iron powder (325 mg, 5.84 mmol) and ammonium chloride (780 mg, 14.5 mmol). The mixture was stirred at 80 °C for 12 h. On completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4- chloro-2-fluoro-5-methoxy-aniline (210 mg, 1.2 mmol, 74%) as a brown oil. 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); m/z ES+ [M+H] ⁺ 176.1. Preparation of Aniline-9: 6-Amino-4-chloro-pyridin-3-ol (A-9) [0528] Step 1. Synthesis of 5-Bromo-4-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2- amine [0529] To a solution of 5-bromo-4-chloro-pyridin-2-amine (25.0 g, 120 mmol) in N,N- dimethylformamide (200 mL) was added sodium hydride (12.5 g, 313 mmol, 60% purity) portion wise at 0 °C. 1-(Chloromethyl)-4-methoxy-benzene (41.5 g, 265 mmol) was then added slowly. The mixture was stirred at 0 °C for 2 h. On completion, the mixture solution was quenched with water (200 mL) slowly at 0 °C and diluted with ethyl acetate (300 mL). The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 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 (400 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 7.14 (d, J = 8.6 Hz, 4H), 6.87 (d, J = 8.8 Hz, 4H), 6.81 (s, 1H), 4.68 (s, 4H), 3.71 (s, 6H). [0530] Step 2. Synthesis of 6-[Bis[(4-methoxyphenyl)methyl]amino]-4-chloro-pyridin-3-ol [0531] 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 tetrahydrofuran (400 mL) at -70 °C was added n-butyl lithium (2.5 M, 21.7 mL) dropwise. The mixture solution was stirred at -70 °C for 1.5 h. 2-Isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (16.1 g, 86.7 mmol) was then added and the mixture was stirred at -70 °C for 0.75 h. The mixture was then warmed to -10 °C. A hydrogen peroxide solution (19.7 g, 173 mmol, 16.7 mL, aq. 30%) was then added. The mixture was stirred at 15 °C for another 1 h. On completion, the mixture is partitioned between ethyl acetate (200 mL), brine (200 mL) and saturated sodium sulfate solution (100 mL). The layers were separated, and the organic layer was dried over sodium sulfate, then concentrated under vacuum. The residue was purified by reverse- phase flash chromatography (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: 200 mL/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, 41%) as a yellow solid. m/z ES+ [M+H] ⁺ 385.3. [0532] Step 3. Synthesis of 6-Amino-4-chloro-pyridin-3-ol [0533] To a solution of 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-pyridin-3-ol (1.00 g, 2.60 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give 6-amino-4-chloro-pyridin-3-ol (200 mg, 1.39 mmol, 47%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 - 9.20 (m, 1H), 7.62 (s, 1H), 6.48 (s, 1H), 5.46 (s, 1H); m/z ES+ [M+H] ⁺ 145.0. Preparation of Aniline-10: 6-Amino-4-chloro-pyridin-3-ol (A-10) [0534] Step 1. Synthesis of Tetrahydrofuran-2-ylmethyl methanesulfonate [0535] To a solution of tetrahydrofuran-2-ylmethanol (1.00 g, 9.79 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (1.68 g, 14.6 mmol) and triethylamine (2.48 g, 24.4 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and concentrated under vacuum to give tetrahydrofuran-2-ylmethyl methanesulfonate (1.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.23 - 4.02 (m, 3H), 3.81 - 3.60 (m, 2H), 3.17 (s, 3H), 2.02 - 1.71 (m, 3H), 1.67 - 1.48 (m, 1H). [0536] Step 2. Synthesis of 2-[(2-Chloro-3-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran [0537] To a solution of tetrahydrofuran-2-ylmethyl methanesulfonate (200 mg, 1.11 mmol) in N,N-dimethylformamide (3.00 mL) was added potassium carbonate (418 mg, 3.03 mmol) and 2- chloro-3-fluoro-4-nitro-phenol (193 mg, 1.01 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2- [(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran (54 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (t, J = 9.2 Hz, 1H), 7.25 (dd, J = 1.6, 9.6 Hz, 1H), 4.34 - 4.19 (m, 2H), 4.17 - 3.98 (m, 1H), 3.85 - 3.61 (m, 2H), 2.09 - 1.88 (m, 2H), 1.87 - 1.68 (m, 2H). [0538] Step 3. Synthesis of 2-[(2-Chloro-3-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran [0539] To a solution of 2-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]tetrahydrofuran (80.0 mg, 290 μmol) in methanol (1.0 mL) and water (1.0 mL) was added iron powder (64.8 mg, 1.16 mmol) and ammonium chloride (155 mg, 2.90 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was filtered and concentrated to give 3-chloro-2-fluoro-4- (tetrahydrofuran-2-ylmethoxy)aniline (83 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.78 - 6.72 (m, 1H), 6.71 - 6.64 (m, 1H), 5.07 - 4.79 (m, 2H), 4.18 - 4.10 (m, 1H), 3.91 (br. s, 2H), 3.79 - 3.65 (m, 2H), 2.01 - 1.88 (m, 2H), 1.83 - 1.67 (m, 2H); m/z ES+ [M+H] ⁺ 246.2. Preparation of Aniline-11: Preparation of 3-chloro-4-(difluoromethoxy)aniline (A-11) [0540] Step 1. Synthesis of 2-Chloro-1-(difluoromethoxy)-4-nitro-benzene [0541] To a solution of 2-chloro-4-nitro-phenol (4.00 g, 23.0 mmol) in water (20.0 mL) and N,N- dimethylformamide (140.0 mL) was added (2-chloro-2,2-difluoro-acetyl)oxysodium (8.78 g, 57.6 mmol) and cesium carbonate (15.0 g, 46.1 mmol). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (200 mL × 3). 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 column chromatography (silica gel, Petroleum ether/Ethyl acetate=1/0 to 9/1) to give 2-chloro- 1-(difluoromethoxy)-4-nitro-benzene (2.50 g, 11.2 mmol, 43%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J = 2.8 Hz, 1H), 8.30 (dd, J = 2.8, 9.2 Hz, 1H), 7.73 - 7.34 (m, 2H). [0542] Step 2. Synthesis of 3-Chloro-4-(difluoromethoxy) aniline [0543] To a solution of 2-chloro-1-(difluoromethoxy)-4-nitro-benzene (2.5 g, 11.2 mmol) in methanol (30.0 mL) was added platinum on carbon (0.50 g, 3% loading) under hydrogen gas. The reaction was stirred at 20 °C for 2 h under hydrogen gas (15 psi). On completion, the reaction mixture was filtered, and the filtrate was concentrated to give 3-chloro-4-(difluoromethoxy) aniline (2.00 g,10.4 mmol, 90%) as a black oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.14 - 6.74 (m, 2H), 6.68 (d, J = 2.6 Hz, 1H), 6.51 (dd, J = 2.6, 8.8 Hz, 1H), 5.39 (m, 2H); m/z ES+[M+H] ⁺ 194.1. Preparation of Aniline-12: 3-Chloro-4-((tetrahydrofuran-3-yl)methoxy)aniline (A-12) [0544] Step 1. Synthesis of 3-((2-Chloro-4-nitrophenoxy)methyl)tetrahydrofuran [0545] To a solution of 2-chloro-1-fluoro-4-nitro-benzene (400 mg, 2.28 mmol) and tetrahydrofuran-3-ylmethanol (300 mg, 2.94 mmol) in N,N-dimethylformamide (10.0 mL) was added sodium hydride (180 mg, 4.50 mmol, 60% in mineral oil) in portions at 0 °C. The reaction was stirred at 0 °C for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-[(2- chloro-4-nitro-phenoxy)methyl]tetrahydrofuran (500 mg, 1.95 mmol, 80%) as a red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 2.8 Hz, 1H), 8.15 (dd, J = 2.8, 9.2 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 4.13 - 4.03 (m, 2H), 3.98 - 3.90 (m, 2H), 3.86 - 3.75 (m, 2H), 2.87 - 2.79 (m, 1H), 2.24 - 2.13 (m, 1H), 1.85 - 1.75 (m, 1H). [0546] Step 2. Synthesis of 3-Chloro-4-((tetrahydrofuran-3-yl)methoxy)aniline [0547] A solution of 3-[(2-chloro-4-nitro-phenoxy)methyl]tetrahydrofuran (450 mg, 1.75 mmol), platinum on carbon (180 mg, 922 μmol, 3% loading) in methanol (5.00 mL) was stirred at 20 °C for 2 h under hydrogen gas (15 psi). On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 3-chloro-4-(tetrahydrofuran-3-ylmethoxy)aniline (380 mg, crude, 86%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.82 - 6.68 (m, 2H), 6.54 (dd, J = 2.8, 8.4 Hz, 1H), 3.95 - 3.82 (m, 4H), 3.82 - 3.71 (m, 2H), 2.81 - 2.67 (m, 1H), 2.17 - 2.04 (m, 1H), 1.82 - 1.70 (m, 1H); m/z ES+[M+H] ⁺ 228.1. Preparation of Aniline-13: 3-Chloro-4-(oxetan-3-ylmethoxy)aniline (A-13) [0548] Step 1. Synthesis of 3-((2-Chloro-4-nitrophenoxy)methyl)oxetane [0549] To a solution of 2-chloro-1-fluoro-4-nitro-benzene (1.00 g, 5.70 mmol) and oxetan-3- ylmethanol (602 mg, 6.84 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (273 mg, 6.84 mmol, 60% in mineral oil). The mixture was stirred at 0 °C for 4 h. On completion, the reaction mixture was quenched by water (2 mL) at 0 °C 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-[(2-chloro-4-nitro-phenoxy)methyl]oxetane (1.35 g, 5.56 mmol, 96%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J = 2.8 Hz, 1H), 8.25 (dd, J = 2.8, 9.2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 4.73 (dd, J = 6.0, 8.0 Hz, 2H), 4.53 - 4.42 (m, 4H), 3.54 - 3.41 (m, 1H). [0550] Step 2. Synthesis of 3-Chloro-4-(oxetan-3-ylmethoxy)aniline [0551] A mixture of 3-[(2-chloro-4-nitro-phenoxy)methyl]oxetane (500 mg, 2.05 mmol), platinum on carbon (267 mg, 1.03 mmol, 3% loading) in methanol (5 mL) was degassed and purged with hydrogen gas × 3, and the mixture was subsequently stirred at 25 °C for 2 h under a hydrogen gas atmosphere (15 Psi). On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give 3-chloro-4-(oxetan-3-ylmethoxy) aniline (450 mg, crude) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.91 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.54 - 6.45 (m, 1H), 5.42 (br .s, 2H), 4.70 - 4.64 (m, 2H), 4.44 - 4.39 (m, 2H), 4.09 (d, J = 6.8 Hz, 1H), 3.37 - 3.25 (m, 1H); m/z ES+ [M+H] ⁺ 214.0. Preparation of Aniline-14: 5-Chloro-6-(cyclopropylmethoxy)pyridin-3-amine (A-14) [0552] Step 1. Synthesis of 3-Chloro-2-(cyclopropylmethoxy)-5-nitropyridine [0553] To a solution of 2,3-dichloro-5-nitro-pyridine (2 g, 10.4 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (622 mg, 15.5 mmol, 60% in mineral oil) at 0 °C, followed by cyclopropylmethanol (747.02 mg, 10.36 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched with water 50 mL and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=1/0 to 1/1) to give 3-chloro-2-(cyclopropylmethoxy)-5-nitro-pyridine (1.2 g, 5.25 mmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (d, J = 2.4 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 4.36 (d, J = 7.2 Hz, 2H), 1.40 - 1.30 (m, 1H), 0.60 - 0.50 (m, 2H), 0.45 - 0.35 (m, 2H). [0554] Step 2. Synthesis of 5-Chloro-6-(cyclopropylmethoxy)pyridin-3-amine [0555] To a solution of 3-chloro-2-(cyclopropylmethoxy)-5-nitro-pyridine (100 mg, 437.38 μmol) in tetrahydrofuran (1.5 mL) was added platinum on carbon (40 mg, 153 μmol, 3% loading). The mixture was stirred at 25 °C for 2 h under hydrogen gas atmosphere (15 psi). On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 5-chloro-6- (cyclopropylmethoxy)pyridin-3-amine (110 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 199.0. Preparation of Aniline 15: 3-Chloro-4-(difluoromethoxy)-2-fluoroaniline (A-15) [0556] Step 1. 2-Cloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-fluorophenol [0557] 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). [0558] Step 2. 1-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-2,5-dimethyl -1H-pyrrole [0559] 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. [0560] Step 3.3-Chloro-4-(difluoromethoxy)-2-fluoroaniline [0561] 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-fluoro-aniline (1.40 g, 6.64 mmol, 50%) as a red oil. ¹ H NMR (400 MHz, DMSO-d6) 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). Preparation of Aniline -16: 1-(4-Amino-2-chloro-3-fluoro-phenyl)cyclopropanecarbonitrile (A- 16) [0562] Step 1. 1-(4-Bromo-3-chloro-2-fluoro-phenyl)-2,5-dimethyl-pyrrole [0563] 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 compound 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 ppm 7.57 - 7.54 (m, 1H), 7.11 - 7.06 (m, 1H), 5.95 (s, 2H), 2.02 (s, 6H). [0564] Step 1-[2-Chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro- phenyl]cyclopropanecarbonitrile [0565] 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 compound 1-[2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenyl]cycl opropanecarbonitrile (200 mg, 692 μmol, 16%) as a yellow solid. m/z ES+ [M+H] ⁺ 289.1. [0566] Step 3. 1-(4-Amino-2-chloro-3-fluoro-phenyl)cyclopropanecarbonitrile [0567] 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 compound 1-(4-amino-2-chloro-3-fluoro- phenyl)cyclopropanecarbonitrile (50 mg, 214 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 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. Preparation of Aniline-17: 3-Chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline (A-17) [0568] Step 1. 3-Chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)aniline [0569] 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 [0570] Step 2. 3-Chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline [0571] 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. Preparation of Aniline-18: 4-Cyclopropoxy-2,3-difluoroaniline (A-18) [0572] Step 1.4-(2,5-Dimethylpyrrol-1-yl)-2,3-difluoro-phenol [0573] 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 compound 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. [0574] Step 2.1-[4-(Cyclopropoxy)-2,3-difluoro-phenyl]-2,5-dimethyl-pyrr ole [0575] 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 compound 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. [0576] Step 3.4-(Cyclopropoxy)-2,3-difluoro-aniline [0577] 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 compound 4-(cyclopropoxy)-2,3- difluoro-aniline (120 mg, 544 μmol, 72%) as a yellow oil. m/z ES+ [M+H] ⁺ 186.2. [0578] Preparation of Aniline-19: 2,3-Difluoro-4-(1-methylcyclobutoxy)aniline (A-19) [0579] Step 1.2-Chloro-3-fluoro-4-(1-methylcyclobutoxy)-1-nitrobenzene [0580] 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). [0581] Step 2.2,3-Difluoro-1-(1-methylcyclobutoxy)-4-nitrobenzene [0582] 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). [0583] Step 3.2,3-Difluoro-4-(1-methylcyclobutoxy)aniline [0584] 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% loading). 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. Preparation of Aniline-20: 3-Chloro-4-(cyclopropylmethoxy)-2-fluoroaniline (A-20) [0585] Step 1.1-(Benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene [0586] 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). [0587] Step 2.2-Chloro-3-fluoro-4-nitrophenol [0588] 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). [0589] Step 3.2-Chloro-1-(cyclopropylmethoxy)-3-fluoro-4-nitrobenzene [0590] 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 (SiO2, 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. 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). [0591] Step 4.3-Chloro-4-(cyclopropylmethoxy)-2-fluoroaniline [0592] 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. Example 1. Preparation of 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 (Compound 1) [0593] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[(5-fluoro-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0594] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (200 mg, 285 μmol) and 5-fluoropyridin-3-amine (128 mg, 570 μmol) in acetonitrile (1.0 mL) was added cesium carbonate (558 mg, 855 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-TLC (Petroleum ether: Ethyl acetate=0:1) to give tert-butyl (3S)-3-[4-[(5-fluoro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin- 6- yl]oxypyrrolidine-1-carboxylate (30 mg, 70.4 μmol, 25%) as a yellow solid. m/z ES+ [M+H] ⁺ 427.3. [0595] Step 2. Synthesis of N-(5-Fluoro-3-pyridyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3, 2- d]pyrimidin-4-amine [0596] To a solution of tert-butyl (3S)-3-[4-[(5-fluoro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidine-1-carboxylate (30.0 mg, 70.4 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated in vacuo to give N-(5-fluoro-3-pyridyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3, 2- d]pyrimidin-4-amine(50 mg crude) as a yellow oil. m/z ES+ [M+H] ⁺ 327.1. [0597] Step 3. Synthesis of 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 [0598] To a solution of N-(5-fluoro-3-pyridyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3, 2- d]pyrimidin-4-amine (30.0 mg, 91.9 μmol) in tetrahydrofuran (0.3 mL) was added a solution of sodium bicarbonate (38.6 mg, 460 μmol) in water (0.3 mL) dropwise at 0 °C over 5 minutes. A solution of prop-2-enoyl chloride (7.49 mg, 82.7 μmol) in tetrahydrofuran (0.3 mL) was subsequently added dropwise at 0 °C. The mixture was stirred at 0 °C for 5 minutes. On completion, the mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%:17%-47%, 10 min) to give 1-[(3S)-3-[4-[(5-fluoro-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (27.4 mg, 72.1 μmol, 78%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (d, J = 10.0 Hz, 1H), 8.99 (s, 1H), 8.71 (s, 1H), 8.53 - 8.45 (m, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.46 (dd, J = 3.6, 9.2 Hz, 1H), 6.74 - 6.55 (m, 1H), 6.28 - 6.13 (m, 2H), 5.75 - 5.62 (m, 1H), 4.12 - 3.80 (m, 2H), 3.78 - 3.67 (m, 2H), 2.32 - 2.15 (m, 2H); m/z ES+ [M+H] ⁺ 381.2. Example 2. Preparation of 1-[(3S)-3-[4-(4-chloro-2,3-difluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 2) [0599] Step 1. Synthesis of tert-Butyl (3S)-3-[4-(4-chloro-2, 3-difluoro-anilino) pyrido [3, 2-d] pyrimidin-6-yl] oxypyrrolidine-1-carboxylate [0600] To a solution of tert-butyl (3S)-3-(4-chloropyrido [3, 2-d] pyrimidin-6-yl) oxypyrrolidine- 1-carboxylate Int-A (100 mg, 285 μmol) in acetonitrile (4.0 mL) was added 4-chloro-2,3-difluoro- aniline (55.9 mg, 342 μmol). The mixture was stirred at 60 °C for 12 h. On completion, the mixture was filtered, and the filter cake was collected. The crude product was triturated with acetonitrile (20 mL) to afford tert-butyl (3S)-3-[4-(4-chloro-2, 3-difluoro-anilino) pyrido [3, 2-d] pyrimidin- 6-yl] oxypyrrolidine-1-carboxylate (65 mg, 0.14 mmol, 47%) as a yellow solid. m/z ES+ [M+H] ⁺ 478.0. [0601] Step 2. Synthesis of N-(4-Chloro-2, 3-difluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl] oxy- pyrido [3, 2-d] pyrimidin-4-amine [0602] To a solution of tert-butyl (3S)-3-[4-(4-chloro-2, 3-difluoro-anilino) pyrido [3, 2-d] pyrimidin-6-yl] oxypyrrolidine-1-carboxylate (65.0 mg, 136 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.23 g, 10.8 mmol, 0.8 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give N-(4-chloro-2, 3-difluoro-phenyl)-6- [(3S)-pyrrolidin-3-yl] oxy-pyrido [3, 2-d] pyrimidin-4-amine (66.0 mg, 0.18 mmol, 98%, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 378.1. [0603] Step 3. Synthesis of 1-[(3S)-3-[4-(4-Chloro-2,3-difluoro-anilino)pyrido[3,2-d]pyr imidin- 6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0604] To a mixture of N-(4-chloro-2,3-difluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy -pyrido[3,2- d]pyrimidin-4-amine (66.0 mg, 174 μmol) and sodium bicarbonate (73.3 mg, 873 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added prop-2-enoyl chloride (15.8 mg, 174 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the mixture was concentrated, the crude product was purified by Prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%:16%-46%, 11.5 min) to give 1-[(3S)-3-[4-(4-chloro-2,3-difluoro-anilino)pyrido[3,2-d]pyr imidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (17.6 mg, 40.8 mmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.56 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.86 - 7.78 (m, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.45 - 7.39 (m, 1H), 6.71 - 6.53 (m, 1H), 6.20 - 6.12 (m, 1H), 6.07 - 5.97 (m, 1H), 5.72 - 5.64 (m, 1H), 4.10 - 3.78 (m, 1H), 3.89 - 3.77 (m, 1H), 3.77 - 3.55 (m, 2H), 2.34 - 2.31 (m, 2H); m/z ES+ [M+H] ⁺ 432.0. Example 3. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan- 1- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (Compound 3)

[0605] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan- 1-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl] oxypyrrolidine-1-carboxylate [0606] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (90.0 mg, 256 μmol) and 3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)aniline A-1 (66.1 mg, 256 μmol) in acetonitrile (5.00 mL) was stirred at 40 °C for 1 h. On completion, the reaction mixture was concentrated to give tert-butyl (3S)-3-[4-[3-chloro-2- fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)anilino]pyrid o[3,2-d]pyrimidin-6-yl] oxypyrrolidine-1-carboxylate (145 mg, 0.25 mmol, 98%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 - 10.46 (m, 1H), 8.74 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 7.62 - 7.51 (m, 2H), 7.22 (dd, J = 1.2, 9.2 Hz, 1H), 6.15 - 5.95 (m, 1H), 4.43 (s, 2H), 3.52 - 3.36 (m, 6H), 2.97 (t, J = 3.2 Hz, 1H), 2.52 (br. s, 2H), 2.28 (br. d, J = 4.4 Hz, 1H), 2.17 - 2.09 (m, 1H), 1.90 (br. t, J = 4.4 Hz, 2H), 1.48 (dd, J = 1.8, 4.4 Hz, 2H), 1.41 (br. s, 9H). [0607] Step 2. Synthesis of N-[3-Chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]p yrimidin-4-amine [0608] A solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (145 mg, 253 μmol) in trifluoroacetic acid (1.0 mL) and dichloromethane (3.00 mL) was stirred at 20 °C for 1 h. On completion, the reaction mixture was concentrated to give N-[3-chloro-2-fluoro-4-(2- oxabicyclo[2.1.1]hexan-1-ylmethoxy)phenyl]-6-[(3S)-pyrrolidi n-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (120 mg, 0.25 mmol, 95%) as a yellow oil. m/z ES+ [M+H] ⁺ 472.2. [0609] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan- 1- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one [0610] To a solution of N-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy )phenyl]- 6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (120 mg, 254 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (74.7 mg, 0.89 mmol) at 0 °C to adjust the pH = 8. Prop-2-enoyl chloride (23.0 mg, 254 μmol) was subsequently added in one portion. The mixture was stirred at 20 °C for 0.25 h. The reaction mixture was concentrated and the resultant residue was purified by Prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase: [water (0.225%FA)-acetonitrile]; B%: 32%-62%, 10min) to give 1-[(3S)-3- [4-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethox y)anilino]pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (47.6 mg, 90.7 μmol, 35%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.45 (s, 1H), 8.14 - 8.08 (m, 1H), 7.65 (dt, J = 3.6, 8.8 Hz, 1H), 7.38 (dd, J = 4.4, 8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.71 - 6.53 (m, 1H), 6.15 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.11 - 5.98 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.40 (s, 2H), 4.12 - 3.48 (m, 6H), 2.96 (t, J = 3.2 Hz, 1H), 2.34 - 2.10 (m, 2H), 1.94 - 1.86 (m, 2H), 1.48 (dd, J = 1.6, 4.4Hz, 2H); m/z ES+ [M+H] ⁺ 526.5. Example 4. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin -6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 4) [0611] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl] oxypyrrolidine-1-carboxylate [0612] To a solution of 3-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)aniline A-2 (30.0 mg, 122 μmol) in acetonitrile (1 mL) was added tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl) oxypyrrolidine-1-carboxylate Int-A (47.1 mg, 134 μmol). The mixture was stirred at 40 °C for 2 h. On completion, the mixture was concentrated under reduced pressure to give tert-butyl (3S)- 3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)anili no]pyrido[3,2-d]pyrimidin-6-yl] oxypyrrolidine-1-carboxylate (68.9 mg, 0.12 mmol, 95%) as a yellow solid. m/z ES+ [M+H] ⁺ 560.3. [0613] Step 2. Synthesis of N-[3-Chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0614] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy) anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (50 mg, 89.2 μmol) in dichloromethane (0.42 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 15 minutes. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (40 mg, 87.1 μmol, 66.2%) as a yellow oil. m/z ES+ [M+H] ⁺ 460.4. [0615] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin -6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0616] To a solution of N-[3-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, 86.9 μmol) in tetrahydrofuran (0.25 mL) and water (0.25 mL) was added sodium bicarbonate (21.9 mg, 260 μmol) to adjust the pH = 7. Prop-2-enoyl chloride (7.87 mg, 86.9 μmol) was subsequently added. The mixture was stirred at 0 °C for 15 minutes. 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%: 30%-60%, 10min) to give 1-[(3S)-3-[4-[3-chloro-2- fluoro-4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d]p yrimidin -6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (11.3 mg, 22.2 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2Hz, 1H), 7.66 (dt, J = 4.0, 8.8 Hz, 1H), 7.39 (dd, J = 4.4, 9.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.72 - 6.51 (m, 1H), 6.16 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.12 - 5.98 (m, 1H), 5.69 (ddd, J = 2.0, 10.4, 18.4 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.09 - 4.04 (m, 1H), 3.89 - 3.76 (m, 4H), 3.73 - 3.65 (m, 2H), 3.60 (dd, J = 5.6, 8.8 Hz, 1H), 3.56 - 3.48 (m, 1H), 2.77 - 2.69 (m, 1H), 2.31 - 2.24 (m, 1H), 2.23 - 2.12 (m, 1H), 2.11 - 2.01 (m, 1H), 1.73 (dt, J = 6.8, 12.8 Hz, 1H); m/z ES+ [M+H] ⁺ 514.5. Example 5. Preparation of 1-[(3S)-3-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (Compound 5) [0617] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate [0618] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (100 mg, 285 μmol) and 5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)aniline A-3 (140 mg, 570 μmol) in acetonitrile (2.0 mL) was stirred at 40 °C for 2 h. On completion, the mixture was filtered to give tert-butyl (3S)-3-[4-[5-chloro-2-fluoro-4- (tetrahydrofuran-3-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidine-1-carboxylate (136 mg, 0.24 mmol, 83%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.94 - 10.51 (m, 1H), 9.04 - 8.68 (m, 1H), 8.48 - 8.15 (m, 1H), 7.86 - 7.33 (m, 3H), 6.24 - 5.92 (m, 1H), 4.27 - 4.00 (m, 5H), 3.60 - 3.37 (m, 5H), 2.11 - 2.06 (m, 3H), 1.80 - 1.66 (m, 2H), 1.42 (d, J = 6.4 Hz, 9H); m/z ES+ [M+H] ⁺ 560.2. [0619] Step 2. Synthesis of N-[5-Chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0620] To a solution of tert-butyl (3S)-3-[4-[5-chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (116 mg, 207 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated to give N-[5- chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]-6-[(3 S)-pyrrolidin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (95.0 mg, 0.21 mmol, 96%) as a brown oil. m/z ES+ [M+H] ⁺ 459.9. [0621] Step 3. Synthesis of 1-[(3S)-3-[4-[5-Chloro-2-fluoro-4-(tetrahydrofuran-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one [0622] To a solution of N-[5-chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]- 6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (95 mg, 207 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (17.3 mg, 207 μmol, 8.03 μL) at 0 °C to adjust the pH = 8. Prop-2-enoyl chloride (18.7 mg, 207 μmol) was subsequently added in one portion. The mixture was stirred at 0 °C for 0.25 h. On completion, the mixture was concentrated, and the crude product was triturated with dimethylsulfoxide (10 mL) to give 1-[(3S)-3-[4-[5- chloro-2-fluoro-4-(tetrahydrofuran-3-ylmethoxy)anilino]pyrid o[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (97.1 mg, 0.19 mmol, 88%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.48 (s, 1H), 8.11 (dd, J = 0.8, 9.2 Hz, 1H), 7.90 (dd, J = 3.2, 8.0 Hz, 1H), 7.41 - 7.30 (m, 2H), 6.70 - 6.52 (m, 1H), 6.15 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 6.09 - 5.96 (m, 1H), 5.68 (ddd, J = 2.4, 10.2, 18.4 Hz, 1H), 4.11 - 3.77 (m, 6H), 3.72 - 3.50 (m, 4H), 2.77 - 2.68 (m, 1H), 2.31 - 2.12 (m, 2H), 2.10 - 2.00 (m, 1H), 1.71 (J = 6.4, 12.8 Hz, 1H); m/z ES+ [M+H] ⁺ 514.3. Example 6. Preparation of 1-[(3S)-3-[4-[5-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (Compound 6) [0623] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[5-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0624] To a solution of tert-butyl (3S)-3-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-C (80 mg, 168 μmol) in N,N- dimethylformamide (1 mL) was added potassium carbonate (69.7 mg, 504 μmol) and bromomethylcyclopropane (90.8 mg, 672 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the 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 in vacuo to give tert-butyl (3S)-3-[4-[5-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (70 mg, 0.13 mmol, 73%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.46 - 8.35 (m, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.87 - 7.78 (m, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 12.0 Hz, 1H), 5.96 - 5.77 (m, 1H), 3.91 (d, J = 6.8 Hz, 2H), 3.72 - 3.61 (m, 1H), 3.46 - 3.28 (m, 3H), 2.24 - 2.17 (m, 1H), 2.12 - 2.04 (m, 1H), 1.34 (d, J = 6.4 Hz, 9H), 1.22 - 1.16 (m, 1H), 0.59 - 0.49 (m, 2H), 0.35 - 0.25 (m, 2H); m/z ES+ [M+H] ⁺ 530.2. [0625] Step 2. Synthesis of N-[5-Chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0626] To a solution of tert-butyl (3S)-3-[4-[5-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (70 mg, 132 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo to give N-[5-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidin-3-y l]oxy-pyrido[3,2-d]pyrimidin-4- amine (80 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 430.2. [0627] Step 3. Synthesis of 1-[(3S)-3-[4-[5-Chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one [0628] To a solution of N-[5-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (56 mg, 130 μmol) in tetrahydrofuran (0.3 mL) was added a solution of sodium bicarbonate (54.7 mg, 651 μmol) in water (0.3 mL) at 0 °C. Prop-2-enoyl chloride (11.8 mg, 130 μmol) in tetrahydrofuran (0.3 mL) was subsequently added dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 5 minutes. On completion, the residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um;mobile phase: [water(0.225%FA)-acetonitrile];B%: 42%-72%,10min) to give 1-[(3S)-3-[4-[5-chloro-4- (cyclopropylmethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin -6-yl]oxypyrrolidin-1-yl]prop-2- en-1-one (34.6 mg, 71.6 μmol, 55%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.48 (s, 1H), 8.12 (dd, J = 1.2, 9.2 Hz, 1H), 7.88 (dd, J = 3.2, 8.2 Hz, 1H), 7.38 (dd, J = 4.0, 8.8 Hz, 1H), 7.26 (d, J = 12.0 Hz, 1H), 6.70 - 6.52 (m, 1H), 6.15 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.09 - 5.95 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.10 - 3.77 (m, 4H), 3.76 - 3.48 (m, 2H), 2.33 - 2.11 (m, 2H), 1.33 - 1.23 (m, 1H), 0.64 - 0.57 (m, 2H), 0.40 - 0.34 (m, 2H); m/z ES+ [M+H] ⁺ 484.3. Example 7. Preparation of 1-[(3S)-3-[4-[5-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (Compound 7) [0629] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[5-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0630] To a solution of tert-butyl (3S)-3-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-C (150 mg, 315 μmol) and bromocyclobutane (85.1 mg, 630 μmol) in N,N-dimethylformamide (3.0 mL) was added potassium carbonate (130 mg, 945 μmol). The mixture was stirred at 80 °C for 3 h. On completion, the mixture was concentrated under vacuum. The crude product was purified by reverse-phase HPLC (0.1% FA condition) to give tert-butyl (3S)-3-[4-[5-chloro-4-(cyclobutoxy)-2-fluoro-anilino]pyrido[ 3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (112 mg, 0.21 mmol, 67%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.48 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.08 (d, J = 12.0 Hz, 1H), 6.01 - 5.89 (m, 1H), 4.83 (t, J = 7.2 Hz, 1H), 3.77 - 3.69 (m, 1H), 3.51 - 3.41 (m, 4H), 2.30 - 2.23 (m, 1H), 2.17 - 2.08 (m, 3H), 1.89 - 1.87 (m, 1H), 1.70 - 1.62 (m, 1H), 1.40 (d, J = 7.2 Hz, 9H); m/z ES+ [M+H] ⁺ 530.2. [0631] Step 2. Synthesis of N-[5-Chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(3S)-pyrroli din-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0632] To a solution of tert-butyl (3S)-3-[4-[5-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (92.0 mg, 173 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated to give N-[5-chloro-4- (cyclobutoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy-p yrido[3,2-d]pyrimidin-4-amine (70.0 mg, 0.16 mmol, 91%) as a yellow oil. m/z ES+ [M+H] ⁺ 430.1. [0633] Step 3. Synthesis of 1-[(3S)-3-[4-[5-Chloro-4-(cyclobutoxy)-2-fluoro-anilino]pyri do[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0634] To a solution of N-[5-chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(3S)-pyrroli din-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, 163 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (13.7 mg, 163 μmol) at 0 °C to adjust the pH = 8. Prop-2-enoyl chloride (14.7 mg, 163 μmol) was subsequently added in one portion. The mixture was stirred at 0 °C for 0.25 h. On completion, the mixture was concentrated to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase: [water (0.225%FA)-acetonitrile]; B%: 44%-74%, 10 min) to give 1-[(3S)-3-[4-[5- chloro-4-(cyclobutoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimid in-6-yl]oxypyrrolidin-1-yl]prop-2- en-1-one (32.1 mg, 66.5 μmol, 40%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.48 (s, 1H), 8.11 (dd, J = 1.2, 9.2 Hz, 1H), 7.87 (dd, J = 2.8, 8.0 Hz, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 7.09 (d, J = 12.0 Hz, 1H), 6.70 - 6.51 (m, 1H), 6.15 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 6.09 - 5.94 (m, 1H), 5.68 (ddd, J = 2.4, 10.0, 18.3 Hz, 1H), 4.84 (quin, J = 7.2 Hz, 1H), 4.10 - 3.76 (m, 2H), 3.74 - 3.46 (m, 2H), 2.41 - 2.35 (m, 1H), 2.30 - 2.22 (m, 1H), 2.22 - 2.02 (m, 3H), 1.95 - 1.78 (m, 2H), 1.70 - 1.64 (m, 1H); m/z ES+ [M+H] ⁺ 484.3. Example 8. Preparation of 1-[(3S)-3-[4-[5-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilin o] pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-o ne (Compound 8) [0635] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[5-chloro-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin -6-yl]oxypyrrolidine-1-carboxylate [0636] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (150 mg, 427 μmol) in acetonitrile (1.0 mL) was added 5-chloro-2-fluoro-4- (oxetan-3-ylmethoxy)aniline A-4 (99.0 mg, 427 μmol). The mixture was stirred at 40 °C for 4 h. On completion, the reaction mixture was filtered. The precipitate was collected and dried in vacuo to give tert-butyl (3S)-3-[4-[5-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilino]p yrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (130 mg, 0.24 mmol, 54%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.47 (dd, J = 2.0, 4.8 Hz, 1H), 8.76 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 12.0 Hz, 1H), 6.04 (d, J = 16.0 Hz, 1H), 4.74 (dd, J = 6.0, 8.0 Hz, 1H), 4.48 (t, J = 6.0 Hz, 2H), 4.38 (d, J = 6.4 Hz, 1H), 4.34 - 4.33 (m, 1H), 3.84 (dd, J = 2.8, 5.6 Hz, 2H), 3.62 (dd, J = 2.8, 6.0 Hz, 2H), 3.44 (s, 1H), 3.42 (s, 1H), 2.32 - 2.27 (m, 1H), 2.20 - 2.09 (m, 1H), 1.41 (d, J = 4.4 Hz, 9H); m/z ES+ [M+H] ⁺ 546.3. [0637] Step 2. Synthesis of N-[5-Chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido [3,2-d]pyrimidin-4-amine [0638] To a solution of tert-butyl (3S)-3-[4-[5-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)anilino] pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (67.0 mg, 122 μmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (61.6 mg, 540 μmol). The mixture was stirred at 25 °C for 10 minutes. On completion, the reaction mixture was concentrated under reduced pressure to give N-[5-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(3S)-p yrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (25.0 mg, 56.2 μmol, 18%) as a brown oil. m/z ES+ [M+H] ⁺ 446.1. [0639] Step 3. Synthesis of 1-[(3S)-3-[4-[5-Chloro-2-fluoro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one [0640] To a solution of N-[5-chloro-2-fluoro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(3S)-p yrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (25.0 mg, 56.0 μmol) in tetrahydrofuran (0.3 mL) and water (0.3 mL) was added sodium bicarbonate (14.1 mg, 168 μmol) followed by prop-2-enoyl chloride (5.07 mg, 56.0 μmol). The mixture was stirred at 0 °C for 10 minutes. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition: column: Waters xbridge 150 x 25mm, 10um; mobile phase: [water (10mM NH ₄ HCO ₃ )-acetonitrile];B%: 24%-54%, 11 min) to give 1-[(3S)-3-[4-[5-chloro-2- fluoro-4-(oxetan-3-ylmethoxy)anilino] pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2- en-1-one (6.92 mg, 13.9 μmol, 23%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 8.49 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 3.6, 8.0 Hz, 1H), 7.43 - 7.34 (m, 2H), 6.72 - 6.52 (m, 1H), 6.16 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 6.10 - 5.97 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.74 (dd, J = 6.0, 8.0 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 4.36 (d, J = 6.4 Hz, 2H), 4.08 (dd, J = 4.8, 12.0 Hz, 1H), 3.52 - 3.50 (m, 1H), 3.50 - 3.48 (m, 1H), 3.59 - 3.40 (m, 2H), 2.32 - 2.25 (m, 1H), 2.22 - 2.15 (m, 1H); m/z ES+ [M+H] ⁺ 500.3. Example 9. Preparation of 1-[(3S)-3-[4-[5-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrami din-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 9) [0641] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[5-chloro-4-(difluoromethoxy) -2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0642] To a solution of tert-butyl (3S)-3-[4-(5-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-C (250 mg, 525 μmol) in N,N- dimethylformamide (7.0 mL) and water (1.0 mL) was added cesium carbonate (342 mg, 1.05 mmol) followed by (2-chloro-2,2-difluoro-acetyl) oxysodium (200 mg, 1.31 mmol). The mixture was stirred at 100 °C for 5 h. On completion, the mixture was poured into the water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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% FA condition) to give tert-butyl (3S)-3-[4-[5-chloro-4- (difluoromethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (73 mg, 0.14 mmol, 25%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.57 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 10.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 6.04 - 5.87 (m, 1H), 3.88 - 3.63 (m, 2H), 3.47 (d, J = 2.8 Hz, 2H), 2.32 - 2.23 (m, 1H), 2.22 - 2.11 (m, 1H), 1.41 (d, J = 6.4 Hz, 9H); m/z ES+ [M+H] ⁺ 526.1. [0643] Step 2. Synthesis of N-[5-Chloro-4- (difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0644] To a solution of tert-butyl (3S)-3-[4-[5-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido [3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (60 mg, 114 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-[5-chloro-4- (difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidin-3-yl]o xy- pyrido[3,2-d]pyrimidin-4-amine (43 mg, 0.10 mmol, 80%) as a brown oil. m/z ES+ [M+H] ⁺ 426.1. [0645] Step 3. Synthesis of 1-[(3S)-3-[4-[5-Chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrami din-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0646] To a solution of N-[5-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)-pyr rolidin-3- yl] oxy-pyrido[3,2-d]pyrimidin-4-amine (43 mg, 100 μmol) in tetrahydrofuran (0.25 mL) and water (0.25 mL) was added sodium bicarbonate (25.4 mg, 302 μmol). Prop-2-enoyl chloride (16.2 mg, 179 μmol) was subsequently added and the mixture stirred at 0 °C for 10 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 C18150x25mm, 10 um; mobile phase: [water (0.225%FA)-acetonitrile]; B%:40%-70%, 10 min) to give 1-[(3S)-3- [4-[5-chloro-4-(difluoromethoxy)-2-fluoro-anilino]pyrido[3,2 -d]pyrami din-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (19.7 mg, 41.1 μmol, 40%) as a white solid. ¹ H NMR (400 MHz, DMSO- d6) δ 9.57 (s, 1H), 8.57 (d, J = 1.2 Hz, 1H), 8.23 (dd, J = 2.4, 8.0 Hz, 1H), 8.16 (dd, J = 1.2, 9.2 Hz, 1H), 7.64 - 7.53 (m, 1H), 7.42 (dd, J = 4.8, 9.2 Hz, 1H), 7.39 - 7.17 (m, 1H), 6.62 (ddd, J = 10.4, 16.8, 31.6 Hz, 1H), 6.16 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 6.07 - 5.94 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 3.91 - 3.79 (m, 2H), 3.72 (s, 2H), 2.40 (m, 1H), 2.24 - 2.16 (m, 1H); m/z ES+ [M+H] ⁺ 480.4. Example 10. Preparation of 1-[(3S)-3-[4-[3-chloro-2- fluoro-4-[(1-fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one (Compound 10)

[0647] Step 1. Synthesis of (1-Fluorocyclopropyl)methyl methanesulfonate [0648] To a solution of (1-fluorocyclopropyl)methanol (200 mg, 2.22 mmol) in dichloromethane (6 mL) was added triethylamine (449 mg, 4.44 mmol) and methanesulfonyl chloride (381 mg, 3.33 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give (1-fluorocyclopropyl)methyl methanesulfonate (240 mg, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.51 - 4.41 (m, 2H), 3.12 - 3.06 (m, 3H), 1.22 (td, J = 7.2, 18.0 Hz, 2H), 0.86 (q, J = 7.8 Hz, 2H). [0649] Step 2. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]oxypyrrolidine-1-carboxylate [0650] A mixture of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate, Int-B (400 mg, 840 μmol), (1- fluorocyclopropyl)methyl methanesulfonate (141 mg, 840 μmol) and potassium carbonate (232 mg, 1.68 mmol) in N,N-dimethylformamide (3 mL) was stirred at 40 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude residue was purified by prep-HPLC (column: Phenomenex luna C18 150x40mm, 15 um; mobile phase: [water (0.1%trifluoroacetic acid)- acetonitrile]; B%:36%-66%, 11 min) to give tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]oxypyrrolidine-1-carboxylate (50 mg, 91.4 μmol, 10.9%) as a white solid. m/z ES+ [M+H] ⁺ 548.2. [0651] Step 3. Synthesis of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0652] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]oxypyrrolidine-1-carboxylate (48 mg, 87.5 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (40 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 447.9. [0653] Step 4. Synthesis of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]oxypyrrolidin-1-yl]prop-2-en-1- one [0654] To a solution of N-[3-chloro-2-fluoro-4-[(1-fluorocyclopropyl)methoxy]phenyl] -6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (38 mg, 84.8 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (7.13 mg, 84.8 μmol) and prop-2-enoyl chloride (7.68 mg, 84.8 μmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%:41%-71%, 9 min) to give 1-[(3S)-3-[4-[3-chloro-2- fluoro-4-[(1-fluorocyclopropyl)methoxy]anilino]pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (12.93 mg, 25.8 μmol, 30%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 8.45 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.40 - 7.36 (m, 1H), 7.14 (d, J = 9.2 Hz, 1H), 6.71 - 6.52 (m, 1H), 6.21 - 5.99 (m, 2H), 5.74 - 5.61 (m, 1H), 4.49 (d, J = 22.4 Hz, 2H), 4.10 - 3.50 (m, 4H), 2.28 - 1.99 (m, 2H), 1.25 - 1.10 (m, 2H), 0.95 - 0.85 (m, 2H); m/z ES+ [M+H] ⁺ 502.0. Example 11. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl ]oxypyrrolidin-1-yl]prop-2- en-1-one (Compound 11)

[0655] Step 1. Synthesis of (1-Fluorocyclobutyl)methyl methanesulfonate [0656] To a solution of (1-fluorocyclobutyl)methanol (100 mg, 960 μmol) in dichloromethane (5 mL) was added triethylamine (291 mg, 2.88 mmol) and methanesulfonyl chloride (165 mg, 1.44 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched by saturated sodium bicarbonate solution (8 mL) at 0 °C, and then extracted with dichloromethane (8 mL × 3). The combined organic layers were washed with brine (8 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (1- fluorocyclobutyl)methyl methanesulfonate (140 mg, 0.77 mmol, 80%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.51 - 4.25 (m, 2H), 3.81 - 3.64 (m, 2H), 3.07 (s, 3H), 2.39 - 2.14 (m, 9H), 1.96 - 1.79 (m, 3H), 1.59 - 1.35 (m, 3H). [0657] Step 2. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl ]oxypyrrolidine-1-carboxylate [0658] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-B (200 mg, 420 μmol) in N,N- dimethylformamide (3 mL) was added potassium carbonate (174 mg, 1.26 mmol) and (1- fluorocyclobutyl)methyl methanesulfonate (153 mg, 841 μmol). The mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 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-TLC (silica gel, Petroleum ether/Ethyl acetate = 3/1) to give tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl ]oxypyrrolidine-1-carboxylate (40 mg, 71.2 μmol, 17%) as a white solid. m/z ES+ [M+H] ⁺ 562.4. [0659] Step 3. Synthesis of N-[3-Chloro-2-fluoro-4-[(1-fluorocyclobutyl)methoxy]phenyl]- 6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0660] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(1-fluorocyclobutyl)methoxy] anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (40 mg, 71.1 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2- fluoro-4-[(1-fluorocyclobutyl)methoxy]phenyl]-6-[(3S)-pyrrol idin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (40 mg, crude, trifluoroacetic acid salt) as a yellow oil, which was used into the next step without further purification. m/z ES+ [M+H] ⁺ 462.2. [0661] Step 4. Synthesis of 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl ]oxypyrrolidin-1-yl]prop-2-en-1- one [0662] To a solution of N-[3-chloro-2-fluoro-4-[(1-fluorocyclobutyl)methoxy]phenyl]- 6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (30 mg, 52.1 μmol, trifluoroacetic acid) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was added sodium bicarbonate (4.38 mg, 52.0 μmol) and prop-2-enoyl chloride (4.71 mg, 52.1 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875x30mm, 3 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%:40%-70%, 7 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-[(1- fluorocyclobutyl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl ]oxypyrrolidin-1-yl]prop-2-en-1- one (15.97 mg, 30.9 μmol, 59%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.76 - 7.60 (m, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 7.18 (br. d, J = 9.2 Hz, 1H), 6.75 - 6.48 (m, 1H), 6.21 - 6.12 (m, 1H), 6.12 - 5.98 (m, 1H), 5.77 - 5.59 (m, 1H), 4.37 (d, J = 23.2 Hz, 2H), 4.10 - 3.52 (m, 4H), 2.38 - 2.13 (m, 6H), 1.88 - 1.76 (m, 1H), 1.73 - 1.52 (m, 1H); m/z ES+ [M+H] ⁺ 516.1. Example 12. Preparation of (S)-1-(3-((4-((3-chloro-4-((3,3-difluorocyclobutyl)methoxy)- 2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one (Compound 12)

[0663] Step 1. Synthesis of (S)-tert-Butyl 3-((4-((3-chloro-4-((3,3-difluorocyclobutyl) methoxy)- 2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli dine-1-carboxylate [0664] A solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-B (0.2 g, 420 μmol), 3-(bromomethyl)-1,1- difluoro-cyclobutane (81.6 mg, 441 μmol), potassium carbonate (116 mg, 840 μmol) in N,N- dimethylformamide (2 mL) was stirred at 40 °C for 16 h. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-tert-butyl 3-((4-((3-chloro-4-((3,3- difluorocyclobutyl)methoxy)-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (0.2 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 580.2. [0665] Step 2. Synthesis of (S)-N-(3-Chloro-4-((3,3-difluorocyclobutyl)methoxy)-2- fluorophenyl)-6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4 -amine [0666] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2- fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (0.2 g, 344 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated in vacuo to give (S)-N-(3- chloro-4-((3,3-difluorocyclobutyl)methoxy)-2-fluorophenyl)-6 -(pyrrolidin-3-yloxy)pyrido[3,2- d]pyrimidin-4-amine (0.2 g, crude, trifluoroacetic acid salt) as a yellow solid; m/z ES+[M+H] ⁺ 480.0. [0667] Step 3. Synthesis of (S)-1-(3-((4-((3-Chloro-4-((3,3-difluorocyclobutyl)methoxy)- 2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one [0668] To a solution of N-[3-chloro-4-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-phe nyl]-6- [(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (0.2 g, 336 μmol, trifluoroacetic acid) and sodium bicarbonate (84.8 mg, 1.01 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (30.4 mg, 336 μmol). The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was concentrated in vacuo. The crude material was purified by prep- HPLC (column: Waters Xbridge 150x25mm, 5 um; mobile phase:[water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%:46%-76%, 8 min) to give (S)-1-(3-((4-((3-chloro-4-((3,3- difluorocyclobutyl)methoxy)-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin- 1-yl)prop-2-en-1-one (50.0 mg, 93.8 μmol, 27%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.45 (s, 1H), 8.18 - 8.04 (m, 1H), 7.76 - 7.59 (m, 1H), 7.46 - 7.30 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.73 - 6.46 (m, 1H), 6.19 - 5.98 (m, 2H), 5.75 - 5.63 (m, 1H), 4.21 (d, J = 5.6 Hz, 2H), 4.12 - 4.03 (m, 1H), 3.85 - 3.64 (m, 3H), 3.55 - 3.40(m, 1H), 2.81 - 2.56 (m, 5H), 2.43 - 2.22 (m, 2H); m/z ES+[M+H] ⁺ 534.1. Example 13. Preparation of 1-[(3S)-3-[4-(3-chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (Compound 13) [0669] Step 1. Synthesis of Spiro[2.3]hexan-5-ol [0670] To a solution of spiro[2.3]hexan-5-one (450 mg, 4.68 mmol) in methanol (10 mL) was added sodium borohydride (266 mg, 7.02 mmol) portion wise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give spiro[2.3]hexan-5-ol (240 mg, 2.45 mmol, 49%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.01 (d, J = 6.4 Hz, 1H), 4.35 - 4.20 (m, 1H), 2.10 (s, 2H), 2.08 (s, 2H), 0.40 - 0.35 (m, 2H), 0.34 - 0.29 (m, 2H). [0671] Step 2. Synthesis of Spiro[2.3]hexan-5-yl methanesulfonate [0672] To a solution of spiro[2.3]hexan-5-ol (240 mg, 2.45 mmol) in dichloromethane (10 mL) was added triethylamine (618 mg, 6.11 mmol) and methanesulfonyl chloride (630 mg, 5.50 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was poured into the water (50 mL) and extracted with dichloromethane (20 mL × 3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give spiro[2.3]hexan-5-yl methanesulfonate (550 mg, 3.13 mmol, 99%) as a red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.22 - 5.10 (m, 1H), 3.16 (s, 3H), 2.49 - 2.46 (m, 2H), 2.38 - 2.32 (m, 2H), 0.49 - 0.43 (m, 4H). [0673] Step 3. Synthesis of tert-Butyl (3S)-3-[4-(3-chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0674] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-B (200 mg, 420 μmol) and spiro[2.3]hexan-5- yl methanesulfonate (148 mg, 840 μmol) in N,N-dimethylformamide (3.00 mL) was added potassium carbonate (174 mg, 1.26 mmol). The mixture was stirred at 80 °C for 14 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 to give tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (260 mg, 0.47 mmol, 96%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.73 - 7.57 (m, 1H), 7.38 (d, J = 9.2 Hz, 1H), 6.94 (dd, J = 1.6, 9.2 Hz, 1H), 6.05 - 5.85 (m, 1H), 5.08 (q, J = 6.4 Hz, 1H), 3.41 (d, J = 13.2 Hz, 2H), 2.48 - 2.46 (m, 2H), 2.42 - 2.39 (m, 2H), 2.39 - 2.34 (m, 4H), 1.40 (d, J = 6.0 Hz, 9H), 0.57 - 0.52 (m, 2H), 0.49 - 0.47 (m, 2H); m/z ES+ [M+H] ⁺ 556.3. [0675] Step 4. Synthesis of N-(3-Chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy-phenyl)-6-[(3 S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0676] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (240 mg, 431 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated to give N-(3-chloro-2- fluoro-4-spiro[2.3]hexan-5-yloxy-phenyl)-6-[(3S)-pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4- amine (190 mg, 0.42 mmol, 84%) as a brown oil. m/z ES+[M+H] ⁺ 456.2. [0677] Step 5. Synthesis of 1-[(3S)-3-[4-(3-Chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one [0678] To a solution of N-(3-chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy-phenyl)-6-[(3 S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (190 mg, 417 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (35.0 mg, 417 μmol) at 0 °C to adjust pH = 8. After that, prop-2-enoyl chloride (37.7 mg, 417 μmol) was added in one portion. The mixture was stirred at 0 °C for 0.25 h. On completion, the mixture was filtered and concentrated to give crude material. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase: [water(0.225%FA)-acetonitrile]; B%:42%-72%, 10 min) to give 1-[(3S)-3-[4-(3-chloro-2-fluoro-4-spiro[2.3]hexan-5-yloxy-an ilino)pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (43.9 mg, 86.2 μmol, 20%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.62 (dt, J = 3.6, 8.8 Hz, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.72 - 6.51 (m, 1H), 6.15 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.10 - 5.97 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 5.08 (m, 1H), 4.07 (dd, J = 4.8, 11.6 Hz, 0.5H), 3.85 - 3.79 (m, 1H), 3.77 - 3.62 (m, 2H), 3.56 - 3.51 (m, 0.5H), 2.56 - 2.53 (m, 2H), 2.42 - 2.37 (m, 3H), 2.27 (dt, J = 4.4, 8.8 Hz, 1H), 0.57 - 0.52 (m, 2H), 0.51 - 0.45 (m, 2H); m/z ES+ [M+H] ⁺ 510.3. Example 14. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro - 4-[(3-methyloxetan-3- yl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one (Compound 14)

[0679] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3- chloro-2-fluoro -4-[(3 –methyloxetan - 3- yl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate [0680] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido [3,2-d] pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-B (150 mg, 315 μmol) and 3-(bromomethyl)-3- methyl-oxetane (54.6 mg, 330 μmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (87.1 mg, 630 μmol). The mixture was stirred at 40 °C for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(3-methyloxetan-3- yl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate (180 mg, crude) as a brown solid; m/z ES+ [M+H] ⁺ 560.3. [0681] Step 2. Synthesis of N-[3-Chloro-2-fluoro-4-[(3-methyloxetan-3-yl)methoxy]phenyl] -6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0682] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[(3-methyloxetan-3- yl)methoxy] anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (160 mg, 285 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2-fluoro-4-[(3-methyloxetan-3-yl)methoxy]phenyl] -6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (163 mg, 284 μmol, 99.4%, trifluoroacetic acid salt) as a white solid. m/z ES+ [M+H] ⁺ 460.2. [0683] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-[(3-methyloxetan-3- yl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one [0684] To a solution of N-[3-chloro-2-fluoro-4-[(3-methyloxetan-3-yl)methoxy]phenyl] -6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (160 mg, 278 μmol, trifluoroacetic acid) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was added sodium bicarbonate (23.4 mg, 278 μmol) and prop-2-enoyl chloride (34.0 mg, 376 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3 um; mobile phase:[water (0.225%FA)-acetonitrile]; B%:32%-62%, 5 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-[(3- methyloxetan-3-yl)methoxy]anilino]pyrido[3,2-d]pyrimidin-6-y l]oxypyrrolidin-1-yl]prop-2-en- 1-one (36.2 mg, 70.5 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.47 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.73 - 7.61 (m, 1H), 7.44 - 7.35 (m, 1H), 7.18 (br. d, J = 8.8 Hz, 1H), 6.73 - 6.54 (m, 1H), 6.23 - 6.00 (m, 2H), 5.76 - 5.61 (m, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.35 (d, J = 6.0 Hz, 2H), 4.24 (s, 2H), 4.10 - 3.76 (m, 2H), 3.75 - 3.51 (m, 2H), 2.40 - 2.15 (m, 2H), 1.43 (s, 3H); m/z ES+ [M+H] ⁺ 514.1. Example 15. Preparation of 1-[(3S)-3-[4-[3-chloro-5- (cyclopropylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxyp yrrolidin-1-yl]prop-2-en-1- one (Compound 15) [0685] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-5- (cyclopropylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxyp yrrolidine-1-carboxylate [0686] To a solution of 3-chloro-5-(cyclopropylmethoxy)aniline A-5 (67.6 mg, 342 μmol) in acetonitrile (1.0 mL) was added tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate Int-A (100 mg, 285 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was concentrated in vacuo to give tert-butyl (3S)-3-[4-[3-chloro- 5-(cyclopropylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]ox ypyrrolidine-1-carboxylate (160 mg, crude) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (dd, J = 3.2, 4.4 Hz, 1H), 8.59 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.43 - 7.22 (m, 3H), 6.66 (s, 1H), 5.98 - 5.87 (m, 1H), 3.66 (d, J = 7.2 Hz, 2H), 3.57 - 3.47 (m, 4H), 2.07 - 2.02 (m, 1H), 1.96 - 1.87 (m, 1H), 1.17 (d, J = 8.4 Hz, 9H), 1.03 - 0.98 (m, 1H), 0.40 - 0.30 (m, 2H), 0.14 - 0.07 (m, 2H); m/z ES+ [M+H] ⁺ 512.2. [0687] Step 2. Synthesis of N-[3-Chloro-5-(cyclopropylmethoxy)phenyl]-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0688] To a solution of tert-butyl (3S)-3-[4-[3-chloro-5- (cyclopropylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxyp yrrolidine-1-carboxylate (130 mg, 254 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo to give N-[3- chloro-5-(cyclopropylmethoxy)phenyl]-6-[(3S)-pyrrolidin-3-yl ]oxy-pyrido[3,2-d]pyrimidin-4- amine (104 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 412.2. [0689] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-5-(cyclopropylmethoxy)anilino]pyrido[ 3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0690] To a solution of N-[3-chloro-5-(cyclopropylmethoxy)phenyl]-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (104 mg, 253 μmol) in tetrahydrofuran (0.30 mL) was added a solution of sodium bicarbonate (106 mg, 1.26 mmol) in water (0.30 mL) dropwise at 0 °C. Prop-2-enoyl chloride (22.9 mg, 253 μmol) in tetrahydrofuran (0.30 mL) was subsequently added dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 5 minutes. On completion, the residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:47%-77%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-5- (cyclopropylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxyp yrrolidin-1-yl]prop-2-en-1-one (49.5 mg, 0.11 mmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.81 - 7.67 (m, 2H), 7.40 (dd, J = 4.0, 9.2 Hz, 1H), 6.79 (s, 1H), 6.73 - 6.53 (m, 1H), 6.29 - 6.09 (m, 2H), 5.75 - 5.59 (m, 1H), 4.10 - 3.78 (m, 4H), 3.77 - 3.48 (m, 2H), 2.42 - 2.24 (m, 2H), 1.29 - 1.20 (m, 1H), 0.64 - 0.52 (m, 2H), 0.38 - 0.32 (m, 2H); m/z ES+ [M+H] ⁺ 466.3. Example 16. Preparation of 1-[(3S)-3-[4-[4-chloro-3-(cyclopropylmethoxy) anilino] pyrido [3, 2-d] pyrimidin-6-yl] oxypyrrolidin-1-yl] prop-2-en-1-one (Compound 16)

[0691] Step 1. Synthesis of tert-Butyl (S)-3-((4-((4-chloro-3- (cyclopropylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidine-1-carboxylate [0692] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (150 mg, 427 μmol) in acetonitrile (3.0 mL) was added 4-chloro-3- (cyclopropylmethoxy)aniline A-6 (84.5 mg, 427 μmol). The mixture was stirred at 60 °C for 12 h. On completion, the mixture was filtered, and the filter cake was collected. The crude product was triturated with acetonitrile (20 mL) at 25 ^o C for 5 mins to give tert-butyl (S)-3-((4-((4-chloro-3- (cyclopropylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidine-1-carboxylate (200 mg, 390 μmol, 91%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.74 (br. s, 1H), 8.91 - 8.82 (m, 1H), 8.29 (d, J = 12.0 Hz, 1H), 7.70 - 7.48 (m, 3H), 7.43 - 7.36 (m, 1H), 6.26 - 6.12 (m, 1H), 3.76 - 3.71 (m, 1H), 3.54 - 3.48 (m, 1H), 3.48 - 3.39 (m, 2H), 2.34 - 2.12 (m, 2H), 1.52 - 1.17 (m, 10H), 0.65 - 0.58 (m, 2H), 0.41 - 0.34 (m, 2H). [0693] Step 2. Synthesis of N-[4-Chloro-3-(cyclopropylmethoxy)phenyl]-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0694] To a solution of tert-butyl (3S)-3-[4-[4-chloro-3- (cyclopropylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxyp yrrolidine-1-carboxylate (180 mg, 351 μmol) in dichloromethane (4.5 mL) was added trifluoroacetic acid (415 mg, 3.65 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under reduced pressure to give N-[4-chloro-3-(cyclopropylmethoxy)phenyl]-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (180 mg, 0.44 mmol, 97%, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 412.1. [0695] Step 3. Synthesis of 1-[(3S)-3-[4-[4-Chloro-3-(cyclopropylmethoxy) anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl] prop-2-en-1-one [0696] To a mixture of N-[4-chloro-3-(cyclopropylmethoxy)phenyl]-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (180 mg, 342 μmol, trifluoroacetic acid) and sodium bicarbonate (143 mg, 1.71 mmol) in tetrahydrofuran (4.5 mL) and water (4.5 mL) was added prop- 2-enoyl chloride (30.9 mg, 342 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. On completion, the mixture was filtered and concentrated. The crude product was purified by Prep- HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)- acetonitrile]; B%:45%-75%, 11 min) to give 1-[(3S)-3-[4-[4-chloro-3-(cyclopropylmethoxy) anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl] prop-2-en-1-one (64.5 mg, 0.14 mmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 8.84 (s, 1H), 8.21 (d, J = 1.6 Hz 1H), 7.94 - 7.73 (m, 1H), 7.64 - 7.54 (m, 1H), 7.50 - 7.32 (m, 2H), 6.82 - 6.51 (m, 1H), 6.27 - 6.09 (m, 2H), 5.75 - 5.59 (m, 1H), 3.99 (d, J = 6.4 Hz, 2H), 3.90 - 3.47 (m, 4H), 2.46 - 2.34 (m, 1H), 2.30 - 2.19 (m, 1H), 1.39 - 1.25 (m, 1H), 0.66 - 0.58 (m, 2H), 0.43 - 0.37 (m, 2H). Example 17. Preparation of 1-[(3S)-3-[4-[5-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (Compound 17) [0697] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[5-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0698] To a solution of 5-(cyclopropylmethoxy)-2-fluoro-aniline A-7 (150 mg, 827 μmol) in acetonitrile (3.0 mL) was added tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate Int-A (149 mg, 426 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was filtered and the precipitate was collected to give tert-butyl (3S)-3-[4-[5-(cyclopropylmethoxy)-2-fluoro-anilino]pyrido[3, 2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (120 mg, 0.24 mmol, 56%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.58 (s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.75 (dd, J = 3.2, 6.8 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 6.83 (dd, J = 8.8, 11.2 Hz, 2H), 6.30 (dd, J = 2.8, 7.2 Hz, 2H), 6.01 (td, J = 3.2, 8.8 Hz, 2H), 5.92 - 5.80 (m, 1H), 5.06 (s, 4H), 3.83 (d, J = 7.2 Hz, 2H), 3.66 (d, J = 6.8 Hz, 4H), 1.41 (br. d, J = 7.2 Hz, 9H), 1.19 - 1.14 (m, 2H). [0699] Step 2. Synthesis of N-[5-(Cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidi n-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0700] To a solution of tert-butyl (3S)-3-[4-[5-(cyclopropylmethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (90.0 mg, 181 μmol) in dichloromethane (1.0 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 to give N-[5- (cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidin-3-y l]oxy-pyrido[3,2-d]pyrimidin-4- amine (70 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 396.2. [0701] Step 3. Synthesis of 1-[(3S)-3-[4-[5-(Cyclopropylmethoxy)-2-fluoro-anilino]pyrido [3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0702] To a solution of N-[5-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidi n-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, 177 μmol) in tetrahydrofuran (0.50 mL) and water (0.2 mL) was added sodium bicarbonate (44.6 mg, 531 μmol). Prop-2-enoyl chloride (16.0 mg, 177 μmol) was subsequently added at 0 °C, the mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%:32%-62%, 11.5 min) to give 1-[(3S)- 3-[4-[5-(cyclopropylmethoxy)-2-fluoro-anilino]pyrido[3,2-d]p yrimidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (38 mg, 84.6 μmol, 46%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.57 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.74 (dt, J = 3.2, 6.4 Hz, 1H), 7.40 (dd, J = 3.6, 9.2 Hz, 1H), 7.26 (dd, J = 9.2, 10.4 Hz, 1H), 6.78 (td, J = 3.6, 8.8 Hz, 1H), 6.70 - 6.51 (m, 1H), 6.15 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.02 - 5.87 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 19.2 Hz, 1H), 4.06 (dd, J = 4.8, 11.6 Hz, 1H), 3.87 - 3.79 (m, 4H), 3.75 (br. s, 2H), 2.41 - 2.18 (m, 2H), 1.32 - 1.17 (m, 1H), 0.65 - 0.51 (m, 2H), 0.39 - 0.28 (m, 2H); m/z ES+ [M+H] ⁺ 450.4. Example 18. Preparation of 1-[(3S)-3-[4-(3-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 18)

[0703] Step 1. Synthesis of 5-Bromo-1-chloro-2-fluoro-3-nitro-benzene [0704] To a solution of 1-chloro-2-fluoro-3-nitro-benzene (2.00 g, 11.4 mmol) in sulfuric acid (9.0 mL) was added N-bromosuccinimide (2.23 g, 12.5 mmol). The mixture was purged with nitrogen gas (× 3) and then stirred at 70 °C for 3 h under nitrogen gas atmosphere. On completion, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 5-bromo-1-chloro-2-fluoro-3-nitro-benzene (3.00 g, 11.8 mmol, 98%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (dd, J = 2.4, 6.0 Hz, 1H), 8.35 (dd, J = 2.4, 6.0 Hz, 1H). [0705] Step 2. Synthesis of 2-(3-Chloro-4-fluoro-5-nitro-phenyl)-4,4,5,5-tetramethyl-1,3 ,2- dioxaborolane [0706] To a mixture of 5-bromo-1-chloro-2-fluoro-3-nitro-benzene (2.00 g, 7.86 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (2.40 g, 9.43 mmol) and potassium acetate (2.31 g, 23.6 mmol) in 1,4-dioxane (20.0 mL) was added [1,1燵- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (287 mg, 393 μmol). The mixture was purged with nitrogen gas and then stirred at 100 °C for 4 h under nitrogen gas atmosphere. On completion, the mixture was quenched with water (100 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 0:1) to give 2-(3-chloro-4-fluoro-5-nitro-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (3.00 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 - 7.44 (m, 2H), 1.32 (s, 12H). [0707] Step 3. Synthesis of 3-Chloro-4-fluoro-5-nitro-phenol [0708] To a mixture of 2-(3-chloro-4-fluoro-5-nitro-phenyl)-4,4,5,5-tetramethyl-1,3 ,2- dioxaborolane (3.00 g, 9.95 mmol) and acetic acid (896 mg, 14.9 mmol, 0.85 mL) in 1,4-dioxane (30 mL) was added hydrogen peroxide (5.64 g, 49.7 mmol, 4.78 mL, 30% purity) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.2 h and at 20 °C for 3 h. On completion, the reaction mixture was cooled down to 0 °C, and then added saturated sodium bisulfite solution to fully quench the excess hydrogen peroxide. The reaction mixture was adjusted with aq. HCl (4 N) to pH = 5-6 and the aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 3-chloro- 4-fluoro-5-nitro-phenol (400 mg, 2.09 mmol, 19%) as a brown solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.42 (dd, J = 3.2, 5.6 Hz, 1H), 7.35 (dd, J = 3.2, 5.6 Hz, 1H). [0709] Step 4. Synthesis of 1-Chloro-2-fluoro-5-methoxy-3-nitro-benzene [0710] To a solution of 3-chloro-4-fluoro-5-nitro-phenol (490 mg, 2.56 mmol) in acetone (10 mL) was added iodomethane (1.82 g, 12.8 mmol, 0.80 mL) and potassium carbonate (1.77 g, 12.8 mmol). The mixture was stirred at 25 °C for 14 h. On completion, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1-chloro-2-fluoro-5- methoxy-3-nitro-benzene (530 mg, 2.77 mmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.68 (dd, J = 3.2, 5.6 Hz, 1H), 7.64 (dd, J = 3.2, 5.6 Hz, 1H), 3.86 (s, 3H). [0711] Step 5. Synthesis of 3-Chloro-2-fluoro-5-methoxy-aniline [0712] To a solution of 1-chloro-2-fluoro-5-methoxy-3-nitro-benzene (530 mg, 2.58 mmol) in methanol (3.0 mL) and water (3.0 mL) was added iron powder (576 mg, 10.3 mmol) and ammonium chloride (1.38 g, 25.8 mmol). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was filtered, and the filtrate was concentrated to give a residue. The residue was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 3-chloro-2-fluoro-5- methoxy-aniline (440 mg, 2.51 mmol, 85%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.27 (dd, J = 2.8, 7.2 Hz, 1H), 6.20 (dd, J = 3.2, 4.8 Hz, 1H), 5.47 (s, 2H), 3.65 (s, 3H); m/z ES+ [M+H] ⁺ 176.1. [0713] Step 6. Synthesis of tert-Butyl (3S)-3-[4-(3-chloro-2-fluoro-5-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0714] A solution of 3-chloro-2-fluoro-5-methoxy-aniline (100 mg, 569 μmol) and tert-butyl (3S)-3-(4-chloropyrido [3,2-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate Int-A (166 mg, 474 μmol) in acetonitrile (3.0 mL) was stirred at 80 °C for 1 h. On completion, the mixture was concentrated to give tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (250 mg, 0.51 mmol, 84%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 - 9.29 (m, 1H), 8.75 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 7.53 - 7.49 (m, 2H), 7.18 - 7.12 (m, 1H), 6.03 - 5.96 (m, 1H), 3.81 (s, 3H), 3.65 (s, 2H), 3.49 (s, 2H), 2.36 - 2.27 (m, 2H), 1.41 (d, J = 4.4 Hz, 9H); m/z ES+ [M+H] ⁺ 490.3. [0715] Step 7. Synthesis of N-(3-Chloro-2-fluoro-5-methoxy-phenyl)-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0716] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (220 mg, 449 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated to give N-(3-chloro-2-fluoro-5-methoxy-phenyl)-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (175 mg, 0.45 mmol, 87%, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 390.1. [0717] Step 8. Synthesis of 1-[(3S)-3-[4-(3-Chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0718] To a solution of N-(3-chloro-2-fluoro-5-methoxy-phenyl)-6-[(3S)-pyrrolidin-3- yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (175 mg, 448 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (37.7 mg, 448 μmol) at 0 °C to adjust the pH = 8. Prop-2- enoyl chloride (40.6 mg, 448 μmol) was subsequently added dropwise and the mixture was stirred at 0 °C for 0.25 h. On completion, the mixture was concentrated. The residue was purified by prep- TLC (Petroleum ether: Ethyl acetate=0:1) to give 1-[(3S)-3-[4-(3-chloro-2-fluoro-5-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (96.3 mg, 0.25 mmol, 44%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 8.58 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.67 (J = 3.2, 6.4 Hz, 1H), 7.42 (dd, J = 4.4, 9.2 Hz, 1H), 7.05 (dd, J = 3.2, 5.6 Hz, 1H), 6.70 - 6.52 (m, 1H), 6.16 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.07 - 5.91 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 19.6 Hz, 1H), 4.09 - 4.03 (m, 0.5H), 3.84 (d, J = 4.8 Hz, 1H), 3.81 (s, 3H), 3.76 - 3.63 (m, 2H), 3.57 - 3.48 (m, 0.5H), 2.43 - 2.34 (m, 1H), 2.30 - 2.16 (m, 1H); m/z ES+ [M+H] ⁺ 444.3. Example 19. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (Compound 19) [0719] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0720] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-B (120 mg, 252 μmol) in N,N- dimethylformamide (2.0 mL) was added potassium carbonate (105 mg, 756 μmol) and 2,2- difluoroethyl trifluoromethanesulfonate (124 mg, 580 μmol). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was quenched with water (10 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 tert-butyl (3S)-3-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (150 mg, crude) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.76 - 7.66 (m, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.20 (dd, J = 1.2, 9.2 Hz, 1H), 6.50 - 6.39 (m, 1H), 6.03 - 5.91 (m, 1H), 4.58 - 4.34 (m, 4H), 3.82 - 3.68 (m, 1H), 3.65 - 3.52 (m, 1H), 2.31 - 2.25 (m, 1H), 2.13 (dd, J = 3.6, 6.4 Hz, 1H), 1.41 (d, J = 6.0 Hz, 9H); m/z ES+ [M+H] ⁺ 540.1. [0721] Step 2. Synthesis of N-[3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0722] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (150 mg, 278 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.50 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-4-(2,2- difluoroethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy -pyrido[3,2-d]pyrimidin-4-amine (122 mg, crude, trifluoroacetic acid salt) as a red oil. m/z ES+ [M+H] ⁺ 440.1. [0723] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(2,2-difluoroethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one [0724] To a solution of N-[3-chloro-4-(2,2-difluoroethoxy)-2-fluoro-phenyl]-6-[(3S)- pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (122 mg, 277 μmol) in tetrahydrofuran (0.30 mL) was added sodium bicarbonate (69.9 mg, 832 μmol) in water (0.30 mL) at 0 °C over 5 minutes. Prop- 2-enoyl chloride (22.6 mg, 250 μmol) in tetrahydrofuran (0.30 mL) was subsequently added dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 5 minutes. On completion, the residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:30%-60%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-4- (2,2-difluoroethoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin -6-yl]oxypyrrolidin-1-yl]prop-2-en- 1-one (48.8 mg, 98.9 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.70 (dt, J = 3.6, 8.8 Hz, 1H), 7.39 (dd, J = 4.4, 9.2 Hz, 1H), 7.20 (d, J = 9.2 Hz, 1H), 6.71 - 6.31 (m, 2H), 6.21 - 5.97 (m, 2H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.52 (dt, J = 3.6, 14.4 Hz, 2H), 4.11 - 3.76 (m, 2H), 3.73 (s, 2H), 2.31 - 2.24 (m, 1H), 2.22 - 2.09 (m, 1H); m/z ES+ [M+H] ⁺ 494.3. Example 20. Preparation of 1-[(3S)-3-[4-[[4-chloro-5-(cyclopropylmethoxy)-2- pyridyl]amino]quinazolin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1 -one (Compound 20) [0725] Step 1. Synthesis of tert-Butyl (3S)-3-(3-cyano-4-nitro-phenoxy)pyrrolidine-1- carboxylate [0726] To a solution of 5-fluoro-2-nitro-benzonitrile (2.00 g, 12.0 mmol) in tetrahydrofuran (20.0 mL) was added sodium hydride (1.93 g, 48.1 mmol, 60% in mineral oil) portionwise and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2.48 g, 13.2 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was carefully quenched by saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=5:1 to 3:1) to give tert-butyl (3S)-3-(3- cyano-4-nitro-phenoxy)pyrrolidine-1-carboxylate (3.50 g, 10.5 mmol, 87%) as a yellow solid. m/z ES+ [M+H] ⁺ 278.1. [0727] Step 2. Synthesis of tert-Butyl (3S)-3-(4-amino-3-cyano-phenoxy)pyrrolidine-1- carboxylate [0728] To a solution of tert-butyl (3S)-3-(3-cyano-4-nitro-phenoxy)pyrrolidine-1-carboxylate (3.50 g, 10.5 mmol) in methanol (10.0 mL) was added platinum on carbon (822 mg, 3.15 mmol) under hydrogen gas. The mixture was stirred at 25 °C for 2 h under hydrogen gas atmosphere. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)-3-(4-amino-3-cyano- phenoxy)pyrrolidine-1-carboxylate (3.00 g, 9.90 mmol, 90%) as a yellow solid. m/z ES+ [M+Na] ⁺ 326.1. [0729] Step 3. Synthesis of tert-Butyl (3S)-3-(4-amino-3-cyano-phenoxy)pyrrolidine-1- carboxylate [0730] To a solution of tert-butyl (3S)-3-(4-amino-3-cyano-phenoxy)pyrrolidine-1-carboxylate (3.00 g, 9.89 mmol) in toluene (30 mL) was added N,N-dimethylformamide dimethyl acetal (3.54 g, 29.6 mmol). The mixture was stirred at 110 °C for 2 h. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)-3-[3-cyano-4- (dimethylaminomethyleneamino)phenoxy]pyrrolidine-1-carboxyla te (3.00 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 359.3. [0731] Step 4. tert-Butyl (3S)-3-[4-[(4-chloro-5-hydroxy-2-pyridyl)amino]quinazolin-6- yl]oxypyrrolidine-1-carboxylate [0732] To a solution of 6-amino-4-chloro-pyridin-3-ol (200 mg, 1.38 mmol) A-9 in toluene (2 mL) was added acetic acid (2.10 g, 34.97 mmol) and tert-butyl (3S)-3-[3-cyano-4- (dimethylaminomethyleneamino)phenoxy]pyrrolidine-1-carboxyla te (330 mg, 922 μmol). The mixture was stirred at 110 °C for 2 h. On completion, the mixture was concentrated under vacuum. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl (3S)-3- [4-[(4-chloro-5-hydroxy-2-pyridyl)amino]quinazolin-6-yl]oxyp yrrolidine-1-carboxylate (100 mg, 0.22 mmol, 25%) as a yellow oil. m/z ES+ [M+H] ⁺ 458.2. [0733] Step 5. Synthesis of tert-Butyl (3S)-3-[4-[[4-chloro-5-(cyclopropylmethoxy)-2- pyridyl]amino]quinazolin-6-yl]oxypyrrolidine-1-carboxylate [0734] To a solution of tert-butyl (3S)-3-[4-[(4-chloro-5-hydroxy-2-pyridyl)amino]quinazolin-6- yl]oxypyrrolidine-1-carboxylate (90.0 mg, 196 μmol) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (81.4 mg, 589 μmol) and bromomethylcyclopropane (53.0 mg, 393 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)-3-[4-[[4-chloro-5-(cyclopropylmethoxy)-2- pyridyl]amino]quinazolin-6-yl]oxypyrrolidine-1-carboxylate (50 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 512.2. [0735] Step 6. Synthesis of N-[4-Chloro-5-(cyclopropylmethoxy)-2-pyridyl]-6-[(3S)-pyrrol idin- 3-yl]oxy-quinazolin-4-amine [0736] To a solution of tert-butyl (3S)-3-[4-[[4-chloro-5-(cyclopropylmethoxy)-2- pyridyl]amino]quinazolin-6-yl]oxypyrrolidine-1-carboxylate (50.0 mg, 97.7 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 h. On completion, the mixture was filtered and concentrated in vacuo to give N-[4-chloro-5-(cyclopropylmethoxy)-2-pyridyl]-6-[(3S)-pyrrol idin-3-yl]oxy-quinazolin-4- amine (40.0 mg, 97.3 μmol, 99%) as a yellow solid. m/z ES+ [M+H] ⁺ 412.0. [0737] Step 7. Synthesis of 1-[(3S)-3-[4-[[4-Chloro-5-(cyclopropylmethoxy)-2- pyridyl]amino]quinazolin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1 -one [0738] To a solution of N-[4-chloro-5-(cyclopropylmethoxy)-2-pyridyl]-6-[(3S)-pyrrol idin-3- yl]oxy-quinazolin-4-amine (40.0 mg, 97.1 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (24.4 mg, 291 μmol) and prop-2-enoyl chloride (8.79 mg, 97.1 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. On completion, the residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase:[water (0.225% FA)- acetonitrile]; B%:50%-80%, 11.5 min) to give 1-[(3S)-3-[4-[[4-chloro-5-(cyclopropylmethoxy)-2- pyridyl]amino]quinazolin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1 -one (7.59 mg, 16.3 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 (d, J = 13.6 Hz, 1H), 8.64 - 8.55 (m, 2H), 8.27 (s, 1H), 8.13 (dd, J = 2.4, 8.8 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.50 (ddd, J = 2.4, 4.8, 9.2 Hz, 1H), 6.71 - 6.53 (m, 1H), 6.16 (ddd, J = 2.4, 6.4, 16.4 Hz, 1H), 5.68 (ddd, J = 2.4, 10.4, 19.6 Hz, 1H), 5.42 - 5.28 (m, 1H), 4.05 (d, J = 7.0 Hz, 2H), 3.86 - 3.74 (m, 2H), 3.74 - 3.63 (m, 2H), 2.29 - 2.13 (m, 2H), 1.32 - 1.22 (m, 1H), 0.65 - 0.56 (m, 2H), 0.41 - 0.35 (m, 2H); m/z ES+ [M+H] ⁺ 466.3. Example 21. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(2,2-difluoroethoxy)anilino]pyrido[ 3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 21) [0739] Step 1. Synthesis of tert-Butyl (3S)-3-[4-(3-chloro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0740] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (100 mg, 285 μmol) in acetonitrile (2.0 mL) was added 4-amino-2-chloro- phenol (45.0 mg, 313 μmol). The mixture was stirred at 60 °C for 2 h. The mixture was filtered and the precipitate was collected to give tert-butyl (3S)-3-[4-(3-chloro-4-hydroxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (120 mg, 0.26 mmol, 88%) as a yellow solid. m/z ES+ [M+H] ⁺ 458.1. [0741] Step 2. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-(2,2- difluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrol idine-1-carboxylate [0742] To a solution of tert-butyl (3S)-3-[4-(3-chloro-4-hydroxy-anilino)pyrido[3,2-d]pyrimidin - 6-yl]oxypyrrolidine-1-carboxylate (120 mg, 218 μmol) in N,N-dimethylformamide (2.0 mL) was added potassium carbonate (181 mg, 655 μmol) and 2,2-difluoroethyl trifluoromethanesulfonate (233 mg, 1.09 mmol). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[4-[3-chloro-4-(2,2- difluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrol idine-1-carboxylate (100 mg, 0.19 mmol, 85%) as a yellow solid. m/z ES+ [M+H] ⁺ 522.2. [0743] Step 3. Synthesis of N-[3-Chloro-4-(2,2-difluoroethoxy)phenyl]-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0744] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(2,2-difluoroethoxy)anilino]pyrido[3,2 - d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, 229 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 h. On completion, the mixture was filtered and concentrated to give N-[3-chloro-4-(2,2- difluoroethoxy)phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3, 2-d]pyrimidin-4-amine (90.0 mg, 0.21 mmol, 92%, trifluoroacetic acid salt) as a yellow solid. m/z ES+ 422.1. [0745] Step 4. Synthesis of 1-[(3S)-3-[4-[3-chloro-4-(2,2-difluoroethoxy)anilino]pyrido[ 3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0746] To a solution of N-[3-chloro-4-(2,2-difluoroethoxy)phenyl]-6-[(3S)-pyrrolidin -3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (90.0 mg, 213 μmol) in tetrahydrofuran (1.0 mL) was added sodium bicarbonate (53.7 mg, 640 μmol) and prop-2-enoyl chloride (19.3 mg, 213 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. 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-[(3S)-3-[4-[3-chloro-4-(2,2- difluoroethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrol idin-1-yl]prop-2-en-1-one (25 mg, 52.6 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (br. d, J = 3.2 Hz, 1H), 8.57 (s, 1H), 8.16 - 8.06 (m, 2H), 7.88 (dd, J = 2.4, 8.8 Hz, 1H), 7.41 - 7.28 (m, 2H), 6.73 - 6.40 (m, 2H), 6.32 - 6.11 (m, 2H), 5.67 (ddd, J = 2.4, 10.4, 24.0 Hz, 1H), 4.43 (dt, J = 3.6, 14.4 Hz, 2H), 4.07 (dd, J = 4.4, 12.0 Hz, 1H), 3.88 - 3.64 (m, 3H), 3.58 - 3.51 (m, 1H), 2.40 - 2.15 (m, 2H); m/z ES+ [M+H] ⁺ 476.2. Example 22. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (Compound 22)

[0747] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate [0748] To a solution of 3-chloro-2-fluoro-4-(tetrahydrofuran-2-ylmethoxy)aniline A-10 (50.0 mg, 203 μmol) in acetonitrile (1.0 mL) was added tert-butyl (3S)-3-(4-chloropyrido[3,2- d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate Int-A (71.3 mg, 203 μmol). The mixture was stirred at 65 °C for 2 h. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-2-ylmethoxy) anilino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (50.0 mg, 89.4 μmol, 43%) as a yellow solid. m/z ES+ [M+H] ⁺ 560.2. [0749] Step 2. Synthesis of N-[3-Chloro-2-fluoro-4-(tetrahydrofuran-2-ylmethoxy)phenyl]- 6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0750] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydrofuran-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (50.0 mg, 89.2 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 h. On completion, the residue was concentrated to give N-[3- chloro-2-fluoro-4-(tetrahydrofuran-2-ylmethoxy)phenyl]-6-[(3 S)-pyrrolidin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (40 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 460.1. [0751] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-(tetrahydrofuran-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one [0752] To a solution of N-[3-chloro-2-fluoro-4-(tetrahydrofuran-2-ylmethoxy)phenyl]- 6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, 86.9 μmol) in tetrahydrofuran (1.0 mL) was added sodium bicarbonate (44.1 mg, 525 μmol) and prop-2-enoyl chloride (9.25 mg, 87.5 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:32%-62%, 11.5 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4- (tetrahydrofuran-2-ylmethoxy)anilino]pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidin-1-yl]prop-2- en-1-one (10.0 mg, 19.5 μmol, 16%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.64 (dt, J = 3.6, 8.8 Hz, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.72 - 6.52 (m, 1H), 6.21 - 5.97 (m, 2H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.28 - 4.16 (m, 1H), 4.15 - 4.05 (m, 2H), 3.87 - 3.75 (m, 3H), 3.74 - 3.49 (m, 3H), 2.31 - 2.12 (m, 2H), 2.07 - 1.91 (m, 2H), 1.90 - 1.73 (m, 2H); m/z ES+ [M+H] ⁺ 514.3. Example 23. Preparation of 1-[(3S)-3-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2 - fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-y l]prop-2-en-1-one (Compound 23) [0753] Step 1. Synthesis of 1-Bicyclo[1.1.1]pentanylmethanol [0754] To a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (500 mg, 4.46 mmol) in tetrahydrofuran (3.0 mL) was added lithium aluminum hydride (220 mg, 5.80 mmol) at 0 °C, then the mixture was stirred at 25 °C for 12 h. On completion, the mixture was carefully quenched by aq. sodium hydroxide solution to adjust the pH = 10. The mixture was subsequently extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-bicyclo[1.1.1]pentanylmethanol (300 mg, 3.06 mmol, 61%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.47 (s, 2H), 2.48 (s, 1H), 1.67 (s, 6H). [0755] Step 2. Synthesis of 1-Bicyclo[1.1.1]pentanylmethyl methanesulfonate [0756] To a solution of 1-bicyclo[1.1.1]pentanylmethanol (250 mg, 2.55 mmol) in tetrahydrofuran (4.0 mL) was added methanesulfonyl chloride (437 mg, 3.82 mmol) and triethylamine (644 mg, 6.37 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 2 h. On completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-bicyclo[1.1.1]pentanylmethyl methanesulfonate (300 mg, 1.70 mmol, 66%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.07 (s, 2H), 2.93 (s, 3H), 2.50 (s, 1H), 1.77 (s, 6H). [0757] Step 3. Synthesis of (3S)-3-[4-[4-(1-Bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fl uoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0758] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-B (300 mg, 630 μmol) and 1- bicyclo[1.1.1]pentanylmethyl methanesulfonate (155 mg, 882 μmol) in N,N-dimethylformamide (2.0 mL) was added potassium carbonate (174 mg, 1.26 mmol). The mixture was stirred at 100 °C for 12 h. On completion, the reaction mixture was filtered. The filtrate was then 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 tert-butyl (3S)-3-[4-[4-(1- bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fluoro-anilino]pyr ido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (345 mg, 0.62 mmol, 76%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.76 - 7.60 (m, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.09 (dd, J = 1.2, 9.2 Hz, 1H), 6.15 - 5.76 (m, 1H), 4.14 (s, 2H), 3.81 - 3.38 (m, 4H), 2.58 - 2.53 (m, 2H), 2.27 (br dd, J = 3.6, 8.0 Hz, 1H), 2.27 (m, 1H), 2.19 - 2.11 (m, 1H), 1.84 (s, 5H), 1.41 (d, J = 5.6 Hz, 9H); m/z ES+ [M+H] ⁺ 556.0. [0759] Step 4. Synthesis of (3S)-3-[4-[4-(1-Bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fl uoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0760] To a solution of tert-butyl (3S)-3-[4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3–chloro-2- fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (170 mg, 305 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was filtered, concentrated in vacuo to give N-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fluoro-phe nyl]-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (140 mg, 0.31 mmol, 80%, trifluoroacetic acid salt) as a white solid. m/z ES+ [M+H] ⁺ 456.0. [0761] Step 5. Synthesis of 1-[(3S)-3-[4-[4-(1-Bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2 - fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-y l]prop-2-en-1-one [0762] To a solution of N-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-hloro-2-fluoro-phen yl]-6- [(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (140 mg, 307 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (25.8 mg, 307 μmol) to adjust the pH = 7. Prop-2-enoyl chloride (22.2 mg, 245 μmol) was subsequently added, and the mixture was stirred at 0 °C for 10 mins. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150x25mm, 10 um; mobile phase:[water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%:50%-80%, 10 min) to give 1-[(3S)-3- [4-[4-(1-bicyclo[1.1.1]pentanylmethoxy)-3-chloro-2-fluoro-an ilino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (24.6 mg, 48.3 μmol, 15%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.64 (m, 1H), 7.39 (dd, J = 4.4, 8.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.76 - 6.49 (m, 1H), 6.16 (m, 1H), 6.11 - 5.99 (m, 1H), 5.69 (m, 1H), 4.14 (s, 2H), 4.11 - 3.48 (m, 4H), 2.57 (s, 1H), 2.31 - 2.16 (m, 2H), 1.84 (s, 6H); m/z ES+ [M+H] ⁺ 510.2. Example 24. Preparation of 1-[(3S)-3-[4-(4-chloro-2,3-difluoro-anilino)-7-fluoro-pyrido [3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 24) [0763] Step 1. Synthesis of 6-Bromo-N-(4-chloro-2,3-difluoro-phenyl)-7-fluoro-pyrido[3,2 - d]pyrimidin-4-amine [0764] A solution of 4-chloro-2,3-difluoro-aniline (316 mg, 1.94 mmol) and 6-bromo-4-chloro- 7-fluoro-pyrido[3,2-d]pyrimidine Int-D (500 mg, 1.91 mmol) in acetonitrile (10 mL) was stirred at 20 °C for 12 h. The reaction mixture was concentrated to give 6-bromo-N-(4-chloro-2,3- difluoro-phenyl)-7-fluoro-pyrido[3,2-d]pyrimidin-4-amine (700 mg, 1.80 mmol, 93%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.79 - 10.40 (m, 1H), 8.69 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.56 - 7.52 (m, 2H); m/z ES+ [M+H] ⁺ 390.9. [0765] Step 2. Synthesis of tert-Butyl (3S)-3-[4-(4-chloro-2,3-difluoro-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0766] A solution of 6-bromo-N-(4-chloro-2,3-difluoro-phenyl)-7-fluoro-pyrido[3,2 - d]pyrimidin-4-amine (700 mg, 1.80 mmol), tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (350 mg, 1.87 mmol), tris(dibenzylideneacetone)dipalladium(0) (140 mg, 152 μmol), cesium carbonate (1.68 g, 5.16 mmol) and di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3- yl]phosphane (154 mg, 303 μmol) in toluene (15.0 mL) was stirred at 110 °C for 12 h under nitrogen gas atmosphere. On completion, the reaction was concentrated under vacuum. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl (3S)-3-[4- (4-chloro-2,3-difluoro-anilino)-7-fluoro-pyrido[3,2-d]pyrimi din-6-yl]oxypyrrolidine-1- carboxylate (100 mg, 0.20 mmol, 8%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.56 (s, 1H), 8.12 (d, J = 10.8 Hz, 1H), 7.70 (br. t, J = 7.6 Hz, 1H), 7.58 - 7.51 (m, 1H), 6.07 (br dd, J = 2.8, 4.0 Hz, 1H), 3.59 - 3.34 (m, 4H), 2.21 (br. s, 2H), 1.41 (br. d, J = 3.2 Hz, 9H); m/z ES+ [M+H] ⁺ 496.1. [0767] Step 3. Synthesis of N-(4-Chloro-2,3-difluoro-phenyl)-7-fluoro-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0768] To a solution of tert-butyl (3S)-3-[4-(4-chloro-2,3-difluoro-anilino)-7-fluoro-pyrido[3, 2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (110 mg, 221 μmol) in dichloromethane (1.50 mL) was added trifluoroacetic acid (0.50 mL). The reaction was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give N-(4-chloro-2,3-difluoro-phenyl)-7-fluoro-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (90.0 mg, 0.23 mmol, 72% yield, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 396.1. [0769] Step 4. Synthesis of 1-[(3S)-3-[4-(4-Chloro-2,3-difluoro-anilino)-7-fluoro-pyrido [3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0770] To a solution of N-(4-chloro-2,3-difluoro-phenyl)-7-fluoro-6-[(3S)-pyrrolidin -3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (90.0 mg, 227 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (66.8 mg, 795 μmol) at 0 °C to adjust the pH = 8. Prop-2- enoyl chloride (20.5 mg, 227 μmol) was subsequently added in one portion, and the mixture was stirred at 20 °C for 0.5 h. On completion, the reaction was concentrated. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150x25 mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:42%-72%, 10 min) to give 1-[(3S)-3-[4-(4-chloro-2,3-difluoro-anilino)-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2 -en-1-one (23.3 mg, 51.9 μmol, 22%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J = 2.4, 10.8 Hz, 1H), 7.75 - 7.66 (m, 1H), 7.55 (t, J = 8.4 Hz, 1H), 6.73 - 6.52 (m, 1H), 6.22 - 6.06 (m, 2H), 5.69 (ddd, J = 2.4, 10.4, 18.8 Hz, 1H), 4.12 - 3.81 (m, 2H), 3.78 - 3.47 (m, 2H), 2.38 - 2.18 (m, 2H); m/z ES+ [M+H] ⁺ 450.2. Example 25. Preparation of 1-[(3S)-3-[4-(2,4-difluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 25) [0771] Step 1. Synthesis of tert-Butyl (3S)-3-[4-(2,4-difluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0772] To a solution of tert-butyl (3S)-3-(4-chloropyrido [3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate Int-A (60.0 mg, 171 μmol) in acetonitrile (1.50 mL) was added 2,4-difluoro-3- methyl-aniline (26.9 mg, 188 μmol). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was concentrated to give tert-butyl (3S)-3-[4-(2,4-difluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (78.0 mg, 0.17 mmol, 85%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.75 (br. s, 1H), 8.75 (s, 1H), 8.27 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 9.2 Hz, 2H), 7.16 (dt, J = 1.2, 8.8 Hz, 1H), 6.00 (d, J = 18.8 Hz, 1H), 3.81 - 3.55 (m, 1H), 3.42 (s, 3H), 2.10 - 1.96 (m, 2H), 1.34 (d, J = 3.2 Hz, 9H). [0773] Step 2. Synthesis of N-(2,4-Difluoro-3-methyl-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy - pyrido[3,2-d]pyrimidin-4-amine [0774] To a solution of tert-butyl (3S)-3-[4-(2,4-difluoro-3-methyl-anilino)pyrido[3,2- d]pyrimidin-6-yl] oxypyrrolidine-1-carboxylate (78.0 mg, 170 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). Then the mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated to give N-(2,4-difluoro-3-methyl-phenyl)-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, 0.17 mmol, 80% yield, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 358.2. [0775] Step 3. Synthesis of 1-[(3S)-3-[4-(2,4-Difluoro-3-methyl-anilino)pyrido[3,2-d]pyr imidin- 6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0776] To a solution of N-(2,4-difluoro-3-methyl-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy - pyrido[3,2-d] pyrimidin-4-amine (60.0 mg, 167 μmol) in water (0.50 mL) and tetrahydrofuran (0.50 mL) was added sodium bicarbonate (42.3 mg, 503 μmol). Prop-2-enoyl chloride (15.2 mg, 167 μmol) was subsequently added at 0 °C and the mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:27%-57%, 11.5 min) to give 1-[(3S)-3-[4-(2,4-difluoro-3-methyl- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (43.0 mg, 0.10 mmol, 61%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 8.49 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.86 - 7.59 (m, 1H), 7.40 (dd, J = 4.4, 9.2 Hz, 1H), 7.16 (t, J = 9.2 Hz, 1H), 6.72 - 6.52 (m, 1H), 6.31 - 5.94 (m, 2H), 5.85 - 5.55 (m, 1H), 4.22 - 3.43 (m, 4H), 2.47 - 2.26 (m, 2H), 2.24 (s, 3H); m/z ES+ [M+H] ⁺ 412.1. Example 26. Preparation of 2-[2-chloro-3-fluoro-4-[[6-[(3S)-1-prop-2-enoylpyrrolidin-3- yl]oxypyrido[3,2-d]pyrimidin-4-yl]amino]phenoxy]acetonitrile (Compound 26) [0777] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-(cyanomethoxy)-2-fluoro- aniline]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0778] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate Int-B (100 mg, 210 μmol) in N,N- dimethylformamide (1 mL) was added potassium carbonate (58.0 mg, 420 μmol) and 2- bromoacetonitrile (26.4 mg, 220 μmol). The mixture was stirred at 40 °C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[4-[3-chloro-4-(cyanomethoxy)-2- fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (150 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 515.3. [0779] Step 2. Synthesis of 2-[2-Chloro-3-fluoro-4-[[6-[(3S)-pyrrolidin-3-yl]oxypyrido[3 ,2- d]pyrimidin-4-yl]amino]phenoxy]acetonitrile [0780] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(cyanomethoxy)-2-fluoro-anilino] pyrido [3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (130 mg, 252 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 2-[2-chloro-3-fluoro-4- [[6-[(3S)-pyrrolidin-3-yl]oxypyrido[3,2-d]pyrimidin-4-yl]ami no]phenoxy]acetonitrile (130 mg, 245 μmol, 97% yield, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 415.3. [0781] Step 3. Synthesis of 2-[2-Chloro-3-fluoro-4-[[6-[(3S)-1-prop-2-enoylpyrrolidin-3- yl]oxypyrido[3,2-d]pyrimidin-4-yl]amino]phenoxy]acetonitrile [0782] To a solution of 2-[2-chloro-3-fluoro-4-[[6-[(3S)-pyrrolidin-3-yl]oxypyrido[3 ,2- d]pyrimidin-4-yl]amino]phenoxy]acetonitrile (130 mg, 245 μmol, trifluoroacetic acid) in tetrahydrofuran (2.5 mL) was added sodium bicarbonate (20.6 mg, 245 μmol) and water (0.5 mL). Prop-2-enoyl chloride (24.4 mg, 270 μmol) was subsequently added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mm, 3 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:30%-60%, 7 min) to give 2-[2-chloro-3-fluoro-4-[[6- [(3S)-1-prop-2-enoylpyrrolidin-3-yl]oxypyrido[3,2-d]pyrimidi n-4-yl]amino]phenoxy]acetonitrile (39.5 mg, 84.4 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.49 (d, J = 1.0 Hz, 1H), 8.12 (dd, J = 1.2, 9.2 Hz, 1H), 7.85 - 7.73 (m, 1H), 7.39 (dd, J = 4.4, 9.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 6.76 - 6.50 (m, 1H), 6.25 - 5.96 (m, 2H), 5.77 - 5.60 (m, 1H), 5.40 (s, 2H), 4.10 – 3.75 (m, 2H), 3.74 - 3.50 (m, 2H), 2.44 - 2.15 (m, 2H); m/z ES+ [M+H] ⁺ 469.1. Example 27. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (Compound 27) [0783] Step 1. Synthesis of Oxetan-2-ylmethyl methanesulfonate [0784] To the solution of oxetan-2-ylmethanol (500 mg, 5.68 mmol), triethylamine (1.44 g, 14.1 mmol) in tetrahydrofuran (10 mL) was added methanesulfonyl chloride (975 mg, 8.51 mmol) slowly at 0 °C, then the mixture was stirred at 25 °C for 2 h. On completion, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give oxetan-2-ylmethyl methanesulfonate (700 mg, 4.22 mmol, 66%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.10 - 5.00 (m, 1H), 4.70 (m, 1H), 4.64 - 4.56 (m, 1H), 4.38 (d, J = 3.8 Hz, 2H), 3.13 (d, J = 0.8 Hz, 3H), 2.84 - 2.73 (m, 1H), 2.71 - 2.59 (m, 1H). [0785] Step 2. Synthesis of 2-[(2-Chloro-3-fluoro-4-nitro-phenoxy)methyl]oxetane [0786] To a solution of 2-chloro-3-fluoro-4-nitro-phenol (400 mg, 2.09 mmol) in N,N- dimethylformamide (2 mL) was added potassium carbonate (577 mg, 4.18 mmol) and oxetan-2- ylmethyl methanesulfonate (451 mg, 2.71 mmol). The mixture was stirred at 100 °C for 32 h. On completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 2- [(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]oxetane (160 mg, 0.63 mmol, 29%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (m, 1H), 7.28 (dd, J = 1.6, 9.6 Hz, 1H), 5.12 - 5.01 (m, 1H), 4.54 (m, 2H), 4.43 (d, J = 3.6 Hz, 2H), 2.81 - 2.72 (m, 1H), 2.68 - 2.57 (m, 1H). [0787] Step 3. Synthesis of 3-Chloro-2-fluoro-4-(oxetan-2-ylmethoxy)aniline [0788] To a suspension of 2-[(2-chloro-3-fluoro-4-nitro-phenoxy)methyl]oxetane (160 mg, 611 μmol) and iron powder (297 mg, 5.32 mmol) in methanol (1.0 mL) and water (1.0 mL) was added ammonium chloride (359 mg, 6.73 mmol). The mixture was stirred at 80 °C for 4 h. On completion, the reaction mixture was diluted with water (5 mL) and saturated sodium carbonate (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give 3-chloro- 2-fluoro-4-(oxetan-2-ylmethoxy)aniline (85 mg, 0.37 mmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.83 - 6.74 (m, 1H), 6.73 - 6.66 (m, 1H), 4.96 (s, 3H), 4.55 - 4.47 (m, 2H), 4.10 - 4.03 (m, 2H), 2.75 - 2.69 (m, 1H), 2.63 - 2.55 (m, 1H). [0789] Step 4. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate [0790] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (120 mg, 342 μmol) in acetonitrile (1.0 mL) was added 3-chloro-2-fluoro-4- (oxetan-2-ylmethoxy)aniline (79.2 mg, 342 μmol) and cesium carbonate (111 mg, 342 μmol), the mixture was stirred at 80 °C for 16 h. On completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL × 3). 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% FA condition) to give tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (20.0 mg, 36.7 μmol, 10%) as a white solid. m/z ES+ [M+H] ⁺ 546.2. [0791] Step 5. Synthesis of N-[3-Chloro-2-fluoro-4-(oxetan-2-ylmethoxy)phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0792] A solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (15.0 mg, 27.4 μmol) in trifluoroacetic acid (924 mg, 8.10 mmol, 0.60 mL) and dichloromethane (1.0 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-(oxetan-2-ylmethoxy)phenyl]-6-[(3S)-pyrrol idin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (12.0 mg, 26.9 μmol, 88%) as a yellow solid. m/z ES+ [M+H] ⁺ 446.2. [0793] Step 6. Synthesis of 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-(oxetan-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one [0794] To a solution of N-[3-chloro-2-fluoro-4-(oxetan-2-ylmethoxy)phenyl]-6-[(3S)-p yrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (12.0 mg, 26.9 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (2.26 mg, 26.9 μmol) at 0瀽C to adjust the pH = 8. Prop-2-enoyl chloride (1.46 mg, 16.1 μmol) was subsequently added, and 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 Synergi Polar-RP 100x25mm, 4 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%:25%-55%, 8 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-2-ylmethoxy)anilin o]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (2.46 mg, 4.92 μmol, 17%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 ( d, J = 3.2 Hz, 1H), 8.52 - 8.35 (m, 1H), 8.20 - 8.08 (m, 1H), 7.75 - 7.62 (m, 1H), 7.44 - 7.33 (m, 1H), 7.22 - 7.08 (m, 1H), 6.70 - 6.51 (m, 1H), 6.25 - 6.13 (m, 1H), 6.13 - 6.00 (m, 1H), 5.77 - 5.63 (m, 1H), 5.15 - 5.01 (m, 1H), 4.64 - 4.45 (m, 2H), 4.30 (s, 2H), 4.12 - 4.00 (m, 1H), 3.86 - 3.77 (m, 1H), 3.72 - 3.64 (m, 2H), 3.59 - 3.45 (m, 2H), 2.30 - 2.24 (m, 1H), 2.22 - 2.13 (m, 1H); m/z ES+ [M+H] ⁺ 500.5. Example 28. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(difluoromethoxy) anilino] pyrido [3,4- d]pyrimidin-6-yl] oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 28) [0795] Step 1. Synthesis of 6-Fluoropyrido[3,4-d]pyrimidin-4-ol [0796] To a solution of 5-amino-2-fluoro-pyridine-4-carboxylic acid (2.00 g, 12.8 mmol) in 2- methoxyethanol (50 mL) was added methanimidoylazanium;acetate (2.67 g, 25.6 mmol). The mixture was stirred at 135 °C for 12 h. The mixture was filtered and the solid was collected to give 6-fluoropyrido [3,4-d]pyrimidin-4-ol (1.80 g, 10.9 mmol, 85%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.66 (s, 1H), 8.80 (s, 1H), 8.20 (s, 1H), 7.68 (d, J = 3.2 Hz, 1H). [0797] Step 2. Synthesis of tert-Butyl (3S)-3-(4-hydroxypyrido[3,4-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate [0798] To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (170 mg, 908 μmol) in dimethylsulfoxide (1.0 mL) was added tert-butyl hydroxy (1 M, 2.7 mL) and 6-fluoropyrido [3,4-d]pyrimidin-4-ol (150 mg, 908 μmol). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was purified by prep-TLC (Petroleum ether:Ethyl acetate = 0:1) to give tert-butyl (3S)-3-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (150 mg, 0.45 mmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.70 - 11.82 (m, 1H), 8.71 (s, 1H), 7.99 (s, 1H), 7.22 (s, 1H), 5.49 (s, 1H), 3.64 - 3.52 (m, 1H), 3.47 - 3.33 (m, 3H), 2.24 - 1.95 (m, 2H), 1.36 (d, J = 8.8 Hz, 9H). [0799] Step 3. Synthesis of tert-Butyl (3S)-3-(4-chloropyrido[3,4-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate [0800] To a solution of tert-butyl (3S)-3-(4-hydroxypyrido[3,4-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (150 mg, 451 μmol) in toluene (2.0 mL) was added phosphorus oxychloride (89.9 mg, 586 μmol) and diisopropylethyl amine (291 mg, 2.26 mmol). The mixture was stirred at 110 °C for 2 h. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)- 3-(4-chloropyrido [3,4-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate (100 mg, crude) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.03 (s, 1H), 7.26 (s, 1H), 5.81 - 5.27 (m, 1H), 3.85 - 3.49 (m, 4H), 2.29 - 2.02 (m, 2H), 1.40 (d, J = 8.0 Hz, 9H). [0801] Step 4. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4- (difluoromethoxy)anilino]pyrido[3,4-d]pyrimidin-6-yl]oxypyrr olidine-1-carboxylate [0802] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,4-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (50.0 mg, 142 μmol) in acetonitrile (2.0 mL) was added 3-chloro-4- (difluoromethoxy)aniline A-11 (27.5 mg, 142 μmol). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)-3-[4-[3-chloro-4- (difluoromethoxy)anilino]pyrido[3,4-d]pyrimidin-6-yl]oxypyrr olidine-1-carboxylate (50 mg, 98.6 μmol, 55%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.78 - 10.19 (m, 1H), 8.99 (s, 1H), 8.74 (s, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.89 (dd, J = 2.4, 8.8 Hz, 1H), 7.55 - 7.40 (m, 1H), 7.32 - 6.99 (m, 1H), 5.80 - 5.43 (m, 1H), 3.72 - 3.58 (m, 1H), 3.55 - 3.31 (m, 3H), 2.30 - 2.09 (m, 2H), 1.40 (d, J = 9.6 Hz, 9H). [0803] Step 5. Synthesis of N-[3-Chloro-4-(difluoromethoxy)phenyl]-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,4-d]pyrimidin-4-amine [0804] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,4- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (50.0 mg, 98.4 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 h. On completion, the mixture was filtered and concentrated to give N-[3-chloro-4- (difluoromethoxy)phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[ 3,4-d]pyrimidin-4-amine (40 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 408.1. [0805] Step 6. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(difluoromethoxy)anilino]pyrido[3,4 - d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0806] To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-6-[(3S)-pyrrolidin-3- yl]oxy- pyrido[3,4-d]pyrimidin-4-amine (40.0 mg, 98.0 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (24.7 mg, 294 μmol) and water (0.5 mL). Prop-2-enoyl chloride (8.88 mg, 98.0 μmol) was subsequently added at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. On completion, the residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:32%-62%, 11.5 min) to give 1-[(3S)- 3-[4-[3-chloro-4-(difluoromethoxy)anilino]pyrido[3,4-d]pyrim idin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (5.00 mg, 10.8 μmol, 10%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 8.97 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.04 - 7.78 (m, 2H), 7.48 - 7.35 (m, 1H), 7.29 - 6.99 (m, 1H), 6.62 (ddd, J = 10.0, 16.4, 30.8 Hz, 1H), 6.16 (ddd, J = 2.4, 8.4, 16.8 Hz, 1H), 5.81 - 5.56 (m, 2H), 4.00 - 3.53 (m, 4H), 2.29 - 2.15 (m, 2H); m/z ES+ [M+H] ⁺ 462.1. Example 29. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(difluoromethoxy) anilino]-7-fluoro- pyrido [3,2-d] pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 29)

[0807] Step 1. Synthesis of 6-Bromo-N-[3-chloro-4-(difluoromethoxy) phenyl]-7-fluoro-pyrido [3,2-d]pyrimidin-4-amine [0808] A solution of 3-chloro-4-(difluoromethoxy) aniline A-11 (300 mg, 1.55 mmol) and 6- bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine Int-D (406 mg, 1.55 mmol) in acetonitrile (12.0 mL) was stirred at 20 °C for 3 h. The reaction mixture was concentrated to give 6-bromo-N-[3- chloro-4-(difluoromethoxy) phenyl]-7-fluoro-pyrido[3,2-d]pyrimidin-4-amine (430 mg, 1.03 mmol, 65%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 8.77 (d, J = 3.2 Hz, 1H), 8.51 - 8.21 (m, 2H), 7.98 (dd, J = 2.4, 9.2 Hz, 1H), 7.49 - 7.02 (m, 2H); m/z ES+[M+H] ⁺ 420.9. [0809] Step 2. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0810] A solution of 6-bromo-N-[3-chloro-4-(difluoromethoxy)phenyl]-7-fluoro-pyri do[3,2- d]pyrimidin-4-amine (620 mg, 1.48 mmol), tris(dibenzylideneacetone)dipalladium(0) (135 mg, 147 μmol), di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]p hosphane (149 mg, 295 μmol) and cesium carbonate (1.44 g, 4.43 mmol) in toluene (5.0 mL) was stirred at 85 °C for 0.2 h under nitrogen gas atmosphere. Then tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (558 mg, 2.98 mmol) in toluene (5.0 mL) was added. The reaction was stirred at 85 °C for 11.8 h under nitrogen gas. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 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-TLC (Petroleum ether: Ethyl acetate = 1/1 under UV 254 nm) to give tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)anilino]-7-fluoro-pyr ido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (160 mg, 0.30 mmol, 18%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 8.62 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 10.4 Hz, 1H), 7.97 (dd, J = 2.4, 8.8 Hz, 1H), 7.46 - 7.07 (m, 2H), 6.32 - 6.16 (m, 1H), 3.56 - 3.47 (m, 2H), 3.28 - 3.24 (m, 2H), 2.39 - 2.14 (m, 2H), 1.39 (s, 9H); m/z ES+[M+H] ⁺ 526.0. [0811] Step 3. Synthesis of N-[3-Chloro-4-(difluoromethoxy)phenyl]-7-fluoro-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0812] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 285 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The reaction was stirred at 20 °C for 1 h. On completion, the reaction mixture was concentrated to give N-[3-chloro- 4-(difluoromethoxy)phenyl]-7-fluoro-6-[(3S)-pyrrolidin-3-yl] oxy-pyrido[3,2-d]pyrimidin-4- amine (120 mg, 0.28 mmol, 88%) as a yellow oil. m/z ES+[M+H] ⁺ 426.0. [0813] Step 4. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(difluoromethoxy)anilino]-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-o ne [0814] To a solution of N-[3-chloro-4-(difluoromethoxy)phenyl]-7-fluoro-6-[(3S)-pyrr olidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (120 mg, 281 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (82.8 mg, 986 μmol) at 0 °C to adjust the pH = 8. Prop-2-enoyl chloride (25.5 mg, 281 μmol) was subsequently added in one portion, and the mixture was stirred at 20 °C for 0.25 h. The reaction was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%: 42%-72%,10min) to give 1-[(3S)-3-[4-[3-chloro-4- (difluoromethoxy)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1- one (48.2 mg, 0.10 mmol, 34%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 8.62 (d, J = 1.2 Hz, 1H), 8.25 - 8.20 (m, 1H), 8.11 (dd, J = 2.4, 10.8 Hz, 1H), 7.97 (dd, J = 2.4, 9.2 Hz, 1H), 7.47 - 7.06 (m, 2H), 6.63 (ddd, J = 2.4, 16.8, 33.6 Hz, 1H), 6.37 - 6.23 (m, 1H), 6.16 (ddd, J = 2.4, 8.4, 16.8 Hz, 1H), 5.68 (ddd, J = 2.4, 10.4, 24.0 Hz, 1H), 4.12 - 3.82 (m, 2H), 3.78 - 3.47 (m, 2H), 2.41 - 2.16 (m, 2H); m/z ES+[M+H] ⁺ 480.1. Example 30. Preparation of (S)-1-(3-((4-((3-(cyclopropylmethyl)-1H-indazol-5- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pro p-2-en-1-one (Compound 30)

[0815] Step 1. Synthesis of 4-Methyl-N'-((5-nitro-2H-indazol-3- yl)methylene)benzenesulfonohydrazide [0816] To a solution of 5-nitro-2H-indazole-3-carbaldehyde (1 g, 5.23 mmol) in methanol (10 mL) was added 4-methylbenzenesulfonohydrazide (1.2 g, 6.28 mmol). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated to give 4-methyl-N'-((5-nitro-2H- indazol-3-yl)methylene)benzenesulfonohydrazide (1.5 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.00 (s, 1H), 11.81 (s, 1H), 8.94 (s, 1H), 8.25 - 8.21 (m, 2H), 7.88 - 7.86 (m, 2H), 7.75 - 7.73 (m, 1H), 7.43 – 7.41 (m, 2H), 2.33 (s, 3H). [0817] Step 2. Synthesis of 3-(Cyclopropylmethyl)-5-nitro-1H-indazole [0818] To a solution of 4-methyl-N'-((5-nitro-2H-indazol-3- yl)methylene)benzenesulfonohydrazide (1.2 g, 3.34 mmol) in 1,4-dioxane (15 mL) was added potassium carbonate (692 mg, 5.01 mmol) and cyclopropylboronic acid (430 mg, 5.01 mmol). The mixture was stirred at 110 °C for 1 h. On completion, the mixture was concentrated. The residue was purified by column chromatography (silica gel, Petroleum ether: Ethyl acetate = 1/0 to 0/1) to give 3-(cyclopropylmethyl)-5-nitro-1H-indazole (0.4 g, 1.84 mmol, 55%) as a yellow solid. NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J = 2.0 Hz, 1H), 8.31 - 8.28 (m, 1H), 7.52 (d, J = 9.2 Hz, 1H), 2.99 (d, J = 7.2 Hz, 2H), 1.27 - 1.23 (m, 1H), 0.66 - 0.61 (m, 2H), 0.37 - 0.33 (m, 2H). [0819] Step 3. Synthesis of 3-(Cyclopropylmethyl)-1H-indazol-5-amine [0820] To a solution of 3-(cyclopropylmethyl)-5-nitro-1H-indazole (0.4 g, 1.84 mmol) in ethyl acetate (20 mL) was added platinum on carbon (400 mg, 3.92 mmol, 3% loading). The mixture was stirred at 25 °C for 3 h under hydrogen gas atmosphere (15 psi). The mixture was concentrated. The crude product was washed with ethyl acetate (20 mL × 3), filtered and concentrated under vacuum to give 3-(cyclopropylmethyl)-1H-indazol-5-amine (0.4 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 188.2. [0821] Step 4. Synthesis of (S)-tert-Butyl 3-((4-((3-(cyclopropylmethyl)-2H-indazol-5-yl)amino) pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0822] To a solution of (S)-tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (0.2 g, 0.57 mmol) Int-A in acetonitrile (2 mL) was added 3-(cyclopropylmethyl)- 2H-indazol-5-amine (0.1 g, 0.57 mmol). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude residue was purified by reversed-phase HPLC (0.1% FA conditions) to give (S)-tert-butyl 3-((4- ((3-(cyclopropylmethyl)-2H-indazol-5-yl)amino)pyrido [3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1- carboxylate (160 mg, 0.32 mmol, 56%) as a white solid. m/z ES+ [M+H] ⁺ 502.3. [0823] Step 5. Synthesis of (S)-N-(3-(Cyclopropylmethyl)-1H-indazol-5-yl)-6-(pyrrolidin- 3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0824] A solution of (S)-tert-butyl 3-((4-((3-(cyclopropylmethyl)-2H-indazol-5- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carbo xylate (67 mg, 0.13 mmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1 mL) was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give (S)-N-(3- (cyclopropylmethyl)-1H-indazol-5-yl)-6-(pyrrolidin-3-yloxy)p yrido[3,2-d]pyrimidin-4-amine (65 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 402.1. [0825] Step 6. Synthesis of (S)-1-(3-((4-((3-(Cyclopropylmethyl)-1H-indazol-5- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pro p-2-en-1-one [0826] To a solution of (S)-N-(3-(cyclopropylmethyl)-1H-indazol-5-yl)-6-(pyrrolidin- 3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (65 mg, 0.16 mmol) and sodium bicarbonate (40 mg, 0.48 mmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added prop-2-enoyl chloride (8.80 mg, 0.97 mmol) at 0 °C. The reaction mixture was stirred at 0 °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 luna C18150x25mm, 10 um; mobile phase: [water (0.2% FA)- acetonitrile]; B%:18%-48%, 12 min) to give (S)-1-(3-((4-((3-(cyclopropylmethyl)-1H-indazol-5- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pro p-2-en-1-one (22.5 mg, 49.5 μmol, 31%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 8.34 (s, 1H), 8.04 (m,1H), 7.70 (m, 1H), 7.53 (m, 1H), 7.33 (m, 1H), 6.74 - 6.56 (m, 1H), 6.30 (m, 1H), 6.18 - 6.04 (m, 1H), 5.76 (m 1H), 4.13 (m, 1H), 3.98 - 3.89 (m, 2H), 3.87 - 3.78 (m, 1H), 3.76 - 3.61 (m, 1H), 2.92 (m, 2H), 2.48 - 2.31 (m, 2H), 1.25 - 1.13 (m, 1H), 0.61 - 0.52 (m, 2H), 0.36 - 0.30 (m, 2H); m/z ES+ [M+H] ⁺ 456.2. Example 31a and 31b. Preparation of 1-((S)-3-((4-((3-chloro-4-(((S)-tetrahydro-2H-pyran-2- yl)methoxy) phenyl)amino) pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one (Compound 31) and 1-((S)-3-((4-((3-chloro-4-(((R)-tetrahydro-2H-pyran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one (Compound 32) [0827] Step 1. Synthesis of 2-[(2-Chloro-4-nitro-phenoxy) methyl]tetrahydropyran [0828] To a solution of 2-chloro-1-fluoro-4-nitro-benzene (2.00 g, 11.3 mmol) and tetrahydropyran-2-ylmethanol (1.46 g, 12.5 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (910 mg, 22.7 mmol, 60% in mineral oil) portionwise at 0 °C. The mixture was stirred at 0 °C for 15 h. On completion, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) at 25 °C and extracted with ethyl acetate (5.0 mL × 3). The combined organic layers were washed with brine (9 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=10/1 to 5/1) to afford 2-[(2- chloro-4-nitro-phenoxy) methyl]tetrahydropyran (2.90 g, 10.7 mmol, 91%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 2.8 Hz, 1H), 8.58 (dd, 2.8 Hz, 9.2 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 4.26 - 4.13 (m, 2H), 3.95 - 3.84 (m, 1H), 3.75 - 3.63 (m, 1H), 3.40 (td, J = 3.6, 10.8 Hz, 1H), 1.89 - 1.78 (m, 1H), 1.72 - 1.63 (m, 1H), 1.49 (m, 4H); m/z ES+ [M+H] ⁺ 272.0. [0829] Step 2. Synthesis of 3-Chloro-4-(tetrahydropyran-2-ylmethoxy)aniline [0830] A mixture of 2-[(2-chloro-4-nitro-phenoxy)methyl]tetrahydropyran (300 mg, 1.10 mmol), platinum on carbon (150 mg, 574.59 μmol, 3% loading) in methanol (3 mL) was degassed and purged with nitrogen gas for 3 times, and then the mixture was stirred at 25 °C for 2 h under hydrogen gas atmosphere. On completion, the mixture was filtered and concentrated to give 3- chloro-4-(tetrahydropyran-2-ylmethoxy)aniline (267 mg, 1.11 mmol, 96%) as a yellow solid. NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.46 (dd, J = 2.4, 8.4 Hz, 1H), 4.90 (s, 2H), 3.92 - 3.87 (m, 1H), 3.86 - 3.73 (m, 2H), 3.57 (dddd, J = 6.0, 10.0, 16.0, 36.0 Hz, 1H), 3.59-3.53 (m, 1H), 1.86 - 1.76 (m, 1H), 1.70 - 1.61 (m, 1H), 1.53 - 1.43 (m, 3H), 1.38 - 1.25 (m, 1H); m/z ES+ [M+H] ⁺ 242.0. [0831] Step 3. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-(tetrahydropyran-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate [0832] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (100 mg, 285 μmol) and 3-chloro-4-(tetrahydropyran-2-ylmethoxy)aniline (82.6 mg, 342 μmol) in acetonitrile (5 mL) was stirred at 80 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, ethyl acetate: petroleum ether = 1:1) to afford tert-butyl (3S)-3-[4-[3-chloro- 4-(tetrahydropyran-2-ylmethoxy)anilino]pyrido[3,2-d]pyrimidi n-6-yl]oxypyrrolidine-1- carboxylate (184 mg, 0.33 mmol, 88%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 8.76 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 9.21H), 7.28 (d, J = 8.8 Hz, 1H), 6.23 - 6.06 (m, 1H), 4.12 - 3.99 (m, 2H), 3.96 - 3.89 (m, 1H), 3.80 - 3.64 (m, 4H), 3.50 (m, 2H), 2.32 - 2.06 (m, 3H), 1.85 (m, 1H), 1.71 (d, J = 14.0 Hz, 1H), 1.51 (s, 3H), 1.41 (d, J = 8.0 Hz, 9H). [0833] Step 4. Synthesis of N-[3-Chloro-4-(tetrahydropyran-2-ylmethoxy)phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0834] To a mixture of tert-butyl (3S)-3-[4-[3-chloro-4-(tetrahydropyran-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (164 mg, 294 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at 25 °C for 2 h. On completion, the mixture was concentrated to give N-[3-chloro-4- (tetrahydropyran-2-ylmethoxy)phenyl]-6-[(3S)-pyrrolidin-3-yl ]oxy-pyrido[3,2-d]pyrimidin-4- amine (130 mg, crude) as a yellow oil; m/z ES+ [M+H] ⁺ 456.0. [0835] Step 5. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(tetrahydropyran-2- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one [0836] To a mixture of N-[3-chloro-4-(tetrahydropyran-2-ylmethoxy)phenyl]-6-[(3S)-p yrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (130 mg, 285 μmol) and sodium bicarbonate (119 mg, 1.43 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added prop-2-enoyl chloride (25.8 mg, 285 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 (column: YMC-Triart Prep C18150 x 40 mm x 7 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 39%-69%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-4-(tetrahydropyran-2-ylmethoxy)anilin o]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (68.3 mg, 0.13 mmol, 46%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.20 - 7.99 (m, 2H), 7.83 (dd, J = 2.8, 9.2 Hz, 1H), 7.38 (dd, J = 4.0, 8.8 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 6.77 - 6.52 (m, 1H), 6.31 - 6.09 (m, 2H), 5.79 - 5.58 (m, 1H), 4.12 - 3.97 (m, 2.5H), 3.92 (d, J = 12.4 Hz, 1H), 3.87 - 3.78 (m, 1.5H), 3.77 - 3.48 (m, 3H), 3.47 - 3.36 (m, 1H), 2.43-2.35 (m, 1H), 2.31 - 2.20 (m, 1H), 1.89 - 1.81 (m, 1H), 1.75 - 1.65 (m, 1H), 1.56 - 1.47 (m, 3H), 1.45 - 1.33 (m, 1H); m/z ES+ [M+H] ⁺ 510.0. [0837] Step 6. 1-((S)-3-((4-((3-Chloro-4-(((S)-tetrahydro-2H-pyran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one and 1-((S)-3-((4-((3-chloro-4-(((R)-tetrahydro-2H-pyran-2-yl)met hoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one and 1-((3S)-3-((4-((3-chloro-4- ((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)amio)pyrido[3,2-d] pyrimidin-6-yl)oxy)pyrrolidin- 1-yl)prop-2-en-1-one (60 mg, 117 μmol) was purified by SFC (column: REGIS(S,S)WHELK- O1(250x25 mm, 10 um); mobile phase: [IPA-acetonitrile]; B%: 50 % - 50 %, 6.1; 240 min) to give 1-((S)-3-((4-((3-chloro-4-(((S)-Tetrahydro-2H-pyran-2-yl)met hoxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (12 mg, 1.96 μmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (d, J = 10.4 Hz, 1H), 8.58 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 10.0 Hz, 1H), 6.71 - 6.63 (m, 1H), 6.24 - 6.13 (m, 2H), 5.72 - 5.63 (m, 1H), 4.07 - 3.95 (m, 3H), 3.93 - 3.90 (m, 1H), 3.89 - 3.75 (m, 2H), 3.74 - 3.63 (m, 3H), 2.45 - 2.15 (m, 2H), 1.90 – 1.65 (m, 2H), 1.55 – 1.45 (m, 3H), 1.42 - 1.36 (m, 1H); m/z ES+ [M+H] ⁺ 510.1. 1-((S)-3-((4-((3-chloro-4-(((R)-tetrahydro-2H-pyran-2-yl)met hoxy)phen yl)amino) pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (12 mg, 1.96 μmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 8.55 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 8.03 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 6.69 - 6.58 (m, 1H), 6.25 - 6.10 (m, 2H), 5.72 - 5.63 (m, 1H), 4.07 - 3.98 (m, 3H), 3.93 - 3.90 (m, 1H), 3.84 - 3.81 (m, 2H), 3.68 - 3.51 (m, 3H), 2.35 - 2.20 (m, 2H), 1.83 – 1.65 (m, 2H), 1.55 – 1.45 (m, 3H), 1.42 - 1.36 (m, 1H); m/z ES+ [M+H] ⁺ 510.1. Example 32. Preparation of 1-[(3S)-3-[4-[3-Chloro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one (Compound 33) [0838] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate [0839] To a solution of tert-butyl (3S)-3-(4-chloropyrido [3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate Int-A (300 mg, 855 μmol) in acetonitrile (1.0 mL) was added 3-chloro-4- (tetrahydrofuran-3-ylmethoxy)aniline A-12 (234 mg, 1.03 mmol). The mixture was stirred at 40 °C for 2 h. On completion, the mixture was filtered and concentrated in vacuo to give a residue. The crude product was purified by SFC (column: DAICEL CHIRALPAK IE (50x250 mm, 10 um); mobile phase:[0.1% NH ₃ water IPA]; B%:15%-15% ,19.8; 500 min) to give tert-butyl (S)-3-((4- ((3-chloro-4-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)amino )pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (150 mg, 0.28 mmol, 30%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 8.55 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 6.12 (d, J = 13.6 Hz, 1H), 4.09 - 3.96 (m, 2H), 3.85 - 3.64 (m, 4H), 3.59 (dd, J = 5.6, 8.8 Hz, 1H), 3.53 - 3.46 (m, 1H), 3.40 (d, J = 10.4 Hz, 2H), 2.75 - 2.67 (m, 1H), 2.31 - 2.21 (m, 1H), 2.18 - 2.07 (m, 1H), 2.07 - 1.97 (m, 1H), 1.79 - 1.65 (m, 1H), 1.41 (d, J = 9.6 Hz, 9H); m/z ES+ [M+H] ⁺ 542.3. And tert-butyl (S)-3-((4-((3-chloro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate (150 mg, 0.28 mmol, 30%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.61 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.90 (m, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.19 (d, J = 14.8 Hz, 1H), 4.12 – 4.05 (m, 2H), 3.8 - 3.84 (m, 4H), 3.75 (m, 1H), 3.67 - 3.64 (m, 1H), 3.48 (d, J = 10.4 Hz, 2H), 2.74 - 2.73 (m, 1H), 2.11 - 2.08 (m, 2H), 2.11 - 2.08 (m, 1H), 1.80 - 1.75 (m, 1H), 1.41 (d, J = 9.6 Hz, 9H); m/z ES+ [M+H] ⁺ 542.2. [0840] Step 2. Synthesis of N-[3-Chloro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0841] To a solution of tert-butyl (S)-3-((4-((3-chloro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate (120 mg, 221 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered and concentrated in vacuo to give N-[3-chloro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]-6- [(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 442.2. [0842] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one [0843] To a solution of N-[3-chloro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]-6- [(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 181 μmol) in tetrahydrofuran (0.30 mL) was added sodium bicarbonate (15.2 mg, 181 μmol) in water (0.30 mL) at 0 °C and then prop- 2-enoyl chloride (16.4 mg, 181 μmol) in tetrahydrofuran (0.30 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 5 minutes. On completion, the solution was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:25%-55%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-4-[[(3R)-tetrahydrofuran- 3-yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolid in-1-yl]prop-2-en-1-one (35.2 mg, 71.1 μmol, 39%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.16 - 8.03 (m, 2H), 7.84 (dd, J = 2.4, 9.2 Hz, 1H), 7.38 (dd, J = 4.0, 9.2 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.71 - 6.52 (m, 1H), 6.28 - 6.11 (m, 2H), 5.75 - 5.60 (m, 1H), 4.10 - 3.77 (m, 6H), 3.75 - 3.50 (m, 4H), 2.75 - 2.68 (m, 1H), 2.31 - 2.16 (m, 2H), 2.11 - 2.00 (m, 1H), 1.77 - 1.67 (m, 1H); m/z ES+ [M+H] ⁺ 496.4. Example 33. Preparation of 1-[(3S)-3-[4-[3-chloro-4-[[(3S)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one (Compound 34) [0844] Step 1. Synthesis of N-[3-chloro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl]-6- [(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0845] To a solution of tert-butyl (S)-3-((4-((3-chloro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate (120 mg, 221 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered and concentrated in vacuo to give N-[3-chloro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl]-6- [(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 442.2. [0846] Step 2. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-[[(3S)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one [0847] To a solution of N-[3-chloro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl]-6- [(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (80 mg, 181 μmol) in tetrahydrofuran (0.30 mL) was added sodium bicarbonate (15.2 mg, 181 μmol) in water (0.30 mL) at 0 °C and then prop- 2-enoyl chloride (9.83 mg, 109 μmol) in tetrahydrofuran (0.30 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 C18 150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:25%-55%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-4- [[(3S)-tetrahydrofuran-3-yl]methoxy]anilino]pyrido[3,2-d]pyr imidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (47.5 mg, 95.9 μmol, 50%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 1.2 Hz, 1H), 8.14 - 8.04 (m, 2H), 7.84 (dd, J = 2.8, 8.8 Hz, 1H), 7.38 (dd, J = 4.0, 9.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.28 - 6.10 (m, 2H), 5.75 - 5.62 (m, 1H), 4.10 - 3.78 (m, 6H), 3.75 - 3.50 (m, 4H), 2.76 - 2.68 (m, 1H), 2.31 - 2.13 (m, 2H), 2.11 - 1.99 (m, 1H), 1.80 - 1.64 (m, 1H); m/z ES+ [M+H] ⁺ 496.5. Example 34. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (Compound 35) [0848] Step 1. Synthesis of tert-Butyl(3S)-3-[4-[3-chloro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxy pyrrolidine-1-carboxylate [0849] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (70.0 mg, 200 μmol) in acetonitrile (1.0 mL) was added 3-chloro-4-(oxetan-3- ylmethoxy)aniline A-13 (51.2 mg, 239 μmol). The mixture was stirred at 40 °C for 3 h. On completion, the reaction mixture was diluted with water 10 mL, filtered and concentrated in vacuo. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 0:1) to give tert-butyl (3S)-3-[4-[3-chloro-4-(oxetan-3-ylmethoxy)anilino]pyrido[3,2 -d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate (40 mg, 75.9 μmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.56 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 6.19 - 6.09 (m, 1H), 4.74 (dd, J = 6.0, 8.0 Hz, 2H), 4.49 (t, J = 6.4 Hz, 2H), 4.31 (d, J = 6.8 Hz, 2H), 3.80 - 3.71 (m, 1H), 3.55 - 3.37 (m, 4H), 2.31 - 2.24 (m, 1H), 2.15 (s, 1H), 1.41 (d, J = 9.2 Hz, 9H); m/z ES+ [M+H] ⁺ 528.2. [0850] Step 2. Synthesis of N-[3-Chloro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(3S)-pyrrolidin -3- yl]oxy-pyrido[3,2-d]pyrimdin-4-amine [0851] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(oxetan-3-ylmethoxy)anilino]pyrido[3,2 - d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (25.0 mg, 47.4 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo to give N-[3-chloro-4-(oxetan-3-ylmethoxy)phenyl]-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (40 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 428.2. [0852] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(oxetan-3-ylmethoxy)anilino]pyrido[ 3,2- d]pyrimidin-6-yl] oxypyrrolidin-1-yl]prop-2-en-1-one [0853] To a solution of N-[3-chloro-4-(oxetan-3-ylmethoxy)phenyl]-6-[(3S)-pyrrolidin -3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (30.0 mg, 70.1 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (5.89 mg, 70.1 μmol) in water (0.5 mL) at 0 °C and then prop-2-enoyl chloride (3.17 mg, 35.1 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 reaction was filtered and concentrated under reduce pressure. the residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mm, 3 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )- acetonitrile]; B%: 25%-55%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-4-(oxetan-3- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (4.5 mg, 9.36 μmol, 13%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 0.8 Hz, 1H), 8.14 - 8.05 (m, 2H), 7.87 (dd, J = 2.4, 8.8 Hz, 1H), 7.38 (dd, J = 4.0, 9.2 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.71 - 6.55 (m, 1H), 6.26 - 6.12 (m, 2H), 5.74 - 5.63 (m, 1H), 4.74 (dd, J = 6.0, 8.0 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 4.32 (d, J = 6.8 Hz, 2H), 4.07 (dd, J = 4.4, 12.0 Hz, 1H), 3.87 - 3.78 (m, 2H), 3.72 - 3.66 (m, 1H), 3.49 - 3.40 (m, 1H), 2.31 - 2.14 (m, 3H); m/z ES+ [M+H] ⁺ 482.2. Example 35. Preparation of 1-[(3S)-3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 36)

[0854] Step 1. Synthesis of tert-Butyl (3S)-3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrroli dine-1-carboxylate [0855] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (90.0 mg, 256 μmol) and 3-chloro-2,4-difluoro-aniline (41.9 mg, 256 μmol) in acetonitrile (1.0 mL) was stirred at 60 °C for 3 h. On completion, the reaction was concentrated to give a residue. The residue was purified by Prep-TLC (Petroleum ether: Ethyl acetate = 0:1) to give tert-butyl (3S)-3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyrimi din-6- yl]oxypyrrolidine-1-carboxylate (70 mg, 131 μmol, 51%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.91 - 7.79 (m, 1H), 7.47 - 7.38 (m, 2H), 6.07 - 5.90 (m, 1H), 3.81 - 3.66 (m, 1H), 3.54 - 3.37 (m, 3H), 2.31 - 2.07 (m, 2H), 1.41 (br. d, J = 6.0 Hz, 9H). [0856] Step 2. Synthesis of N-(3-Chloro-2,4-difluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy - pyrido[3,2-d]pyrimidin-4-amine [0857] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2,4-difluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxy pyrrolidine-1-carboxylate (60 mg, 125 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol, 0.30 mL). The reaction was stirred at 20 °C for 2 h. On completion, the reaction mixture was concentrated to give N-(3-chloro-2,4-difluoro- phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4 -amine (50.0 mg, crude) as a white solid. m/z ES+ [M+H] ⁺ 378.0. [0858] Step 3. Synthesis of 1-[(3S)-3-[4-(3-Chloro-2,4-difluoro-anilino)pyrido[3,2-d]pyr imidin- 6-yl]oxypyrrolidin-1-yl] prop-2-en-1-one [0859] To a solution of N-(3-chloro-2,4-difluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy - pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, 132 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (38.9 mg, 463.2 μmol) at 0 °C to adjust the pH = 8. Prop-2- enoyl chloride (11.9 mg, 132 μmol, 10.7 μL) was subsequently added in one portion. The mixture was stirred at 20 °C for 0.25 h. On completion, the reaction was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Welch Xtimate C18150x25mm, 5 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 35%-65%, 10 min) to give 1-[(3S)-3-[4-(3-chloro- 2,4-difluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolid in-1-yl]prop-2-en-1-one (17.77 mg, 41.2 μmol, 30%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 8.50 (s, 1H), 8.14 (dd, J = 1.2, 9.0 Hz, 1H), 7.85 (ddt, J = 3.6, 5.6, 8.8 Hz, 1H), 7.48 - 7.33 (m, 2H), 6.73 - 6.48 (m, 1H), 6.16 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.11 - 5.96 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.12 - 3.47 (m, 4H), 2.41 - 2.13 (m, 2H); m/z ES+ [M+H] ⁺ 432.1. Example 36. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-on (Compound 37) [0860] Step 1. Synthesis of 2-Chloro-1-(cyclobutoxy)-3-fluoro-4-nitro-benzene [0861] To a mixture of 2-chloro-3-fluoro-4-nitro-phenol Int-E (300 mg, 1.57 mmol) in N,N- dimethylformamide (6 mL) was added potassium carbonate (649 mg, 4.70 mmol) and bromocyclobutane (634 mg, 4.70 mmol). The mixture was stirred at 80 °C for 12 h. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC (0.1% HCl conditions) to give 2-chloro-1-(cyclobutoxy)-3-fluoro-4-nitro- benzene (140 mg, 570 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (t, J = 9.2 Hz, 1H), 7.05 - 6.93 (m, 1H), 5.00 - 4.86 (m, 1H), 2.51 - 2.43 (m, 4H), 2.13 - 2.00 (m, 2H), 1.84 - 1.72 (m, 1H), 1.69 - 1.57 (m, 1H). [0862] Step 2. Synthesis of 3-Chloro-4-(cyclobutoxy)-2-fluoro-aniline [0863] To a mixture of 2-chloro-1-(cyclobutoxy)-3-fluoro-4-nitro-benzene (140 mg, 570 μmol) in tetrahydrofuran (3 mL) was added platinum on carbon (70 mg, 268 μmol, 3% loading). The mixture was stirred at 25 °C for 2 h under hydrogen gas. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 3-chloro-4-(cyclobutoxy)-2-fluoro- aniline (120 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 216.0. [0864] Step 3. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0865] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (125 mg, 356 μmol) in acetonitrile (2 mL) was added 3-chloro-4-(cyclobutoxy)- 2-fluoro-aniline (92.2 mg, 428 μmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and the precipitate was collected, dried under reduced pressure to give tert- butyl (3S)-3-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro-anilino]pyrido[ 3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (180 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 530.2. [0866] Step 4. Synthesis of N-[3-Chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(3S)-pyrroli din-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0867] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(cyclobutoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (60 mg, 113 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol, 0.1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(3S)-pyrroli din-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (60 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 430.1. [0868] Step 5. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(cyclobutoxy)-2-fluoro-anilino]pyri do[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0869] To a solution of N-[3-chloro-4-(cyclobutoxy)-2-fluoro-phenyl]-6-[(3S)-pyrroli din-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (60 mg, 110 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (18.5 mg, 220 μmol), followed by prop- 2-enoyl chloride (11.9 mg, 132 μmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:55%-75%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-4- (cyclobutoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]o xypyrrolidin-1-yl]prop-2-en-1-one (15.6 mg, 32.3 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.46 (s, 1H), 8.12 (dd, J = 8.8, 0.8 Hz, 1H), 7.70 - 7.57 (m, 1H), 7.45 - 7.35 (m, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.76 - 6.47 (m, 1H), 6.23 - 5.98 (m, 2H), 5.79 - 5.58 (m, 1H), 4.92 - 4.81 (m, 1H), 4.13 – 3.76 (m, 2H), 3.75 - 3.48 (m, 2H), 2.42 - 2.33 (m, 2H), 2.33 - 2.05 (m, 4H), 1.92 - 1.78 (m, 1H), 1.75 - 1.60 (m, 1H); m/z ES+ [M+H] ⁺ 484.1. Example 37. Preparation of (S)-1-(3-((4-((3-chloro-2-cyclopropoxy-4- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one (Compound 38) [0870] Step 1. Synthesis of 2-Chloro-3-cyclopropoxy-1-fluoro-4-nitrobenzene [0871] To a solution of 2-chloro-1,3-difluoro-4-nitrobenzene (1 g, 5.17 mmol) and cyclopropanol (300 mg, 5.17 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (3.37 g, 10.33 mmol). The mixture was stirred at 30 °C for 8 h. 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 (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) to give 2-chloro-3-cyclopropoxy-1-fluoro-4-nitrobenzene (500 mg, 2.16 mmol, 42%) as a yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 - 7.70 (m, 1H), 7.09 - 6.95 (m, 1H), 4.45 - 4.36(m, 1H), 0.98 - 0.93 (m, 2H), 0.70 - 0.62 (m, 2H). [0872] Step 2. Synthesis of 3-Chloro-2-cyclopropoxy-4-fluoroaniline [0873] To a solution of 2-chloro-3-cyclopropoxy-1-fluoro-4-nitrobenzene (500 mg, 2.16 mmol) in ethyl acetate (5 mL) was added platinum on carbon (300 mg, 3% loading). The mixture was stirred at 15 °C for 2 h under hydrogen gas atmosphere at 15 psi. On completion, the reaction mixture was filtered and concentrated in vacuo to give 3-chloro-2-cyclopropoxy-4-fluoroaniline (400 mg, 1.99 mmol, 92%) as a brown oil. m/z ES+ [M+H] ⁺ 202.0. [0874] Step 3. Synthesis of tert-Butyl (S)-3-((4-((3-chloro-2-cyclopropoxy-4- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi ne-1-carboxylate [0875] The mixture of 3-chloro-2-cyclopropoxy-4-fluoroaniline (100 mg, 0.50 mmol) and (S)- tert-butyl 3-((4-chloropyrido [3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate Int-A (174 mg, 0.50 mmol) in acetonitrile (2 mL) was stirred at 60 °C for 2 h. On completion, the reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. And the residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate = 0/1 to 1/1) to give tert-butyl (S)-3-((4-((3-chloro-2-cyclopropoxy-4- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi ne-1-carboxylate (110 mg, 0.21 mmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.10 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.08 (t, J = 8.8 Hz, 1H), 5.79 (s, 1H), 4.38 (s, 1H), 3.91 - 3.67 (m, 2H), 3.65 - 3.52 (m, 2H), 2.32 (s, 2H), 1.52 - 1.45 (m, 9H), 1.09 - 0.87 (m, 2H), 0.75 - 0.59 (m, 2H); m/z ES+ [M+H] ⁺ 516.2. [0876] Step 4. Synthesis of (S)-N-(3-Chloro-2-cyclopropoxy-4-fluorophenyl)-6-(pyrrolidin -3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0877] A mixture of tert-butyl (S)-3-((4-((3-chloro-2-cyclopropoxy-4- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi ne-1-carboxylate (100 mg, 0.194 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (2 mL) was stirred at 15 °C for 20 min. On completion, the mixture was concentrated in vacuo to give (S)-N-(3-chloro-2-cyclopropoxy-4- fluorophenyl)-6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4 -amine (100 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 416.2. [0878] Step 5. Synthesis of (S)-1-(3-((4-((3-Chloro-2-cyclopropoxy-4- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one [0879] To a solution of (S)-N-(3-chloro-2-cyclopropoxy-4-fluorophenyl)-6-(pyrrolidin -3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (80 mg, 0.192 mmol) and sodium bicarbonate (70.7 mg, 0.960 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (15.67 mg, 0.173 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 crude material was purified prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:45%-75%, 10 min) to give (S)-1-(3-((4-((3-chloro-2-cyclopropoxy-4- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one (37.7 mg, 80.4 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (d, J = 7.2 Hz, 1H), 8.91 - 8.78 (m, 1H), 8.78 - 8.70 (m, 1H), 8.20 - 8.08 (m, 1H), 7.26 - 7.20 (m, 1H), 7.12 - 7.04 (m, 1H), 6.60 - 6.39 (m, 2H), 5.92 - 5.82 (m, 1H), 5.78 - 5.68 (m, 1H), 4.46 - 4.33 (m, 1H), 4.14 - 4.01 (m, 1H), 4.00 - 3.76 (m, 3H), 2.52 - 2.33 (m, 2H), 1.05 - 0.91 (m, 2H), 0.78 - 0.62 (m, 2H); m/z ES+ [M+H] ⁺ 470.0. Example 38. Preparation of 1-[(3S)-3-[4-[4-(difluoromethoxy)-3-fluoro-anilino]pyrido[3, 2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 39) [0880] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[4-(difluoromethoxy)-3-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxpyrrolidine-1-carboxyl ate [0881] To a solution of 4-(difluoromethoxy)-3-fluoro-aniline (83.3 mg, 470 μmol) in acetonitrile (1.5 mL) was added tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (150 mg, 427 μmol). The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was filtered and the precipitate was collected to give tert-butyl (3S)-3-[4-[4- (difluoromethoxy)-3-fluoro-anilino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (169 mg, 0.34 mmol, 65%) as a gray solid. m/z ES+ [M+H] ⁺ 492.2. [0882] Step 2. Synthesis of N-[4-(Difluoromethoxy)-3-fluoro-phenyl]-6-[(3S)-pyrrolidin-3 - yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0883] A solution of tert-butyl (3S)-3-[4-[4-(difluoromethoxy)-3-fluoro-anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (140 mg, 284 μmol) in trifluoroacetic acid (0.4 mL) and dichloromethane (2 mL) was stirred at 25 °C for 1 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-[4-(difluoromethoxy)-3-fluoro- phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4 -amine (100 mg, 0.26 mmol, 76%) as a brown oil. m/z ES+ [M+H] ⁺ 392.1. [0884] Step 3. Synthesis of 1-[(3S)-3-[4-[4-(Difluoromethoxy)-3-fluoro-anilino]pyrido[3, 2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0885] To a solution of N-[4-(difluoromethoxy)-3-fluoro-phenyl]-6-[(3S)-pyrrolidin-3 -yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (100 mg, 255 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (64.4 mg, 766 μmol). Prop-2-enoyl chloride (20.8 mg, 230 μmol) was subsequently added, and the mixture was stirred at 0 °C for 45 minutes. 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, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:34%-64%, 1 0min) to give 1-[(3S)-3-[4-[4- (difluoromethoxy)-3-fluoro-anilino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1- one (40.6 mg, 91.2 μmol, 34%) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.72 (d, J = 3.2 Hz, 1H), 8.67 (d, J = 1.6 Hz, 1H), 8.39 (t, J = 2.4 Hz, 1H), 8.17 (dd, J = 1.2, 9.2 Hz, 1H), 8.12 (dd, J = 2.4, 9.2 Hz, 1H), 7.65 (dd, J = 0.8, 9.2 Hz, 1H), 7.43 (dd, J = 4.4, 9.2 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.31 - 6.22 (m, 1H), 6.22 - 6.09 (m, 2H), 5.76 - 5.59 (m, 1H), 4.12 - 3.79 (m, 2H), 3.77 - 3.46 (m, 2H), 2.44 - 2.35 (m, 1H), 2.36 - 2.13 (m, 1H); m/z ES+ [M+H] ⁺ 446.1. Example 39. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(trifluoromethoxy)anilino]pyrido[3, 2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 40)

[0886] Step Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4- (trifluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyr rolidine-1-carboxylate [0887] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1carboxylate Int-A (100 mg, 285 μmol) in acetonitrile (1.0 mL) was added 3-chloro-4- (trifluoromethoxy)aniline (66.3 mg, 314 μmol). The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was filtered to give tert-butyl (3S)-3-[4-[3-chloro-4- (trifluoromethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyr rolidine-1-carboxylate (170 mg, 0.32 mmol, 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 9.33 - 9.25 (m, 1H), 8.79 - 8.61 (m, 2H), 8.42 (d, J = 8.8 Hz, 1H), 8.14 (dd, J = 1.2, 8.8 Hz, 1H), 8.05 - 7.91 (m, 1H), 6.72 - 6.54 (m, 1H), 4.23 - 4.09 (m, 1H), 3.92 (dd, J = 2.4, 8.8 Hz, 1H), 3.85 (d, J = 9.2 Hz, 2H), 2.79 - 2.64 (m, 1H), 2.63 - 2.52 (m, 1H), 1.83 (d, J = 8.4 Hz, 9H); m/z ES+ [M+H] ⁺ 526.1. [0888] Step 2. Synthesis of N-[3-Chloro-4-(trifluoromethoxy)phenyl]-6-[(3S)-pyrrolidin-3 - yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0889] A solution of tert-butyl (3S)-3-[4-[3-chloro-4-(trifluoromethoxy)anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (120 mg, 228 μmol) in dichloromethane (2.0 mL) and trifluoroacetic acid (0.4 mL) was stirred at 25 °C for 30 minutes. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-[3-chloro-4- (trifluoromethoxy)phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido [3,2-d]pyrimidin-4-amine (100 mg, 0.24 mmol, 87%) as a yellow oil. m/z ES+ [M+H] ⁺ 426.1. [0890] Step 3. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(trifluoromethoxy)anilino]pyrido[3, 2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0891] To a solution of N-[3-chloro-4-(trifluoromethoxy)phenyl]-6-[(3S)-pyrrolidin-3 -yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (100 mg, 234 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (59.1 mg, 704 μmol). Prop-2-enoyl chloride (17.0 mg, 187 μmol) was subsequently added, and the mixture was stirred at 0 °C for 30 minutes. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a crude residue. The crude product 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 min) to give 1-[(3S)-3- [4-[3-chloro-4-(trifluoromethoxy)anilino]pyrido[3,2-d]pyrimi din-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (20.4 mg, 42.6 μmol, 17%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.72 (d, J = 3.2 Hz, 1H), 8.67 (d, J = 1.6 Hz, 1H), 8.39 (t, J = 2.4 Hz, 1H), 8.17 (dd, J = 1.2, 9.2 Hz, 1H), 8.12 ( dd, J = 2.4, 9.2 Hz, 1H), 7.65 (dd, J = 0.8, 9.2 Hz, 1H), 7.43 (dd, J = 4.4, 9.2 Hz, 1H), 6.73 - 6.55 (m, 1H), 6.22 - 6.09 (m, 2H), 5.76 - 5.59 (m, 1H), 4.12 - 3.79 (m, 2H), 3.77 - 3.46 (m, 2H), 2.44 - 2.35 (m, 1H), 2.36 - 2.13 (m, 1H); m/z ES+ [M+H] ⁺ 480.1. Example 40. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (Compound 41) [0892] Step 1. Synthesis of 2-Chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol [0893] To a solution of 4-amino-2-chloro-3-fluoro-phenol (160 mg, 990 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (22.5 mg, 198 μmol) and hexane-2,5- dione (1355 mg, 1.19 mmol). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was poured into the water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-4-(2,5- dimethylpyrrol-1-yl)-3–fluoro-phenol (220 mg, 734 μmol, 93%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 7.17 (t, J = 8.8 Hz, 1H), 6.93 (m, 1H), 5.80 (s, 2H), 1.91 (s, 6H); m/z ES+ [M+H] ⁺ 240.1. [0894] Step 2. Synthesis of 1-[3-Chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-2,5-dimethy l- pyrrole [0895] To a solution of 2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (200 mg, 834 μmol) and (2-chloro-2,2-difluoro-acetyl)oxysodium (445 mg, 2.92 mmol) in N,N- dimethylformamide (4.9 mL) and water (0.7 mL) was added cesium carbonate (543 mg, 1.67 mmol). The mixture was stirred at 100 °C for 4 h. On completion, the mixture was poured over water (10 mL) and extracted with ethyl acetate (30 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 (silica gel, petroleum ether: ethyl acetate = 10:1) to give 1-[3-chloro-4- (difluorom ethoxy)-2-fluoro-phenyl]-2,5-dimethyl-pyrrole (220 mg, 645 μmol, 77%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 - 7.29 (m, 3H), 5.86 (s, 2H), 1.94 (s, 6H); m/z ES+ [M+H] ⁺ 290.1. [0896] Step 3. Synthesis of 3-Chloro-4-(difluoromethoxy)-2-fluoro-aniline [0897] To a solution of 1-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-2,5-dimethy l-pyrrole (200 mg, 690 μmol) in ethanol (3.0 mL) was added hydroxylamine hydrochloride (1.44 g, 20.7 mmol) and triethyl amine (279 mg, 2.76 mmol). The mixture was stirred at 80 °C for 24 h. On completion, the mixture was poured over water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 3-chloro-4-(difluoromethoxy)-2-fluoro-aniline (110 mg, 0.52 mmol, 60%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.22- 6.85 (s, 2H), 6.80 - 6.66 (m, 1H), 5.48 (s, 2H); m/z ES+ [M+H] ⁺ 212.1. [0898] Step 4. Synthesis of tert-Butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0899] To a solution of 3-chloro-4-(difluoromethoxy)-2-fluoro-aniline (100 mg, 472 μmol) in acetonitrile (1.0 mL) was added tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate Int-A (165 mg, 472 μmol). The mixture was stirred at 60 °C for 4 h. On completion, the reaction mixture was filtered, concentrated in vacuo to give a residue. The crude product was purified by reverse-phase HPLC (0.1% FA condition conditions) to give tert- butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]pyr ido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (70.0 mg, 0.13 mmol, 26%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 8.52 (s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.99 - 7.86 (m, 1H), 7.57 (s, 1H), 7.40 - 7.34 (m, 1H), 6.03 - 5.91 (m, 1H), 3.88 - 3.68 (m, 1H), 3.52 - 3.38 (m, 3H), 2.30 - 2.24 (m, 1H), 2.21 - 2.10 (m, 1H), 1.42 (d, J = 5.4 Hz, 9H); m/z ES+ [M+H] ⁺ 526.1. [0900] Step 5. Synthesis of N-[3-Chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0901] A solution of tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido3,2-d] pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (60.0 mg, 114 μmol) in trifluoroacetic acid (1.85 g, 16.2 mmol) and dichloromethane (1.0 mL) was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was filtered, concentrated in vacuo to give N-[3-chloro-4- (difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidin-3-yl]o xy-pyrido[3,2-d]pyrimidin-4-amine (48.0 mg, 91.4 μmol, 98%) as a red solid. m/z ES+ [M+H] ⁺ 426.1. [0902] Step 6. Synthesis of 1-[(3S)-3-[4-[3-Chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one [0903] To a solution of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)-pyr rolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (48.0 mg, 112 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (33.1 mg, 394 μmol) until the pH = 8 at 0 °C. Prop- 2-enoyl chloride (10.2 mg, 112 μmol) was subsequently added, and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered, concentrated in vacuo to give a residue. The crude material was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%:38%-68%, 11.5 min) to give 1-[(3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (20.9 mg, 43.6 μmol, 37%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.53 (s, 1H), 8.22 - 8.12 (m, 1H), 7.90 (m, 1H), 7.57-7.27 (s, 3H), 6.60 - 6.59 (m, 1H), 6.63 (m, 1H), 6.11 - 6.06 (m, 1H), 5.69 (m, 1H), 4.08-3.78 (dd, J = 4.8, 12.0 Hz, 2H), 3.77 - 3.48 (m, 2H), 2.47 (m, 1H), 2.25 - 2.14 (m, 1H); m/z ES+ [M+H] ⁺ 480.1. Example 41. Preparation of 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in- 6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 42)

[0904] Step 1. Synthesis of 6-Fluoropyrido[3,4-d]pyrimidin-4-ol [0905] A solution of 5-amino-2-fluoro-pyridine-4-carboxylic acid (1.00 g, 6.41 mmol) and formimidamide acetate (1.33 g, 12.8 mmol) in 2-methoxyethanol (20.0 mL) was stirred at 140 °C for 12 h. On completion, the mixture was concentrated to give a crude material. The residue was wished by aq. sodium bicarbonate solution and water, which was further dried to give 6- fluoropyrido[3,4-d]pyrimidin-4-ol (900 mg, 5.45 mmol, 85%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.64 (s, 1H), 8.78 (s, 1H), 8.19 (s, 1H), 7.67 (d, J = 2.8 Hz, 1H); m/z ES+ [M+H] ⁺ 166.0. [0906] Step 2. Synthesis of 4-Chloro-6-fluoro-pyrido [3,4-d]pyrimidine [0907] A mixture of 6-fluoropyrido[3,4-d]pyrimidin-4-ol (300 mg, 1.82 mmol), phosphorus oxychloride (362 mg, 2.36 mmol, 219 μL) and diisopropylethyl amine (1.17 g, 9.08 mmol, 1.58 mL) in toluene (10 mL) was degassed and purged with nitrogen gas × 3. The mixture was then stirred at 110 °C for 4 h under nitrogen gas atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give 4-chloro-6-fluoro-pyrido[3,4-d]pyrimidine (300 mg, 1.64 mmol, 65%) as a brown oil. m/z ES+ [M+H] ⁺ 184.1. [0908] Step 3. Synthesis of N-(3-Chloro-2-fluoro-phenyl)-6-fluoro-pyrido[3,4-d]pyrimidin -4- amine [0909] A solution of 4-chloro-6-fluoro-pyrido[3,4-d]pyrimidine (300 mg, 1.63 mmol) and 3- chloro-2-fluoro-aniline (285 mg, 1.96 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 3 h. On completion, the mixture was concentrated to give a residue. The residue was purified by prep- TLC (Petroleum ether: Ethyl acetate = 1:1) to give N-(3-chloro-2-fluoro-phenyl)-6-fluoro- pyrido[3,4-d]pyrimidin-4-amine (210 mg, 0.72 mmol, 43%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 9.04 - 8.92 (m, 1H), 8.63 (s, 1H), 8.16 (s, 1H), 7.56 (s, 2H), 7.32 (t, J = 8.0 Hz, 1H); m/z ES+ [M+H] ⁺ 293.0. [0910] Step 4. Synthesis of tert-Butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0911] To a solution of N-(3-chloro-2-fluoro-phenyl)-6-fluoro-pyrido[3,4-d]pyrimidin -4-amine (190 mg, 649 μmol) and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (122 mg, 649 μmol) in dimethylsulfoxide(3.00 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 1.95 mL). The mixture was stirred at 120 °C for 2 h. On completion, the mixture was concentrated to give a residue. The crude product was triturated with ethyl acetate (5.0 mL) at 25 °C to give tert- butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6-yl]oxypyrrolidine-1- carboxylate (350 mg, 0.76 mmol, 40%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.26 (s, 1H), 7.75 (s, 1H), 7.11 (s, 1H), 6.85 - 6.77 (m, 3H), 5.32 - 5.27 (m, 1H), 3.25 (s, 4H), 2.55 (s, 2H), 1.77 (s, 9H); m/z ES+ [M+H-100] ⁺ 460.1. [0912] Step 5. Synthesis of N-(3-Chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,4-d]pyrimidin-4-amine [0913] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimidin- 6- yl]oxypyrrolidine-1-carboxylate (300 mg, 652 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol, 3.0 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give N-(3-chloro-2-fluoro-phenyl)-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,4-d]pyrimidin-4-amine (230 mg, 0.64 mmol, 24%) as a yellow oil. m/z ES+ [M+H]+ 360.1. [0914] Step 6. Synthesis of 1-[(3S)-3-[4-(3-Chloro-2-fluoro-anilino)pyrido[3,4-d]pyrimid in-6- yl]oxy-pyrrolidin-1-yl]prop-2-en-1-one [0915] To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyr ido[3,4- d]pyrimidin-4-amine (230 mg, 639 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added sodium bicarbonate (53.7 mg, 639 μmol) at 0 °C to adjust the pH = 8. Prop-2-enoyl chloride (57.9 mg, 639 μmol, 52.1 μL) was subsequently added in one portion, and the mixture was stirred at 0 °C for 0.25 h. On completion, the mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18150x25mm, 10 um; mobile phase:[water (0.225%FA)-acetonitrile]; B%: 28%-58%, 11.5 min) to give 1-[(3S)-3-[4-(3-chloro-2-fluoro- anilino)pyrido[3,4-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (11.7 mg, 28.3 μmol, 4.0%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 - 9.92 (m, 1H), 8.94 (s, 1H), 8.51 - 8.42 (m, 1H), 7.82 - 7.73 (m, 1H), 7.50 (d, J = 6.0 Hz, 2H), 7.33 - 7.26 (m, 1H), 6.71 - 6.52 (m, 1H), 6.15 (ddd, J = 2.4, 8.4, 16.8 Hz, 1H), 5.72 - 5.58 (m, 2H), 4.01 - 3.76 (m, 2H), 3.73 - 3.64 (m, 2H), 2.30 - 2.12 (m, 2H); m/z ES+ [M+H] ⁺ 414.0. Example 42. Preparation of 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-quinazolin -6- yl]oxypyrrolidin-1-yl] prop-2-en-1-one (Compound 43) [0916] Step 1. Synthesis of tert-Butyl (3S)-3-(2-fluoro-4-nitro-phenoxy)pyrrolidine-1- carboxylate [0917] To a solution of 1,2-difluoro-4-nitro-benzene (2.00 g, 12.6 mmol, 1.39 mL) and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2.47 g, 13.2 mmol) in N,N-dimethylformamide (30 mL) was added cesium carbonate (8.19 g, 25.1 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 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 = 6/1 to 2/1) to afford tert-butyl (3S)-3- (2-fluoro-4-nitro-phenoxy)pyrrolidine-1-carboxylate (3.90 g, 11.9 mmol, 95%) as a brown oil; m/z ES+ [M-56+H] ⁺ 271.0. [0918] Step 2. tert-Butyl (3S)-3-(4-amino-2-fluoro-phenoxy)pyrrolidine-1-carboxylate [0919] To a solution of tert-butyl (3S)-3-(2-fluoro-4-nitro-phenoxy)pyrrolidine-1-carboxylate (3.9 g, 11.9 mmol) in ethyl acetate (50 mL) was added platinum on carbon (1.5 g, 287 μmol, 3% purity) under nitrogen gas. The mixture was stirred at 25 °C for 2 h under hydrogen gas (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (3S)- 3-(4-amino-2-fluoro-phenoxy)pyrrolidine-1-carboxylate (3.5 g, 11.8 mmol, 99%) as a yellow oil. m/z ES+ [M-56+H] ⁺ 241.0. [0920] Step 3. Synthesis of tert-Butyl (3S)-3-(4-amino-5-bromo-2-fluoro-phenoxy) pyrrolidine - 1-carboxylate [0921] To a solution of tert-butyl (3S)-3-(4-amino-2-fluoro-phenoxy)pyrrolidine-1-carboxylate (3.5 g, 11.8 mmol) in acetonitrile (35 mL) was added N-bromosuccinimide (1.89 g, 10.6 mmol) portion wise at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, Petroleum ether / Ethyl acetate = 6/1 to1/1) to give tert-butyl (3S)-3-(4-amino-5-bromo- 2-fluoro-phenoxy)pyrrolidine-1-carboxylate (3.7 g, 9.89 mmol, 83%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.07 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 12.0 Hz, 1H), 4.73 (s, 1H), 3.96 (s, 1H), 3.69 - 3.45 (m, 4H), 2.24 - 2.21 (m, 1H), 2.01 (s, 1H), 1.49 (s, 9H). [0922] Step 4. Synthesis of tert-Butyl (3S)-3-(4-amino-5-cyano-2-fluoro-phenoxy)pyrrolidine- 1-carboxylate [0923] To a solution of tert-butyl (3S)-3-(4-amino-5-bromo-2-fluoro-phenoxy)pyrrolidine-1- carboxylate (1.00 g, 2.67 mmol) and zinc cyanide (187 mg, 1.60 mmol) in N,N’-dimethylacetamide (10 mL) was added tris(dibenzylideneacetone)dipalladium(0) (244 mg, 266 μmol) and DavePhos (157 mg, 399 μmol) under nitrogen gas. The mixture was stirred at 110 °C for 3 h under nitrogen gas. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine 30 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude material. The residue was purified by column chromatography (silica gel, Petroleum ether /Ethyl acetate = 6/1 to 1/1) to give tert- butyl (3S)-3-(4-amino-5-cyano-2-fluoro-phenoxy)pyrrolidine-1-carbo xylate (800 mg, 2.49 mmol, 93%) as a white oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.99 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 12.0 Hz, 1H), 4.74 (s, 1H), 4.35 (s, 2H), 3.74 - 3.46 (m, 4H), 2.26 - 2.14 (m, 1H), 2.06 - 2.01 (m, 1H), 1.49 (s, 10H). [0924] Step 5. Synthesis of tert-Butyl (3S)-3-[5-cyano-4-(dimethylaminomethyleneamino)-2- fluoro-phenoxy]pyrrolidine-1-carboxylate [0925] To a solution of tert-butyl (3S)-3-(4-amino-5-cyano-2-fluoro-phenoxy)pyrrolidine-1- carboxylate (750 mg, 2.33 mmol) in toluene (15 mL) was added N,N-dimethylformamide dimethyl acetal (834 mg, 7.00 mmol, 0.930 mL). The mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give tert-butyl (3S)-3-[5-cyano-4- (dimethylaminomethyleneamino)-2-fluoro-phenoxy]pyrrolidine-1 -carboxylate (880 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 377.3. [0926] Step 6. Synthesis of tert-Butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-quinazolin- 6-yl]oxypyrrolidine-1-carboxylate [0927] To a solution of tert-butyl (3S)-3-[5-cyano-4-(dimethylaminomethyleneamino)-2-fluoro- phenoxy]pyrrolidine-1-carboxylate (880 mg, 2.34 mmol) in acetic acid (8.0 mL) was added 3- chloro-2-fluoro-aniline (408 mg, 2.81 mmol) and toluene (8.0 mL). The mixture was stirred at 110 °C for 3 h. The reaction mixture 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 tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-quinazolin-6- yl]oxypyrrolidine-1- carboxylate (550 mg, 1.15 mmol, 49%) as a yellow solid; m/z ES+ [M+H] ⁺ 477.2. [0928] Step 7. Synthesis of N-(3-Chloro-2-fluoro-phenyl)-7-fluoro-6-[(3S)-pyrrolidin-3-y l]oxy- quinazolin-4-amine [0929] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-quinazolin-6- yl]oxypyrrolidine-1-carboxylate (200 mg, 419 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro-phenyl)- 7-fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-quinazolin-4-amine (160 mg, 325 μmol, 78% yield, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 377.1. [0930] Step 8. Synthesis of 1-[(3S)-3-[4-(3-Chloro-2-fluoro-anilino)-7-fluoro-quinazolin -6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0931] To a solution of N-(3-chloro-2-fluoro-phenyl)-7-fluoro-6-[(3S)-pyrrolidin-3-y l]oxy- quinazolin-4-amine (158 mg, 322 μmol, trifluoroacetic acid) and sodium bicarbonate (135 mg, 1.61 mmol) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was added prop-2-enoyl chloride (26.2 mg, 289 μmol, 23.6 μL). The mixture was stirred at 0 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5 um; mobile phase:[water (10 mM NH ₄ HCO ₃ )- acetonitrile]; B%:30%-60%, 9 min) to afford 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro- quinazolin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (38.3 mg, 77.4 μmol, 24%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 8.44 (s, 1H), 8.18 - 8.03 (m, 1H), 7.64 (d, J = 12.0 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.39 - 7.23 (m, 1H), 6.73 - 6.56 (m, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.76 - 5.65 (m, 1H), 5.37 - 5.22 (m, 1H), 4.08 - 3.79 (m, 2H), 3.79 - 3.45 (m, 2H), 2.40 - 2.21 (m, 2H); m/z ES+ [M+H] ⁺ 431.0. Example 43. Preparation of 1-[(3S)-3-[4-[[5-chloro-6-(cyclopropylmethoxy)-3-pyridyl] amino] quinazolin-6-yl] oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 44) [0932] Step 1. Synthesis of tert-Butyl (3S)-3-(3-cyano-4-nitro-phenoxy)pyrrolidine-1- carboxylate [0933] To a stirred solution of 5-fluoro-2-nitro-benzonitrile (500 mg, 3.01 mmol) in N,N- dimethylformamide (2.0 mL) was added potassium carbonate (1.25 g, 9.03 mmol) and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (620 mg, 3.31 mmol). The mixture was stirred at 80 °C for 2 h. 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 (50 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=1/0 to 1/1) to give tert-butyl (3S)-3-(3-cyano-4-nitro-phenoxy)pyrrolidine-1-carboxylate (800 mg, 2.16 mmol, 72%) as a yellow solid. m/z ES+ [M-56] ⁺ 278.3. [0934] Step 2. Synthesis of tert-Butyl (3S)-3-(4-amino-3-cyano-phenoxy)pyrrolidine-1- carboxylate [0935] To a solution of tert-butyl (3S)-3-(3-cyano-4-nitro-phenoxy)pyrrolidine-1-carboxylate (700 mg, 2.10 mmol) in ethyl acetate (4 mL) was added platinum on carbon (300 mg, 1.15 mmol, 3% loading). The mixture was stirred at 25 °C for 2 h under hydrogen gas (15 psi). On completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (3S)- 3-(4-amino-3-cyano-phenoxy)pyrrolidine-1-carboxylate (600 mg, crude) as a yellow solid. m/z ES+ [M-56] ⁺ 248.1. [0936] Step 3. Synthesis of tert-Butyl (3S)-3-[3-cyano-4-[(E)- dimethylaminomethyleneamino]phenoxy]pyrrolidine-1-carboxylat e [0937] To a solution of tert-butyl (3S)-3-(4-amino-3-cyano-phenoxy)pyrrolidine-1-carboxylate (150 mg, 494 μmol) in toluene (3.0 mL) was added N,N-dimethylformamide dimethylacetal (177 mg, 1.48 mmol). The mixture was stirred at 80 °C for 3 h. On completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl (3S)-3-[3-cyano-4-[(E)- dimethylaminomethyleneamino]phenoxy]pyrrolidine-1-carboxylat e (170 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 349.1. [0938] Step 4. Synthesis of tert-Butyl (3S)-3-[4-[[5-chloro-6-(cyclopropylmethoxy)-3- pyridyl]amino]quinazolin-6-yl]oxypyrrolidine-1-carboxylate [0939] To a solution of tert-butyl (3S)-3-[3-cyano-4-[(E)- dimethylaminomethyleneamino]phenoxy]pyrrolidine-1-carboxylat e (170 mg, 474 μmol) in acetic acid (1 mL) and toluene (1 mL) was added 5-chloro-6-(cyclopropylmethoxy)pyridin-3-amine A- 14 (104 mg, 522 μmol). The mixture was stirred at 110 °C for 3 h. On completion, the reaction mixture was concentrated under reduced pressure to give crude material. The residue was purified by prep-TLC (silica gel, Petroleum ether/Ethyl acetate = 1/1) to give tert-butyl (3S)-3-[4-[[5- chloro-6-(cyclopropylmethoxy)-3-pyridyl]amino]quinazolin-6-y l]oxypyrrolidine-1-carboxylate (130 mg, 228 μmol, 48%) as a yellow solid; m/z ES+ [M+H] ⁺ 512.2. [0940] Step 5. Synthesis of N-[5-Chloro-6-(cyclopropylmethoxy)-3-pyridyl]-6-[(3S)-pyrrol idin- 3-yl]oxy-quinazolin-4-amine [0941] To a solution of tert-butyl (3S)-3-[4-[[5-chloro-6-(cyclopropylmethoxy)-3- pyridyl]amino]quinazolin-6-yl]oxypyrrolidine-1-carboxylate (130 mg, 254 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). 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-6-(cyclopropylmethoxy)-3-pyridyl]-6-[(3S)-pyrrol idin-3-yl]oxy- quinazolin-4-amine (130 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H] ⁺ 412.1. [0942] Step 6. Synthesis of 1-[(3S)-3-[4-[[5-Chloro-6-(cyclopropylmethoxy)-3- pyridyl]amino]quinazolin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1 -one [0943] To a solution of N-[5-chloro-6-(cyclopropylmethoxy)-3-pyridyl]-6-[(3S)-pyrrol idin-3- yl]oxy-quinazolin-4-amine (50 mg, 121 μmol) in tetrahydrofuran (2.0 mL) and water (1 mL) was added sodium bicarbonate (20.4 mg, 243 μmol), followed by prop-2-enoyl chloride (13.2 mg, 146 μmol). The mixture was stirred at 25 °C for 1 h. 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 150x25mm, 10 um; mobile phase: [water (0.225% FA)- acetonitrile]; B%:21%-51%, 10 min) to give 1-[(3S)-3-[4-[[5-chloro-6-(cyclopropylmethoxy)-3- pyridyl]amino]quinazolin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1 -one (11.4 mg, 24.5 μmol, 20%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 8.52 - 8.33 (m, 3H), 8.00 - 7.87 (m, 1H), 7.82 - 7.70 (m, 1H), 7.65 - 7.48 (m, 1H), 6.73 - 6.50 (m, 1H), 6.25 - 6.08 (m, 1H), 5.75 - 5.59 (m, 1H), 5.37 - 5.11 (m, 2H), 4.05 - 3.66 (m, 4H), 3.54 - 3.45 (m, 1H), 2.30 - 2.07 (m, 5H), 1.86 - 1.61 (m, 2H); m/z ES+ [M+H] ⁺ 466.1. Example 44. Preparation of 1-[(3S)-3-[4-(3-bromo-2-fluoro-4-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 45) [0944] Step 1. Synthesis of 2-Bromo-3-fluoro-1-methoxy-4-nitro-benzene [0945] To a stirred solution of 2-bromo-1,3-difluoro-4-nitro-benzene (0.5 g, 2.10 mmol) in methanol (5 mL) was added sodium methoxide (5 M in tetrahydrofuran, 0.42 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate = 1/0 to 20/1) to give 2-bromo-3-fluoro-1-methoxy-4-nitro-benzene (180 mg, 720 μmol, 34%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (t, J = 8.8 Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 4.05 (s, 3H). [0946] Step 2. Synthesis of 3-Bromo-2-fluoro-4-methoxy-aniline [0947] To a solution of 2-bromo-3-fluoro-1-methoxy-4-nitro-benzene (180 mg, 720 μmol) in tetrahydrofuran (3 mL) was added platinum on carbon (188 mg, 720 μmol, 3% loading). The mixture was stirred at 25 °C for 1 h under hydrogen gas (15 psi). On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 3-bromo-2-fluoro-4- methoxy-aniline (150 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 220.3. [0948] Step 3. Synthesis of tert-Butyl (3S)-3-[4-(3-bromo-2-fluoro-4-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0949] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (125 mg, 356 μmol) in acetonitrile (2.0 mL) was added 3-bromo-2-fluoro-4- methoxy-aniline (94.1 mg, 428 μmol). The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was filtered and the precipitate was collected, concentrated under reduced pressure to give tert-butyl (3S)-3-[4-(3-bromo-2-fluoro-4-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (180 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 536.1. [0950] Step 4. Synthesis of N-(3-Bromo-2-fluoro-4-methoxy-phenyl)-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0951] To a solution of tert-butyl (3S)-3-[4-(3-bromo-2-fluoro-4-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (60 mg, 112 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (12.8 mg, 112 μmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-(3-bromo-2- fluoro-4-methoxy-phenyl)-6-[(3S)-pyrrolidin-3-yl] oxy-pyrido[3,2-d]pyrimidin-4-amine (60 mg, crude, trifluoroacetic acid) as a yellow solid. m/z ES+ [M+H] ⁺ 434.0. [0952] Step 5. Synthesis of 1-[(3S)-3-[4-(3-Bromo-2-fluoro-4-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0953] To a solution of N-(3-bromo-2-fluoro-4-methoxy-phenyl)-6-[(3S)-pyrrolidin-3-y l] oxy- pyrido[3,2-d]pyrimidin-4-amine (60 mg, 109 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (18.4 mg, 219 μmol), followed by prop-2-enoyl chloride (11.9 mg, 131 μmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875x30mm, 3 um; mobile phase:[water (0.1%FA)-acetonitrile]; B%:26%-56%, 7 min) to give 1-[(3S)-3-[4-(3-bromo-2-fluoro-4-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (16.8 mg, 34.4 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.27 - 10.00 (m, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.82 - 7.65 (m, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 6.79 - 6.50 (m, 1H), 6.24 - 6.00 (m, 2H), 5.80 - 5.59 (m, 1H), 3.94 (s, 3H), 4.10 - 3.52 (m, 4H), 2.40 - 2.13 (m, 2H); m/z ES+ [M+H] ⁺ 488.1. Example 45. Preparation of 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrimido[5,4- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 46) [0954] Step 1. Synthesis of 4,6-Dichloropyrimido[5,4-d]pyrimidine [0955] To a solution of 6-chloropyrimido [5,4-d]pyrimidin-4-ol (400 mg, 2.19 mmol) in thionyl chloride (4.0 mL) was added N,N-dimethylformamide (240 mg, 3.29 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was filtered and concentrated to give 4,6- dichloropyrimido[5,4-d]pyrimidine (400 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 8.23 (s, 1H). [0956] Step 2. Synthesis of 6-Chloro-N-(3-chloro-2-fluoro-phenyl)pyrimido [5,4-d] pyrimidin- 4-amine [0957] To a solution of 4,6-dichloropyrimido[5,4-d]pyrimidine (400 mg, 1.99 mmol) in acetonitrile (5.0 mL) was added 3-chloro-2-fluoro-aniline (289 mg, 1.99 mmol). The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 6-chloro-N-(3-chloro-2-fluoro-phenyl) pyrimido[5,4-d] pyrimidin-4- amine (600 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.72 (s, 1H), 8.31 - 8.24 (m, 1H), 7.65 - 7.52 (m, 3H), 7.31 (dt, J = 1.2, 8.0 Hz, 1H). [0958] Step 3. Synthesis of tert-Butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrimido[5,4- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0959] To a solution of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrimido[5,4-d]pyrimidi n-4- amine (200 mg, 644 μmol) in toluene (2.0 mL) was added tert-butyl (3S)-3-hydroxypyrrolidine- 1-carboxylate (132 mg, 709 μmol), cesium carbonate (630 mg, 1.93 mmol), ditert-butyl-[2-(1,3,5- triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (65.3 mg, 128 μmol) and tris(dibenzylideneacetone)dipalladium (59.0 mg, 64.4 μmol). The mixture was stirred at 80 °C for 2 h under nitrogen gas. On completion, the mixture was purified by reverse-phase HPLC to give tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrimido[5,4-d]pyrimidi n-6-yl]oxypyrrolidine-1- carboxylate (50 mg, 0.11 mmol, 10%) as a yellow solid. m/z ES+ [M+H] ⁺ 461.1. [0960] Step 4. Synthesis of N-(3-Chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy- pyrimido[5,4-d]pyrimidin-4-amine [0961] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrimido[5,4- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (20.0 mg, 43.3 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (4.95 mg, 43.3 μmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give N-(3-chloro-2-fluoro-phenyl)-6-[(3S)- pyrrolidin-3-yl]oxy-pyrimido[5,4-d]pyrimidin-4-amine (15 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 361.0. [0962] Step 5. Synthesis of 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)pyrimido[5,4-d]pyrim idin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0963] To a solution of N-(3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyr imido[5,4- d]pyrimidin-4-amine (7.80 mg, 21.6 μmol) in water (0.5 mL) and tetrahydrofuran (0.5 mL) was added sodium bicarbonate (5.45 mg, 64.6 μmol) and prop-2-enoyl chloride (1.96 mg, 21.6 μmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture 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-[(3S)-3-[4-(3-chloro-2-fluoro- anilino)pyrimido[5,4-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]pro p-2-en-1-one (2.91 mg, 7.03 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (d, J = 2.0 Hz, 1H), 8.60 - 8.44 (m, 2H), 7.81 - 7.67 (m, 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 6.72 - 6.51 (m, 1H), 6.16 (ddd, J = 2.4, 6.8, 16.8 Hz, 1H), 5.97 - 5.83 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 19.2 Hz, 1H), 4.05 - 3.78 (m, 2H), 3.77 - 3.55 (m, 2H), 2.40 - 2.34 (m, 1H), 2.22 (s, 1H); m/z ES+ [M+H] ⁺ 415.4. Example 46. Preparation of 1-[(3S)-3-[4-(2,3,4-trifluoroanilino)pyrido[3,2-d]pyrimidin- 6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 47) [0964] Step 1. Synthesis of tert-Butyl (3S)-3-[4-(2,3,4-trifluoroanilino)pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidine-1-carboxylate [0965] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (100 mg, 285 μmol) in acetonitrile (2.0 mL) was added 2,3,4-trifluoroaniline (62.9 mg, 427 μmol). The mixture was stirred at 80 °C for 2 h. The mixture was filtered and concentrated to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 1:1) to give tert-butyl (3S)-3-[4-(2,3,4-trifluoroanilino)pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (75.0 mg, 0.16 mmol, 51%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.49 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.49 - 7.31 (m, 2H), 5.98 (d, J = 12.4 Hz, 1H), 3.74 (t, J = 10.7 Hz, 1H), 3.52 - 3.41 (m, 3H), 2.35 - 2.09 (m, 2H), 1.40 (d, J = 6.4 Hz, 9H). [0966] Step 2. Synthesis of 6-[(3S)-Pyrrolidin-3-yl]oxy-N-(2,3,4-trifluorophenyl)pyrido[ 3,2- d]pyrimidin-4-amine [0967] To a solution of tert-butyl (3S)-3-[4-(2,3,4-trifluoroanilino)pyrido[3,2-d]pyrimidin-6-y l] oxypyrrolidine-1-carboxylate (70.0 mg, 151 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 h. The mixture was filtered and concentrated to give 6-[(3S)-pyrrolidin-3-yl]oxy-N-(2,3,4- trifluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (54.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 362.1. [0968] Step 3. Synthesis of 1-[(3S)-3-[4-(2,3,4-Trifluoroanilino)pyrido[3,2-d]pyrimidin- 6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0969] To a solution of 6-[(3S)-pyrrolidin-3-yl]oxy-N-(2,3,4-trifluorophenyl)pyrido[ 3,2- d]pyrimidin-4-amine (54.0 mg, 149 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (37.6 mg, 448 μmol) and water (0.5 mL). Prop-2-enoyl chloride (13.5 mg, 149 μmol) was subsequently added at 0 °C, and the mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase: [water (0.225% FA)-acetonitrile]; B%:28%-58%, 11.5 min) to give 1-[(3S)-3-[4-(2,3,4-trifluoroanilino)pyrido[3,2-d]pyrimidin- 6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (17.0 mg, 40.9 μmol, 27%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.59 - 8.32 (m, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.75 - 7.55 (m, 1H), 7.50 - 7.29 (m, 2H), 6.75 - 6.47 (m, 1H), 6.28 - 5.93 (m, 2H), 5.79 - 5.54 (m, 1H), 4.12 - 3.77 (m, 2H), 3.68 - 3.47 (m, 2H), 2.33 - 2.13 (m, 2H); m/z ES+ [M+H] ⁺ 416.1. Example 47. Preparation of 1-[(3S)-3-[4-[(5-chloro-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 48) [0970] Step 1. Synthesis of tert-Butyl (3S)-3-[4-[(5-chloro-3-pyridyl)amino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [0971] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (80.0 mg, 228 μmol), 5-chloropyridin-3-amine (50.0 mg, 388 μmol) and cesium carbonate (240 mg, 736 μmol) in acetonitrile (4.0 mL) was stirred at 80 °C for 4 h. On completion, the reaction was concentrated. The residue was purified by Prep-TLC (Petroleum ether : Ethyl acetate = 1 : 1) to give tert-butyl (3S)-3-[4-[(5-chloro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin- 6- yl]oxypyrrolidine-1-carboxylate (70.0 mg, 0.16 mmol, 68%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77 (s, 1H), 9.10 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.64 (t, J = 2.0 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.26 - 6.06 (m, 1H), 3.82 - 3.68 (m, 1H), 3.55 - 3.36 (m, 3H), 2.29 - 2.07 (m, 2H), 1.41 (br. d, J = 10.4 Hz, 9H); m/z ES+ [M+H] ⁺ 443.2. [0972] Step 2. Synthesis of N-(5-Chloro-3-pyridyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3, 2- d]pyrimidin-4-amine [0973] To a solution of tert-butyl (3S)-3-[4-[(5-chloro-3-pyridyl)amino]pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidine-1-carboxylate (60.0 mg, 135 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.3 mL). The reaction was stirred at 20 °C for 0.5 h. On completion, the reaction mixture was concentrated to give N-(5-chloro-3-pyridyl)-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES +[M+H] ⁺ 343.1. [0974] Step 3. Synthesis of 1-[(3S)-3-[4-[(5-Chloro-3-pyridyl)amino]pyrido[3,2-d]pyrimid in-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0975] To a solution of N-(5-chloro-3-pyridyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3, 2- d]pyrimidin-4-amine (50.0 mg, 145 μmol) in water (0.50 mL) and tetrahydrofuran (0.50 mL) was added sodium bicarbonate (42.9 mg, 510 μmol) at 0 °C to adjust the pH = 8. Prop-2-enoyl chloride (13.2 mg, 145 μmol) was subsequently added in one portion, and the mixture was stirred at 20 °C for 0.25 h. On completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction was purified by Prep-HPLC (column: Phenomenex luna C18150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:24%-54%, 11.5 min) to give 1-[(3S)-3-[4-[(5-chloro-3- pyridyl)amino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl ]prop-2-en-1-one (22.7 mg, 57.3 μmol, 38%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77 (br. d, J = 3.2 Hz, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.64 (t, J = 2.0 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 4.4, 9.2 Hz, 1H), 6.73 - 6.54 (m, 1H), 6.28 - 6.11 (m, 2H), 5.75 - 5.60 (m, 1H), 4.16 - 3.78 (m, 2H), 3.76 - 3.45 (m, 2H), 2.35 - 2.13 (m, 2H); m/z ES+[M+H] ⁺ 397.1. Example 48. Preparation of 1-[(3S)-3-[4-(4-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (Compound 49)

[0976] Step 1. Synthesis of tert-Butyl (3S)-3-[4-(4-chloro-2-fluoro-5-methoxy- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [0977] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate Int-A (150 mg, 427 μmol), 4-chloro-2-fluoro-5-methoxy-aniline A-8 (90.1 mg, 513 μmol) in acetonitrile (0.5 mL) was stirred at 80 °C for 2 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=1/0 to 1/1) to give tert-butyl (3S)-3-[4-(4-chloro-2-fluoro-5- methoxy-anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1 -carboxylate (100 mg, 0.20 mmol, 42%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.48 (s, 1H), 8.14 - 7.99 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 10.0 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 5.86 (d, J = 12.8 Hz, 1H), 3.82 (s, 3H), 3.78 - 3.50 (m, 2H), 3.41 - 3.30 (m, 2H), 2.25 - 2.05 (m, 2H), 1.34 (d, J = 6.8 Hz, 9H); m/z ES+ [M+H] ⁺ 490.2. [0978] Step 2. Synthesis of N-(4-Chloro-2-fluoro-5-methoxy-phenyl)-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine [0979] To a mixture of tert-butyl (3S)-3-[4-(4-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (80.0 mg, 163 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (528 mg, 4.63 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 30 min. On completion, the mixture was concentrated to give N-(4-chloro-2- fluoro-5-methoxy-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[ 3,2-d]pyrimidin-4-amine (60 mg, 0.15 mmol, 84%, trifluoroacetic acid salt) as a brown oil. m/z ES+ [M+H] ⁺ 390.1. [0980] Step 3. Synthesis of 1-[(3S)-3-[4-(4-Chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2 - d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [0981] To a solution of N-(4-chloro-2-fluoro-5-methoxy-phenyl)-6-[(3S)-pyrrolidin-3- yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (60.0 mg,153 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (12.9 mg, 153 μmol) at 0 °C. Prop-2-enoyl chloride (11.1 mg, 123 μmol) in tetrahydrofuran (0.2 mL) was subsequently added dropwise at 0 °C, and the resulting mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase:[water (0.225% FA)-acetonitrile]; B%:35%-65%, 10 min) to give 1-[(3S)-3-[4-(4-chloro-2-fluoro-5-methoxy-anilino)pyrido[3,2 -d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (25.8 mg, 59.6 μmol, 35%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 8.55 (d, J = 1.2 Hz, 1H), 8.15 (dd, J = 1.2, 9.2 Hz, 1H), 7.84 (dd, J = 2.4, 7.2 Hz, 1H), 7.61 (d, J = 10.0 Hz, 1H), 7.41 (dd, J = 4.4, 9.2 Hz, 1H), 6.72 - 6.52 (m, 1H), 6.16 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 6.08 - 5.94 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 18.0 Hz, 1H), 4.07 (dd, J = 4.8, 11.6 Hz, 1H), 3.90 (s, 3H), 3.87 - 3.81 (m, 2H), 3.77 - 3.65 (m, 2H), 3.59 - 3.48 (m, 1H), 3.58 - 3.47 (m, 1H), 2.40 - 2.14 (m, 2H); m/z ES+ [M+H] ⁺ 444.4. Example 49. Preparation of (S)-1-(3-((4-((3-chloro-4-cyclopropoxy-2-fluorophenyl)amino) - pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one [0982] Step 1. 1-(3-Chloro-4-cyclopropoxy-2-fluorophenyl)-2,5-dimethyl-1H-p yrrole [0983] To a solution of 2-chloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-fluorophenol (300 mg, 1.26 mmol) in N,N-dimethylformamide (3 mL) and bromocyclopropane (4.53 g, 37.7 mmol) was added potassium carbonate (346 mg, 2.52 mmol). The mixture was stirred at 180 °C for 10 hr under microwave. 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 (100 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 = 20:1) to give compound 1-(3-chloro-4-cyclopropoxy-2-fluorophenyl)-2,5-dimethyl-1H-p yrrole (200 mg, 0.72 mmol, 50%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 - 7.09 (m, 2H), 5.95 - 5.89 (m, 2H), 3.87 - 3.87 (m, 1H), 3.91 - 3.84 (m, 1H), 2.01 (s, 6H), 0.95 - 0.88 (m, 4H). [0984] Step 2. 3-Chloro-4-cyclopropoxy-2-fluoroaniline [0985] A mixture of 1-(3-chloro-4-cyclopropoxy-2-fluorophenyl)-2,5-dimethyl-1H-p yrrole (190 mg, 0.68 mmol), hydrazine hydrate (944 mg, 13.6 mmol), triethylamine (343 mg, 3.7 mmol) in ethanol (10 mL) and water (2 mL) was stirred at 100 °C for 2 days 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 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 3-chloro-4-cyclopropoxy-2-fluoroaniline (130 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 201.7; [0986] Step 3. tert-Butyl (S)-3-((4-((3-chloro-4-cyclopropoxy-2-fluorophenyl)amino)pyr ido- [3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0987] A mixture of 3-chloro-4-cyclopropoxy-2-fluoroaniline (120 mg, 0.60 mmol), tert-butyl (S)-3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (209 mg, 0.41 mmol) in acetonitrile (2 mL) was stirred at 60 °C for 2 hr. On completion, the reaction mixture was directly purified by reversed-phase HPLC (0.1% formic acid condition) to give compound tert-butyl (S)- 3-((4-((3-chloro-4-cyclopropoxy-2-fluorophenyl)amino)pyrido[ 3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (110 mg, 0.21 mmol, 37%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.72 (s, 1H), 8.69 - 8.56 (m, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.26 - 7.18 (m, 2H), 5.73 - 5.65 (m, 1H), 3.92 - 3.76 (m, 2H), 3.74 - 3.43 (m, 3H), 2.32 (s, 2H), 1.49 (s, 9H), 0.92 - 0.82 (m, 4H); m/z ES+ [M+H] ⁺ 516.0. [0988] Step 4. (S)-N-(3-chloro-4-cyclopropoxy-2-fluorophenyl)-6-(pyrrolidin -3-yloxy)pyrido- [3,2-d]pyrimidin-4-amine [0989] A mixture of tert-butyl (S)-3-((4-((3-chloro-4-cyclopropoxy-2-fluorophenyl)amino)- pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (230 mg, 0.554 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (2 mL) was stirred at 15 °C for 30 min under nitrogen atmosphere. On completion, the mixture was concentrated in vacuo to give compound (S)-N-(3-chloro-4-cyclopropoxy-2-fluorophenyl)-6-(pyrrolidin -3-yloxy)pyrido[3,2-d]pyrimidin- 4-amine (250 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 416.1. [0990] Step 5. (S)-1-(3-((4-((3-chloro-4-cyclopropoxy-2-fluorophenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0991] To a solution of (S)-N-(3-chloro-4-cyclopropoxy-2-fluorophenyl)-6-(pyrrolidin -3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (230 mg, 0.49 mmol) and sodium bicarbonate (182 mg, 2.5 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (39.3 mg, 0.49 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 diluted with acetonitrile (3 mL) and filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge 150x25 mmx 5 um; mobile phase: [water(10mM NH ₄ HCO ₃ )-acetonitrile]; B%: 43%-73%,8 min) to give compound (S)-1-(3-((4-((3-chloro-4-cyclopropoxy-2-fluorophenyl)amino) pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (101 mg, 0.21 mmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 12.4 Hz, 1H), 8.74 (d, J = 3.2 Hz, 1H), 8.66 – 8.55 (m, 1H), 8.19 (t, J = 7.2 Hz, 1H), 7.27 - 7.20 (m, 2H), 6.58 - 6.37 (m, 2H), 5.83 - 5.67 (m, 2H), 4.10 - 4.01 (m, 1H), 3.97 - 3.70 (m, 4H), 2.54 - 2.26 (m, 2H), 0.96 - 0.80 (m, 4H); m/z ES+ [M+H] ⁺ 470.0. Example 50. Preparation of (S)-1-(3-((4-((3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl) amino)- pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one [0992] Step 1. 1-(4-(Bromodifluoromethoxy)-3-chloro-2-fluorophenyl)-2,5-dim ethyl-1H- pyrrole [0993] To a solution of 2-chloro-4-(2,5-dimethylpyrrol-1-yl)-3-fluoro-phenol (1.5 g, 6.26 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (4.32 g, 31.3 mmol) and dibromo(difluoro)methane (6.57 g, 31.3 mmol). The mixture was stirred at 80 °C for 2 hr. 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 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 1/1) to give 1-[4- [bromo(difluoro)methoxy]-3-chloro-2-fluoro-phenyl]-2,5-dimet hyl-pyrrole (1.4 g, 3.80 mmol, 61%) as a yellow solid. m/z ES+ [M+H] ⁺ 369.9. [0994] Step 2. 1-(3-Chloro-2-fluoro-4-(trifluoromethoxy)phenyl)-2,5-dimethy l-1H-pyrrole [0995] To a solution of 1-[4-[bromo(difluoro)methoxy]-3-chloro-2-fluoro-phenyl]-2,5- dimethyl- pyrrole (1.4 g, 3.80 mmol) in dichloromethane (15 mL) was added silver tetrafluoroborate (1.11 g, 5.70 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (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, which was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15 um; mobile phase: [water(trifluoroacetic acid)- acetonitrile]; B%: 61%-91%,11min) to afford 1-[3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl]- 2,5-dimethyl-pyrrole (240 mg, 780 μmol, 21%) as an off-white solid. DMSO- d6) δ 7.27 - 7.19 (m, 2H), 5.96 (s, 2H), 2.02 (s, 6H). [0996] Step 3. 3-Chloro-2-fluoro-4-(trifluoromethoxy)aniline [0997] To a solution of 1-[3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-2,5-dimethy l-pyrrole (190 mg, 617 μmol) in ethanol (10 mL) and water (2 mL) was added hydrazine hydrate (1.29 g, 18.5 mmol) and triethylamine (312 mg, 3.09 mmol). The mixture was stirred at 110 °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 3-chloro-2-fluoro-4-(trifluoromethoxy)aniline (200 mg, crude) as a brown solid. m/z ES+ [M+H] ⁺ 229.9. [0998] Step 4. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxyl ate [0999] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (250 mg, 713 μmol) in acetonitrile (5 mL) was added 3-chloro-2-fluoro-4- (trifluoromethoxy)aniline (164 mg, 713 μmol). The mixture was stirred at 40 °C for 2 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=5/1 to 1/1) to give tert-butyl (3S)- 3-[4-[3-chloro-2-fluoro-4-(trifluoromethoxy)anilino]pyrido[3 ,2-d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate (200 mg, 368 μmol, 52%) as a yellow solid. m/z ES+ [M+H] ⁺ 544.2. [01000] Step 5. (S)-N-(3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl)-6-(pyrr olidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01001] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(trifluoromethoxy)anilino]- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (200 mg, 368 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2- fluoro-4-(trifluoromethoxy)phenyl]-6-[(3S)-pyrrolidin-3-yl]o xy-pyrido[3,2-d]pyrimidin-4-amine (200 mg, 358 μmol, 98%) as a brown oil. m/z ES+ [M+H] ⁺ 444.0. [01002] Step 6. (S)-1-(3-((4-((3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl) amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01003] To a solution of N-[3-chloro-2-fluoro-4-(trifluoromethoxy)phenyl]-6-[(3S)-pyr rolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (200 mg, 451 μmol) in tetrahydrofuran (8 mL) and water (3 mL) was added sodium bicarbonate (189 mg, 2.25 mmol) and prop-2-enoyl chloride (40.8 mg, 451 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. 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 prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 50%- 80%, 10 min) to afford 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(trifluoromethoxy)anilino] pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (103 mg, 207 μmol, 46%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.57 (s, 1H), 8.27 - 8.15 (m, 1H), 8.13 - 8.06 (m, 1H), 7.60 (br. d, J = 9.2 Hz, 1H), 7.43 (dd, J = 4.8, 9.2 Hz, 1H), 6.76 - 6.48 (m, 1H), 6.17 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 6.08 - 5.94 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 18.8 Hz, 1H), 4.13 - 3.81 (m, 2H), 3.77 - 3.55 (m, 2H), 2.42 - 2.19 (m, 2H); m/z ES+ [M+H] ⁺ 497.9. Example 51. Preparation of 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01004] Step 1. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01005] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (0.2 g, 420 μmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (116 mg, 841 μmol) and [(2S)-tetrahydrofuran-2-yl]methyl methanesulfonate (114 mg, 630 μmol). The mixture was stirred at 25 °C for 2 hr. 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 sodium sulfate, filtered and concentrated under reduced pressure in vacuo to give tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4- (((S)-tetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (250 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 560.2. [01006] Step 2. N-(3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2-yl)methoxy)ph enyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01007] To a solution of tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate (0.25 g, 446 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2-yl)methoxy)ph enyl)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (250 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 460.2. [01008] Step 3. 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2-y l)methoxy)phenyl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01009] To a solution of N-(3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-2-yl)methoxy)ph enyl)-6- (((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (0.2 g, 349 μmol) in tetrahydrofuran (2 mL) and water (1 mL) was added potassium carbonate (48.1 mg, 348 μmol) and prop-2-enoyl chloride (31.5 mg, 348 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%: 32%-62%,15min) to give 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((S)- tetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrim idin-6-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one (44.3 mg, 85.3 μmol, 24%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d6) δ 9.60 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.39 - 7.30 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.71 - 6.54 (m, 1H), 6.21 - 5.97 (m, 2H), 5.69 - 5.60 (m, 1H), 4.29 - 4.14 (m, 2H), 4.13 - 4.08 (m, 1H), 3.91 - 3.50 (m, 6H), 2.42 - 2.20 (m, 2H), 2.07 - 1.73 (m, 4H); m/z ES+ [M+H] ⁺ 513.9. Example 52. Preparation of 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01010] Step 1. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01011] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (0.2 g, 420.26 μmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (116 mg, 841 μmol) and [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (114 mg, 630 μmol). The mixture was stirred at 25 °C for 2 hr. 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 sodium sulfate, filtered and concentrated under reduced pressure in vacuo to give tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4- (((R)-tetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d ]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (250 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 560.2. [01012] Step 2. N-(3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)ph enyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01013] To a solution of tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate (0.25 g, 446 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)ph enyl)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (250 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 460.2. [01014] Step 3. 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01015] To a solution of N-(3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)ph enyl)-6- (((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (0.2 g, 348 μmol) in tetrahydrofuran (2 mL) and water (1 mL) was added potassium carbonate (48.1 mg, 348 μmol) and prop-2-enoyl chloride (31.5 mg, 348 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(formic acid)- acetonitrile]; B%: 32%-62%,15 min) to give 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)- tetrahydrofuran-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrim idin-6-yl)oxy) pyrrolidin-1- yl)prop-2-en-1-one (24.9 mg, 48.0 μmol, 14%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.60 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.39 - 7.35 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.73 - 6.52 (m, 1H), 6.21 - 6.00 (m, 2H), 5.69 - 5.60 (m, 1H), 4.29 - 4.14 (m, 2H), 4.14 - 4.08 (m, 1H), 3.88 - 3.51 (m, 6H), 2.45 - 2.18 (m, 2H), 2.08 - 1.74 (m, 4H); m/z ES+ [M+H] ⁺ 513.9. Example 53. Preparation of 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01016] Step 1. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01017] To a solution of tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolid ine-1-carboxylate (300 mg, 630 μmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (261 mg, 1.89 mmol) and [(3S)-tetrahydrofuran-3-yl]methyl methanesulfonate (227 mg, 1.26 mmol). The mixture was stirred at 60 °C for 16 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 3), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl(S)-3-((4-((3-chloro-2- fluoro-4-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)amino)pyr ido[3,2-d] pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (400 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 560.0. [01018] Step 2. N-(3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-3-yl)methoxy)ph enyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01019] To a solution of tert-butyl(S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofu ran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate (200 mg, 357 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated in vacuo to give N-(3-chloro-2- fluoro-4-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2- d]pyrimidin-4-amine (200 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 460.2. [01020] Step 3. 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01021] To a solution of N-(3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-3-yl)methoxy)ph enyl)-6- (((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (200 mg, 348 μmol) in tetrahydrofuran (1 mL) was added sodium bicarbonate (87.8 mg, 1.05 mmol) in water (1 mL). Then prop-2-enoyl chloride (28.4 mg, 314 μmol) was added. The mixture was stirred at 0 °C for 0.2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 31%-61%, 10 min) to give 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one (37.9 mg, 72.9 μmol, 21%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.44 - 7.33 (m, 1H), 7.17 - 7.07 (m, 1H), 6.70 - 6.50 (m, 1H), 6.19 - 6.12 (m, 1H), 6.11 - 5.97 (m, 1H), 5.72 - 5.63 (m, 1H), 4.13 - 4.05 (m, 2H), 3.85 - 3.76 (m, 4H), 3.73 - 3.62 (m, 4H), 2.76 - 2.67 (m, 1H), 2.40 - 2.18 (m, 2H), 2.09 - 2.00 (m, 1H), 1.77 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 514.0. Example 54. Preparation of 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01022] Step 1. tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01023] To a solution of tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolid ine-1-carboxylate (300 mg, 630 μmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (261 mg, 1.89 mmol) and [(3R)-tetrahydrofuran-3-yl]methyl methanesulfonate (227 mg, 1.26 mmol). The mixture was stirred at 60 °C for 16 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 3), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (S)-3-((4-((3-chloro-2- fluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)amino)pyr ido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (380 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 560.0. [01024] Step 2. N-(3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)ph enyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01025] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate (190 mg, 339 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated in vacuo to give N-(3-chloro-2-fluoro-4- (((R)-tetrahydrofuran-3-yl)methoxy)phenyl)-6-(((S)-pyrrolidi n-3-yl)oxy)pyrido [3,2-d]pyrimidin- 4-amine (190 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 460.2. [01026] Step 3. 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01027] To a solution of N-(3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)ph enyl)-6- (((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (190 mg, 331 μmol) in tetrahydrofuran (1 mL) was added sodium bicarbonate (83.4 mg, 993 μmol) in water (1 mL). Then prop-2-enoyl chloride (27.0 mg, 298 μmol) was added. The mixture was stirred at 0 °C for 0.2 hr. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(formic acid)-acetonitrile]; B%: 31%-61%, 10 min) to give 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one (40.2 mg, 77.3 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (d, J = 5.6 Hz, 1H), 8.48 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.44 - 7.36 (m, 1H), 7.17 - 7.10 (m, 1H), 6.71 - 6.52 (m, 1H), 6.19 - 6.12 (m, 1H), 6.12 - 5.99 (m, 1H), 5.74 - 5.62 (m, 1H), 4.13 - 4.05 (m, 2H), 3.86 - 3.76 (m, 4H), 3.72 - 3.61 (m, 4H), 2.78 - 2.68 (m, 1H), 2.41 - 2.17 (m, 2H), 2.09 - 1.99 (m, 1H), 1.77 - 1.67 (m, 1H); m/z ES+ [M+H] ⁺ 514.0. Example 55. Preparation of (S)-1-(3-((4-((3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phe nyl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one

[01028] Step 1. 2,3-Dichloro-1-(1-methylcyclopropoxy)-4-nitrobenzene [01029] To a solution of 1-methylcyclopropanol (515 mg, 7.14 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (381 mg, 9.52 mmol, 60% in mineral oil) portionwise at 0 °C. The mixture was stirred 0 °C for 15 min. And 2,3-dichloro-1-fluoro-4-nitro-benzene (1 g, 4.76 mmol) was added portionwise at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched by aqueous ammonium chloride (10 mL) dropwise at 0 °C, and then extracted with ethyl acetate (20 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 2,3-dichloro-1-(1- methylcyclopropoxy)-4-nitro-benzene (1.5 g, crude) as a brown oil. [01030] Step 2. 2-Chloro-3-fluoro-1-(1-methylcyclopropoxy)-4-nitrobenzene [01031] A solution of 2,3-dichloro-1-(1-methylcyclopropoxy)-4-nitro-benzene (0.1 g, 381 μmol), cesium fluoride (86.9 mg, 572 μmol) in dimethyl sulfoxide (3 mL) was stirred at 140 °C for 16 hr. The reaction mixture was quenched by addition water (20 mL) at 25 °C, 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, filtered and concentrated under reduced pressure to give 2-chloro-3-fluoro-1-(1- methylcyclopropoxy)-4-nitro-benzene (0.1 g, crude) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (t, J = 9.2, 1H), 7.42 - 7.5 (m, 1H), 1.56 (s, 3H), 1.05 - 1.85 (m, 6H). [01032] Step 3. 3-Chloro-2-fluoro-4-(1-methylcyclopropoxy)aniline [01033] To a solution of 2-chloro-3-fluoro-1-(1-methylcyclopropoxy)-4-nitro-benzene (50 mg, 203 μmol) in ethanol (1 mL) and water (0.4 mL) was added iron powder (56.8 mg, 1.02 mmol) and ammonium chloride (87.1 mg, 1.63 mmol). The mixture was stirred at 80 °C for 30 min. The reaction mixture was filtered and 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 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-2-fluoro-4-(1-methylcyclopropoxy)aniline (60 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 216.0. [01034] Step 4. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(1- methylcyclopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) oxy)pyrrolidine-1-carboxylate [01035] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (85 mg, 242 μmol) in acetonitrile (3 mL) was added 3-chloro-2-fluoro-4-(1- methylcyclopropoxy)aniline (54.9 mg, 254 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was 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 tert-butyl (3S)- 3-[4-[3-chloro-2-fluoro-4-(1-methylcyclopropoxy)anilino]pyri do[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (80 mg, 128 μmol, 53%) as a brown solid. m/z ES+ [M+H] ⁺ 530.1. [01036] Step 5. (S)-N-(3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl)-6-( pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01037] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(1- methylcyclopropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypy rrolidine-1-carboxylate (80 mg, 128 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give N-[3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl]-6-[(3S) -pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (60 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 430.1. [01038] Step 6. (S)-1-(3-((4-((3-Chloro-2-fluoro-4-(1-methylcyclopropoxy)phe nyl)amino)pyrido- [3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01039] To a solution of N-[3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl]-6-[(3S) - pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (60 mg, 110 μmol) in tetrahydrofuran (2 mL) and water (0.5 mL) was added sodium bicarbonate (46.3 mg, 551 μmol) and prop-2-enoyl chloride (9.98 mg, 110 μmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 5 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: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water(formic acid)- acetonitrile]; B%: 45%-75%,7 min) and lyophilized to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(1- methylcyclopropoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypy rrolidin-1-yl]prop-2-en-1-one (33.5 mg, 68.9 μmol, 62%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.47 (s, 1H), 8.12 (dd, J = 1.2, 9.2 Hz, 1H), 7.67 (dt, J = 4.0, 8.8 Hz, 1H), 7.39 (dd, J = 4.4, 9.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 6.72 - 6.52 (m, 1H), 6.16 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.12 - 5.98 (m, 1H), 5.69 (m, 1H), 4.11 - 3.50 (m, 4H), 2.42 - 2.14 (m, 2H), 1.57 (s, 3H), 1.05 - 0.95 (m, 2H), 0.91 - 0.82 (m, 2H); m/z ES+ [M+H] ⁺ 484.0. Example 56. Preparation of (S)-1-(3-((4-((3-chloro-2-fluoro-4-(1-methylcyclobutoxy)phen yl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01040] Step 1. 2,3-Dichloro-1-(1-methylcyclobutoxy)-4-nitrobenzene [01041] To a mixture of 1-methylcyclobutanol (369 mg, 4.29 mmol) in tetrahydrofuran (10.0 mL) was added sodium hydride (171 mg, 4.29 mmol, 60% in mineral oil) portionwise at 0 °C, the reaction mixture was stirred at 0 °C for 30 min. Then 2,3-dichloro-1-fluoro-4-nitro-benzene (600 mg, 2.86 mmol) was added into the mixture, the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (25 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=100/0 to 40/60) to give 2,3-dichloro-1-(1-methylcyclobutoxy)-4-nitro-benzene (500 mg, 1.81 mmol, 63%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 9.2 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 2.63 - 2.44 (m, 2H), 2.35 - 2.22 (m, 2H), 1.99 - 1.70 (m, 2H), 1.63 (s, 3H). [01042] Step 2. 2-Chloro-3-fluoro-1-(1-methylcyclobutoxy)-4-nitrobenzene [01043] A suspension of 2,3-dichloro-1-(1-methylcyclobutoxy)-4-nitro-benzene (500 mg, 1.81 mmol) and cesium fluoride (412 mg, 2.72 mmol) in dimethyl sulfoxide (10 mL) was stirred at 140 °C for 12 hr. On completion, the reaction mixture was 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 2-chloro-3-fluoro-1-(1- methylcyclobutoxy)-4-nitro-benzene (500 mg, crude) as a yellow oil without further purification. [01044] Step 3. 3-Chloro-2-fluoro-4-(1-methylcyclobutoxy)aniline [01045] To a mixture of 2-chloro-3-fluoro-1-(1-methylcyclobutoxy)-4-nitro-benzene (480 mg, 1.85 mmol) in tetrahydrofuran (5 mL) was added Pt/V/C (1.61 g, 1.85 mmol, 3% loading). The reaction mixture was stirred at 25 °C under hydrogen (15 psi) atmosphere for 10 min. On completion, the reaction mixture was filtered and concentrated in vacuo to give 3-chloro-2-fluoro- 4-(1-methylcyclobutoxy)aniline (350 mg, 1.52 mmol, 82%) as a black solid without further purification. m/z ES+[M+H] ⁺ 230.2. [01046] Step 4. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(1- methylcyclobutoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)o xy)pyrrolidine-1-carboxylate [01047] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - car boxylate (150 mg, 427 μmol) and 3-chloro-2-fluoro-4-(1-methylcyclobuto xy)aniline (117 mg, 513 μmol) in acetonitrile (3.0 mL) was stirred at 80 °C for 12 hr. On completion, the reaction mixture was 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 column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/0 to 48/52) to give tert-butyl (3S)-3-[4-[3-chloro-2- fluoro-4-(1-methylcyclobutoxy)anilino]pyrido[3,2-d]pyrimidin -6-yl]oxypyrrolidine-1- carboxylate (170 mg, 312 μmol, 73%) as a red solid. m/z ES+[M+H] ⁺ 544.2. [01048] Step 5. (S)-N-(3-chloro-2-fluoro-4-(1-methylcyclobutoxy)phenyl)-6-(p yrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01049] To a mixture of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(1-methylcyclobutoxy)anilin o]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (170 mg, 312 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol), the reaction mixture was stirred at 25 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(1-methylcyclobutoxy)phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (120 mg, 270 μmol, 86%) as a red oil without further purification. m/z ES+[M+H] ⁺ 444.2. [01050] Step 6. (S)-1-(3-((4-((3-chloro-2-fluoro-4-(1-methylcyclobutoxy)phen yl)amino)pyrido[- 3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01051] To a mixture of N-[3-chloro-2-fluoro-4-(1-methylcyclobutoxy)phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (120 mg, 270 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (22.7 mg, 270 μmol) at 0 °C to pH= 7~8, and then prop-2-enoyl chloride (24.4 mg, 270 μmol) was added. The reaction mixture was stirred at 0 °C for 10 min. 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 reversed-phase HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water(NH ₄ HCO ₃ )-acetonitrile]; B%: 52%-82%, 10 min) to give 1- [(3S)-3-[4-[3-chloro-2-fluoro-4-(1-methylcyclobutoxy)anilino ]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (42.3 mg, 84.9 μmol, 31%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.46 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.69 - 7.53 (m, 1H), 7.42 - 7.34 (m, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.24 - 5.95 (m, 2H), 5.75 - 5.60 (m, 1H), 4.13 - 4.02 (m, 0.5H), 3.86 - 3.72 (m, 2H), 3.67 (d, J = 13.6 Hz, 1H), 3.56 - 3.50 (m, 0.5H), 2.43 - 2.37 (m, 2H), 2.36 - 2.26 (m, 2H), 2.25 - 2.19 (m, 2H), 1.83 - 1.69 (m, 2H), 1.57 (s, 3H); m/z ES+[M+H] ⁺ 498.0. Example 57. Preparation of (S)-1-(3-((4-((4-(2-(azetidin-1-yl)-2-oxoethoxy)-3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one [01052] Step 1. tert-Butyl (S)-3-((4-((4-(2-(azetidin-1-yl)-2-oxoethoxy)-3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi ne-1-carboxylate [01053] To a mixture of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (200 mg, 420 μmol) in 1-methylpyrrolidin-2-one (5.0 mL) was added sodium phosphate (275 mg, 1.68 mmol) and 1-(azetidin-1-yl)-2-chloro- ethanone (168 mg, 1.26 mmol). The reaction mixture was stirred at 40 °C for 12 hr. On completion, the reaction mixture was quenched by water (10 mL) and then 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 0/1) to give tert-butyl (3S)-3-[4-[4-[2-(azetidin-1-y l)-2-oxo-ethoxy]-3-chloro-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (160 mg, 279 μmol, 66%) as a white solid. m/z ES+[M+H] ⁺ 573.1. [01054] Step 2. (S)-1-(azetidin-1-yl)-2-(2-chloro-3-fluoro-4-((6-(pyrrolidin -3-yloxy)pyrido[3,2- d]pyrimidin-4-yl)amino)phenoxy)ethan-1-one [01055] To a mixture of tert-butyl (3S)-3-[4-[4-[2-(azetidin-1-yl)-2-oxo-ethoxy]-3-chloro-2- fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (90.0 mg, 157 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 mxiture was concentrated in vacuo to give compound (S)-1-(azetidin-1-yl)-2-(2-chloro-3-fluoro-4-((6-(pyrrolidin -3- yloxy)pyrido[3,2-d]pyrimidin-4-yl)amino)phenoxy)ethan-1-one (70.0 mg, 148 μmol, 94%) as a yellow solid without purification. m/z ES+[M+H] ⁺ 473.1. [01056] Step 3. (S)-1-(3-((4-((4-(2-(azetidin-1-yl)-2-oxoethoxy)-3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one [01057] To a mixture of 1-(azetidin-1-yl)-2-[2-chloro-3-fluoro-4-[[6-[(3S)-pyrrolidi n-3- yl]oxypyrido[3,2-d]pyrimidin-4-yl]amino]phenoxy]ethanone (70.0 mg, 148 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (12.4 mg, 148 μmol) to pH=7~8, and then prop-2-enoyl chloride (13.4 mg, 148 μmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.3 hr. On completion, the reaction mixture was quenched by water (2.0 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 reversed-phase HPLC (column: Phenomenex Synergi C18 150 x 25 mm, 10 um; mobile phase: [water(0.225%formic acid)-acetonitrile]; B%: 22%-52%, 10 min) to give compound (S)-1-(3-((4-((4-(2-(azetidin-1-yl)- 2-oxoethoxy)-3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyri midin-6-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one (52.0 mg, 97.6 μmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.70 - 7.56 (m, 1H), 7.45 - 7.34 (m, 1H), 6.98 (d, J = 9.2 Hz, 1H), 6.73 - 6.50 (m, 1H), 6.21 - 6.12 (m, 1H), 6.11 - 5.98 (m, 1H), 5.75 - 5.62 (m, 1H), 4.81 (s, 2H), 4.29 (t, J = 7.6 Hz, 2H), 4.13 - 4.04 (m, 0.5H), 3.93 (t, J = 7.6 Hz, 2H), 3.84 - 3.62 (m, 3H), 3.58 - 3.49 (m, 0.5H), 2.36 - 2.12 (m, 4H); m/z ES+[M+H] ⁺ 527.0. Example 58. Preparation of (S)-1-(3-((4-((3-chloro-4-ethoxy-2-fluorophenyl)amino)pyrido [3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01058] Step 1. tert-Butyl (S)-3-((4-((3-chloro-4-ethoxy-2-fluorophenyl)amino)pyrido[3, 2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [01059] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (200 mg, 420 μmol) in acetonitrile (1.5 mL) was added potassium carbonate (145 mg, 1.05 mmol) and iodoethane (78.6 mg, 504 μmol). The mixture was stirred at 60 °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 tert-butyl (3S)-3-[4-(3-chloro-4-ethoxy-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (140 mg, 252 μmol, 59%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.73 - 7.51 (m, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.16 - 6.99 (m, 1H), 6.11 - 5.85 (m, 1H), 4.29 - 4.13 (m, 2H), 3.87 - 3.67 (m, 1H), 3.59 - 3.37 (m, 3H), 2.44 - 2.19 (m, 2H), 1.99 (s, 1H), 1.44 - 1.38 (m, 1H), 1.43 - 1.38 (m, 1H), 1.45 - 1.38 (m, 1H), 1.44 - 1.37 (m, 9H), 1.26 - 1.13 (m, 1H); m/z ES+ [M+H] ⁺ 504.2. [01060] Step 2. (S)-N-(3-Chloro-4-ethoxy-2-fluorophenyl)-6-(pyrrolidin-3-ylo xy)pyrido[3,2- d]pyrimidin-4-amine [01061] To a solution of tert-butyl (3S)-3-[4-(3-chloro-4-ethoxy-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, 198 μmol) in dichloromethane (1 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-ethoxy-2- fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyri midin-4-amine (80 mg, crude) as a brown liquid. m/z ES+ [M+H] ⁺ 404.1. [01062] Step 3. (S)-1-(3-((4-((3-Chloro-4-ethoxy-2-fluorophenyl)amino)pyrido [3,2-d]pyrimidin- 6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01063] To a solution of N-(3-chloro-4-ethoxy-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-y l]oxy- pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 198 μmol) in tetrahydrofuran (0.75 mL) and water (0.75 mL) was added sodium bicarbonate (41.6 mg, 495 μmol) to adjust pH ~ 7. Then prop-2- enoyl chloride (17.9 mg, 198 μmol) was added at 0 °C. 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: Phenomenex luna C18150x25 mm 10 um; mobile phase: [water (0.225% FA) - acetonitrile]; B%: 31% - 61%, 10 min) to give 1-[(3S)-3-[4-(3-chloro-4- ethoxy-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrro lidin-1-yl]prop-2-en-1-one (33.3 mg, 73 μmol, 35%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.75 - 7.49 (m, 1H), 7.44 - 7.19 (m, 1H), 7.09 (d, J = 9.2 Hz, 1H), 6.82 - 6.51 (m, 1H), 6.26 - 5.94 (m, 2H), 5.78 - 5.49 (m, 1H), 4.25 - 4.13 (m, 2H), 3.93 - 3.44 (m, 4H), 2.43 - 2.35 (m, 1H), 2.45 - 2.34 (m, 1H), 2.45 - 2.31 (m, 1H), 1.40 (t, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 458.2. Example 59. Preparation of (S)-1-(3-((4-((3-chloro-4-(2,2-difluoropropoxy)-2-fluorophen yl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one

[01064] Step 1. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(2- oxopropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01065] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (450 mg, 946 μmol), potassium carbonate (392 mg, 2.84 mmol) and potassium iodide (15.7 mg, 94.6 μmol) in N,N-dimethylformamide (5.0 mL) was added 1-chloropropan-2-one (105 mg, 1.13 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 4 hr. 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 column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1:1 to 1:2) to give tert-butyl (3S)-3-[4-(4-acetonyloxy-3-chloro-2- fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (214 mg, 402 μmol, 43%) as a yellow solid. m/z ES+ [M+H] ⁺ 532.1. [01066] Step 2. tert-Butyl (S)-3-((4-((3-chloro-4-(2,2-difluoropropoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi ne-1-carboxylate [01067] To a solution of tert-butyl (3S)-3-[4-(4-acetonyloxy-3-chloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (210 mg, 395 μmol) in dichloromethane (4.0 mL) was added diethylaminosulfur trifluoride (95.5 mg, 592 μmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 12 hr. 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 column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1:1 to 1:2) to give tert-butyl (3S)- 3-[4-[3-chloro-4-(2,2-difluoropropoxy)-2-fluoro-anilino]pyri do[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (112 mg, 202 μmol, 51%) as a yellow solid. m/z ES+ [M+H] ⁺ 554.0. [01068] Step 3. (S)-N-(3-Chloro-4-(2,2-difluoropropoxy)-2-fluorophenyl)-6-(p yrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01069] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(2,2-difluoropropoxy)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (110 mg, 199 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462mg, 4.05 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to N-[3- chloro-4-(2,2-difluoropropoxy)-2-fluoro-phenyl]-6-[(3S)-pyrr olidin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (96 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 454.1. [01070] Step 4. (S)-1-(3-((4-((3-Chloro-4-(2,2-difluoropropoxy)-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one [01071] To a solution of N-[3-chloro-4-(2,2-difluoropropoxy)-2-fluoro-phenyl]-6-[(3S) - pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (90 mg, 198 μmol) in tetrahydrofuran (0.9 mL) was added a solution of sodium bicarbonate (133 mg, 1.59 mmol) in water (0.3 mL), and then prop-2-enoyl chloride (16.2 mg, 179 μmol) was added dropwise 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: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water(formic acid) - acetonitrile]; B%: 40% - 70%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-4-(2,2- difluoropropoxy)-2-fluoro-anilino]pyrido[3,2-d]pyrimidin-6-y l]oxypyrrolidin-1-yl]prop-2-en-1- one (47 mg, 93 μmol, 47%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.46 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.77 - 7.63 (m, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 7.20 (d, J = 9.2 Hz, 1H), 6.70 - 6.53 (m, 1H), 6.20 - 5.98 (m, 1H), 6.11 - 5.98 (m, 1H), 5.72 - 5.63 (m, 1H), 4.49 (t, J = 12.4 Hz, 2H), 4.10 - 3.76 (m, 2H), 3.74 - 3.49 (m, 2H), 2.41 - 2.14 (m, 2H), 1.80 (t, J = 19.2 Hz, 3H); m/z ES+ [M+H] ⁺ 508.0. Example 60. Preparation of (S)-1-(3-((4-((3-chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolid in-1-yl)prop-2-en-1-one [01072] Step 1. 3-(2-Chloro-3-fluoro-4-nitrophenoxy)-1-methyl-1H-pyrazole [01073] To a mixture of 2-chloro-1,3-difluoro-4-nitro-benzene (2.00 g, 10.3 mmol) and 1- methylpyrazol-3-ol (1.01 g, 10.3 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (3.57 g, 25.8 mmol), the reaction 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 (60 mL x 2). The combined organic layers were washed with brine (60 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 5/1) to give 3-(2-chloro-3-fluoro-4-nitro-phenoxy)-1-methyl-pyrazole (620 mg, 2.28 mmol, 22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.20-8.12 (m, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 1.6, 9.6 Hz, 1H), 6.10 (d, J = 2.0 Hz, 1H), 3.79 (s, 3H); m/z ES+[M+H]+ 272.1. [01074] Step 2. 3-Chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline [01075] To a mixture of 3-(2-chloro-3-fluoro-4-nitro-phenoxy)-1-methyl-pyrazole (600 mg, 2.21 mmol) in ethanol (3.0 mL) and water (3.0 mL) was added ammonium chloride (1.18 g, 22.0 mmol) and iron powder (616 mg, 11.0 mmol). The reaction mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give 3- chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy-aniline (500 mg, 2.07 mmol, 93%) as a red oil without purification. m/z ES+[M+H] ⁺ 242.1. [01076] Step 3. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolid ine-1-carboxylate [01077] A mixture of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrroli dine-1- carboxylate (200 mg, 570 μmol) and 3-chloro-2-fluoro-4-(1-methylpyrazol-3-y l)oxy-aniline (137 mg, 570 μmol) in acetonitrile (2.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched by 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 (3S)-3-[4-[3-chloro-2- fluoro-4-(1-methylpyrazol-3-yl)oxy-ani lino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (200 mg, 359 μmol, 63%) as a yellow solid without purification. m/z ES+[M+H] ⁺ 556.0. [01078] Step 4. 3-Chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3-yl)oxy)aniline [01079] To a mixture of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (180 mg, 323 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 0.5 hr. On completion, the reaction mxiture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-[ (3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (120 mg, 263 μmol, 81%) as a yellow oil without purification. m/z ES+[M+H] ⁺ 456.1. [01080] Step 5. (S)-1-(3-((4-((3-Chloro-2-fluoro-4-((1-methyl-1H-pyrazol-3- yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolid in-1-yl)prop-2-en-1-one [01081] To a mixture of N-[3-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy-phenyl]-6-[ (3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (120 mg, 263 μmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added sodium bicarbonate (22.1 mg, 263 μmol) at 0 °C to pH 7~8, and then prop-2-enoyl chloride (23.8 mg, 263 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 (30mL 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 C18150 x 25 mm 10 um; mobile phase: [water(formic acid)- acetonitrile]; B%: 30% - 60%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(1-methylpyrazol-3-yl)oxy- anilino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (110 mg, 212 μmol, 80%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.49 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 4.4, 9.2 Hz, 1H), 7.11 (br. d, J = 9.2 Hz, 1H), 6.73 - 6.50 (m, 1H), 6.23 - 6.11 (m, 1H), 6.10 - 5.97 (m, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.74 - 5.63 (m, 1H), 4.07 (dd, J = 5.2, 12.0 Hz, 1H), 3.86 - 3.76 (m, 2H), 3.75 (s, 3H), 3.70 - 3.66 (m, 1H), 3.57 - 3.50 (m, 1H), 2.38 - 2.12 (m, 2H); m/z ES+[M+H] ⁺ 510.0. Example 61. Preparation of (S)-1-(3-((4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3- chloro- 2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01082] Step 1. tert-Butyl (S)-3-((4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-chl oro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi ne-1-carboxylate [01083] A solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (0.08 g, 168 μmol), 2-oxabicyclo[2.1.1]hexan-4- ylmethyl 4-methylbenzenesulfonate (67.6 mg, 252 μmol) and potassium carbonate (46.4 mg, 336 μmol) in N,N-dimethylformamide (2 mL) was stirred at 80 °C for 16 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (S)-3-((4-((4-((2- oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-chloro-2-fluorophenyl )amino)pyrido[3,2-d]pyrimidin- 6-yl)oxy)pyrrolidine-1-carboxylate (0.08 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 572.2. [01084] Step 2. (S)-N-(4-((2-Oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-chloro-2 -fluorophenyl)-6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine [01085] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (0.07 g, 122 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 (S)-N-(4- ((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-chloro-2-fluoroph enyl)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (0.07 g, crude, TFA) as a yellow solid. m/z ES+[M+H] ⁺ 472.1. [01086] Step 3. (S)-1-(3-((4-((4-((2-Oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3- chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidi n-1-yl)prop-2-en-1-one [01087] To a solution of N-[3-chloro-2-fluoro-4-(2-oxabicyclo[2.1.1]hexan-4-ylmethoxy )phenyl]- 6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (0.07 g, 119 μmol, TFA) and sodium bicarbonate (30.1 mg, 358 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2- enoyl chloride (10.8 mg, 119 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 150 x 25 mm 5 um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 37% - 67%, 9 min) to give (S)-1-(3-((4-((4-((2-oxabicyclo[2.1.1]hexan-4- yl)methoxy)-3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrim idin-6-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one (0.016 g, 30.4 μmol, 25%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (d, J = 1.2 Hz, 1 H), 8.06 (dd, J = 9.2, 3.2 Hz, 1 H), 7.94 - 8.01 (m, 1 H), 7.34 (dd, J = 9.2, 4.4 Hz, 1 H), 6.95 - 7.08 (m, 1 H), 6.54 - 6.77 (m, 1 H), 6.23 - 6.37 (m, 1 H), 5.89 - 6.04 (m, 1 H), 5.79 - 5.75 (m, 1 H), 4.61 (s, 1 H), 4.43 (s, 2 H), 4.12 (dd, J = 12.4, 4.8 Hz, 1 H), 3.80 - 3.97 (m, 3 H), 3.78 (s, 2 H), 3.64 - 3.73 (m, 1 H), 2.29 - 2.51 (m, 2 H), 2.02 (d, J = 5.2 Hz, 2 H), 1.65 (dd, J = 4.8, 1.6 Hz, 2 H); m/z ES+[M+H] ⁺ 526.1. Example 62. Preparation of (S)-1-(3-((4-((4-(difluoromethoxy)-2,3-difluorophenyl)amino) - pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one [01088] Step 1. tert-Butyl (S)-3-((4-((4-(difluoromethoxy)-2,3-difluorophenyl)amino)pyr ido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [01089] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (0.5 g, 1.09 mmol) and sodium;2-chloro-2,2- difluoro-acetate (249 mg, 1.63 mmol) in N,N-dimethylformamide (10 mL) was added sodium carbonate (231 mg, 2.18 mmol). The mixture solution was stirred at 100 °C for 2 hr. On completion, the mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL × 2). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (S)-3-((4-((4-(difluoromethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli dine-1-carboxylate (250 mg, 491 μmol, 45%) as a pale yellow solid. m/z ES+ [M+H] ⁺ 510.2. [01090] Step 2. (S)-N-(4-(Difluoromethoxy)-2,3-difluorophenyl)-6-(pyrrolidin -3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01091] To a solution of tert-butyl (3S)-3-[4-[4-(difluoromethoxy)-2,3-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (150 mg, 294 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 (S)-N-(4- (difluoromethoxy)-2,3-difluorophenyl)-6-(pyrrolidin-3-yloxy) pyrido[3,2-d]pyrimidin-4-amine (160 mg, crude, TFA salt) as a brown oil. m/z ES+ [M+H] ⁺ 410.2. [01092] Step 3. (S)-1-(3-((4-((4-(Difluoromethoxy)-2,3-difluorophenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01093] To a solution of (S)-N-(4-(difluoromethoxy)-2,3-difluorophenyl)-6-(pyrrolidin -3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (160 mg, 306 μmol, TFA salt) in tetrahydrofuran (3 mL) and water (3 mL) was added sodium bicarbonate (77 mg, 917 μmol) and prop-2-enoyl chloride (28 mg, 306 μmol) at 0 °C. Then 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 × 25 mm, 5 um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 41% - 71%, 10 min) and re-purified by prep-HPLC (column: Phenomenex C1870 × 30 mm × 3 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 35% - 65%, min) to give (S)-1-(3-((4-((4-(difluoromethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one (70.5 mg, 149 μmol, 49%) as a yellow solid. ¹ H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.14 – 8.07 (m, 2H), 7.42 - 7.39 (m, 1H), 7.28 - 7.23 (m, 1H), 6.95 (t, J = 73.2 Hz, 1H), 6.76 - 6.59 (m, 1H), 6.35 - 6.30 (m, 1H), 6.05 - 5.98 (m, 1H), 5.82 - 5.75 (m, 1H), 4.17 - 3.92 (m, 1H), 3.88 - 3.69 (m, 3H), 2.50 - 2.46 (m, 1H), 2.41 - 2.38 (m, 1H); m/z ES+ [M+H] ⁺ 464.0. Example 63. Preparation of (S)-1-(3-((4-((4-(cyclopropylmethoxy)-2,3-difluorophenyl)ami no)- pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one [01094] Step 1. tert-Butyl (S)-3-((4-((4-(cyclopropylmethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli dine-1-carboxylate [01095] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (250 mg, 544 μmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (150.41 mg, 1.09 mmol) and bromomethylcyclopropane (88.15 mg, 653 μmol). The mixture was stirred at 40 °C for 2 hr. On completion, The reaction mixture was concentrated under reduced pressure to give tert-butyl (S)-3-((4-((4- (cyclopropylmethoxy)-2,3-difluorophenyl)amino)pyrido[3,2-d]p yrimidin-6-yl)oxy)pyrrolidine-1- carboxylate (200 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 514.2. [01096] Step 2. (S)-N-(4-(Cyclopropylmethoxy)-2,3-difluorophenyl)-6-(pyrroli din-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01097] To a solution of tert-butyl (S)-3-((4-((4-(cyclopropylmethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli dine-1-carboxylate (0.1 g, 195 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (385.00 mg, 3.38 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give (S)-N-(4-(cyclopropylmethoxy)-2,3-difluorophenyl)-6-(pyrroli din-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (100 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 414.3. [01098] Step 3. (S)-1-(3-((4-((4-(Cyclopropylmethoxy)-2,3-difluorophenyl)ami no)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01099] To a solution of (S)-N-(4-(cyclopropylmethoxy)-2,3-difluorophenyl)-6-(pyrroli din-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (0.1 g, 190 μmol, TFA salt) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (26.20 mg, 190 μmol) and prop-2-enoyl chloride (17.16 mg, 190 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: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 35% - 65%, 10 min) to give (S)-1-(3-((4-((4-(cyclopropylmethoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one (22.34 mg, 47.31 μmol, 25%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.51 - 8.44 (m, 1H), 8.12 - 8.00 (m, 1H), 7.50 - 7.36 (m, 2H), 7.14 - 7.02 (m, 1H), 6.70 - 6.51 (m, 1H), 6.22 - 5.98 (m, 2H), 5.69 – 5.55 (m, 1H), 4.12 - 3.79 (m, 4H), 3.78 - 3.60 (m, 2H), 2.41 - 2.22 (m, 2H), 1.35 - 1.20 (m, 1H), 0.68 - 0.55 (m, 2H), 0.43 - 0.34 (m, 2H); m/z ES+ [M+H] ⁺ 468.3. Example 64. Preparation of (S)-1-(3-((4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop -2-en-1-one [01100] Step 1. tert-Butyl (S)-3-((4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amin o)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxyl ate [01101] A solution of 6-bromo-N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7-f luoro- pyrido[3,2-d]pyrimidin-4-amine (480 mg, 1.10 mmol), tris(dibenzylideneacetone)dipalladium (100 mg, 109 μmol), ditert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]ph osphane (111 mg, 219 μmol) and cesium carbonate (1.07 g, 3.29 mmol) in toluene (5.00 mL) was stirred at 85 °C for 0.2 hr under nitrogen atmosphere. Then a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1- carboxylate (216 mg, 1.15 mmol) in toluene (5.00 mL) was added. The reaction was stirred at 85 °C for 3.8 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 a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7- fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (50.0 mg, 92 μmol, 8%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.72 (s, 1H), 8.51 (s, 1H), 8.11 (d, J = 10.4 Hz, 1H), 7.87 - 7.75 (m, 1H), 7.60 - 7.18 (m, 2H), 6.07 (br. dd, J = 4.4, 6.0 Hz, 1H), 3.87 - 3.69 (m, 1H), 3.57 - 3.42 (m, 3H), 2.32 - 2.12 (m, 2H), 1.41 (br. d, J = 3.2 Hz, 9H). [01102] Step 2. (S)-N-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-7-fluoro -6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01103] A solution of tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxyl ate (50.0 mg, 91.9 μmol) in trifluoroacetic acid (336 mg, 2.95 mmol, 218 μL) and dichloromethane (2.00 mL) was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated to give N-[3-chloro-4- (difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-6-[(3S)-pyrrolid in-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (41.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 444.1. [01104] Step 3. (S)-1-(3-((4-((3Chloro-4-(difluoromethoxy)-2-fluorophenyl)am ino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01105] To a solution of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-6- [(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (41.0 mg, 92.4 μmol) in tetrahydrofuran (0.50 mL) and water (0.5 mL) was added sodium bicarbonate (23.3 mg, 277 μmol) at 0 °C until pH stabilized at 8. After that, prop-2-enoyl chloride (10.0 mg, 110 μmol, 9.01 μL) was added. The mixture was stirred at 20 °C for 0.25 hr. On completion, the reaction mixture was concentrate to give a crude product. The crude product was purified by Prep-HPLC (column: Phenomenex Luna C18100 x 30 mm, 5 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 42% - 72%, 8 min) to give 1-[(3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] -7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (15.1 mg, 30.3 μmol, 29%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 8.51 (s, 1H), 8.11 (dd, J = 2.4, 10.8 Hz, 1H), 7.81 (dt, J = 2.4, 8.8 Hz, 1H), 7.60 - 7.18 (m, 2H), 6.67 -6.56 (m, 1H), 6.24 - 6.06 (m, 2H), 5.73 – 5.68 (m, 1H), 4.18 - 3.80 (m, 2H), 3.78 - 3.46 (m, 2H), 2.40 - 2.34 (m, 1H), 2.29 - 2.14 (m, 1H); m/z ES+ [M+H] ⁺ 498.1. Example 65. Preparation of (S)-1-(3-((4-((3-chloro-4-(cyclopropylmethoxy)-2-fluoropheny l)- amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one [01106] Step 1. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-hydroxyphenyl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxyl ate [01107] To a mixture of tert-butyl (3S)-3-[[6-cyano-5-(dimethylaminomethyleneamino)-3-fluoro- 2-pyridyl]oxy]pyrrolidine-1-carboxylate (130 mg, 345 μmol) in acetic acid (1 mL) and toluene (1 mL) was added 4-amino-2-chloro-3-fluoro-phenol (61.2 mg, 379 μmol), then the mixture was stirred at 110 °C for 3 hr. On completion, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered and contracted in vacuo to give tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4- hydroxy-anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyr rolidine-1-carboxylate (175 mg, crude) as a brown oil. m/z ES+ [M+H] ⁺ 494.0. [01108] Step 2. tert-Butyl (S)-3-((4-((3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)a mino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carbox ylate [01109] To a mixture of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 304 μmol) in N,N- dimethylformamide (0.5 mL) was added potassium carbonate (84.0 mg, 607 μmol) and bromomethylcyclopropane (45.1 mg, 334 μmol), then the mixture was stirred at 60 °C for 2 hr. On completion, the reaction mixture was poured into water (20 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were 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=1/2) to afford tert-butyl (3S)-3-[4-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-anilino]-7-fluoro-pyrido[3,2-d ]pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (56.0 mg, 93.4 μmol, 30%) as a yellow oil. m/z ES+ [M+H] ⁺ 548.1. [01110] Step 3. (S)-N-(3-Chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)-7-flu oro-6-(pyrrolidin- 3-yloxy)pyrido[3,2-d]pyrimidin-4-amine [01111] A mixture of tert-butyl (3S)-3-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino] -7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxyl ate (42.0 mg, 76.7 μmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) was stirred at 25 °C for 20 mins. On completion, the mixture was concentrated under reduced pressure to give N-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]-7-fluoro-6-[(3S)-pyrro lidin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (44.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 448.0. [01112] Step 4. (S)-1-(3-((4-((3-Chloro-4-(cyclopropylmethoxy)-2-fluoropheny l)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01113] To a mixture of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-7-fluoro -6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (42.0 mg, 93.8 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.1 mL) was added sodium bicarbonate (15.8 mg, 188 μmol) and prop-2-enoyl chloride (10.2 mg, 113 μmol), then the mixture was stirred at 0 °C for 20 mins. On completion, the reaction mixture was poured into water (15 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 150 × 25 mm, 10 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 43% - 73%, 8 min) to give 1-[(3S)-3-[4-[3-chloro-4-(cyclopropylmethoxy)-2- fluoro-anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrr olidin-1-yl]prop-2-en-1-one (22.6 mg, 44.9 μmol, 47%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.64 (s, 1H), 8.45 (s, 1H), 8.08 - 8.05 (m, 1H), 7.58 - 7.53 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.71 - 6.54 (m, 1H), 6.19 - 6.13 (m, 2H), 5.72 - 5.65 (m, 1H), 4.10 - 4.00 (m, 2H), 3.87 - 3.51 (m, 4H), 2.42 - 2.23 (m, 1H), 2.31 - 2.23 (m, 1H), 1.31 - 1.26 (m, 1H), 0.64 - 0.59 (m, 2H), 0.39 - 0.37 (m, 2H); m/z ES+ [M+H] ⁺ 502.3. Example 66. Preparation of (S)-1-(3-((8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01114] Step 1. tert-Butyl (S)-3-((8-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrroli dine-1-carboxylate [01115] A mixture of tert-butyl (3S)-3-(4-chloropyrimido[5,4-d]pyrimidin-6-yl)oxypyrrolidine -1- carboxylate (74.0 mg, 210 μmol) and 3-chloro-4-(difluoromethoxy)-2-fluoro-aniline (53.41 mg, 252 μmol) in acetonitrile (1 mL) was stirred at 40 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated in ethyl acetate (2 mL) to afford compound tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]oxypyrrolidine-1-carbo xylate (105 mg, 194 μmol, 92%) as a yellow solid. m/z ES+ [M+H] ⁺ 527.1. [01116] Step 2. (S)-N-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-6-(pyrro lidin-3- yloxy)pyrimido[5,4-d]pyrimidin-4-amine [01117] A mixture of tert-butyl (3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]oxypyrrolidine-1-carbo xylate (105 mg, 199 μmol) in trifluoroacetic acid (0.2 mL) 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-(difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrro lidin-3-yl]oxy-pyrimido[5,4- d]pyrimidin-4-amine (105 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 426.8. [01118] Step 3. (S)-1-(3-((8-((3-Chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01119] To a mixture of N-[3-chloro-4-(difluoromethoxy)-2-fluoro-phenyl]-6-[(3S)-pyr rolidin-3- yl]oxy-pyrimido[5,4-d]pyrimidin-4-amine (105 mg, 194 μmol, TFA salt) in tetrahydrofuran (2 mL) and water (0.5 mL) was added sodium bicarbonate (32.6 mg, 388 μmol). Then prop-2-enoyl chloride (19.3 mg, 214 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was poured into methanol (0.5 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (FA) - ACN]; B%: 42% - 72%, 10.5min) to afford 1-[(3S)-3-[4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] pyrimido[5,4-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (23.6 mg, 49.1 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 9.40 (d, J = 4.0 Hz, 1H), 8.58 (s, 1H), 7.77 - 7.72 (m, 1H), 7.59 - 7.20 (m, 2H), 6.70 - 6.52 (m, 1H), 6.20 - 6.14(m, 1H), 5.98 - 5.87 (m, 1H), 5.73 -5.65 (m, 1H), 4.05 - 3.79 (m, 2H), 3.77 - 3.50 (m, 2H), 2.43 - 2.26 (m, 2H); m/z ES+ [M+H] ⁺ 481.0. Example 67. Preparation of (S)-1-(3-((8-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01120] Step 1. tert-Butyl (S)-3-((8-((3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrroli dine-1-carboxylate [01121] To a mixture of tert-butyl (3S)-3-(4-chloropyrimido[5,4-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (80.0 mg, 227 μmol) in acetonitrile (1 mL) was added 3-chloro- 4-(cyclopropylmethoxy)-2-fluoro-aniline (58.9 mg, 273 μmol) and then the mixture was stirred at 40 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl (3S)-3-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino] pyrimido[5,4- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (139 mg, 225 μmol, 99%) as a yellow oil. m/z ES+ [M+H] ⁺ 531.1. [01122] Step 2. (S)-N-(3-Chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)-6-(py rrolidin-3- yloxy)pyrimido[5,4-d]pyrimidin-4-amine [01123] A mixture of tert-butyl (3S)-3-[4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]pyrimido[5,4-d]pyrimidin-6-yl]oxypyrrolidine-1-carbo xylate (110 mg, 207 μmol) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.1 mL) was stirred at 25 °C for 10 mins. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)-pyrrolidin-3-y l]oxy-pyrimido[5,4-d]pyrimidin- 4-amine (110 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 431.1. [01124] Step 3. (S)-1-(3-((8-((3-Chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01125] To a mixture of N-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrimido[5,4-d]pyrimidin-4-amine (110 mg, 255 μmol) in anhydrous tetrahydrofuran (1.5 mL) and water (0.1 mL) was added prop-2-enoyl chloride (23.1 mg, 255 μmol) and sodium bicarbonate (21.5 mg, 255 μmol). The mixture was stirred at 0 °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 C18100 x 30mm 5 um; mobile phase: [water(formic acid)- acetonitrile]; B%: 37%-67%, 8 min) to give 1-[(3S)-3-[4-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-anilino]pyrimido[5,4-d]pyrimid in-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (30.3 mg, 60.0 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 9.36 (d, J = 2.4 Hz, 1H), 8.51 (s, 1H), 7.52 -7.48 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.71 - 6.53 (m, 1H), 6.21 – 6.09 (m, 1H), 5.99 - 5.84 (m, 1H), 5.74 - 5.63 (m, 1H), 4.04 - 3.96 (m, 2H), 3.95 - 3.76 (m, 2H), 3.75 - 3.49 (m, 2H), 2.32 - 2.18 (m, 2H), 1.36 - 1.23 (m, 1H), 0.66 - 0.55 (m, 2H), 0.44 - 0.32 (m, 2H); m/z ES+ [M+H] ⁺ 484.9. Example 68. Preparation of 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydro-2H-pyran -2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01126] Step 1. (S)-(Tetrahydro-2H-pyran-2-yl)methyl methanesulfonate [01127] To a mixture of [(2S)-tetrahydropyran-2-yl]methanol (100 mg, 860 μmol) in dichloromethane (2.0 mL) was added triethylamine (174 mg, 1.72 mmol), and then methanesulfonyl chloride (147 mg, 1.29 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched by water (20.0 mL) and aqueous sodium bicarbonate (10.0 mL), extracted with dichloromethane (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give [(2S)-tetrahydropyran-2- yl]methyl methanesulfonate (200 mg, crude) as a yellow oil without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.18 - 4.16 (m, 2H), 4.03 – 3.99 (m, 1H), 3.64 – 3.55 (m, 1H), 3.49 – 3.38 (m, 1H), 3.06 (s, 3H), 1.95 – 1.81 (m, 1H), 1.60 - 1.52 (m, 4H), 1.41 - 1.29 (m, 1H). [01128] Step 2. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((S)-tetrahydro-2H-pyran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01129] To a mixture of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 315 μmol) in N,N-dimethylformamide (4.0 mL) was added potassium carbonate (87.1 mg, 630 μmol). Then [(2S)-tetrahydropyran-2- yl]methyl methanesulfonate (91.8 mg, 472 μmol) was added and the reaction mixture was stirred at 80 °C for 3 hrs. 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 column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 20/80) to give compound tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4- [[(2S)-tetrahydropyran-2-yl]methoxy]aniline]pyrido[3,2-d]pyr imidin-6-yl]oxypyrrolidine-1- carboxylate (70.0 mg, 121 μmol, 38%) as a yellow solid. m/z ES+[M+H] ⁺ 574.3. [01130] Step 3. N-(3-chloro-2-fluoro-4-(((S)-tetrahydro-2H-pyran-2-yl)methox y)phenyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01131] To a mixture of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[[(2S)-tetrahydropyran-2-yl]m e thoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-c arboxylate (70.0 mg, 121 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.08 g, 9.45 mmol), the reaction mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[[(2S)-tetrahydropyran-2-yl]methoxy]p henyl]-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, crude, TFA) as a yellow oil. m/z ES+[M+H] ⁺ 474.2. [01132] Step 4. 1-((S)-3-((4-((3-Chloro-2-fluoro-4-(((S)-tetrahydro-2H-pyran -2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01133] To a mixture of N-[3-chloro-2-fluoro-4-[[(2S)-tetrahydropyran-2-yl]methoxy]p henyl]-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, 105 μmol) in water (1.0 mL) and tetrahydrofuran (1.0 mL) was added sodium bicarbonate (8.86 mg, 105 μmol) at 0 °C to pH = 7~8, and then prop-2-enoyl chloride (9.55 mg, 105 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 h. On completion, the reaction mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (20.0 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 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 37%-67%, 10 min) to give compound 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-[[(2S)-tetrahydropyran-2- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one (18.3 mg, 34.1 μmol, 32%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.66 – 7.61 (m, 1H), 7.40 – 7.36 (m, 1H), 7.11 (d, J = 9.6 Hz, 1H), 6.66 – 6.57 (m, 1H), 6.19 – 6.13 (m, 2H), 5.72 – 5.67 (m, 1H), 4.11 – 4.07 (m, 2H), 3.92 (d, J = 11.2 Hz, 1H), 3.81 – 3.76 (m, 2H), 3.71 – 3.61 (m, 4H), 2.31 – 2.26 (m, 2H), 1.86 – 1.83 (m, 1H), 1.70 (d, J = 12.0 Hz, 1H), 1.55 – 1.37 (m, 4H); m/z ES+[M+H] ⁺ 527.9. Example 69. Preparation of 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran -2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01134] Step 1. (R)-(tetrahydro-2H-pyran-2-yl)methyl methanesulfonate [01135] To a solution of [(2R)-tetrahydropyran-2-yl]methanol (100 mg, 860 μmol) and triethylamine (174 mg, 1.72 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (147 mg, 1.29 mmol). The mixture was stirred at 0 °C for 2 hrs. On completion, the reaction mixture was quenched by addition ice water 10 mL at 0 °C, 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 [(2R)- tetrahydropyran-2-yl]methyl methanesulfonate (150 mg, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.20 - 4.16 (m, 2H), 4.02 (d, J = 11.2 Hz, 1H), 3.66 - 3.58 (m, 1H), 3.51 - 3.41 (m, 1H), 3.07 (s, 3H), 1.95 - 1.87 (m, 1H), 1.60 (s, 2H), 1.56 - 1.51 (m, 2H), 1.44 - 1.32 (m, 1H). [01136] Step 2. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01137] To a solution of [(2R)-tetrahydropyran-2-yl]methyl methanesulfonate (91.8 mg, 472 μmol) and tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2-d] pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (150 mg, 315 μmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (87.1 mg, 630 μmol). The mixture was stirred at 80 °C for 6 hrs. On completion, the reaction mixture was quenched by addition 50 mL water at 25 °C, and then extracted with ethyl acetate (50 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 (3S)-3-[4-[3-chloro-2-fluoro-4-[[(2R)-tetrahydropyran-2-yl]m ethoxy]anilino]- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (180 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 574.3. [01138] Step 3. N-(3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran-2-yl)methox y)phenyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01139] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[[(2R)-tetrahydropyran-2- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate (180 mg, 313 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (35.7 mg, 313 μmol). 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-[[(2R)-tetrahydropyran-2-yl]methoxy]phenyl ]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (150 mg, crude) as a yellow oil. m/z ES+ 474.2. [01140] Step 4. N-(3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran-2-yl)methox y)phenyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01141] To a solution of N-[3-chloro-2-fluoro-4-[[(2R)-tetrahydropyran-2-yl]methoxy]p henyl]-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (150 mg, 316 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (26.5 mg, 316 μmol) to pH = 7~8, then prop-2-enoyl chloride (28.6 mg, 316 μmol) was added to the mixture. The mixture was stirred at 0 °C for 5 min. On completion, the reaction mixture was quenched by addition water 10 mL at 0 °C, and then 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 prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 37%-70%,11min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-[[(2R)-tetrahydropyran-2-y l]methoxy]anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (50.7 mg, 96.0 μmol, 30%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.44 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.63 (dt, J = 3.6, 8.8 Hz, 1H), 7.37 (dd, J = 4.4, 9.2 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.18-6.12 (m, 1H), 6.10 - 5.97 (m, 1H), 5.71-5.64 (m, 1H), 4.11 - 4.06 (m, 2H), 3.91 (d, J = 11.6 Hz, 1H), 3.85 - 3.72 (m, 2H), 3.72 - 3.51 (m, 4H), 2.40 - 2.15 (m, 2H), 1.83 (dd, J = 2.8, 8.8 Hz, 1H), 1.70 (d, J = 12.0 Hz, 1H), 1.58 - 1.34 (m, 4H); m/z ES+ [M+H] ⁺ 528.0. Example 70. Preparation of 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran -3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01142] Step 1. (R)-(Tetrahydro-2H-pyran-3-yl)methyl methanesulfonate [01143] To a solution of [(3S)-tetrahydropyran-3-yl]methanol (60.0 mg, 516 μmol) in dichloromethane (2.0 mL) was added triethylamine (157 mg, 1.55 mmol, 216 μL), then methanesulfonyl chloride (118 mg, 1.03 mmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1.5 hrs. On completion, the reaction mixture was quenched by addition water 30 mL at 0 °C and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give [(3R)-tetrahydropyran-3-yl]methyl methanesulfonate (104 mg, crude) as a yellow oil. [01144] Step 2. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01145] To a solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 315 μmol) and [(3R)-tetrahydropyran-3- yl]methyl methanesulfonate (73.5 mg, 378 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (131 mg, 946 μmol). The mixture was stirred at 80 °C for 12 hrs. On completion, the reaction mixture was quenched by addition water 50 mL at 25 °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 tert-butyl (3S)- 3-[4-[3-chloro-2-fluoro-4-[[(3R)-tetrahydropyran-3-yl]methox y]anilino]pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidine-1-carboxylate (172 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 574.1. [01146] Step 3. N-(3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran-3-yl)methox y)phenyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01147] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-[[(3R)-tetrahydropyran-3-yl] methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1 -carboxylate (172 mg, 300 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-[[(3R)-tetrahydropyran-3-yl]methoxy]p henyl]-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (195 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 474.0. [01148] Step 4. 1-((S)-3-((4-((3-chloro-2-fluoro-4-(((R)-tetrahydro-2H-pyran -3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01149] To a solution of N-[3-chloro-2-fluoro-4-[[(3R)-tetrahydropyran-3-yl]methoxy]p henyl]-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (195 mg, 332 μmol, TFA salt) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (223 mg, 2.65 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (27.0 mg, 298 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 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: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water(FA)- ACN]; B%: 41%-71%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-[[(3R)-tetrahydropyran- 3-yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolid in-1-yl]prop-2-en-1-one (34.1 mg, 64.6 μmol, 19%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ )煩 9.60 (s, 1H), 8.45 (s, 1H), 8.15 - 8.06 (m, 1H), 7.69 - 7.57 (m, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.71 - 6.52 (m, 1H), 6.15 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.11 - 5.98 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.10 - 4.01 (m, 2H), 3.99 - 3.90 (m, 1H), 3.87 - 3.61 (m, 4H), 3.59 - 3.37 (m, 2H), 3.31 (s, 1H), 2.41 - 2.02 (m, 3H), 1.93 - 1.80 (m, 1H), 1.68 - 1.38 (m, 3H); m/z ES+ [M+H] ⁺ 528.0. Example 71. Preparation of (S)-1-(3-((4-((3-chloro-2-fluoro-4-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01150] Step 1. (Tetrahydro-2H-pyran-4-yl)methyl methanesulfonate [01151] To a mixture of tetrahydropyran-4-ylmethanol (1.00 g, 8.61 mmol) in dichloromethane (15.0 mL) was added triethylamine (1.74 g, 17.2 mmol), and then methanesulfonyl chloride (1.48 g, 12.9 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched by water (40 mL) and aqueous sodium bicarbonate (10.0 mL), and then 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 tetrahydropyran-4-ylmethyl methanesulfonate (1.60 g, crude) as a yellow oil. ¹ H NMR (400 MHz, 400 MHz, CDCl ₃ ) δ 4.07 (d, J = 6.8 Hz, 2H), 4.05 - 3.96 (m, 2H), 3.50 – 3.35 (m, 2H), 3.02 (s, 3H), 2.11 - 1.95 (m, 1H), 1.75 – 1.60 (m, 2H), 1.45 - 1.33 (m, 2H). [01152] Step 2. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01153] To a mixture of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (300 mg, 630 μmol) in N,N-dimethylformamide (5.0 mL) was added potassium carbonate (174 mg, 1.26 mmol), and then tetrahydropyran-4- ylmethyl methanesulfonate (122 mg, 630 μmol) was added. The reaction mixture was stirred at 80 °C for 12 hrs. 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 tert-butyl (3S)-3-[4-[3-chloro-2- fluoro-4-(tetrahydropyran-4-ylmethoxy)anilino]pyrido[3,2-d]p yrimidin-6-yl]oxypyrrolidine-1- carboxylate (250 mg, 435 μmol, 69%) as a red solid. m/z ES+[M+H] ⁺ 574.1. [01154] Step 3. (S)-N-(3-chloro-2-fluoro-4-((tetrahydro-2H-pyran-4-yl)methox y)phenyl)-6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine [01155] To a mixture of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydropyran-4- ylmethoxy)anil ino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (250 mg, 435 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaciton mxiture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give N-[3-chloro-2-fluoro-4-(tetrahydropyran-4-ylmethoxy)phenyl]- 6-[(3S)- pyrrolidin-3-yl]oxypyrido[3,2-d]pyrimidin-4-amine (180 mg, 379 μmol, 87%) as a yellow solid without purification. m/z ES+[M+H] ⁺ 474.0. [01156] Step 4. (S)-1-(3-((4-((3-chloro-2-fluoro-4-((tetrahydro-2H-pyran-4-y l)methoxy)phenyl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01157] To a mixture of N-[3-chloro-2-fluoro-4-(tetrahydropyran-4-ylmethoxy)phenyl]- 6-[(3S)- pyr rolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (180 mg, 379 μmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was added sodium bicarbonate (31.9 mg, 379 μmol) at 0 °C to pH = 7~8, and then prop-2-enoyl chloride (34.3 mg, 379 μmol) was added. The reaction mixture was stirred at 0 °C for 30 min. 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 a residue. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 33%-63%, 10 min) to give 1- [(3S)-3-[4-[3-chloro-2-fluoro-4-(tetrahydropyran-4-ylmethoxy )anilino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (119 mg, 222 μmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.44 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.70 – 7.55 (m, 1H), 7.42 – 7.30 (m, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.71 - 6.52 (m, 1H), 6.22 - 5.95 (m, 2H), 5.75 – 5.55 (m, 1H), 4.15 – 4.08 (m, 1H), 4.01 (d, J = 6.4 Hz, 2H), 3.98 – 3.75 (m, 2H), 3.86 - 3.77 (m, 1H), 3.76 - 3.61 (m, 2H), 3.57 - 3.44 (m, 1H), 3.33 (br. s, 1H), 2.38 - 2.14 (m, 2H), 2.12 - 2.02 (m, 1H), 1.71 (d, J = 12.0 Hz, 2H), 1.45 - 1.34 (m, 2H); m/z ES+[M+H] ⁺ 527.9. Example 72. Preparation of 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01158] Step 1. (R)-(tetrahydrofuran-3-yl)methyl methanesulfonate [01159] To a solution of [(3S)-tetrahydrofuran-3-yl]methanol (100 mg, 979 μmol) in dichloromethane (2 mL) was added trimethylamine (297 mg, 2.94 mmol, 409 μL), the mixture was stirred at 0 °C for 10 min. Then methylsulfonyl methanesulfonate (512 mg, 2.94 mmol) was added and the mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched by addition water 30 mL at 20 °C and then extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered and concentrated in vacuo to give [(3R)-tetrahydrofuran-3-yl]methyl methanesulfonate (203 mg, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 4.24 - 4.07 (m, 2H), 3.94 - 3.80 (m, 2H), 3.80 - 3.60 (m, 2H), 3.08 - 2.98 (m, 3H), 2.76 - 2.62 (m, 1H), 2.16 - 2.04 (m, 1H), 1.71 - 1.62 (m, 1H). [01160] Step 2. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01161] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (153 mg, 333 μmol) and [(3R)-tetrahydrofuran -3- yl]methylmethanesulfonate (100 mg, 333 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (138 mg, 999 μmol). The mixture was stirred at 80 °C for 12 hrs. 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 x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (3S)-3-[4-[2,3-difluoro-4- [[(3R)-tetrahydrofuran-3-yl]methoxy]anilino]pyrido[3,2-d]pyr imidin-6-yl]oxypyrrolidine-1- carboxylate (182 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 544.2. [01162] Step 3. N-(2,3-difluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl) -6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01163] To a solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate (182 mg, 335 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give N-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl ]-6-[(3S)-pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (223 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 444.0. [01164] Step 4. 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3-yl)met hoxy)phenyl)amino)- pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one [01165] To a solution of N-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl ]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (223 mg, 400 μmol, TFA salt) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (269 mg, 3.20 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (32.6 mg, 360 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 then 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: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 33%-57%,8 min) to give 1-[(3S)-3-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin -1-yl]prop-2-en-1-one (36.2 mg, 72.8 μmol, 18%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 8.45 (s, 1H), 8.11 (dd, J = 1.2, 9.2 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 7.13 (t, J = 8.4 Hz, 1H), 6.71 - 6.52 (m, 1H), 6.22 - 5.99 (m, 2H), 5.74 - 5.61 (m, 1H), 4.13 - 3.75 (m, 6H), 3.72 - 3.47 (m, 4H), 2.77 - 2.65 (m, 1H), 2.41 - 2.13 (m, 2H), 2.10 - 1.99 (m, 1H), 1.74 - 1.63 (m, 1H); m/z ES+ [M+H] ⁺ 497.9. Example 73. Preparation of 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01166] Step 1. (R)-(tetrahydrofuran-2-yl)methyl methanesulfonate [01167] To a mixture of [(2R)-tetrahydrofuran-2-yl]methanol (100 mg, 979 μmol) in dichloromethane (3 mL) was added trimethylamine (297 mg, 2.94 mmol), the mixture was stirred at 0 °C for 10 min. Then methylsulfonyl methanesulfonate (511 mg, 2.94 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by water (5 mL) and extracted with 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 [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (200 mg, crude) as a black oil. ¹ H NMR (400 MHz, CDCl3) δ 4.29 - 4.22 (m, 1H), 4.22 - 4.14 (m, 2H), 3.94 - 3.77 (m, 2H), 3.11 - 3.02 (m, 3H), 2.09 - 1.99 (m, 1H), 1.98 - 1.88 (m, 2H), 1.75 - 1.63 (m, 1H). [01168] Step 2. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01169] To a mixture of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, 217 μmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (60.1 mg, 435 μmol), and then [(2R)-tetrahydrofuran-2- yl]methyl methanesulfonate (47.0 mg, 261 μmol) was added. The reaction mixture was stirred at 40 °C for 2 hrs. On completion, the reaction mixture was poured into water (30 mL), extracted with 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 tert- butyl (3S)-3-[4-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methox y]anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, crude) as a colorless oil. m/z ES+[M+H] ⁺ 544.0. [01170] Step 3. N-(2,3-difluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl) -6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01171] To a mixture of tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2- yl]methoxy]a nilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxyl ate (100 mg, 183 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-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]phenyl ]-6-[(3S)-pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, crude, TFA salt) as a yellow solid. m/z ES+[M+H] ⁺ 444.2. [01172] Step 4. 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2-yl)met hoxy)phenyl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01173] To a mixture of N-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]phenyl ]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, 157 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (13.2 mg, 157 μmol) at 0 °C to pH = 7~8, and then prop-2-enoyl chloride (14.2 mg, 157 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 h. On completion, the reaction mixture was quenched by water (10 mL) and extracted with 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 crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 27%-57%, 10 min) to give 1-[(3S)-3-[4-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2-yl]met hoxy]anilino]- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-o ne (36.3 mg, 70.2 μmol, 44%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.50 - 8.39 (m, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.51 - 7.41 (m, 1H), 7.40 - 7.33 (m, 1H), 7.12 (t, J = 8.8 Hz, 1H), 6.77 - 6.42 (m, 1H), 6.24 - 5.93 (m, 2H), 5.73 - 5.61 (m, 1H), 4.25 - 4.16 (m, 1H), 4.15 - 4.06 (m, 2H), 3.86 - 3.64 (m, 5H), 3.63 - 3.40 (m, 1H), 2.37 - 2.14 (m, 2H), 2.08 - 1.96 (m, 1H), 1.96 - 1.78 (m, 2H), 1.77 - 1.62 (m, 1H); m/z ES+[M+H] ⁺ 498.0. Example 74. Preparation of 1-((S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one

[01174] Step 1. (S)-(Tetrahydrofuran-2-yl)methyl methanesulfonate [01175] To a solution of [(2S)-tetrahydrofuran-2-yl]methanol (100 mg, 979 μmol) in dichloromethane (5 mL) was added triethylamine (297 mg, 2.94 mmol), the mixture was stirred at 0 °C for 30 min. Then methylsulfonyl methanesulfonate (511 mg, 2.94 mmol) was added into the mixture, and the mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated under reduced pressure to remove dichloromethane. The residue was diluted with water 20 mL and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give [(2S)-tetrahydrofuran-2-yl]methyl methanesulfonate (180 mg, crude) as a yellow oil. [01176] Step 2. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01177] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (70.0 mg, 152 μmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (42.1 mg, 304 μmol) and [(2S)-tetrahydrofuran-2- yl]methyl methanesulfonate (41.1 mg, 228 μmol). The mixture was stirred at 80 °C for 2 hrs. On completion, the residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[4-[2,3-difluoro-4- [[(2S)-tetrahydrofuran-2-yl]methoxy]anilino]pyrido[3,2-d]pyr imidin-6-yl]oxypyrrolidine-1- carboxylate (80.0 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 544.3. [01178] Step 3. N-(2,3-difluoro-4-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl) -6-(((S)-pyrrolidin- 3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01179] To a solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate (80.0 mg, 147 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 10 min. On completion, the mixture was concentrated in vacuo to give N- [2,3-difluoro-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]phenyl]- 6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (65.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 444.2. [01180] Step 4. 1-((S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2-yl)met hoxy)phenyl)amino)- pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one [01181] To a solution of N-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]phenyl ]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (65.0 mg, 146 μmol) in tetrahydrofuran (5 mL) and water (5 mL) was added sodium bicarbonate (12.3 mg, 146 μmol) to pH = 8, then prop- 2-enoyl chloride (13.2 mg, 146 μmol) was added into the mixture. The mixture was stirred at 0 °C for 5 min. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 32%-62%, 10 min) to give 1-[(3S)-3-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran- 2-yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolid in-1-yl]prop-2-en-1-one (18.4 mg, 37.0 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (d, J = 4.4 Hz, 1H), 8.49 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.40 (dd, J = 3.6, 9.2 Hz, 1H), 7.17 - 7.10 (m, 1H), 6.71 - 6.54 (m, 1H), 6.20-6.02 (m, 1H), 6.12 - 6.00 (m, 1H), 5.73-5.65 (m, 1H), 4.25- 4.19(m, 1H), 4.17 - 4.05 (m, 2H), 3.85 - 3.65 (m, 5H), 3.59 - 3.50 (m, 1H), 2.44 - 2.13 (m, 2H), 2.10 - 1.99 (m, 1H), 1.98 - 1.80 (m, 2H), 1.76 - 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 498.0. Example 75. (S)-1-(3-((4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2, 3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one

[01182] Step 1. tert-Butyl (S)-3-((4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli dine-1-carboxylate [01183] A solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (0.06 g, 131 μmol), 2-oxabicyclo[2.1.1]hexan-4- ylmethyl 4-methylbenzenesulfonate (52.6 mg, 196 μmol), potassium carbonate (36.1 mg, 261 μmol) in N,N-dimethylformamide (3 mL) was stirred at 80 °C for 16 hrs. The reaction mixture was quenched by 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 by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[4-[2,3-difluoro-4-(2- oxabicyclo[2.1.1]hexan-4-ylmethoxy)anilino]pyrido[3,2-d]pyri midin-6-yl]oxypyrrolidine-1- carboxylate (0.07 g, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 556.2. [01184] Step 2. (S)-N-(4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2,3-difluo rophenyl)-6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine [01185] To a solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (0.07 g, 126 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 h. The mixture was concentrated in vacuo to give N-[2,3-difluoro-4-(2- oxabicyclo[2.1.1]hexan-4-ylmethoxy)phenyl]-6-[(3S)-pyrrolidi n-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (0.07 g, crude, TFA salt) as a yellow oil. [01186] Step 3. (S)-1-(3-((4-((4-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2, 3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01187] To a solution of N-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4-ylmethoxy)phen yl]-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (0.07 g, crude, TFA salt), sodium bicarbonate (31.0 mg, 369 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2- enoyl chloride (11.1 mg, 123 μmol). 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: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 35%-65%,9 min) to give 1-[(3S)-3-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-4-ylm ethoxy)anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin [01188] -1-yl]prop-2-en-1-one (0.026 g, 51.0 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.49 – 7.45 (m ,1H), 7.39 – 7.36 (m, 1H), 7.14 (t, J = 8.4 Hz , 1H), 6.68 – 6.54 (m, 1H), 6.19 – 6.14 (m, 1H), 6.09 – 6.01 (m, 1H), 5.72 – 5.66 (m, 1H), 4.53 (s, 1H), 4.47 (s, 2H), 4.09 – 3.49 (m, 6H), 2.34 – 2.17 (m, 2H), 1.87 – 1.83 (m, 2H), 1.54 – 1.51 (m, 2H); m/z ES+ [M+H] ⁺ 510.0. Example 76. Preparation of (S)-1-(3-((4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2, 3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01189] Step 1. tert-Butyl (S)-3-((4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2,3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli dine-1-carboxylate [01190] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, 218 μmol) and 1-(iodomethyl)-2- oxabicyclo[2.1.1]hexane (58.5 mg, 261 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (90.2 mg, 653 μmol). The mixture was stirred at 40 °C for 12 h. 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 (3S)-3-[4-[2,3-difluoro-4-(2- oxabicyclo[2.1.1]hexan-1-ylmethoxy)anilino]pyrido[3,2-d]pyri midin-6-yl]oxypyrrolidine-1- carboxylate (132 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 556.0. [01191] Step 2. (S)-N-(4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2,3-difluo rophenyl)-6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine [01192] To a solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1- ylmethoxy)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (132 mg, 238 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give N-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)phen yl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (165 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 456.0. [01193] Step 3. (S)-1-(3-((4-((4-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-2, 3- difluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrroli din-1-yl)prop-2-en-1-one [01194] To a solution of N-[2,3-difluoro-4-(2-oxabicyclo[2.1.1]hexan-1-ylmethoxy)phen yl]-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (165 mg, 290 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (195 mg, 2.32 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (23.6 mg, 261 μmol, 21.3 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 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 x 25 mm, 5 um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 34%-64%,9 min) to give 1-[(3S)-3-[4-[2,3-difluoro-4-(2- oxabicyclo[2.1.1]hexan-1-ylmethoxy)anilino]pyrido[3,2-d]pyri midin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (22.2 mg, 43.6 μmol, 15%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.46 (s, 1H), 8.11 (dd, J = 0.8, 9.2 Hz, 1H), 7.51 - 7.42 (m, 1H), 7.38 (dd, J = 4.4, 9.2 Hz, 1H), 7.21 - 7.12 (m, 1H), 6.70 - 6.52 (m, 1H), 6.18 - 6.07 (m, 1H), 6.11 - 5.99 (m, 1H), 5.74 - 5.61 (m, 1H), 4.39 (s, 2H), 4.11 - 3.75 (m, 2H), 3.74 - 3.47 (m, 4H), 2.96 (t, J = 3.2 Hz, 1H), 2.40 - 2.16 (m, 2H), 1.92 - 1.83 (m, 2H), 1.47 (dd, J = 1.6, 4.4 Hz, 2H); m/z ES+ [M+H] ⁺ 509.9. Example 77. Preparation of 1-((S)-3-((4-((2,5-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidin-1-yl)prop-2-en-1-one [01195] Step 1. tert-Butyl (S)-3-((4-((2,5-difluoro-4-hydroxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [01196] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (1.00 g, 2.85 mmol) in acetonitrile (8 mL) was added 4-amino-2,5-difluoro-phenol (434 mg, 2.99 mmo). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was filtered and the filtered cake was concentrated under reduced pressure to give tert-butyl (3S)- 3-[4-(2,5-difluoro-4-hydroxy-anilino)pyrido[3,2-d]pyrimidin- 6-yl]oxypyrrolidine-1-carboxylate (1.20 g, 2.61 mmol, 92%) as a green solid. m/z ES+ [M+H] ⁺ 460.2. [01197] Step 2. tert-Butyl (S)-3-((4-((2,5-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrr olidine-1-carboxylate [01198] To a solution of tert-butyl (3S)-3-[4-(2,5-difluoro-4-hydroxy-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 327 μmol) and [(3R)-tetrahydrofuran-3- yl]methyl methanesulfonate (98.1 mg, 326 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (135 mg, 979 μmol). The mixture was stirred at 60 °C for 12 h. 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 (3S)-3-[4-[2,5-difluoro-4- [[(3R)-tetrahydrofuran-3-yl]methoxy]anilino]pyrido[3,2-d]pyr imidin-6-yl]oxypyrrolidine-1- carboxylate (205 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 544.1. [01199] Step 3. N-(2,5-difluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl) -6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01200] To a solution of tert-butyl (3S)-3-[4-[2,5-difluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin e-1-carboxylate (150 mg, 276 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give N-[2,5-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl ]-6-[(3S)-pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (151 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 444.0. [01201] Step 4. 1-((S)-3-((4-((2,5-difluoro-4-(((R)-tetrahydrofuran-3-yl)met hoxy)phenyl)amino)- pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one [01202] To a solution of N-[2,5-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl ]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (150 mg, 269 μmol, trifluoroacetic acid salt) in tetrahydrofuran (1.5 mL) was added a solution of sodium bicarbonate (181 mg, 2.15 mmol) in water (0.5 mL), and then prop-2-enoyl chloride (21.9 mg, 242 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 then 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-TLC (silica gel, petroleum ether: ethyl acetate= 0:1) and re-purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 34%-64%, 10 min) to give 1-[(3S)-3-[4-[2,5-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]met hoxy]anilino]- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-o ne (1.94 mg, 3.90 μmol, 1.4%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.49 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.87 - 7.72 (m, 1H), 7.44 - 7.29 (m, 2H), 6.73 - 6.47 (m, 1H), 6.18 - 6.08 (m, 1H), 6.08 - 5.94 (m, 1H), 5.74 - 5.61 (m, 1H), 4.10 - 3.76 (m, 6H), 3.74 - 3.53 (m, 4H), 2.74 - 2.66 (m, 1H), 2.41 - 2.15 (m, 2H), 2.10 - 1.98 (m, 1H), 1.74 - 1.60 (m, 1H); m/z ES+ [M+H] ⁺ 498.0. Example 78. Preparation of 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidin-1-yl)prop-2-en- 1-one [01203] Step 1. (R)-(tetrahydrofuran-3-yl)methyl methanesulfonate [01204] To a solution of [(3S)-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 h. On completion, the mixture was poured into water (30 mL) and extracted with ethyl acetate (40 mL). The organic layers were dried by sodium sulfate, filtered and concentrated in vacuo to give [(3R)-tetrahydrofuran-3-yl]methyl methanesulfonate (1.07 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.25 - 4.05 (m, 2H), 3.95 - 3.81 (m, 2H), 3.80 - 3.71 (m, 1H), 3.65 (m, J = 4.8, 9.2 Hz, 1H), 3.07 - 3.00 (m, 3H), 2.79 - 2.61 (m, 1H), 2.17 - 2.06 (m, 1H), 1.73 - 1.61 (m, 1H). [01205] Step 2. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidine-1-carboxylate [01206] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, 209 μmol) in N,N- dimethylformamide (0.5 mL) was added potassium carbonate (28.9 mg, 209 μmol) and [(3R)- tetrahydrofuran-3-yl]methyl methanesulfonate (45.3 mg, 251 μmol), the mixture was stirred at 60 °C for 20 h. Then the mixture was stirred at 80 °C for 1 h. On completion, the reaction mixture was diluted with brine (40 mL) and then 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 prep-TLC (silica gel, petroleum ether/ethyl acetate=1/2) to give tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(3R)- tetrahydrofuran-3-yl]methoxy]anilino]-7-fluoro-pyrido[3,2d]p yrimidin-6-yl]oxypyrrolidine-1- carboxylate (21 mg, 33.5 μmol, 16%) as a yellow oil. m/z ES+ [M+H] ⁺ 562.1. [01207] Step 3. N-(2,3-difluoro-4-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl) -7-fluoro-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01208] To a solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxy pyrrolidine-1-carboxylate (20.0 mg, 35.6 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL), the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl ]-7-fluoro-6- [(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (20 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 462.0. [01209] Step 4. 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-3-yl)met hoxy)phenyl)amino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop -2-en-1-one [01210] To a solution of N-[2,3-difluoro-4-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl ]-7- fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4- amine (20.0 mg, 34.7 μmol) in tetrahydrofuran (2 mL) and water (0.2 mL) was added sodium bicarbonate (5.84 mg, 69.5 μmol). Then prop-2-enoyl chloride (3.77 mg, 41.7 μmol) was added at 0 °C, and the mixture was stirred at 25 °C for 1 h. On completion, the mixture was diluted with methanol (20 mL), then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 32%-62%, 10.5 min) to give 1-[(3S)-3-[4-[2,3-difluoro-4-[[(3R)- tetrahydrofuran-3-yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (9.33 mg, 17.9 μmol, 51%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.68 (s, 1H), 8.56 - 8.38 (m, 1H), 8.16 - 8.01 (m, 1H), 7.47 - 7.29 (m, 1H), 7.20 - 7.04 (m, 1H), 6.76 - 6.47 (m, 1H), 6.28 - 6.01 (m, 2H), 5.80 - 5.56 (m, 1H), 4.16 - 3.76 (m, 6H), 3.75 - 3.55 (m, 4H), 2.76 - 2.68 (m, 1H), 2.34 (s, 1H), 2.26 - 2.20 (m, 1H), 2.10 - 2.01 (m, 1H), 1.76 - 1.65 (m, 1H); m/z ES+ [M+H] ⁺ 516.3. Example 79. Preparation of 1-((S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidin-1-yl)prop-2-en- 1-one [01211] Step 1. (S)-(Tetrahydrofuran-3-yl)methyl methanesulfonate [01212] To a solution of [(3R)-tetrahydrofuran-3-yl]methanol (0.5 g, 4.90 mmol ) in dichloromethane (8 mL) was added triethylamine (1.49 g, 14.7 mmol) and methylsulfonyl methanesulfonate (2.56 g, 14.7 mmol) at 0 °C, then the mixture was stirred at 0 - 25 °C for 2 h. On completion, the 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 to give [(3S)- tetrahydrofuran-3-yl]methyl methanesulfonate (827 mg, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.21 - 4.16 (m, 1H), 4.14 - 4.09 (m, 1H), 3.90 - 3.80 (m, 2H), 3.78 - 3.70 (m, 1H), 3.66 - 3.60 (m, 1H), 3.01 (s, 3H), 2.67 - 2.57 (m, 1H), 2.16 - 2.12 (m, 1H), 1.72 - 1.60 (m, 1H). [01213] Step 2. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-3- yl)methoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidine-1-carboxylate [01214] To a mixture of [(3S)-tetrahydrofuran-3-yl]methyl methanesulfonate (84.9 mg, 471 μmol) and potassium carbonate (43.4 mg, 314 μmol) in N,N-dimethylformamide (0.8 mL) was added tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro-pyrido[3 ,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (150 mg, 314 μmol). Then the mixture was stirred at 60 °C for 12 h. On completion, the reaction mixture was diluted with water (60 mL), and then extracted with ethyl acetate (20 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 perp-TLC (petroleum ether/ethyl acetate= 1/3) to give tert-butyl (3S)-3-[4-[2,3-difluoro-4- [[(3S)-tetrahydrofuran-3-yl]methoxy]anilino]-7-fluoro-pyrido [3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (88.0 mg, 157 μmol, 50%) as a yellow oil. m/z ES+ [M+H] ⁺ 562.1. [01215] Step 3. N-(2,3-difluoro-4-(((S)-tetrahydrofuran-3-yl)methoxy)phenyl) -7-fluoro-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01216] A mixture of tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxy pyrrolidine-1-carboxylate (50.0 mg, 89.0 μmol) in dichloromethane (2 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 1 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl ]-7-fluoro-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (45 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 462.0. [01217] Step 4. 1-((S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-3-yl)met hoxy)phenyl)amino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop -2-en-1-one [01218] To a mixture of N-[2,3-difluoro-4-[[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl ]-7-fluoro- 6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (45.0 mg, 97.5 μmol) in tetrahydrofuran (4.5 mL) and water (2 mL) was added sodium bicarbonate (16.4 mg, 195 μmol) and prop-2-enoyl chloride (10.6 mg, 117 μmol), then the mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was diluted with water (60 mL), and then extracted with ethyl acetate (20 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 prep-HPLC (column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water (FA)- acetonitrile]; B%: 32%-62%, 10.5 min) to give 1-[(3S)-3-[4-[2,3-difluoro-4-[[(3S)- tetrahydrofuran-3-yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (20.9 mg, 38.9 μmol, 40%) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 8.46 (s, 1H), 8.09 - 8.03 (m, 1H), 7.44 - 7.37 (m, 1H), 7.14 (t, J = 8.4 Hz, 1H), 6.72 - 6.55 (m, 1H), 6.23 - 6.08 (m, 2H), 5.75 - 5.60 (m, 1H), 4.12 - 4.03 (m, 2H), 3.93 - 3.74 (m, 4H), 3.73 - 3.46 (m, 4H), 2.77 - 2.66 (m, 1H), 2.44 - 2.34 (m, 1H), 2.31 - 2.17 (m, 1H), 2.10 - 2.00 (m, 1H), 1.74 - 1.64 (m, 1H); m/z ES+ [M+H] ⁺ 516.3. Example 80. Preparation of (S)-1-(3-((4-((4-(difluoromethoxy)-2,3-difluorophenyl)amino) -7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one

[01219] Step 1. tert-Butyl (S)-3-((4-((4-(difluoromethoxy)-2,3-difluorophenyl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxyl ate [01220] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (200 mg, 419 μmol) and potassium carbonate (174 mg, 1.26 mmol) in N,N-dimethylformamide (4 mL) and water (0.5 mL) was added (2-chloro-2,2-difluoro-acetyl)oxysodium (192 mg, 1.26 mmol), the mixture was stirred at 100 °C for 2 h. On completion, the mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried and concentrated in vacuo to give a residue. The residue was purified with column chromatography (petroleum ether : ethyl acetate =4:1) to give tert-butyl (3S)-3-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]- 7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carbox ylate (80.0 mg, 152 μmol, 36%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80 - 8.71 (m, 2H), 8.69 - 8.57 (m, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.20 - 7.11 (m, 1H), 6.79 - 6.36 (m, 1H), 5.78 - 5.70 (m, 1H), 3.88 - 3.83 (m, 1H), 3.76 - 3.54 (m, 3H), 2.43 - 2.30 (m, 2H), 1.49 (s, 9H); m/z ES+ [M+1] ⁺ 528.0. [01221] Step 2. (S)-N-(4-(Difluoromethoxy)-2,3-difluorophenyl)-7-fluoro-6-(p yrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01222] To a solution of tert-butyl (3S)-3-[4-[4-(difluoromethoxy)-2,3-difluoro-anilino]-7-fluor o- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (70.0 mg, 133 μmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (3 mL), the mixture was stirred at 20 °C for 0.5 h. On completion, the mixture was concentrated in vacuo to give N-[4-(difluoromethoxy)- 2,3-difluoro-phenyl]-7-fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-py rido[3,2-d]pyrimidin-4-amine (70.0 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+1] ⁺ 427.9. [01223] Step 3. (S)-1-(3-((4-((4-(Difluoromethoxy)-2,3-difluorophenyl)amino) -7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01224] To a solution of N-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-7-fluoro-6-[(3S) - pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, crude, trifluoroacetic acid salt) and sodium bicarbonate (21.7 mg, 259 μmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was added prop-2-enoyl chloride (14.0 mg, 155 μmol), the mixture was stirred at 20 °C for 10 min. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified with prep-HPLC [column: Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-ACN]; B%: 35%-65%, 10.5 min] to give 1-[(3S)-3-[4-[4- (difluoromethoxy)-2,3-difluoro-anilino]-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (38.7 mg, 80.2 μmol, 62%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.76 (s, 1H), 8.52 (s, 1H), 8.11 (dd, J = 2.4, 10.6 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.57 - 7.14 (m, 2H), 6.73 - 6.53 (m, 1H), 6.25 - 6.07 (m, 2H), 5.76 - 5.63 (m, 1H), 4.14 - 3.81 (m, 2H), 3.79 - 3.49 (m, 2H), 2.43 - 2.23 (m, 2H); m/z ES+ [M+H] ⁺ 482.2. Example 81. Preparation of (S)-1-(3-((4-((4-(cyclopropylmethoxy)-2,3-difluorophenyl)ami no)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01225] Step 1. tert-Butyl (S)-3-((4-((4-(cyclopropylmethoxy)-2,3-difluorophenyl)amino) -7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxyl ate [01226] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (0.10 g, 209 μmol) in N,N- dimethylformamide (0.5 mL) was added potassium carbonate (30.0 mg, 209 μmol) and bromomethylcyclopropane (28.3 mg, 209 μmol). The mixture was stirred at 60 °C for 12 h. On completion, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered and contracted in vacuo to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether/ethyl acetate=1/1) to afford tert-butyl (3S)-3-[4-[4-(cyclopropylmethoxy)-2,3-difluoro- anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxy-pyrrolidin e-1-carboxylate (50.0 mg, 88.2 μmol, 42%) as a brown oil. m/z ES+ [M+H] ⁺ 532.0. [01227] Step 2. (S)-N-(4-(cyclopropylmethoxy)-2,3-difluorophenyl)-7-fluoro-6 -(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [01228] A mixture of tert-butyl (3S)-3-[4-[4-(cyclopropylmethoxy)-2,3-difluoro-anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxyl ate (40.0 mg, 75.3 μmol) in dichloromethane (2 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 30 min. On completion, the mixture was concentrated under reduced pressure to give N-[4- (cyclopropylmethoxy)-2,3-difluoro-phenyl]-7-fluoro-6-[(3S)-p yrrolidin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (42.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 432.0. [01229] Step 3. (S)-1-(3-((4-((4-(cyclopropylmethoxy)-2,3-difluorophenyl)ami no)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01230] To a mixture of N-[4-(cyclopropylmethoxy)-2,3-difluoro-phenyl]-7-fluoro-6-[( 3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (32.0 mg, 74.2 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.5 mL) was added sodium bicarbonate (12.5 mg, 148 μmol) and prop-2-enoyl chloride (8.06 mg, 89.0 μmol). Then the mixture was stirred at 0 °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 C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 40%-70%, 8 min) to give 1-[(3S)-3-[4-[4- (cyclopropylmethoxy)-2,3-difluoro-anilino]-7-fluoro-pyrido[3 ,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (21.4 mg, 43.9 μmol, 59%) as a pink solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.45 (s, 1H), 8.08 - 8.05 (m, 1H), 7.39 - 7.34 (m, 1H), 7.09 - 7.05 (m, 1H), 6.70 - 6.53 (m, 1H), 6.19 - 6.17 (m, 1H), 6.15 - 6.12 (m, 1H), 5.72 - 5.65 (m, 1H), 3.99 (d, J = 4.0 Hz, 2H), 3.88 - 3.82 (m, 2H), 3.74 - 3.51 (m, 2H), 2.44 - 2.36 (m, 1H), 2.31 - 2.22 (m, 1H), 1.33 - 1.23 (m, 1H), 0.63 - 0.59 (m, 2H), 0.39 - 0.35 (m, 2H); m/z ES+ [M+H] ⁺ 486.2. Example 82. Preparation of 1-((S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidin-1-yl)prop-2-en- 1-one [01231] Step 1. (S)-(Tetrahydrofuran-2-yl)methyl methanesulfonate [01232] To a solution of [(2S)-tetrahydrofuran-2-yl]methanol (200 mg, 1.96 mmol) in dichloromethane (5 mL) was added methylsulfonyl methanesulfonate (1.02 g, 5.87 mmol) and triethylamine (594 mg, 5.87 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the 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 [(2S)- tetrahydrofuran-2-yl]methyl methanesulfonate (350 mg, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.32 - 4.21 (m, 1H), 4.21 - 4.14 (m, 2H), 3.94 - 3.78 (m, 2H), 3.07 (d, J = 1.2 Hz, 3H), 2.12 - 1.83 (m, 3H), 1.76 - 1.63 (m, 1H). [01233] Step 2. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2-yl)methox y)phenyl)- amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1 -carboxylate [01234] To a solution of [(2S)-tetrahydrofuran-2-yl]methyl methanesulfonate (56.6 mg, 314 μmol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (136 mg, 419 μmol) and tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro-pyrido[3 ,2-d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate (100 mg, 209 μmol). The mixture was stirred at 60 °C for 12 h. On completion, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 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, dichloromethane : ethyl acetate = 1:1) to give tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxy pyrrolidine-1-carboxylate (30.0 mg, 42.8 μmol, 20%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 - 8.29 (m, 1H), 7.78 (d, J = 10.0 Hz, 1H), 6.91 - 6.83 (m, 1H), 5.78 - 5.70 (m, 1H), 4.25 - 4.21 (m, 2H), 4.09 (d, J = 5.2 Hz, 2H), 3.94 - 3.91 (m, 2H), 3.69 - 3.60 (m, 2H), 2.08 - 2.02 (m, 5H), 1.91 - 1.82 (m, 2H), 1.75 (s, 1H), 1.72 - 1.71 (m, 1H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 562.5. [01235] Step 3. N-(2,3-difluoro-4-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl) -7-fluoro-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01236] To a solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxy pyrrolidine-1-carboxylate (80.0 mg, 142 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]phenyl ]-7- fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4- amine (65.0 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 462.1. [01237] Step 4. 1-((S)-3-((4-((2,3-difluoro-4-(((S)-tetrahydrofuran-2-yl)met hoxy)phenyl)amino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop -2-en-1-one [01238] To a solution of N-[2,3-difluoro-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]phenyl ]-7- fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4- amine (65.0 mg, 141 μmol) in anhydrous tetrahydrofuran (0.8 mL) and water (0.8 mL) was added sodium bicarbonate (23.7 mg, 282 μmol) at 0 °C. Then prop-2-enoyl chloride (15.3 mg, 169 μmol) was added into the mixture and the mixture was stirred at 0 °C for 0.5 h. On completion, the reaction mixture was diluted with methanol (2 mL) and 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 (ammonium bicarbonate)- acetonitrile]; B%: 30% - 60%, 8 min) to give 71-[(3S)-3-[4-[2,3- difluoro-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]anilino]-7-fl uoro-pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (6.53 mg, 12.1 μmol, 8.6%) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 8.46 (s, 1H), 8.07 (d, J = 10.0 Hz, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 6.76 - 6.48 (m, 1H), 6.27 - 6.06 (m, 2H), 5.74 - 5.66 (m, 1H), 4.26 - 4.06 (m, 3H), 3.89 - 3.52 (m, 6H), 2.38 - 2.22 (m, 2H), 2.04 - 1.99 (m, 1H), 1.97 - 1.79 (m, 2H), 1.77 - 1.66 (m, 1H); m/z ES+ [M+18] ⁺ 516.3. Example 83. Preparation of 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidin-1-yl)prop-2-en- 1-one [01239] Step 1. (R)-(Tetrahydrofuran-2-yl)methyl methanesulfonate [01240] To a solution of [(2R)-tetrahydrofuran-2-yl]methanol (250 mg, 2.45 mmol) in dichloromethane (4 mL) was added triethylamine (743 mg, 7.34 mmol), then methylsulfonyl methanesulfonate (1.28 g, 7.34 mmol) was added into the mixtrue at 0 °C. The mixture was stirred at 25°C for 2 h. On completion, the reaction mixture was diluted with dichloromethane (30 mL), and the organic layers were washed with water (20 mL × 3). The organic layer was then dried by sodium sulfate, filtered and concentrated in vacuo to give [(2R)-tetrahydrofuran-2-yl]methyl methanesulfonate (670 mg, 3.72 mmol, crude) as a brown oil. [01241] Step 2. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl )oxy)pyrrolidine-1-carboxylate [01242] To a solution of tert-butyl (3S)-3-[4-(2,3-difluoro-4-hydroxy-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, 209 μmol) and potassium carbonate (28.9 mg, 209 μmol) in N,N-dimethylformamide (0.5 mL) was added [(2R)- tetrahydrofuran-2-yl]methyl methanesulfonate (75.5 mg, 418 μmol). The mixture was stirred at 60 °C for 16 h. On completion, the mixture was partitioned between dichloromethane (20 mL) and water (60 mL). The separated organic layer was washed with water (60 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue.The residue was purified by prep-TLC (silicon dioxide, dichloromethane:ethyl acetate = 1:1) to give tert-butyl (3S)-3-[4-[2,3- difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]anilino]-7-fl uoro-pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (36 mg, 59.5 μmol, 28%) as a yellow oil. m/z ES+ [M+H] ⁺ 562.3. [01243] Step 3. N-(2,3-difluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl) -7-fluoro-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [01244] A solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxy pyrrolidine-1-carboxylate (36.0 mg, 64.1 μmol) in trifluoroacetic acid (0.05 mL) and dichloromethane (0.5 mL) was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]phenyl ]-7-fluoro-6-[(3S)-pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (36 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 462.1. [01245] Step 4. 1-((S)-3-((4-((2,3-difluoro-4-(((R)-tetrahydrofuran-2-yl)met hoxy)phenyl)amino)- 7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop -2-en-1-one [01246] To a solution of N-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2-yl]methoxy]phenyl ]-7- fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4- amine (36.0 mg, crude, trifluoroacetic acid) and prop-2-enoyl chloride (6.79 mg, 75.0 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.3 mL) was added sodium bicarbonate (5.26 mg, 62.6 μmol). The mixture was stirred at 25 °C for 0.1 h. On completion, the reaction mixture was diluted with methanol (20 mL) and concentrated in vacuo to give a residue. Then the residue was purified by prep-HPLC [Phenomenex luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)- acetonitrile]; B%: 32%- 62%, 10.5 min] to give 1-[(3S)-3-[4-[2,3-difluoro-4-[[(2R)-tetrahydrofuran-2- yl]methoxy]anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxy pyrrolidin-1-yl]prop-2-en-1-one (22.8 mg, 43.8 μmol, 70%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 8.45 (s, 1H), 8.10 - 8.04 (m, 1H), 7.38 (m, 1H), 7.12 (m, 1H), 6.78 - 6.46 (m, 1H), 6.26 - 6.05 (m, 2H), 5.75 - 5.63 (m, 1H), 4.25 - 4.17 (m, 1H), 4.17 - 4.11 (m, 1H), 4.10 - 4.06 (m, 1H), 3.92 - 3.73 (m, 3H), 3.73 - 3.48 (m, 3H), 2.43 - 2.21 (m, 2H), 2.10 - 1.98 (m, 1H), 1.95 - 1.80 (m, 2H), 1.66 (m, 1H); m/z ES+ [M+H] ⁺ 516.3. Example 84. Preparation of 1-[2-chloro-3-fluoro-4-[[6-[(3S)-1-prop-2-enoylpyrrolidin-3- yl]oxypyrido[3,2-d]pyrimidin-4-yl]amino]phenyl]cyclopropanec arbonitrile

[01247] Step 1. tert-butyl (3S)-3-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [01248] A solution of 1-(4-amino-2-chloro-3-fluoro-phenyl)cyclopropanecarbonitrile (36.0 mg, 171 μmol) and tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (50.0 mg, 142 μmol) in acetonitrile (1 mL) was stirred at 60 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give compound tert-butyl (3S)-3-[4-[3- chloro-4-(1-cyanocyclopropyl)-2-fluoro-anilino]pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (80.0 mg, crude) as a yellow solid. m/z ES+[M+H] ⁺ 525.1 [01249] Step 2. 1-[2-Chloro-3-fluoro-4-[[6-[(3S)-pyrrolidin-3-yl]oxypyrido[3 ,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile [01250] To a solution of tert-butyl (3S)-3-[4-[3-chloro-4-(1-cyanocyclopropyl)-2-fluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (60.0 mg, 114 μmol) in dichloromethane (0.6 mL) was added hydrochloric acid /dioxane (4 M, 0.2 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give compound 1-[2-chloro-3-fluoro-4-[[6-[(3S)-pyrrolidin-3-yl]oxypyrido[3 ,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile (65.0 mg, crude) as a yellow solid. m/z ES+[M+H] ⁺ 425.1 [01251] Step 3. 1-[2-Chloro-3-fluoro-4-[[6-[(3S)-1-prop-2-enoylpyrrolidin-3- yl]oxypyrido[3,2- d]pyrimidin-4-yl]amino]phenyl]cyclopropanecarbonitrile [01252] To a solution of 1-[2-chloro-3-fluoro-4-[[6-[(3S)-pyrrolidin-3-yl]oxypyrido[3 ,2- d]pyrimidin-4-yl]amino]phenyl]cyclopropanecarbonitrile (50 mg, 117 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (20.0 mg, 235μmol), then prop-2- enoyl chloride (5.33 mg, 58 μmol, 4.80 μL) 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 C18150 x 25 mm, 10 um; mobile phase: [water (formic acid)- acetonitril]; B%: 38%-68%, 10 min) to give compound 1-[2-chloro- 3-fluoro-4-[[6-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]oxypyrido [3,2-d]pyrimidin-4- yl]amino]phenyl]cyclopropanecarbonitrile (5.98 mg, 12.5 μmol, 11%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 - 9.62 (m, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.42 (dd, J = 4.0, 9.2 Hz, 1H), 6.71 - 6.53 (m, 1H), 6.21 - 6.11 (m, 1H), 6.06 - 5.94 (m, 1H), 5.73 - 5.63 (m, 1H), 3.86 - 3.78 (m, 2H), 3.70 (d, J = 14.0 Hz, 2H), 2.28 - 2.12 (m, 2H), 1.84 - 1.77 (m, 2H), 1.54 - 1.49 (m, 2H); m/z ES+[M+H] ⁺ 478.9. Example 85 Preparation of 2-chloro-3-fluoro-4-[[7-fluoro-6-[(3S)-1-prop-2-enoylpyrroli din-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-yl]amino]benzonitrile [01253] Step 1. tert-Butyl (3S)-3-[4-(3-chloro-4-cyano-2-fluoro-anilino)-7-fluoro-pyrid o[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [01254] A solution of tert-butyl (3S)-3-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (110 mg, 298 μmol) and 4-amino-2-chloro-3-fluoro-benzonitrile (153 mg, 895 μmol) in acetic acid (1.5 mL) was stirred at 60 °C for 16 h. On completion, the mixture was concentrated in vacuo to give tert-butyl (3S)-3-[4-(3-chloro-4-cyano-2-fluoro- anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine -1-carboxylate (150 mg, crude) as a yellow solid which was used for next step directly. m/z ES+ [M+1] ⁺ 503.3. [01255] Step 2. 2-Chloro-3-fluoro-4-[[7-fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-p yrido[3,2- d]pyrimidin-4-yl]amino]benzonitrile [01256] A solution of tert-butyl (3S)-3-[4-(3-chloro-4-cyano-2-fluoro-anilino)-7-fluoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 299 μmol) in hydrogen chloride/dioxane (2 mL) was stirred at 20 °C for 1 h. On completion, the reaction mixture was poured into ethyl acetate (20 mL), resulting in the formation of much precipitate. The solid was collected by filtration and dried in vacuo to give 2-chloro-3-fluoro-4-[[7-fluoro-6-[(3S)-pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-yl]amino]benzonitrile (110 mg, 153 μmol, 51%, hydrogen chloride salt) as a gray solid. m/z ES+ [M+1] ⁺ 403.2. [01257] Step 3. 2-Chloro-3-fluoro-4-[[7-fluoro-6-[(3S)-1-prop-2-enoylpyrroli din-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-yl]amino]benzonitrile [01258] To a solution of 2-chloro-3-fluoro-4-[[7-fluoro-6-[(3S)-pyrrolidin-3-yl]oxy-p yrido[3,2- d]pyrimidin-4-yl]amino]benzonitrile (100 mg, 228 μmol, hydrogen chloride salt) and sodium bicarbonate (57.4 mg, 683 μmol) in tetrahydrofuran (3 mL) and water (2 mL) was added prop-2- enoyl chloride (16.5 mg, 182 μmol), the mixture was stirred at 20 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified with prep-HPLC [column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water(FA)-ACN]; B%: 36%-66%, 10.5 min] to give 2-chloro-3-fluoro-4-[[7-fluoro-6-[(3S)-1-prop-2-enoylpyrroli din-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-yl]amino]benzonitrile (10.5 mg, 21.7 μmol, 9%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.69 (s, 1H), 8.46 - 8.31 (m, 1H), 8.20 (dd, J = 2.4, 10.6 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 6.73 - 6.54 (m, 1H), 6.23 - 6.13 (m, 1H), 6.13 - 6.01 (m, 1H), 5.76 - 5.63 (m, 1H), 4.14 - 3.91 (m, 1H), 3.90 - 3.74 (m, 2H), 3.73 - 3.47 (m, 1H), 2.48 - 2.25 (m, 2H); m/z ES+ [M+H] ⁺ 456.1. Example 86. Preparation of (S)-1-(3-((4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)- 5-fluoroquinazolin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[01259] Step 1. 4-((3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-5-flu oroquinazolin-6- ol [01260] To a solution of 6-bromo-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-5- fluoroquinazolin-4-amine (0.5 g, 1.15 mmol) in dioxane (3 mL) and water (3 mL) was added tris(dibenzylideneacetone)dipalladium (104 mg, 114 μmol), potassium hydroxide (192 mg, 3.44 mmol) and ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (97.3 mg, 229 μmol). The mixture was stirred at 80 °C for 12 h under nitrogen. On completion, the mixture was filtered and concentrated under reduced pressure to give 4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-5-fluoroquinazolin-6-ol (100 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 374.2. [01261] Step 2. tert-Butyl (S)-3-((4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amin o)-5- fluoroquinazolin-6-yl)oxy)pyrrolidine-1-carboxylate [01262] To a solution of 4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-5- fluoroquinazolin-6-ol (60 mg, 160 μmol) in N,N-dimethyl formamide (1 mL) was added potassium phosphate (44.4 mg, 321 μmol) and tert-butyl (3R)-3-methylsulfonyloxypyrrolidine-1-carboxylate (426 mg, 1.61 mmol). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was 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 (S)-3-((4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)-5-fluoroquinazolin-6 -yl)oxy)pyrrolidine-1- carboxylate (20.0 mg, 36.8 μmol, 23%) as a white solid. m/z ES+ [M+H] ⁺ 543.1. [01263] Step 3. (S)-N-(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-5-fluoro -6-(pyrrolidin-3- yloxy)quinazolin-4-amine [01264] To a solution of tert-butyl (S)-3-((4-((3-chloro-4-(difluoromethoxy)-2- fluorophenyl)amino)-5-fluoroquinazolin-6-yl)oxy)pyrrolidine- 1-carboxylate (20.0 mg, 36.8 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (385 mg, 3.38 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered and concentrated under reduced pressure to give (S)-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-5-fluoro -6- (pyrrolidin-3-yloxy)quinazolin-4-amine (20.0 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H] ⁺ 443.2. [01265] Step 4. (S)-1-(3-((4-((3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)-5- fluoroquinazolin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01266] To a solution of (S)-N-(3-chloro-4-(difluoromethoxy)-2-fluorophenyl)-5-fluoro -6- (pyrrolidin-3-yloxy)quinazolin-4-amine (20.0 mg, 35.9 μmol) in tetrahydrofuran (0.5 mL) and water (0.25 mL) was added potassium carbonate (4.96 mg, 35.9 μmol) and prop-2-enoyl chloride (3.25 mg, 35.9 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 x 50 mm, 3 um; mobile phase: [water (FA)-ACN]; B%: 35%- 65%, 10 min) to give (S)-1-(3-((4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)a mino)-5- fluoroquinazolin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (4.43 mg, 8.83 μmol, 25%) as an off- white solid. ¹ H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.98 - 7.95 (m, 1H), 7.88 - 7.85 (m, 1H), 7.71- 7.60 (m, 1H), 7.24 - 7.20 (m, 1H), 7.17 - 6.78 (m, 1H), 6.75 - 6.59 (m, 1H), 6.38 - 6.29 (m, 1H), 5.80 - 5.75 (m, 1H), 5.39 - 5.24 (m, 1H), 4.02 - 3.76 (m, 4H), 2.47 - 2.26 (m, 2H); m/z ES+ [M+H] ⁺ 496.8. Example 87. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1 -yl]prop-2-en-1-one

[01267] Step 1. tert-Butyl (3S)-3-[4-(4-bromo-3-chloro-2-fluoro-anilino)pyrido[3,2-d]py rimidin- 6-yl]oxypyrrolidine-1-carboxylate [01268] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (300 mg, 855 μmol) in acetonitrile (5 mL) was added 4-bromo-3-chloro-2-fluoro- aniline (201 mg, 898 μmol), the mixture was stirred at 25 °C for 1 h. Then the mixture was stirred at 60 °C for 20 hr. On completion, the mixture was washed with ethyl acetate (25 mL) and then filtered. The filtered cake was collected to give tert-butyl (3S)-3-[4-(4-bromo-3-chloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (326 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 8.90 - 8.79 (m, 1H), 8.31 (d, J = 9.2 Hz, 1H), 7.82 - 7.79 (m, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.61 - 7.53 (m, 1H), 6.13 - 5.96 (m, 1H), 3.51 (s, 4H), 2.31 - 2.09 (m, 2H), 1.40 (d, J = 4.4 Hz, 9H). [01269] Step 2. N-(4-Bromo-3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl ]oxy-pyrido[3,2- d]pyrimidin-4-amine [01270] To a solution of tert-butyl (3S)-3-[4-(4-bromo-3-chloro-2-fluoro-anilino)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (326 mg, 605 μmol) in dichloromethane (7 mL) was added trifluoroacetic acid (2.16 g, 18.9 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 added dichloromethane (30 mL), then the mixture was concentrated under reduced pressure to give N-(4-bromo-3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl ]oxy-pyrido[3,2- d]pyrimidin-4-amine (320 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+ [M+H] ⁺ 439.9. [01271] Step 3. 9H-Fluoren-9-ylmethyl (3S)-3-[4-(4-bromo-3-chloro-2-fluoro- anilino)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late [01272] To a solution of N-(4-bromo-3-chloro-2-fluoro-phenyl)-6-[(3S)-pyrrolidin-3-yl ]oxy- pyrido[3,2-d]pyrimidin-4-amine (300 mg, 542 μmol) in dichloromethane (20 mL) was added triethylamine (82.4 mg, 814 μmol) and 9H-fluoren-9-ylmethyl carbonochloridate (154 mg, 597 μmol), the mixture was stirred at 0 °C for 1.5 hr. Then the mixture was stirred at 25 °C for 16.5 hr. Then 9H-fluoren-9-ylmethyl carbonochloridate (70.2 mg, 271 μmol) and triethylamine (137 mg, 1.36 mmol) was added and the mixture was stirred at 25 °C for 2 hr. On completion, the mixture was diluted with dichloromethane (25 mL) and washed with water (50 mL × 2). The organic layer was 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=2/1 to dichloromethane/methyl alcohol = 10/1) to give 9H-fluoren-9-ylmethyl (3S)-3-[4-(4-bromo-3-chloro-2-fluoro-anilino)pyrido[3,2-d]py rimidin-6-yl]oxypyrrolidine-1- carboxylate (312 mg, 321 μmol, 59%) as a yellow solid. m/z ES+ [M+H] ⁺ 661.9. [01273] Step 4. 9H-Fluoren-9-ylmethyl (3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate [01274] To an 15 mL vial equipped with a stir bar was added 9H-fluoren-9-ylmethyl (3S)-3-[4-(4- bromo-3-chloro-2-fluoro-anilino)pyrido[3,2-d]pyrimidin-6-yl] oxypyrrolidine-1-carboxylate (180 mg, 272 μmol), 3-(bromomethyl)oxetane (53.4 mg, 354 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (3.06 mg, 2.72 μmol), nickel chloride-dtbbpy (1.63 mg, 4.09 μmol), bis(trimethylsilyl)silyl-trimethyl- silane (67.7 mg, 272 μmol), sodium carbonate (57.7 mg, 544 μmol) in 1,2-dimethoxyethane (3 mL). The vial was sealed and placed under nitrogen, which was then stirred and irradiated with a 10 W blue LED lamp (3 cm away), with cooling watr to keep the reaction temperature at 25 °C for 14 hr. On completion, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with water (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, dichloromethane:methyl alcohol=20:1) to give 9H-fluoren-9-ylmethyl (3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate (104 mg, 93.3 μmol, 34%) as a yellow oil. m/z ES+ [M+H] ⁺ 652.1. [01275] Step 5. N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethyl)phenyl]-6-[(3S)-py rrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine [01276] To a mixture of 9H-fluoren-9-ylmethyl (3S)-3-[4-[3-chloro-2-fluoro-4-(oxetan-3- ylmethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate (100 mg, 153 μmol) in dichloromethane (3 mL) was added piperidine (261 mg, 3.07 mmol), the mixture was stirred at 25 °C for 4 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 condition) to give N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethyl)phenyl]-6-[(3S)-py rrolidin-3-yl]oxy-pyrido[3,2- d]pyrimidin-4-amine (53.0 mg, 102 μmol, 66%) as a yellow oil. m/z ES+ [M+H] ⁺ 430.1. [01277] Step 6. 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-(oxetan-3-ylmethyl)anilino ]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [01278] To a mixture of N-[3-chloro-2-fluoro-4-(oxetan-3-ylmethyl)phenyl]-6-[(3S)-py rrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (43.0 mg, 100 μmol) in tetrahydrofuran (2 mL) and water (0.7 mL) was added sodium bicarbonate (16.8 mg, 200 μmol), then the mixture was added prop- 2-enoyl chloride (9.05 mg, 100 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 (Welch Xtimate C18 150 x 25 mm, 5 um; mobile phase: [water(NH3H2O)-ACN]; B%: 27%-57%, 8 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4- (oxetan-3-ylmethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypy rrolidin-1-yl]prop-2-en-1-one (25.6 mg, 50.6 μmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 - 8.62 (m, 1H), 7.70 - 7.64 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H), 6.97 (dd, J = 2.4, 8.0 Hz, 1H), 6.57 (dd, J = 4.4, 9.2 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.87 - 5.70 (m, 1H), 5.32 (dd, J = 2.4, 6.4, 16.8 Hz, 1H), 5.25 - 5.11 (m, 1H), 4.90 - 4.81 (m, 1H), 3.85 (dd, J = 6.0, 7.6 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.26 - 2.96 (m, 2H), 2.89 - 2.68 (m, 2H), 2.57 - 2.53 (m, 1H), 2.31 (d, J = 7.6 Hz, 2H), 1.51 - 1.27 (m, 2H); m/z ES+ [M+H] ⁺ 663.1. Example 88. Preparation of 1-[(3S)-3-[4-[3-chloro-4-(2,2,2-trifluoroethyl)anilino]-7-fl uoro- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-o ne

[01279] Step 1. tert-Butyl (3S)-3-[4-[3-chloro-4-(2,2,2-trifluoroethyl)anilino]-7-fluor o- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [01280] To a mixture of tert-butyl (3S)-3-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (100 mg, 271 μmol) in acetonitrile (0.5 mL) was added 3-chloro- 4-(2,2,2-trifluoroethyl)aniline (56.8 mg, 271 μmol), then the mixture was stirred at 40 °C for 1 h. On completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (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 = 3/2) to give tert-butyl (3S)-3-[4-[3-chloro-4-(2,2,2-trifluoroethyl)anilino]-7- fluoro-pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxyl ate (50.0 mg, 88.3 μmol, 33%) as a white gum. m/z ES+ [M+H] ⁺ 542.1 [01281] Step 2. N-[3-chloro-4-(2,2,2-trifluoroethyl)phenyl]-7-fluoro-6-[(3S) -pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine [01282] A mixture of tert-butyl (3S)-3-[4-[3-chloro-4-(2,2,2-trifluoroethyl)anilino]-7-fluor o- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (40.0 mg, 73.8 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL) was stirred 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give N-[3-chloro-4-(2,2,2- trifluoroethyl)phenyl]-7-fluoro-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 441.9 [01283] Step 3. 1-[(3S)-3-[4-[3-Chloro-4-(2,2,2-trifluoroethyl)anilino]-7-fl uoro-pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [01284] To a mixture of N-[3-chloro-4-(2,2,2-trifluoroethyl)phenyl]-7-fluoro-6-[(3S) -pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (40.0 mg, 72.0 μmol, trifluoroacetic acid salt) in anhydrous tetrahydrofuran (1 mL) and water (0.1 mL) was added sodium bicarbonate (6.05 mg, 72.0 μmol) and prop-2-enoyl chloride (7.16 mg, 79.2 μmol), then the mixture was stirred at 0 °C for 0.5 h. On completion, the solvent was carefully removed in vacuo to give a residue. The crude product was purified by prep-HPLC (column: Welch Ultimate C18150 x 25 mm, 5 um; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 10.5 min) to give 1-[(3S)-3-[4-[3-chloro-4-(2,2,2- trifluoroethyl)anilino]-7-fluoro-pyrido[3,2-d]pyrimidin-6-yl ]oxypyrrolidin-1-yl]prop-2-en-1-one (21.3 mg, 42.7 μmol, 59%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.65 (d, J = 1.2 Hz, 1H), 8.20 (s, 1H), 8.11 (dd, J = 2.4, 10.8 Hz, 1H), 7.97 (dd, J = 1.6, 8.8 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 6.75 - 6.52 (m, 1H), 6.42 - 6.22 (m, 1H), 6.22 - 6.11 (m, 1H), 5.78 - 5.60 (m, 1H), 4.13 - 3.81 (m, 3H), 3.79 - 3.43 (m, 3H), 2.48 - 2.35 (m, 1H), 2.31 - 2.17 (m, 1H); m/z ES+ [M+H] ⁺ 495.9. Example 89. Preparation of 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrol idin-1-yl]prop-2-en-1-one [01285] Step 1. tert-Butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)anilino ]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [01286] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (150 mg, 427 μmol) and 3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)aniline (194 mg, 427 μmol) in acetonitrile (3.5 mL) was stirred at 40 °C for 7 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate= 2:1) to give tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrol idine-1-carboxylate (180 mg, 286 μmol, 67%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (d, J = 2.8 Hz, 1H), 8.93 - 8.84 (m, 1H), 8.12 (d, J = 8.8 Hz 1H), 7.3 (s, 1H), 7.25 - 7.18 (m, 1H), 5.70 - 5.68 (m, 1H), 3.86 - 3.59 (m, 7H), 2.33 ( s, 2H), 1.49 (s, 9H); m/z ES+ [M+H] ⁺ 542.9. [01287] Step 2. N-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)phenyl]-6-[(3S) -pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine [01288] To a solution of tert-butyl (3S)-3-[4-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrol idine-1-carboxylate (160 mg, 295 μmol) in dichloromethane (8 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-chloro-2- fluoro-4-(2,2,2-trifluoroethyl)phenyl]-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4- amine (160 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H] ⁺ 442.0. [01289] Step 3. 1-[(3S)-3-[4-[3-Chloro-2-fluoro-4-(2,2,2-trifluoroethyl)anil ino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one [01290] To a solution of N-[3-chloro-2-fluoro-4-(2,2,2-trifluoroethyl)phenyl]-6-[(3S) -pyrrolidin- 3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (160 mg, 287 μmol, trifluoroacetic acid) in water (1 mL) and anhydrous tetrahydrofuran (5 mL) was added sodium bicarbonatev (48.3 mg, 575 μmol) at 0 °C. Then prop-2-enoyl chloride (26.0 mg, 287 μmol) 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 dimethylformamide (2 mL), then concentrated to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C18150 x 25 um, 10 um; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 10 min) to give 1-[(3S)-3-[4-[3-chloro-2-fluoro-4-(2,2,2- trifluoroethyl)anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrol idin-1-yl]prop-2-en-1-one (57.9 mg, 110 μmol, 38%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.56 (d, J = 1.2 Hz, 1H), 8.16 (dd, J = 1.2, 9.2 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.48 - 7.40 (m, 2H), 6.69 - 6.55 (m, 1H), 6.20 - 6.14 (m, 1H), 6.06 - 5.97 (m, 1H), 5.72 - 5.66 (m, 1H), 4.10 - 3.81 (m, 4H), 3.74 - 3.48 (m, 2H), 2.42 - 2.18 (m, 2H); m/z ES+ [M+H] ⁺ 496.0. Example 90. Preparation of 1-[(3S)-3-[4-[4-(cyclopropoxy)-2,3-difluoro-anilino]pyrido[3 ,2- d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one

[01291] Step 1. tert-Butyl (3S)-3-[4-[4-(cyclopropoxy)-2,3-difluoro-anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate [01292] A mixture of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1 - carboxylate (150 mg, 428 μmol) and 4-(cyclopropoxy)-2,3-difluoro-aniline (103 mg, 556 μmol) in acetonitrile (0.5 mL) was stirred at 40 °C for 5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give compound tert-butyl (3S)-3-[4-[4-(cyclopropoxy)- 2,3-difluoro-anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolid ine-1-carboxylate (0.2 g, 336 μmol, 79%) as a yellow solid. m/z ES+ [M+H] ⁺ 500.4. [01293] Step 2. N-[4-(Cyclopropoxy)-2,3-difluoro-phenyl]-6-[(3S)-pyrrolidin- 3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine [01294] A solution of tert-butyl (3S)-3-[4-[4-(cyclopropoxy)-2,3-difluoro-anilino]pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (0.2 g, 400 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 compound N-[4-(cyclopropoxy)-2,3-difluoro- phenyl]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4 -amine (0.15 g, 323 μmol, 81%) as a yellow oil. m/z ES+ [M+H] ⁺ 400.3. [01295] Step 3. 1-[(3S)-3-[4-[4-(Cyclopropoxy)-2,3-difluoro-anilino]pyrido[3 ,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one [01296] To a mixture of N-[4-(cyclopropoxy)-2,3-difluoro-phenyl]-6-[(3S)-pyrrolidin- 3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (0.15 g, 376 μmol) in tertrhydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (94.7 mg, 1.13 mmol) and prop-2-enoyl chloride (30.6 mg, 338 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. 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 x 25 mm, 10 um; mobile phase: [water(FA)-ACN]; B%: 35%-65%, 10 min) to give compound 1-[(3S)-3-[4-[4-(cyclopropoxy)-2,3-difluoro- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (29.06 mg, 62.2 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.41 - 7.29 (m, 2H), 6.70 - 6.53 (m, 1H), 6.20 - 5.99 (m, 2H), 5.68 (ddd, J = 2.4, 10.4, 18.4 Hz, 1H), 4.11 - 4.01 (m, 1H), 3.86 - 3.47 (m, 4H), 2.37 - 2.07 (m, 2H), 0.88 - 0.81 (m, 2H), 0.81 - 0.73 (m, 2H); m/z ES+ [M+H] ⁺ 454.0. Example 91. Preparation of (S)-1-(3-((4-((2,3-difluoro-4-(1-methylcyclobutoxy)phenyl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01297] Step 1. tert-Butyl (S)-3-((4-((2,3-difluoro-4-(1-methylcyclobutoxy)phenyl)- amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxyl ate [01298] A mixture of tert-butyl (S)-3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine- 1- carboxylate (100 mg, 285 μmol) and 2,3-difluoro-4-(1-methylcyclobutoxy)aniline (67 mg, 314 μmol) in acetonitrile (1 mL) was stirred at 25 ℃ for 4 hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl (S)-3-((4-((2,3-difluoro-4-(1-methylcyclobutoxy)- phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-c arboxylate (170 mg, crude) as a black solid. m/z ES+ [M+H] ⁺ 528.2. [01299] Step 2. (S)-N-(2,3-Difluoro-4-(1-methylcyclobutoxy)phenyl)-6-(pyrrol idin-3-yloxy)- pyrido[3,2-d]pyrimidin-4-amine [01300] To a solution of tert-butyl (3S)-3-[4-[2,3-difluoro-4-(1-methylcyclobutoxy)- anilino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxy late (90 mg, 171 μmol) in dichloromethane (1 mL) was added zinc bromide (760 mg, 3.37 mmol). The mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was concentrated under reduced pressure to give (S)-N- (2,3-difluoro-4-(1-methylcyclobutoxy)phenyl)-6-(pyrrolidin-3 -yloxy)pyrido[3,2-d]pyrimidin-4- amine (73 mg, crude) as a yellow gum. m/z ES+ [M+H] ⁺ 428.0. [01301] Step 3. (S)-1-(3-((4-((2,3-Difluoro-4-(1-methylcyclobutoxy)phenyl)am ino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [01302] To a solution of (S)-N-(2,3-difluoro-4-(1-methylcyclobutoxy)phenyl)-6-(pyrrol idin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (73 mg, 171 μmol) in anhydrous tetrahydrofuran (1 mL) and water (0.2 mL) was added sodium bicarbonate (143 mg, 1.71 mmol) to adjust pH ~ 8. Then prop-2-enoyl chloride (7.77 mg, 85.8 μmol) was added into the mixture at 0 ℃. The mixture was stirred at 0 ℃ 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 x 25 mm, 5 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 53%-73%, 8 min) to give (S)-1- (3-((4-((2,3-difluoro-4-(1-methylcyclobutoxy)phenyl)amino)py rido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (25.2 mg, 52.3 μmol, 31%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.47 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.48 - 7.34 (m, 2H), 6.91 (t, J = 8.8 Hz, 1H), 6.72 - 6.52 (m, 1H), 6.15 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.11 - 5.98 (m, 1H), 5.68 (ddd, J = 2.4, 10.2, 18.8 Hz, 1H), 4.11 - 3.47 (m, 4H), 2.42 - 2.25 (m, 4H), 2.19 - 2.13 (m, 2H), 1.85 - 1.63 (m, 2H), 1.54 (s, 3H); m/z ES+ [M+H] ⁺ 482.0. Example 92. Preparation of (S)-1-(3-((4-((3-chloro-2-fluoro-4-(1-methylcyclopropoxy)- phenyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrol idin-1-yl)prop-2-en-1-one

[01303] Step 1.2,3-Dichloro-1-(1-methylcyclopropoxy)-4-nitro-benzene [01304] To a solution of 1-methylcyclopropanol (260 mg, 3.61 mmol) in anhydrous tetrahydrofuran (10 mL) was added sodium hydride (143 mg, 3.58 mmol, 60% in mineral oil) at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. Then 2,3-dichloro-1-fluoro-4-nitro-benzene (500 mg, 2.38 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 2,3-dichloro-1-(1-methylcyclopropoxy)-4-nitro- benzene (420 mg, 1.60 mmol, 67%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 1.62 (s, 3H), 1.15 - 1.08 (m, 2H), 0.90 - 0.82 (m, 2H). [01305] Step 2.2-Chloro-3-fluoro-1-(1-methylcyclopropoxy)-4-nitrobenzene [01306] To a solution of 2,3-dichloro-1-(1-methylcyclopropoxy)-4-nitro-benzene (200 mg, 763 μmol) in dimethylsulfoxide (3 mL) was added cesium fluoride (250 mg, 1.65 mmol). The mixture was stirred at 140 °C for 16 hr. The reaction mixture was quenched by addition water 2 mL at 0 °C, and then extracted with ethyl acetate (2 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=100/1 to 10/1) to give 2-chloro-3-fluoro-1-(1-methylcyclopropoxy)- 4-nitrobenzene (180 mg, 249 μmol, 33%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.33 (s, 1H), 8.16 - 8.00 (m, 1H), 7.21 - 6.87 (m, 1H), 1.63 (s, 3H), 1.16 - 1.08 (m, 2H), 0.90 - 0.82 (m, 2H). [01307] Step 3.3-Chloro-2-fluoro-4-(1-methylcyclopropoxy)aniline [01308] A mixture of 2-chloro-3-fluoro-1-(1-methylcyclopropoxy)-4-nitrobenzene (180 mg, 733 μmol) and Pt/V/C (80 mg, 12.3 μmol, 3% loading) in ethyl acetate (5 mL) was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 20 °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 prep-TLC (silicon dioxide, petroleum ether: ethyl acetate = 3:1) to give 3-chloro-2-fluoro-4-(1-methylcyclopropoxy)aniline (50 mg, 232 μmol, 32%) as a yellow oil. m/z ES+ [M+H] ⁺ 216.0. [01309] Step 4. tert-Butyl (S)-3-((4-((3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl )- amino)-7-fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1 -carboxylate [01310] A mixture of tert-butyl (3S)-3-(4-chloro-7-fluoro-pyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (82.5 mg, 224 μmol) and 3-chloro-2-fluoro-4-(1- methylcyclopropoxy)aniline (50 mg, 232 μmol) in acetonitrile (1.5 mL) was stirred at 25 °C for 4 hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl (S)-3-((4-((3- chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl)amino)-7-fluo ropyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (140 mg, crude) as a yellow solid. m/z ES+ [M+H] ⁺ 548.2. [01311] Step 5. (S)-N-(3-Chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl)-7-f luoro-6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine [01312] To a solution of tert-butyl (S)-3-((4-((3-chloro-2-fluoro-4-(1- methylcyclopropoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimi din-6-yl)oxy)pyrrolidine-1- carboxylate (130 mg, 237 μmol) in dichloromethane (3 mL) was added zinc bromide (520 mg, 2.31 mmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give (S)-N-(3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl)-7- fluoro-6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (140 mg, crude) as a yellow gum. m/z ES+ [M+H] ⁺ 448.0. [01313] Step 6. (S)-1-(3-((4-((3-Chloro-2-fluoro-4-(1-methylcyclopropoxy)phe nyl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2 -en-1-one [01314] To a solution of (S)-N-(3-chloro-2-fluoro-4-(1-methylcyclopropoxy)phenyl)-7-f luoro-6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (140 mg, 313 μmol) in anhydrous tetrahydrofuran (2 mL) and water (0.4 mL) was added sodium bicarbonate (78.8 mg, 938 μmol) to adjust pH ~ 8. Then prop-2-enoyl chloride (20.6 mg, 228 μmol, 18.6 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 x 25 mm, 5 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 45%-75%, 8 min) to give (S)-1-(3-((4-((3-chloro-2-fluoro-4-(1- methylcyclopropoxy)phenyl)amino)-7-fluoropyrido[3,2-d]pyrimi din-6-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one (42.7 mg, 85 μmol, 27%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.64 (br. s, 1H), 8.45 (s, 1H), 8.07 (dd, J = 2.4, 10.8 Hz, 1H), 7.59 (dt, J = 3.2, 8.8 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 6.72 - 6.52 (m, 1H), 6.23 - 6.06 (m, 2H), 5.69 (ddd, J = 2.4, 10.2, 17.2 Hz, 1H), 4.12 - 3.48 (m, 4H), 2.43 - 2.20 (m, 2H), 1.56 (s, 3H), 1.02 - 0.97 (m, 2H), 0.88 - 0.83 (m, 2H); m/z ES+ [M+H] ⁺ 501.9 Example 93. Synthesis and Characterization of Additional Exemplary Compounds [01315] Additional exemplary compounds were synthesized following the procedures described herein. Characterizations of the compounds are shown in Table A below. Table A Example 94. Biological Activity of Exemplary Compounds [01316] Tables B and C assign each compound a potency code: A, B, C, D, or E. According to the code, A represents an IC ₅₀ value <20 nM; B represents an IC ₅₀ 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 and <500 nM; and E represents an IC ₅₀ value ≥500 nM. Table B

Table C

EQUIVALENTS [01317] 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. [01318] 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.