RELATED APPLICATION

[001] This application claims priority to, and the benefit of, U.S. Application No. 63/211,913, 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, -O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl;

W ² is, =CR ^W2 -, or =N-;

R ^W2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl;

X ¹ is -CH ₂ -, -O-, -NH-, -N(R ^x1a )-*, or -NH-CH(R ^x1a )-*, wherein * denotes attachment to

R ^x1a is C ₁ -C ₆ alkyl optionally substituted with one or more OH; Y is C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ;

R ^Y is oxo, cyano, halogen, OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, - O-( C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ - C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O- (C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl) is optionally substituted with one or more R ^Y1 ;

R ^Y1 is halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 3- to 9- membered heterocycloalkyl is optionally substituted with one or more halogen;

Z is -NH-, -O-, -N(C ₁ -C ₆ alkyl)-, 3- to 9-membered heterocycloalkyl, -NH-(3- to 9- membered heterocycloalkyl)-*, (3- to 9-membered heterocycloalkyl)-NH-*, or -O-(3- to 9- membered heterocycloalkyl)-*, wherein * denotes attachment to -C(=O)-R ¹ , and wherein the 3- to 9-membered heterocycloalkyl, -NH-(3- to 9-membered heterocycloalkyl), (3- to 9-membered heterocycloalkyl)-NH-, or -O-(3- to 9-membered heterocycloalkyl) is optionally substituted with one or more R ^z ;

R ^z is OH, oxo, cyano, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9- membered heterocycloalkyl, or two R ^z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen;

R ¹ is cyano, C ₃ -C ₈ cycloalkyl, -HC=CH ₂ , -(CH ₂ )n-N(C ₁ -C ₆ alkyl) ₂ , -HC=CHR ^1a or-C=C- (C ₁ -C ₆ alkyl);

R ^1a is -CH ₂ -N(CI-C ₆ alkyl) ₂ or -(C=O)-O-(C ₁ -C ₆ alkyl); and wherein n is 0, 1, 2, or 3.

[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 1-2).

[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 1-10).

[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.

[Oi l] 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 ^WI -, or =N-;

R ^W1 is H, halogen, -O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl;

W ² is, =CR ^W2 -, or =N-;

R ^w2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl;

X ¹ is -CH ₂ -, -O-, -NH-, -N( R ^x1a )-*, or -NH-CH(R ^x1a )-*, wherein * denotes attachment to

R ^x1a is C ₁ -C ₆ alkyl optionally substituted with one or more OH;

Y is C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y ;

R ^Y is oxo, cyano, halogen, OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, - O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl), wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxyl, C ₃ - C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 9-membered heteroaryl, -O- (C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9- membered heteroaryl) is optionally substituted with one or more R ^Y1 ;

R ^Y1 is halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 3- to 9- membered heterocycloalkyl is optionally substituted with one or more halogen;

Z is -NH-, -O-, -N(C ₁ -C ₆ alkyl)-, 3- to 9-membered heterocycloalkyl, -NH-(3- to 9- membered heterocycloalkyl)-*, (3- to 9-membered heterocycloalkyl)-NH-*, or -O-(3- to 9- membered heterocycloalkyl)-*, wherein * denotes attachment to -C(=O)-R ¹ , and wherein the 3- to 9-membered heterocycloalkyl, -NH-(3- to 9-membered heterocycloalkyl), (3- to 9-membered heterocycloalkyl)-NH-, or -O-(3- to 9-membered heterocycloalkyl) is optionally substituted with one or more R ^z ;

R ^z is OH, oxo, cyano, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₆ cycloalkyl, or 3- to 9- membered heterocycloalkyl, or two R ^z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen;

R ¹ is cyano, C ₃ -C ₈ cycloalkyl, — HC=CH ₂ , -(CH ₂ ) _n -N(C ₁ -C ₆ alkyl) ₂ , — HC=CHR ^1a or - C≡C— (C ₁ -C ₆ alkyl); R ^1a is -CH ₂ -N(C ₁ -C ₆ alkyl) ₂ or -(C=O)-O-(C ₁ -C ₆ alkyl); and wherein n is 0, 1, 2, or 3.

[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, -O(C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkyl;

W ² is, =CR ^W2 -, or =N-;

R ^w2 is H, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl;

X ¹ is -CH ₂ -, -O-, -NH-, -N(R ^x1a )-*, or -NH-CH(R ^x1a )-*, wherein * denotes attachment to

Y;

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 ;

R ^Y is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl, wherein the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxyl is optionally substituted with one or more R ^Y1 ;

R ^Y1 is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 3- to 9- membered heterocycloalkyl is optionally substituted with one or more halogen;

Z is -NH-, -O-, 3- to 9 -membered heterocycloalkyl, -NH-(3- to 9 -membered heterocycloalkyl)-*, (3- to 9-membered heterocycloalkyl)-NH-*, or -O-(3- to 9-membered heterocycloalkyl)-*, wherein * denotes attachment to -C(=O)-R ¹ , and wherein the 3- to 9- membered heterocycloalkyl, -NH-(3- to 9-membered heterocycloalkyl), (3- to 9-membered heterocycloalkyl)-NH-, or -O-(3- to 9-membered heterocycloalkyl) is optionally substituted with one or more R ^z ;

R ^z is C ₁ -C ₆ alkyl;

R ¹ is -HC=CH ₂ , -(CH ₂ )n-N(C ₁ -C ₆ alkyl) ₂ , -HC=CHR ^1a or-C=C-(C ₁ -C ₆ alkyl); R ^1a is -CH ₂ -N(C ₁ -C ₆ alkyl) ₂ or -(C=O)-O-(C ₁ -C ₆ alkyl); and wherein n is 0, 1, 2, or 3.

[020] It is understood that, for a compound of Formula (I), W ¹ , R ^wl , W ² , R ^w2 , X ¹ , R ^x1a , Y, R ^Y , R ^Y1 , Z, R ^Z , R ¹ , R ^1a , and n can each be, where applicable, selected from the groups described herein, and any group described herein for any of W ¹ , R ^wl , W ² , R ^w2 , X ¹ , R ^x1a , Y, R ^Y , R ^Y1 , Z, R ^z , R ¹ , R ^1a , and n can be combined, where applicable, with any group described herein for one or more of the remainder of W ¹ , R ^wl , W ² , R ^w2 , X ¹ , R ^x1a , Y, R ^Y , R ^Y1 , Z, R ^z , R ¹ , R ^1a , and n.

Variables W ¹ , W ² , R ^W1 , and R ^{W 2}

[021] In some embodiments, W ¹ is =CR ^W1 -. In some embodiments, W ¹ is =CH-.

[022] In some embodiments, W ¹ is =N-.

[023] In some embodiments, R ^W1 is H, halogen, C ₁ -C ₆ alkyl, or -O-(C ₁ -C ₆ alkyl).

[024] In some embodiments, R ^W1 is H.

[025] In some embodiments, W ² is =CR ^W2 -. In some embodiments, W ² is =CH-. In some embodiments, W ² is =CF-. In some embodiments, W ² is =C-O-(C ₁ -C ₆ alkyl).

[026] In some embodiments, W ² is =N-.

[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 -O-(C ₁ -C ₆ alkyl).

[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, R ^W2 is -O-(C ₁ -C ₆ alkyl). In some embodiments, R ^W2 is -O-CH ₃ . [032] In some embodiments, W ¹ is =CR ^w1 - and W ² is =CR ^W2 -.

[033] In some embodiments, W ¹ is N and W ² is =CR ^W2 -.

[034] In some embodiments, W ¹ is =CR ^W1 - and W ² is N.

[035] In some embodiments, W ¹ is CH and W ² is CH.

[036] In some embodiments, W ¹ is N and W ² is CH.

[037] In some embodiments, W ¹ is CH and W ² is N.

[038] In some embodiments, W ¹ is N and W ² is N.

Variables X ¹ , Y, R ^Y , and R ^Y1

[039] In some embodiments, X ¹ is -NH-, -N(CH ₃ )- or -O-.

[040] In some embodiments, X ¹ is -NH-. In some embodiments, X ¹ is -O-.

[041] In some embodiments, Y is C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₃ -C ₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y .

[042] 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 .

[043] In some embodiments, Y is C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl.

[044] In some embodiments, Y is C ₆ -C ₁₀ aryl. In some embodiments, Y is phenyl.

[045] In some embodiments, Y is 5- to 9-membered heteroaryl. In some embodiments, Y is indazole.

[046] In some embodiments, Y is optionally substituted with one R ^Y .

[047] In some embodiments, Y is optionally substituted with two R ^Y .

[048] In some embodiments, Y is optionally substituted with three R ^Y .

[049] In some embodiments, R ^x1a is C ₁ -C ₆ alkyl optionally substituted with one or more OH.

[050] In some embodiments, R ^x1a is C ₁ -C ₆ alkyl substituted with one or more OH.

[051] In some embodiments, R ^Y is oxo, cyano, 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 .

[052] In some embodiments, R ^Y is oxo, cyano, halogen, or OH.

[053] In some embodiments, 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, 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, or 5- to 9-membered heteroaryl is optionally substituted with one or more R ^Y1 .

[054] In some embodiments, R ^Y is -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9- membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl), wherein the -O-(C ₃ -C ₈ cycloalkyl), -O-(C ₆ -C ₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or -O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R ^Y1 .

[055] In some embodiments, R ^Y is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxyl.

[056] In some embodiments, R ^Y is halogen. In some embodiments, R ^Y is fluorine. In some embodiments, R ^Y is chlorine. In some embodiments, R ^Y is bromine. In some embodiments, R ^Y is iodine.

[057] In some embodiments, R ^Y is C ₁ -C ₆ alkyl, hi some embodiments, R ^Y is Ci alkyl, hi some embodiments, R ^Y is C2 alkyl. In some embodiments, R ^Y is C3 alkyl. In some embodiments, R ^Y is C4 alkyl. In some embodiments, R ^Y is C5 alkyl. In some embodiments, R ^Y is C ₆ alkyl.

[058] In some embodiments, R ^Y is C ₁ -C ₆ alkoxyl. In some embodiments R ^Y is Ci alkoxyl. In some embodiments, R ^Y is C2 alkoxyl. In some embodiments, R ^Y is C3 alkoxyl. In some embodiments, R ^Y is C4 alkoxyl. In some embodiments, R ^Y is C5 alkoxyl. In some embodiments, R ^Y is C ₆ alkoxyl.

[059] In some embodiments, R ^Y1 is halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more halogen. [060] In some embodiments, R ^Y1 is halogen or OH.

[061] In some embodiments, R ^Y1 is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C ₆ -C ₁₀ aryl or 3- to 9-membered heterocycloalkyl is optionally substituted with one or more halogen. [062] In some embodiments, R ^Y1 is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₃ -C ₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5- to 9 -membered heteroaryl.

[063] In some embodiments, R ^Y is substituted with one R ^Y1 .

[064] In some embodiments, R ^Y1 is C ₆ -C ₁₀ aryl, or 5- to 9-membered heteroaryl.

[065] In some embodiments, R ^Y1 is C ₆ -C ₁₀ aryl. In some embodiments, R ^Y1 is phenyl.

[066] In some embodiments, R ^Y1 is optionally substituted with one halogen. In some embodiments, R ^{Y 1} is optionally substituted with fluorine. [067] In some embodiments, R ^Y1 is 5- to 9-membered heteroaryl. In some embodiments, R ^Y1 is pyridyl.

[068] In some embodiments, R ^Y is C ₆ -C ₁₀ aryl or 5- to 9-membered heteroaryl, and X ¹ is -O- or -NH-.

Variables Z, R ^z , R ¹ , R ^1a , and n.

[069] In some embodiments, Z is -NH-, --OO-, -N(C ₁ -C ₆ alkyl) 3- to 9-membered heterocycloalkyl, -NH-(3- ttoo 9-membered heterocycloalkyl)-*, (3- to 9-membered heterocycloalkyl)-NH-*, or -O-(3- to 9-membered heterocycloalkyl)-*, wherein ** denotes attachment to -C(=O)-R ¹ , and wherein the 3- to 9-membered heterocycloalkyl, -NH-(3- to 9- membered heterocycloalkyl), (3- to 9-membered heterocycloalkyl)-NH-, or -O-(3- to 9-membered heterocycloalkyl) is optionally substituted with one or more R ^z .

[070] In some embodiments, Z is -NH-, 3- to 9-membered heterocycloalkyl, (3- to 9-membered heterocycloalkyl)-NH-, or -O-(3- to 9-membered heterocycloalkyl), wherein the 3- to 9-membered heterocycloalkyl, (3- to 9-membered heterocycloalkyl)-NH-, oorr -O-(3- to 9-membered heterocycloalkyl) is optionally substituted with one or more R ^z .

[071] In some embodiments, Z is -NH-.

[072] In some embodiments, Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9- membered heterocycloalkyl is optionally substituted with one or more R ^z .

[073] In some embodiments, Z is (3- to 9-membered heterocycloalkyl)-NH-, wherein the (3- to 9-membered heterocycloalkyl)-NH- is optionally substituted with one or more R ^z .

[074] In some embodiments, Z is -O-(3- to 9-membered heterocycloalkyl), wherein the -O-(3- to 9-membered heterocycloalkyl) is optionally substituted with one or more R ^z . [075] IInn ssoommee embodiments, ZZ iiss 33 --mmeemmbbeerreedd heterocycloalkyl, (3 -membered heterocycloalkyl)-NH-, or -O-(3-membered heterocycloalkyl). In some embodiments, Z is 4- membered heterocycloalkyl, (4-membered heterocycloalkyl)-NH-, oorr -O-(4-membered heterocycloalkyl). In some embodiments, Z is 5-membered heterocycloalkyl, (5-membered heterocycloalkyl)-NH-, or -O-(5-membered heterocycloalkyl). In some embodiments, Z is 6- membered heterocycloalkyl, (6-membered heterocycloalkyl)-NH-, oorr -O-(6-membered heterocycloalkyl). In some embodiments, Z is 7 -membered heterocycloalkyl, (7 -membered heterocycloalkyl)-NH-, or -O-(7-membered heterocycloalkyl). In some embodiments, Z is 8- membered heterocycloalkyl, (8-membered heterocycloalkyl)-NH-, oorr -O-(8-membered heterocycloalkyl). In some embodiments, Z is 9-membered heterocycloalkyl, (9-membered heterocycloalkyl)-NH-, or -O-(9-membered heterocycloalkyl).

[076] In some embodiments, the 3- to 9-membered heterocycloalkyl of Z is 2,5- diazabicyclo[2.2.1]heptyl, piperidinyl, l,6-diazaspiro[3.3]heptyl, azetidinyl, or pyrrolidinyl.

[077] In some embodiments, Z is 2,5-diazabicyclo[2.2.1]heptyl. In some embodiments, Z is piperidinyl. In some embodiments, Z is l,6-diazaspiro[3.3]heptyl. In some embodiments, Z is azetidinyl.

[078] In some embodiments, Z is (azetidinyl)-NH-. In some embodiments, Z is -O- (pyrrolidinyl). hi some embodiments, Z is -O-(azetidinyl). In some embodiments, Z is -O- (piperidinyl).In some embodiments, Z is -O-(3- to 9-membered heterocycloalkyl) optionally substituted with one or more R ^z .

[079] In some embodiments, R ^z is OH, oxo, cyano, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, C ₁ -C ₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R ^z together with the carbon they are attached to form a C ₃ -C ₆ cycloalkyl; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more OH or halogen.

[080] In some embodiments, R ^z is OH, oxo, cyano, or halogen.

[081] In some embodiments, R ^z is C ₁ -C ₆ alkyl. In some embodiments, R ^z is C ₁ alkyl. In some embodiments, R ^z is C ₂ alkyl. In some embodiments, R ^z is C ₃ alkyl. In some embodiments, R ^z is C4 alkyl. In some embodiments, R ^z is C ₅ alkyl. In some embodiments, R ^z is C ₆ alkyl.

[082] In some embodiments, Z is 3- to 9-membered heterocycloalkyl and R ^z is C ₁ -C ₆ alkyl.

[083] In some embodiments, R ¹ is -HC=CH ₂ , -(CH ₂ ) _n -N(Me) ₂ , -HC=CHR ^1a , or -C=C-CH ₃ . [084] In some embodiments, R ¹ is -HC=CH ₂ . In some embodiments, R ¹ is -(CH ₂ )n-N(Me)2. In some embodiments, R ¹ is -(CH ₂ )2-N(Me)2. In some embodiments, R ¹ is -HC=CHR ^1a . In some embodiments, R ¹ is -C≡C-CH ₃ .

[085] In some embodiments R ^1a is -(C=O)-O-(C ₁ -C ₆ alkyl), or -(C=O)-O-(C ₁ -C ₆ alkyl).

[086] In some embodiments, R ^1a is -(C=O)-O-(C ₁ -C ₆ alkyl). In some embodiments, R ^1a is - (C=O)-O-(C ₁ -C ₆ alkyl).

[087] In some embodiments, n is 0, 1, 2, or 3.

[088] In some embodiments, n is 2.

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

[090] In some embodiments, the compound is of formula (I-f) or (I-g):

wherein, m is 0, 1, 2, 3, 4, or 5; 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 or stereoisomer thereof.

[092] In some embodiments, the compound is selected from a compound described in Table I, or a pharmaceutically acceptable salt thereof.

[093] In some embodiments, the compound is selected from a compound described in Table I. d d r Co r

Y ^ XX

I pc

[094] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of a compound disclosed herein.

[095] Tn some embodiments, the compound is an isotopic derivative of a compound described in Table I, or a pharmaceutically acceptable salt thereof.

[096] In some embodiments, the compound is an isotopic derivative of a compound described in Table I.

[097] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[098] Tn some embodiments, the isotopic derivative is a deuterium labeled compound.

[099] In some embodiments, the isotopic derivative is a deuterium labeled compound of a compound of the Formulae disclosed herein. [0100] In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I.

[0102] 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%.

[0103] 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.

[0104] 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. [0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.”

[0110] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0111] 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).

[0112] 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. [0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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. [0118] 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”.

[0119] 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.

[0120] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0121] 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).

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0127] 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.

[0128] 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 monohydrate, 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.

[0129] 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 analyzed 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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 A-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0136] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C 1 -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.

[0137] 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. [0138] 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

[0139] In some aspects, the present disclosure provides a method of preparing a compound disclosed herein.

[0140] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein.

[0141] 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.

[0142] In some aspects, the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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 aa 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.

[0148] 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. [0149] 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.

[0150] 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.

[0151] The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art.

[0152] 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 aass 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.

[0153] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0154] 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.

[0155] 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.

[0156] 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).

[0157] General routes for the preparation of a compound of the application are described in Schemes 1 and 2.

Biological Assays

[0158] 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.

[0159] 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.

[0160] 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.

[0161] In some embodiments, the biological assay is described in the Examples herein.

[0162] In some embodiments, the biological assay is an assay measuring cell proliferation.

[0163] 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.

[0164] 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, hi some embodiments, the resistant populations may be washed and plated to select for selective growth (e.g., IL-3 independent growth).

[0165] 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.

[0166] 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

[0167] 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

[0168] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.

[0169] 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. [0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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 com 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.

[0182] 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.

[0183] 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).

[0184] 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.

[0185] 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

[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 therapeutically effective amount of a compound described herein. [0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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. [0192] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a compound described herein.

[0193] 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. [0194] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a composition 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 therapeutically effective amount of 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 therapeutically effective amount of 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 compound 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 compound 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 the subject; and ii) administering to the subject in need of the treatment a composition 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 the subject; and ii) administering to the subject in need of the treatment a composition 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 therapeutically effective amount of 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 therapeutically effective amount of 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 compound 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 compound described herein.

[0205] 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.

[0206] 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. [0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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. [0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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).

[0218] 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).

[0219] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer.

[0220] In some aspects, the present disclosure provides a compound described herein for use in the treatment of cancer.

[0221 ] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer.

[0222] In some aspects, the present disclosure provides a composition described herein for use in the treatment of cancer.

[0223] 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.

[0224] 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. [0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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).

[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.

[0233] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for treating cancer.

[0234] 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.

[0235] 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. [0236] 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.

[0237] 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.

[0238] 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.

[0239] 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. [0240] 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.

[0241] 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.

[0242] 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).

[0243] In some aspects, the present disclosure provides use of a compound described herein for preventing or treating cancer.

[0244] In some aspects, the present disclosure provides use of a compound described herein in for treating cancer.

[0245] 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. [0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] In some embodiments, cancer is a solid tumor.

[0254] 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.

[0255] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof.

[0256] In some embodiments, the cancer is glioblastoma.

[0257] In some embodiments, the cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR).

[0258] In some embodiments, the oncogenic variant is an oncogenic variant in an ErbB receptor. [0259] In some embodiments, the oncogenic variant in the ErbB receptor is an allosteric variant. [0260] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor.

[0261] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR). [0262] In some embodiments, the ErbB receptor is a HER2 receptor.

[0263] In some embodiments, the oncogenic variant is an oncogenic variant in an epidermal growth factor receptor (EGFR).

[0264] In some embodiments, the oncogenic variant in the EGFR is an allosteric variant.

[0265] In some embodiments, the oncogenic variant is an oncogenic variant of a HER2 receptor. [0266] In some embodiments, the oncogenic variant in the HER2 receptor is an allosteric variant. [0267] In some embodiments, the oncogenic variant in the EGFR is an EGFR variant III (EGFR- Viii) variant.

[0268] 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.

[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, 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 Cl 90- 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.

[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 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.

[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, 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 eexxoonn 20 oorr aa portion thereof comprises aa 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 AS V, 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 andN771 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; (1) 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 YDS 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 STEAS V for the SV between positions 768 and 769 of SEQ ID NO: 1.

[0272] 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-□660, EGFR-□768 or any combination thereof.

[0273] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor. [0274] 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.

[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 phenylalanine (F) 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 tyrosine (Y) for a serine (S) at position 310 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 glutamine (Q) for an arginine (R) at position 678 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 leucine (L) 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 a methionine (M) for a valine (V) at position 777 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 isoleucine (I) for a valine (V) at position 842 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 an alanine (A) 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 proline (P) 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, 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.

[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, 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). hi 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 ED 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 EC 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 ERE between positions 755 and 757 of SEQ ID NO: 2; (1) 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; (ft) 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; (11) 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.

[0285] 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-□ 16, HER2C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.

[0286] 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).

[0287] 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.

[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 an oncogenic variation in a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS or wherein.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[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 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] In some embodiments, the therapeutically effective amount induces a period of remission.

[0300] In some embodiments, the compound induces a period of remission. [0301] In some embodiments, the therapeutically effective amount improves a prognosis of the subject.

[0302] In some embodiments, the compound improves a prognosis of the subject.

[0303] 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. [0304] In some embodiments, the use comprises treating the subject with a Non-Type I inhibitor. [0305] In some embodiments, the composition comprises a Non-Type I inhibitor.

[0306] 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.

Definitions

[0307] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0308] 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.

[0309] 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.

[0310] 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 or 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.

[0311] 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.

[0312] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In some embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). The term “ C ₂ -C ₆ ” includes alkenyl groups containing two to six carbon atoms. The term “C ₃ -C ₆ ” includes alkenyl groups containing three to six carbon atoms.

[0313] 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.

[0314] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In some embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). The term “C ₂ -C ₆ ” includes alkynyl groups containing two to six carbon atoms. The term “C ₃ -C ₆ ” includes alkynyl groups containing three to six carbon atoms. As used herein, “C ₂ -C ₆ alkenylene linker” or “C ₂ -C ₆ alkynylene linker” is intended to include C ₂ , C ₃ , C ₄ , C ₅ or C ₆ chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C ₂ -C ₆ alkenyl ene linker is intended to include C ₂ , C ₃ , C ₄ , C ₅ or C ₆ alkenylene linker groups.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,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-lH-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 ttoo be non-aromatic (e.g., 4, 5,6,7- tetrahydrobenzo [c] i soxazolyl) . [0319] 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.

[0320] 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., No O 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).

[0321] 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.

[0322] 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][l,3]dioxole-5-yl).

[0323] 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.

[0324] 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.

[0325] 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.

[0326] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O". [0327] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0328] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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.

[0341] 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.

[0342] 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 etal., 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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 maybe 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.

[0353] 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 ELD (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.

[0354] 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.

[0355] 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 com 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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. [0361] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0362] 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.

[0363] 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.

[0364] 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.

[0365] 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-l -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.

[0366] 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. [0367] 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.

[0368] 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.

[0369] 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.

[0370] 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.

[0371] 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 [0372] A wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of:

1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq Igtfedhfls Iqrmfnncev

61 vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala

121 vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf

181 qnhlgscqkc dpscpngscw gageencqkl tkllcaqqcs 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 eclpqanmit 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 Imdeedmddv vdadeylipq

1021 qgf fsspsts rtpllsslsa tsnnstvaci drnglqscpi kedsflqrys sdptgalted

1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps rdphyqdphs tavgnpeyln

1141 tvqptcvnst fdspahwaqk gshqisldnp dyqqdf fpke akpngifkgs taenaeylrv

1201 apqssefiga (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank Accession No. CAA25240).

[0373] 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 Isflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng

121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq Icyqdtilwk difhknnqla

181 Itlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp Iptdccheqc

241 aagctgpkhs dclaclhfnh sgicelhcpa Ivtyntdtfe smpnpegryt fgascvtacp

301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan

361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre Igsglalihh nthlcfvhtv

481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec

541 veecrvlqgl preyvnarhc Ipchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc

601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp Itsiisavvg

661 illvvvlgw fgilikrrqq kirkytmrrl Iqetelvepl tpsgampnqa qmrilketel

721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp

781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr

841 Ivhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft

901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger Ipqppictid vymimvkcwm

961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda

1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt Iglepseeea prsplapseg

1081 agsdvfdgdl gmgaakglqs Ipthdpsplq rysedptvpl psetdgyvap Itcspqpeyv

1141 nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq

1201 ggaapqphpp pafspafdnl yywdqdpper gappstfkgt ptaenpeylg Idvpv (SEQ

ID NO: 2, corresponding to receptor tyrosine-protein kinase erbB-2 isoform a precursor [Homo sapiens] and GenBank Accession No. NP_004439).

[0374] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas Isflqdiqev qgyvliahnq

61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk

121 ggvliqrnpq Icyqdtilwk difhknnqla Itlidtnrsr achpcspmck gsrcwgesse

181 dcqsltrtvc aggcarckgp Iptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa

241 Ivtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr

301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta

361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi

421 swlglrslre Igsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla

481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc Ipchpecqpq

541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc

601 thscvdlddk gcpaeqrasp Itsiisavvg illvvvlgw fgilikrrqq kirkytmrrl

661 Iqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv

721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql mpygclldhv

781 renrgrlgsq dllnwcmqia kgmsyledvr Ivhrdlaarn vlvkspnhvk itdfglarll

841 dideteyhad ggkvpikwma lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger Ipqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq

961 nedlgpaspl dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss

1021 strsgggdlt Iglepseeea prsplapseg agsdvfdgdl gmgaakglqs Ipthdpsplq

1081 rysedptvpl psetdgyvap Itcspqpeyv nqpdvrpqpp spregplpaa rpagatlerp

1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnl yywdqdpper

1201 gappstfkgt ptaenpeylg Idvpv (SEQ ID NO: 3, corresponding to receptor tyrosineprotein kinase erbB-2 isoform b [Homo sapiens] and GenBank Accession No. NP_001005862).

[0375] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

1 mprgswkpqv ctgtdmklrl paspethldm Irhlyqgcqv vqgnleltyl ptnasls flq

61 diqevqgyvl iahnqvrqvp Iqrlrivrgt qlfednyala vldngdplnn ttpvtgaspg

121 glrelqlrsl teilkggvli qrnpqlcyqd tilwkdifhk nnqlaltlid tnrsrachpc

181 spmckgsrcw gessedcqsl trtvcaggca rckgplptdc cheqcaagct gpkhsdclac

241 Ihfnhsgice Ihcpalvtyn tdtfesmpnp egrytfgasc vtacpynyls tdvgsctlvc

301 plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa gckkifgsla

361 flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw pdslpdlsvf qnlqvirgri

421 Ihngaysltl 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 Ivepltpsga mpnqaqmril ketelrkvkv Igsgafgtvy

721 kgiwipdgen vkipvaikvl rentspkank eildeayvma gvgspyvsrl Igicltstvq

781 Ivtqlmpygc 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). [0376] 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 Isflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng

121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq Icyqdtilwk difhknnqla

181 Itlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp Iptdccheqc

241 aagctgpkhs dclaclhfnh sgicelhcpa Ivtyntdtfe smpnpegryt fgascvtacp

301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan

361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp

421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre Igsglalihh nthlcfvhtv

481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec

541 veecrvlqgl preyvnarhc Ipchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc

601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp Itsiisavvg

661 illvvvlgvv fgilikrrqq kirkytmrrl Iqetelvepl tpsgampnqa qmrilketel

721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp

781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr

841 Ivhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft

901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger Ipqppictid 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).

[0377] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:

1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas Is flqdiqev qgyvliahnq

61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk

121 ggvliqrnpq Icyqdtilwk difhknnqla Itlidtnrsr achpcspmck gsrcwgesse

181 dcqsltrtvc aggcarckgp Iptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa

241 Ivtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr

301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta

361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre Igsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla

481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc Ipchpecqpq

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

[0378] 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 Di chi oromethane

DMSO Dimethylsulfoxide

EA ethyl acetate

ES / ESI electrospray ionisation

HPLC high-performance liquid chromatography

IPA Isopropylalcohol

EC liquid chromatography

MS mass spectrometry

NMR nuclear magnetic resonance

Py Pyridine

RT retention time

SFC supercritical fluid chromatography

TEA trifluoroacetic acid

THE T etrahy drofuran

TEC thin layer chromatography

Preparation of common intermediates and anilines:

Intermediate A: Synthesis of 6-Chloro-4-((3-chloro-2-fluorophenyl)amino)-l,5-naphthyridin e- 3 -carbonitrile (Int-A)

[0379] Step 1. Synthesis of Methyl 3-amino-6-chloropicolinate

[0380] To a solution of 3-amino-6-chloro-pyridine-2-carboxylic acid (2.4 g, 13.9 mmol) in toluene (40 mL) and methanol (20 mL) was added (trimethylsilyl)diazomethane (2 M in n-hexane, 20.9 mL) dropwise at 25 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/l to 0/1) to afford methyl 3-amino-6-chloropicolinate (2 g, 10.7 mmol, 77%) as a yellow solid. ¹ H NMR (400 MHz, DMS(M) 8 7.37 (d, J= 8.8 Hz, 1H), 7.31 (d, J= 8.8 Hz, 1H), 6.89 (s, 2H), 3.81 (s, 3H).

[0381] Step 2. Synthesis of Methyl 6-chloro-3-(((dimethylamino)methylene)amino)picolinate [0382] To a solution of methyl 3-amino-6-chloropicolinate (1.9 g, 10.18 mmol) in toluene (40 mL) was added 1,1-dimethoxy-N ,N -dimethylmethanamine (3.64 g, 30.6 mmol). The mixture was stirred at 100 °C for 3 hr. The reaction mixture was concentrated under reduced pressure to give methyl 6-chloro-3-(((dimethylamino)methylene)amino)picolinate (2.3 g, 9.52 mmol, 94%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (s, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.37 (d, J= 8.8 Hz, 1H), 3.71 (s, 3H), 2.95 (s, 3H), 2.82 (s, 3H).

[0383] Step 3. Synthesis of 6-Chloro-4-hydroxy-l,5-naphthyridine-3 -carbonitrile

[0384] To a solution of acetonitrile (1.40 g, 34.1 mmol) in tetrahydrofuran (20 mL) was added n- butyl lithium (2.5 M in toluene, 8.19 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min. Then methyl 6-chloro-3-(((dimethylamino)methylene)amino)picolinate (1.65 g, 6.83 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred at -78 °C for 2 hr. The reaction mixture was quenched with acetic acid (15 mL) at 25 °C, and stirred for 30 min. The mixture was then diluted with water (50 mL). The resulting brown precipitate was filtered, collected and triturated with ethyl acetate (5 mL) to afford 6-chloro-4-hydroxy-l,5-naphthyridine- 3 -carbonitrile (700 mg, 3.40 mmol, 50%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.86 (d, J= 8.8 Hz, 1H).

[0385] Step 4. Synthesis of 4, 6-Dichloro-1,5-naphthyridine-3 -carbonitrile

[0386] To a solution of 6-chloro-4-hydroxy- 1 ,5 -naphthyridine-3 -carbonitrile (200 mg, 973 μmol) in toluene (8 mL) was added phosphorus oxychloride (298 mg, 1.95 mmol) and diisopropylethylamine (503 mg, 3.89 mmol). The mixture was stirred at 110 °C for 12 hr. On completion, the mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/l to 1/1) to afford 4,6-dichloro-l,5- naphthyridine-3 -carbonitrile (100 mg, 446 μmol, 46%) as a yellow solid, m/z ES+ [M+H] ⁺ 223.9. [0387] Step 5. Synthesis of 6-Chloro-4-((3-chloro-2-fluorophenyl)amino)-l,5-naphthyridin e-3- carbonitrile

[0388] To a solution of 4,6-dichloro-l,5-naphthyridine-3-carbonitrile (100 mg, 446 μmol) in acetonitrile (0.5 mL) was added 3 -chloro-2 -fluoro-aniline (65.0 mg, 446 μmol). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was filtered and solid was concentrated under reduced pressure to give 6-chloro-4-(3 -chloro-2 -fluoro-anilino)-l,5-naphthyridine-3 -carbonitrile (130 mg, 390 μmol, 87%) as a white solid. NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.85 (s, 1H), 8.48 (d, J= 8.8 Hz, 1H), 8.04 (d, J= 8.8 Hz, 1H), 7.70 - 7.60 (m, 1H), 7.56 (t, J= 6.8 Hz, 1H), 7.40 - 7.30 (m, 1H); m/z ES+ [M+H] ⁺ 331.1.

Preparation of Intermediate B: 4, 6-Dichloro-l,5-naphthyridine-3 -carbonitrile (Int-B)

[0389] Step 1. Methyl 3-amino-6-chloro-pyridine-2-carboxylate [0390] To a solution of 3 -amino-6-chloro-pyridine-2 -carboxylic acid (15.0 g, 86.9 mmol) in methanol (225 mL) was added thionyl chloride (13.4 g, 113 mmol) dropwise. The mixture was stirred at 70 °C for 16 hr. On completion, the reaction mixture was concentrated under reduced pressure to give compound methyl 3 -amino-6-chloro-pyridine-2 -carboxylate (15.0 g, 77.2 mmol, 89%) as a yellow solid, m/z ES+ [M+H] ⁺ 187.0.

[0391] Step 2. Methyl 6-chloro-3-[(E)-dimethylaminomethyleneamino]pyridine-2 -carboxylate [0392] To a solution of methyl 3-amino-6-chloro-pyridine-2-carboxylate (500 mg, 2.68 mmo) in toluene (7 mL) was added N, N -dimethylformamide dimethyl acetal (958 mg, 8.04 mmol). The mixture was stirred at 100 °C for 3 hr. On completion, the reaction mixture was concentrated under reduced pressure to give compound methyl 6-chloro-3-[(E)- dimethylaminomethyleneamino]pyridine-2-carboxylate (600 mg, 2.23 mmol, 83%) as a yellow solid. m/z ES+ [M+H] ⁺ 242.0.

[0393] Step 3. 6-Chloro-4-hydroxy-l,5-naphthyridine-3-carbonitrile

[0394] To a solution of acetonitrile (1.02 g, 24.8 mmol) in tetrahydrofuran (6 mL) was added n- butyl lithium (2.5 M in tetrahydrofuran, 2.98 mL) dropwise at -78 °C and the mixture was then stirred at -78 °C for 30 min. Then a solution of methyl 6-chloro-3-[(E)- dimethylaminomethyleneamino]pyridine-2-carboxylate (600 mg, 2.48 mmol) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at -78 °C for 12 h. On completion, the reaction mixture was quenched by acetic acid (5 mL) at 25 °C, and then stirred for 30 min. The resulting solution was then diluted with water (40 mL), resulting in the formation of much brown solid. The suspension was filtered and the filtered cake was collected, concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (5 mL) for 10 min to give compound 6-chloro-4-hydroxy- 1, 5 -naphthyridine-3 -carbonitrile (200 mg, 973 μmol, 39%) as a yellow solid. 'll NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.65 (d, J= 8.8 Hz, 1H).

[0395] Step 4. 4,6-Dichloro-l,5-naphthyridine-3-carbonitrile

[0396] To a mixture of 6-chloro-4-hydroxy- 1,5 -naphthyridine-3 -carbonitrile (0.2 g, 973 μmol) in toluene (5 mL) was added diisopropylethylamine (377 mg, 2.92 mmol) and phosphorus oxychloride (224 mg, 1.46 mmol) in one portion. The mixture was then heated to 100 °C and stirred for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to give compound 4,6-dichloro-l,5-naphthyridine-3-carbonitrile (160 mg, 643 μmol, 66%) as a yellow solid, m/z ES+ [M+H] ⁺ 224.1.

Intermediate C: 6-Chloro-4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)ami no)-l,5- naphthyridine-3 -carbonitrile (Int-C)

[0397] Step 1. 6-Chloro-4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-l ,5-naphthyridine- 3 -carbonitrile

[0398] A mixture of 4,6-dichloro-l,5-naphthyridine-3-carbonitrile (0.15 g, 670 μmol) and 3- chloro-4-(difluoromethoxy)-2 -fluoro-aniline (184 mg, 870 μmol) in acetonitrile (3 mL) was stirred at 25 °C for 16 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound 6-chloro-4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-l ,5- naphthyridine-3-carbonitrile (0.25 g, 451 μmol, 67%) as a yellow solid, m/z ES+ [M+H] ⁺ 399.0.

Intermediate D: 6-Chloro-4-((3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl) amino)-l,5- naphthyridine-3 -carbonitrile (Int-D)

[0399] Step 1. 6-Chloro-4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino ]-l,5- naphthyridine-3 -carbonitrile

[0400] A mixture of 4,6-dichloro-l,5-naphthyridine-3-carbonitrile (50.0 mg, 223 μmol) and 3- chloro-4-(cyclopropylmethoxy)-2 -fluoro-aniline (52.9 mg, 245 μmol) in acetonitrile (2 mL) was stirred at 25 °C for 16 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound 6-chloro-4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino ]-l,5- naphthyridine-3-carbonitrile (60.0 mg, 96.7 μmol, 43%) as a yellow solid, m/z ES+ [M+H] ⁺ 403.0.

Intermediate E: Methyl (S)-3-amino-6-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)- 5- fluoropicolinate (Int-E)

[0401] Step 1. terZ-Butyl (S)-3-((3-fluoro-5-nitropyridin-2-yl)oxy)pyrrolidine-l-carbo xylate [0402] To a mixture of tert-butyl (3 S)-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 wZ%). The mixture was stirred at 25 °C for 1 hour. Then a solution of 2-chloro-3-fluoro-5 -nitropyridine (5.19 g, 29.4 mmol) in anhydrous tetrahydrofuran (20 mL) was added and the mixture 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 x 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (3S)-3-[(3-fluoro-5-nitro-2-pyridyl)oxy]pyrrolidine-l-carbox ylate (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. [0403] Step 2. tert-Butyl (S)-3-((5-amino-3-fluoropyridin-2-yl)oxy)pyrrolidine-l -carboxylate [0404] To a mixture of tert-butyl (3S)-3-[(3-fluoro-5-nitro-2-pyridyl)oxy]pyrrolidine-l- carboxylate (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-l -carboxylate (4 g, crude) as a yellow solid, m/z ES+ [M+H] ⁺ 241.9.

[0405] Step 3. tert-Butyl (S)-3-((5-amino-6-bromo-3-fluoropyridin-2-yl)oxy)pyrrolidine -l- carboxylate

[0406] A mixture of tert-butyl (3S)-3-[(5-amino-3-fluoro-2-pyridyl)oxy]pyrrolidine-l- 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 x 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/l to 3:1) to give tert-butyl (3S)-3-[(5-amino-6-bromo-3-fluoro- 2-pyridyl)oxy]pyrrolidine-l -carboxylate (4 g, 12.5 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, CDCh) 8 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.

[0407] Step 4. Methyl (S)-3-amino-6-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)- 5- fluoropicolinate

[0408] 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-l- 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/l to 4/1) to give methyl 3-amino-6-[(3S)-l-tert-butoxycarbonylpyrrolidin-3-yl]oxy-5- fluoro-pyridine-2-carboxylate (4.00 g, 11.1 mmol, 69%) as a yellow solid. ¹ H NMR (400MHz, 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. Preparation of Aniline 1: 3-Chloro-4-(difluoromethoxy)-2 -fluoroaniline (A-1)

[0410] 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-l-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).

[0411] Step 2. 1 -(3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)-2,5 -dimethyl- 1 H -pyrrole [0412] A solution of 2-chloro-4-(2,5-dimethylpyrrol-l-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- dimethylformarnide (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 l-[3-chloro- 4-(difluoromethoxy)-2-fluoro-phenyl]-2,5-dimethyl-pyrrole (3.60 g, crude) as a black oil.

[0413] Step 3. 3-Chloro-4-(difluoromethoxy)-2-fluoroaniline

[0414] To a solution of l-[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-d ₆ ) δ 7.03 (t, J= 74.0 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.73 (t, J= 9.2 Hz, 1H), 5.47 (s, 2H). Preparation of Aniline-2: 3-Chloro-4-(cyclopropylmethoxy)-2-fluoroaniline (A-2)

[0415] Step 1. l-(Benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene

[0416] To a solution of 2-chloro-l,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 l-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).

[0417] Step 2. 2-Chloro-3-fluoro-4-nitrophenol

[0418] To a solution of l-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 121 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).

[0419] Step 3. 2-Chloro-l-(cyclopropylmethoxy)-3-fhioro-4-nitrobenzene

[0420] To a solution of 2-chloro-3-fluoro-4-nitro-phenol (385 mg, 2.01 mmol) in N,N- dimethylformamide (1.0 mL) and acetonitrile (1.0 mL) was added sodium carbonate (305 mg, 2.21 mmol) and then the mixture was stirred at 25 °C for 0.5 hr. After that, bromomethylcyclopropane (352 mg, 2.61 mmol) was added dropwise into the mixture and the mixture was stirred at 100 °C for 16 hr. On completion, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=7/3 to 3/7) to give 2-chloro-l-(cyclopropylmethoxy)-3-fluoro-4-nitro-benzene (330 mg, 1.35 mmol, 66%) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.24 (t, J= 9.2 Hz, 1H), 7.25 (dd, J= 1.6, 9.6 Hz, 1H), 4.19 (d, J= 7.2 Hz, 2H), 1.41 - 1.29 (m, 1H), 0.79 - 0.59 (m, 2H), 0.48 - 0.38 (m, 2H).

[0421] Step 4. 3-Chloro-4-(cyclopropylmethoxy)-2-fluoroaniline

[0422] 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. Synthesis of (S)-6-((l-acryloylpyrrolidin-3-yl)oxy)-4-((3-chloro-2- fluorophenyl)amino)-l,5-naphthyridine-3-carbonitrile (Compound 12)

[0423] Step 1. Synthesis of tert- Butyl (S)-3-((8-((3-chloro-2-fhiorophenyl)amino)-7-cyano-l,5- naphthyridin-2-yl)oxy)pyrrolidine- 1 -carboxylate [0424] To a solution of 6-chloro-4-(3-chloro-2-fluoro-anilino)-l,5-naphthyridine-3-c arbonitrile (90 mg, 270 μmol) in dimethyl sulfoxide (2 mL) was added potassium tert-butoxide (121 mg, 1.08 mmol) and tert-butyl (3S) -3 -hydroxypyrrolidine- 1 -carboxylate (152 mg, 810 μmol). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3,S)-3-[[8- (3-chloro-2-fluoro-anilino)-7 -cyano- 1 ,5-naphthyridin-2-yl]oxy]pyrrolidine- 1 -carboxylate (110 mg, 227 μmol, 84%) as a yellow solid, m/z ES+ [M+H] ⁺ 484.1.

[0425] Step 2. Synthesis of (S)-4-((3-Chloro-2-fluorophenyl)amino)-6-(pyrrolidin-3-yloxy )-l,5- naphthyridine-3 -carbonitrile

[0426] To aa solution of tert-butyl (3*S)-3-[[8-(3-chloro-2-fluoro-anilino)-7-cyano-l,5- naphthyridin-2-yl]oxy]pyrrolidine-l -carboxylate (130 mg, 269 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (556 mg, 4.88 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give (5)-4-((3-chloro-2- fluorophenyl)amino)-6-(pyrrolidin-3-yloxy)-l,5-naphthyridine -3-carbonitrile (160 mg, crude, trifluoroacetic acid) as a brown oil. m/z ES+ [M+H] ⁺ 384.1.

[0427] Step 3. Synthesis of (S)-6-((l-Acryloylpyrrolidin-3-yl)oxy)-4-((3-chloro-2- fhiorophenyl)amino)-l,5-naphthyridine-3-carbonitrile

[0428] To a solution of (S)-4-((3-chloro-2-fluorophenyl)amino)-6-(pyrrolidin-3-yloxy )-l,5- naphthyridine-3-carbonitrile (160 mg, 321 μmol, trifluoroacetic acid) in tetrahydrofuran (3 mL) and water (2 mL) was added sodium bicarbonate (81.0 mg, 964 μmol) and prop-2-enoyl chloride (30.5 mg, 337 μmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with water (5 mL) and filtered. The filter cake was washed with water (5 mL) and then concentrated under reduced pressure to give ( ₁ S)-6-((l-acryloylpyrrolidin-3-yl)oxy)-4-((3-chloro-2- fluorophenyl)amino)-l, 5 -naphthyridine-3 -carbonitrile (74.8 mg, 160 μmol, 50%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.54 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 7.65 (br. t, J= 7.2 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.40 - 7.31 (m, 2H), 6.72 - 6.50 (m, 1H), 6.24 - 6.03 (m, 2H), 5.74 - 5.62 (m, 1H), 4.04 - 3.46 (m, 4H), 2.39 - 2.08 (m, 2H); m/z ES+ [M+H] ⁺ 438.3. Example 2. Synthesis of 6-((lS,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4- ((3- chloro-2-fluorophenyl)amino)-l,5-naphthyridine-3-carbonitril e (Compound 1)

[0429] Step 1. Synthesis of tert-Butyl (lS,4S)-5-(8-((3-chloro-2-fluorophenyl)amino)-7-cyano- l,5-naphthyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carb oxylate

[0430] To a solution of 6-chloro-4-(3-chloro-2-fluoro-anilino)-l,5-naphthyridine-3-c arbonitrile (330 mg, 990 μmol) in N-methyl pyrrolidinone (4 mL) was added diisopropylethylamine (256 mg, 1.98 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (196 mg, 990 μmol). The mixture was stirred at 100 °C for 2 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/l to 0/1) to give tert-butyl (1S,4S)-5-[8-(3-chloro-2-fluoro-anilino)-7-cyano-l,5- naphthyridin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate (450 mg, 909 μmol, 92%) as a brown oil. m/z ES+ [M+H] ⁺ 495.1.

[0431] Step 2. Synthesis of 6-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-((3-chloro- 2- fluorophenyl)amino)-l,5-naphthyridine-3-carbonitrile

[0432] To aa solution of tert-butyl (1S,4S)-5-[8-(3-chloro-2-fluoro-anilino)-7-cyano-l,5- naphthyridin -2 -yl] -2, 5 -diazabicyclo [2.2. l]heptane-2 -carboxylate (250 mg, 505 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1 mL). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give 6-((1S,4S)-2,5-diazabicyclo[2.2. l]heptan-2-yl)-4-((3-chloro-2-fluorophenyl)amino)-l ,5- naphthyridine-3-carbonitrile (250 mg, crude, trifluoroacetic acid) as a brown oil. m/z ES+ [M+H] ⁺ 395.2. [0433] Step 3. Synthesis of 6-((1S,4S)-5- Acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-((3- chloro-2-fluorophenyl)amino)- 1 ,5-naphthyridine-3-carbonitrile

[0434] To aa solution of 6-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-((3-chloro- 2- fluorophenyl)amino)-l, 5 -naphthyridine-3 -carbonitrile (250 mg, 491 μmol, trifluoroacetic acid) in tetrahydrofuran (2.5 mL) was added sodium bicarbonate (41.2 mg, 491 μmol), water (0.5 mL) and prop-2 -enoyl chloride (48.9 mg, 540 μmol). 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: Phenomenex Cl 8 75x30mm, 3um; mobile phase: [water(FA)- ACN]; B%: 25%-55%, 7 min) to give 6-(( 1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)- 4-((3-chloro-2-fhiorophenyl)amino)-l,5-naphthyridine-3-carbo nitrile (25 mg, 55.7 μmol, 8.8%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 - 9.41 (m, 1H), 8.44 - 8.23 (m, 1H), 8.08 - 7.91 (m, 1H), 7.65 - 7.58 (m, 1H), 7.56 - 7.48 (m, 1H), 7.36 - 7.28 (m, 1H), 6.89 - 6.36 (m, 1H), 6.24 - 6.09 (m, 1H), 5.71 - 5.63 (m, 1H), 5.10 - 4.90 (m, 1H), 3.74 - 3.63 (m, 2H), 3.60 - 3.45 (m, 4H), 2.11 - 1.94 (m, 2H). m/z ES+ [M+H] ⁺ 449.1.

Example 3. Synthesis of 6-(l-Acryloylpiperidin-3-yl)-4-((3-chloro-2-fluorophenyl)ami no)- l,7-naphthyridine-3 -carbonitrile (Compound 2)

[0435] Step 1. Synthesis of tert- Butyl (6-chloropyridin-3-yl)carbamate [0436] To a mixture of 6-chloropyridin-3 -amine (3.00 g, 23.3 mmol) in 1,4-dioxane (30 mL) was added di-tert-butyl dicarbonate (5.60 g, 25.6 mmol, 5.90 mL). The reaction mixture was stirred at 100 °C for 48 hr. On completion, the reaction mixture was concentrated in vacuo to give tert-butyl (6-chloropyridin-3-yl)carbamate (5.30 g, 23.1 mmol, 99%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.72 (s, 1H), 8.45 (d,J= 2.4 Hz, 1H), 7.91 (dd, J= 2.4, 8.8 Hz, 1H), 7.40 (d, J= 8.8 Hz, 1H), 1.47 (s, 9H).

[0437] Step 2. Synthesis of 5-((tert-Butoxycarbonyl)amino)-2-chloroisonicotinic acid

[0438] To a mixture of tert-butyl (6-chloropyridin-3-yl)carbamate (4.50 g, 19.6 mmol) and N ¹ ,N ¹ ,N ² ,N ² -tetramethylethane-1,2-diamine (8.00 g, 68.8 mmol) in tetrahydrofuran (200 mL) was added n -butyl lithium (2.5 M in toluene, 27.5 mL) dropwise at -78 °C. The mixture was slowly warmed to -10 °C and stirred at -10 °C for 3 hr. Then the mixture was re-cooled to -78 °C, and carbon dioxide (30 psi) was bubbled into the mixture at -78 °C for 2 hr. Then the mixture was slowly warmed to 20 °C and stirred at 20 °C for 12 hr. On completion, the reaction mixture was carefully quenched with water (200 mL) and then added hydrochloric acid (1 M) to adjust pH = 5-6. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-((tert-butoxycarbonyl)amino)-2-chloroisonicotinic acid (2.60 g, crude) as a yellow solid, m/z ES+ [M+H] ⁺ 273.3.

[0439] Step 3. Synthesis of Methyl 5-((tert-butoxycarbonyl)amino)-2-chloroisonicotinate

[0440] To a solution of 5-((tert-butoxycarbonyl)amino)-2-chloroisonicotinic acid (2.00 g, 7.33 mmol) in dichloromethane ( 10 mL) and methanol (5 mL) was added (trimethylsilyl)diazomethane (2 M in n-hexane, 7.33 mL). The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was carefully concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate 1:1) to give methyl 5-((tert-butoxycarbonyl)amino)-2- chloroisonicotinate (1.00 g, 3.50 mmol, 47%) as a yellow solid.

[0441] Step 4. Synthesis of tert- Butyl (6-chloro-4-(2-cyanoacetyl)pyridin-3-yl)carbamate

[0442] To a mixture of acetonitrile (1.15 g, 27.9 mmol) in tetrahydrofiiran (100 mL) was added n -butyl lithium (2.5 M in toluene, 10.0 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 0.5 hr. Then methyl 5 -((tert-butoxycarbonyl)amino) -2 -chloroisonicotinate (1.00 g, 3.49 mmol) in tetrahydrofiiran (30 mL) was added dropwise at -78 °C. The mixture was slowly warmed to 20 °C and stirred at 20 °C for 6 hr. On completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl (6- chloro-4-(2-cyanoacetyl)pyridin-3-yl)carbamate (1 g, 3.38 mmol, 97%) as a white solid, m/z ES+ [M+H] ⁺ 296.1.

[0443] Step 5. Synthesis of 6-Chloro-4-hydroxy-l,7-naphthyridine-3 -carbonitrile

[0444] To a solution of tert-butyl (6-chloro-4-(2-cyanoacetyl)pyridin-3-yl)carbamate (900 mg, 3.04 mmol) in dimethylformamide (1 mL) was added 1 , 1 -dimethoxy-/V,/V-dimethylmethanamine (8.07 g, 67.7 mmol). The mixture was stirred at 20 °C for 18 hr. On completion, the mixture was concentrated under vacuum. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 6-chloro-4-hydroxy-l,7-naphthyridine-3-carbonitrile (400 mg, 1.85 mmol, 61%) as a yellow solid. ¹ H NMR (400 MHz, DMSOd ₆ ) δ 8.88 (s, 1H), 8.79 (s, 1H), 7.96 (s, 1H); m/z ES+ [M+H] ⁺ 206.1.

[0445] Step 6. Synthesis of 4, 6-Dichloro-l,7-naphthyridine-3 -carbonitrile

[0446] A solution of 6-chloro-4-hydroxy-l,7-naphthyridine-3-carbonitrile (370 mg, 1.80 mmol) and dimethylformamide (13.1 mg, 179 μmol) in thionyl chloride (12.1 g, 102 mmol) was stirred at 80 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give 4,6-dichloro-l,7- naphthyridine-3 -carbonitrile (400 mg, crude) as a yellow oil.

[0447] Step 7. Synthesis of 6-Chloro-4-((3-chloro-2-fluorophenyl)amino)-l,7-naphthyridin e-3- carbonitrile

[0448] To a solution of 4, 6-dichloro-l,7-naphthyridine-3 -carbonitrile (400 mg, 1.79 mmol) and 3-chloro-2-fluoro-aniline (389 mg, 2.68 mmol) in acetonitrile (2 mL) was added potassium carbonate (740 mg, 5.36 mmol). The mixture was stirred at 60 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 1/1) to give 6-chloro-4-(3-chloro-2-fluoro-anilino)-l,7- naphthyridine-3-carbonitrile (400 mg, 1.20 mmol, 67%) as a yellow solid, 'll NMR (400 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 8.60 (s, 1H), 7.65 - 7.55 (m, 1H), 7.54 - 7.45 (m, 1H), 7.33 (t, J= 8.4 Hz, 1H); m/z ES+ [M+H] ⁺ 332.7.

[0449] Step 8. Synthesis of tert-Butyl 5-(4-((3-chloro-2-fluorophenyl)amino)-3-cyano-l,7- naphthyridin-6-yl)-3,6-dihydropyridine- 1 (2H) -carboxylate

[0450] A mixture of 6-chloro-4-(3-chloro-2-fluoro-anilino)-l,7-naphthyridine-3-c arbonitrile (300 mg, 900 μmol), tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H- pyridine-1 -carboxylate (556 mg, 1.80 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (63.2 mg, 90.0 μmol) and cesium carbonate (1.17 g, 3.60 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was degassed and purged with nitrogen gas (3x), and then the mixture was stirred at 110 °C for 12 hrs under nitrogen gas atmosphere. On completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 5-[4-(3-chloro-2-fluoro- anilino)-3-cyano-l,7-naphthyridin-6-yl]-3,6-dihydro-2H-pyrid ine-l-carboxylate (0.4 g, 0.83 mmol, 92%) as a yellow solid, m/z ES+ [M+H] ⁺ 480.1.

[0451] Step 9. Synthesis of tert-Butyl 3-(4-((3-chloro-2-fluorophenyl)amino)-3-cyano-l,7- naphthyridin-6-yl)piperidine- 1 -carboxylate

[0452] To a solution of tert-butyl 5-[4-(3-chloro-2-fluoro-anilino)-3-cyano-l,7-naphthyridin-6- yl] -3, 6-dihydro-2H-pyridine-l -carboxylate (380 mg, 791 μmol) in tetrahydro furan (20 mL) was added palladium on activated carbon (200 mg, 791 μmol, 10 wt. % loading) and magnesium oxide (31.9 mg, 791 μmol). The mixture was stirred at 25 °C for 2 hr under hydrogen (15 psi). On completion, the mixture was filtered with celite and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1) to give tert-butyl 3-[4-(3- chloro-2-fluoro-anilino)-3-cyano-l,7-naphthyridin-6-yl] piperidine- 1 -carboxylate (150 mg, 0.31 mmol, 39%) as a yellow solid, m/z ES+ [M+H] ⁺ 482.2.

[0453] Step 10. Synthesis of 4-((3-Chloro-2-fluorophenyl)amino)-6-(piperidin-3-yl)-l,7- naphthyridine-3 -carbonitrile

[0454] To a solution of tert-butyl 3-[4-(3-chloro-2-fluoro-anilino)-3-cyano-l,7-naphthyridin-6- yl]piperidine-l -carboxylate (130 mg, 269 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (30.7 mg, 269 μmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the solution was concentrated in vacuo to give 4-(3-chloro-2-fluoro-anilino)-6-(3- piperidyl)-l,7-naphthyridine-3-carbonitrile (103 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H] ⁺ 382.0.

[0455] Step 11. Synthesis of 6-(l-Acryloylpiperidin-3-yl)-4-((3-chloro-2-fluorophenyl)ami no)- 1 ,7-naphthyridine-3 -carbonitrile

[0456] To a solution of 4-(3-chloro-2-fluoro-anilino)-6-(3-piperidyl)-l,7-naphthyrid ine-3- carbonitrile (103 mg, 269 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (22.6 mg, 269 μmol). Then prop-2-enoyl chloride (26.8 mg, 296 μmol, 24 pL) was added. The mixture was stirred at 0 °C for 15 min. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mm, 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 38%-62%, 8 min) to give 6-(l- acryloylpiperidin-3-yl)-4-((3-chloro-2-fluorophenyl)amino)-l ,7-naphthyridine-3-carbonitrile (31.0 mg, 71.1 μmol, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 - 10.14 (m, 1H), 9.22 (s, 1H), 8.63 (d, J= 4.8 Hz, 1H), 8.27 (s, 1H), 7.53 (s, 1H), 7.43 (d, J= 7.60 Hz, 1H), 7.32 - 7.26 (m, 1H), 6.93 - 6.81 (m, 1H), 6.11 (dd, J= 17.6, 9.2 Hz, 1H), 5.68 (t, J= 10.0 Hz, 1H), 4.85 - 4.44 (m, 1H), 4.35 - 4.12 (m, 1H), 3.42 - 3.37 (m, 1H), 3.10 (t, J= 12.8 Hz, 1H), 3.01 - 2.93 (m, 1H), 2.88 - 2.80 (m, 1H), 2.73 (t, J= 12.0 Hz, 1H), 2.20 - 2.09 (m, 1H), 1.98 - 1.81 (m, 2H), 1.64 - 1.45 (m, 1H); m/z ES+ [M+H] ⁺ 436.4.

Example 4. Preparation of 4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(lS,4S) -5- prop-2-enoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-l,5-naphthy ridine-3-carbonitrile

[0457] Step 1. tert- Butyl (1S,4S)-5-[8-[3-chloro-4-(difhioromethoxy)-2-fluoro-anilino] -7- cyano- 1 ,5-naphthyridin-2-yl]-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate

[0458] To aa mixture of 6-chloro-4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-l ,5- naphthyridine-3 -carbonitrile (0.25 g, 626 μmol) and tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (137 mg, 689 μmol) in N-methyl pyrrolidone (3 mL) was added diisopropylethylamine (162 mg, 1.25 mmol) in one portion. The mixture was then heated to 130 °C and stirred for 16 h. On completion, the reaction mixture was quenched by water 30 mL at 25 °C, and then diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=l/l) to give compound tert-butyl (1S,4S)-5-[8-[3-chloro-4-(difhioromethoxy)-2-fhioro-anilino] -7-cyano-l,5-naphthyridin-2-yl]- 2.5-diazabicyclo[2.2. l]heptane-2-carboxylate (0.15 g, 257 μmol, 41%) as a yellow solid, m/z ES+ [M+H] ⁺ 561.2.

[0459] Step 22.. 4-[3-Chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(lS,4S) -2,5- diazabicyclo[2.2.1 ]heptan-2-yl]- 1 ,5 -naphthyridine-3-carbonitrile

A solution of tert-butyl (lS,4S)-5-[8-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino] -7-cyano-

1.5-naphthyridin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-c arboxylate (0.15 g, 267 μmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (3 mL) was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound 4- [3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(lS,4S)-2 ,5-diazabicyclo[2.2.1]heptan-2-yl]-

1.5 -naphthyridine-3 -carbonitrile (0.12 g, 253 μmol, 94%) as a yellow solid, m/z ES+ [M+H] ⁺ 461.1.

[0460] Step 3. 4-[3-Chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(lS,4S) -5-prop-2-enoyl-

2,5-diazabicyclo[2.2.1 ]heptan-2-yl] - 1 ,5-naphthyridine-3-carbonitrile

[0461] To a mixture of 4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(lS,4S) -2,5- diazabicyclo[2.2.1]heptan-2-yl]-l,5-naphthyridine-3-carbonit rile (0.12 g, 260 μmol) in tetrahydrofuran (3 mL) and water (3 mL) was added prop-2-enoyl chloride (21.2 mg, 234 pmol) and sodium bicarbonate (65.6 mg, 781 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C 18 150 x 25 mm, 10 um; mobile phase: [water (FA)-ACN]; B%: 32%-62%, 10 min) to give compound 4-[3-chloro- 4-(difluoromethoxy)-2-fluoro-anilino] -6-[( 1 S ,4S)-5-prop-2-enoyl-2, 5 -diazabicyclo [2.2.1 ]heptan- 2-yl]-l,5-naphthyridine-3-carbonitrile (43.1 mg, 83.8 μmol, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 - 9.28 (m, 1H), 8.30 (d, J= 2.0 Hz, 1H), 8.00 (dd, J= 3.6, 9.2 Hz, 1H), 7.68 - 7.54 (m, 1H), 7.45 - 6.99 (m, 3H), 6.86 - 6.35 (m, 1H), 6.14 (ddd, 7 = 2.4, 5.6, 16.8 Hz, 1H), 5.79 - 5.39 (m, 2H), 5.08 - 4.88 (m, 1H), 3.74 - 3.61 (m, 2H), 3.58 - 3.49 (m, 2H), 2.11 - 1.92 (m, 2H); m/z ES+ [M+H] ⁺ 515.0. Example 5. Preparation of 4-[3-chloro-4-(cycIopropylmethoxy)-2-fluoro-anilino]-6-[(lS, 4S)-

5-prop-2-enoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-l,5-na phthyridine-3-carbonitrile

[0462] Step 1. tert- Butyl (lS,4S)-5-[8-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anili no]-7- cyano- 1 ,5-naphthyridin-2-yl]-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate

[0463] To a mixture of 6-chloro-4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino ]-l,5- naphthyridine-3-carbonitrile (60.0 mg, 149 μmol) and tert-butyl (lS,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (44.2 mg, 223 μmol) in 1 -methylpyrrolidin-2-one (2 mL) was added diisopropylethylamine (57.7 mg, 446 μmol) in one portion. The mixture was then stirred at 130 °C for 16 h. On completion, the reaction mixture was quenched by addition water (20 mL) at 20 °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 (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give compound tert-butyl (lS,4S)-5-[8-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anili no]-7-cyano-l,5-naphthyridin-2- yl]-2, 5-diazabicyclo[2.2. l]heptane-2 -carboxylate (40.0 mg, 65.8 μmol, 44%) as a yellow solid. m/z ES+ [M+H] ⁺ 565.3.

[0464] Step 22.. 4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(lS, 4S)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl]- 1 ,5-naphthyridine-3-carbonitrile

[0465] A solution of tert-butyl (lS,4S)-5-[8-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- anilino]-7-cyano- 1 ,5-naphthyridin-2-yl]-2,5-diazabicyclo[2.2. l]heptane-2 -carboxylate (40.0 mg, 70.8 μmol) in di chloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound 4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(lS, 4S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl]-l,5-naphthyridine-3-carbonitrile (35.0 mg, 55.6 μmol, 79%, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H] ⁺ 465.3.

[0466] Step 3. 4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(lS, 4S)-5-prop-2- enoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-l,5-naphthyridine- 3-carbonitrile

[0467] To a mixture of 4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(lS, 4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-l,5-naphthyridine-3-carbonit rile (35.0 mg, 75.3 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (6.13 mg, 67.8 μmol) and sodium bicarbonate (19.0 mg, 226 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 150 x 25 mm, 10 um; mobile phase: [water (FA)-ACN]; B%: 33%-63%, 10 min) to give compound 4-[3-chloro- 4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(lS,4S)-5-prop-2 -enoyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]-l,5-naphthyridine-3-carbonit rile (17.9 mg, 33.8 μmol, 45%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 - 9.25 (m, 1H), 8.25 (d, J= 1.6 Hz, 1H), 7.98 (dd, J= 3.6, 9.2 Hz, 1H), 7.53 - 7.36 (m, 1H), 7.23 - 6.96 (m, 2H), 6.86 - 6.35 (m, 1H), 6.18 - 6.10 (m, 1H), 5.72 - 5.62 (m, 2H), 5.17 - 4.77 (m, 1H), 4.01 (d, J= 7.2 Hz, 2H), 3.76 - 3.62 (m, 2H), 3.18 - 3.02 (m, 2H), 2.09 - 1.90 (m, 2H), 1.40 - 1.18 (m, 1H), 0.64 - 0.57 (m, 2H), 0.42 - 0.32 (m, 2H); m/z ES+ [M+H] ⁺ 519.0.

Example 6. Preparation of 6-((lS,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4- ((3- chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-7-fluoro-l, 5-naphthyridine-3- carbonitrile

[0468] Step 1. Methyl 3-amino-6-chloro-5-fluoropicolinate

[0469] To a solution of methyl 3-amino-5-fluoro-pyridine-2-carboxylate (880 mg, 5.17 mmol) inN,N- dimethylformamide (8 mL) was added N-chlorosuccinimide (725 mg, 5.43 mmol) and acetic acid (311 mg, 5.17 mmol). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was directly purified by reversed-phase HPLC (0.1% formic acid condition) to give methyl 3- amino-6-chloro-5-fluoropicolinate (930 mg, 4.55 mmol, 88%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.10 (d, J= 10.0 Hz, 1H), 3.89 (s, 3H).

[0470] Step 2. 2-Chloro-4-((7-fluoro-6-nitroquinazolin-4-yl)amino)phenol

[0471] To a solution of methyl 3-amino-6-chloro-5-fluoro-pyridine-2-carboxylate (0.97 g, 4.74 mmol) in toluene (10 mL) was added 1 , 1 -dimethoxy -N,N- dimethylmethanamine (1.69 g, 14.2 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was concentrated in vacuo to give 2-chloro-4-((7-fluoro-6-nitroquinazolin-4-yl)amino)phenol (1.30 g, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 260.1.

[0472] Step 3. 6-Chloro-7-fluoro-4-hydroxy-l,5-naphthyridine-3-carbonitrile

[0473] To a solution of acetonitrile (1.74 g, 42.4 mmol) in anhydrous tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in tetrahydrofuran, 5.08 mL) dropwise at -75 °C. The mixture was stirred at -75 °C for 0.5 h. Then aa solution of methyl 6-chloro-3- (dimethylaminomethyleneamino)-5-fluoro-pyridine-2-carboxylat e (1.1 g, 4.24 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise into the mixture at -75 °C. The mixture was then slowly warmed to 25 °C and stirred at 25 °C for 12 h. The mixture was quenched by acetic acid (20 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 6-chloro-7-fluoro-4-hydroxy-l,5- naphthyridine-3-carbonitrile (0.1 g, 447 μmol, 11%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 8.00 (d, J= 9.2 Hz, 1H).

[0474] Step 4. tert-Butyl (lS,4S)-5-(7-cyano-3-fluoro-8-hydroxy-l,5-naphthyridin-2-yl) -2,5- diazabicyclo[2.2.1 ]heptane-2 -carboxylate

[0475] To a solution of 6-chloro-7-fluoro-4-hydroxy-l,5-naphthyridine-3-carbonitrile (170 mg, 760 μmol) in 1 -methylpyrrolidin-2-one (1.5 mL) was added tert-butyl (lS,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (301 mg, 1.52 mmol) and diisopropylethylamine (295 mg, 2.28 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was purified by reversed- phase HPLC (0.1% formic acid condition) to give tert-butyl (lS,4S)-5-(7-cyano-3-fluoro-8- hydroxy-l,5-naphthyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan e-2-carboxylate (50 mg, 130 μmol, 17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 7.65 (d, J= 12.4 Hz, 1H), 4.95 (s, 1H), 4.46 (d, J= 19.6 Hz, 1H), 3.75 (d, J= 9.2 Hz, 2H), 3.56 - 3.52 (m, 2H), 1.91 (d, J= 11.2 Hz, 2H), 1.37 (d, J- 19.6 Hz, 9H).

[0476] Step 5. tert-Butyl (lS,4S)-5-(8-chloro-7-cyano-3-fluoro-l,5-naphthyridin-2-yl)- 2,5- diazabicyclo[2.2.1 ]heptane-2 -carboxylate

[0477] To a solution of tert-butyl (lS,4S)-5-(7-cyano-3-fluoro-8-hydroxy-l,5-naphthyridin-2- yl)-2, 5-diazabicyclo[2.2. l]heptane-2 -carboxylate (35.0 mg, 90.8 μmol) in toluene (0.5 mL) was added diisopropylethylamine (47.0 mg, 363 μmol) and phosphorus oxychloride (18.1 mg, 118 μmol). The mixture was stirred at 90 °C for 2 h. The mixture was concentrated in vacuo to give tert-butyl (lS,4S)-5-(8-chloro-7-cyano-3-fluoro-l,5-naphthyridin-2-yl)- 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (40 mg, crude) as a black oil. m/z ES+ [M+H] ⁺ 404.2.

[0478] Step 6. 6-((lS,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-((3-chloro- 4-

(difluoromethoxy)-2-fluorophenyl)amino)-7 -fluoro- 1 ,5 -naphthyridine-3 -carbonitrile

[0479] To aa solution of 6-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-((3-chloro- 4- (difluoromethoxy)-2-fluorophenyl)amino)-7 -fluoro- 1 ,5 -naphthyridine-3 -carbonitrile (35.0 mg, 86.7 μmol) in isopropanol (0.5 mL) was added 3 -chloro-4-(difluoromethoxy)-2 -fluoro-aniline (20.2 mg, 95.3 μmol) and aqueous hydrochloric acid (1 M, 8.67 μL). The mixture was stirred at 80 °C for 12 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4-((3-chloro-4-(difluorometh oxy)-2-fluorophenyl)amino)-7- fluoro- 1, 5 -naphthyridine-3 -carbonitrile (35.0 mg, 66.7 μmol, 77%) as a yellow solid, m/z ES+ [M+H] ⁺ 479.1.

[0480] Step 77.. 6-((lS,4S)-5-Acryloyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4- ((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)-7 -fluoro- 1 ,5 -naphthyridine-3 -carbonitrile

[0481] To a solution of 4-[3-chloro-4-(difhioromethoxy)-2-fluoro-anilino]-6-[(lS,4S) -2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-fluoro-l,5-naphthyridine-3 -carbonitrile (35.0 mg, 66.7 μmol) in anhydrous tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (22.4 mg, 267 μmol) and prop-2-enoyl chloride (5.43 mg, 60 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified byprep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water (formic acid)- acetonitrile]; B%: 42%-72%,10 min) to give 6-((lS,4S)-5-acryloyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4-((3-chloro-4-(difluorometh oxy)-2-fluorophenyl)amino)-7- fluoro- 1,5 -naphthyridine-3 -carbonitrile (13.7 mg, 25.7 μmol, 39%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.32 (d, J= 1.6 Hz, 1H), 7.72 (dd, J= 1.6, 13.2 Hz, 1H), 7.51 (dt, J= 1.6,

8.8 Hz, 1H), 7.24 (d, J= 9.6 Hz, 1H), 7.19 - 6.79 (m, 1H), 6.79 - 6.39 (m, 1H), 6.28 (ddd, J= 2.0, 4.4, 16.8 Hz, 1H), 5.75 (ddd, J- 1.6, 10.4, 17.6 Hz, 1H), 5.40 (d, J= 16.0 Hz, 1H), 5.01 (d, J =

14.8 Hz, 1H), 4.05 - 3.93 (m, 1H), 3.87 - 3.76 (m, 2H), 3.74 - 3.58 (m, 1H), 2.19 - 1.99 (m, 2H); m/z ES+ [M+H] ⁺ 532.9.

Example 7. Preparation of 4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(3S)-l-

[0482] Step 1. tert-Butyl (3S)-3-[[8-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7 -cyano-

1.5-naphthyridin-2-yl]oxy]pyrrolidine- 1 -carboxylate

[0483] To a mixture of tert-butyl (3S)-3-hydroxypyrrolidine-l-carboxylate (93.82 mg, 501 μmol) in dimethylsulfoxide (3 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 502 μL) in one portion at 25 °C. The mixture was stirred at 25 °C for 30 min. Then 6-chloro-4-[3-chloro- 4-(difluoromethoxy)-2-fluoro-anilino]-l,5-naphthyridine-3-ca rbonitrile (100 mg, 251 μmol) was added and the mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was quenched by addition water (30 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 (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give compound terZ-butyl (3S)-3-[[8-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7 -cyano-

1.5-naphthyridin-2-yl]oxy]pyrrolidine-l -carboxylate (30.0 mg, 38.2 μmol, 15%) as a yellow oil. m/z ES+ [M+H] ⁺ 550.2.

[0484] Step 2. 4-[3-Chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(3S)-py rrolidin-3-yl]oxy-

1.5-naphthyridine-3 -carbonitrile

[0485] A solution of tert-butyl (3S)-3-[[8-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-7 - cyano-l,5-naphthyridin-2-yl]oxy]pyrrolidine-l -carboxylate (20.0 mg, 36.4 μmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to give compound 4- [3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(3S)-pyrr olidin-3-yl]oxy-l,5-naphthyridine- 3 -carbonitrile (15.0 mg, crude) as a yellow oil. m/z ES+ [M+H] ⁺ 450.1.

[0486] Step 3. 4-[3-Chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(3S)-1- prop-2- enoylpyrrolidin-3 -yl]oxy- 1 ,5-naphthyridine-3 -carbonitrile

[0487] To a mixture of 4-[3-chloro-4-(difluoromethoxy)-2-fluoro-anilino]-6-[(3S)-py rrolidin-3- yl]oxy-l,5-naphthyridine-3-carbonitrile (15 mg, 33.35 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (8.40 mg, 100 μmol) and prop-2-enoyl chloride (3.02 mg, 33.4 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm, 10 um; mobile phase: [water (FA)- ACN]; B%: 37%-67%, 10 min) to give compound 4-[3-chloro-4-(difluoromethoxy)-2-fluoro- anilino]-6-[(3S)-l -prop-2 -enoylpyrrolidin-3-yl]oxy-l,5-naphthyridine-3-carbonitrile (6.45 mg, 12.8 μmol, 38%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 - 9.57 (m, 1H), 8.54 (s, 1H), 8.23 (dd, J= 0.8, 9.2 Hz, 1H), 7.73 - 7.61 (m, 1H), 7.47 - 7.26 (m, 3H), 6.72 - 6.50 (m, 1H), 6.20 - 6.01 (m, 2H), 5.67 (ddd, J= 2.4, 10.3, 18.0 Hz, 1H), 4.03 - 3.73 (m, 4H), 2.35 - 2.17 (m, 2H); m/z ES+ [M+H] ⁺ 504.0. -

[0488] Step 1. tert-Butyl (3S)-3-[[8-[3-chloro-4-(cyclopropylmethoxy)-2-fhioro-anilino ]-7- cyano- 1 ,5-naphthyridin-2-yl]oxy]pyrrolidine- 1 -carboxylate

[0489] To a mixture of 6-chloro-4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino ]-l,5- naphthyridine-3-carbonitrile (200 mg, 496 μmol) and tert-butyl (3S)-3-hydroxypyrrolidine-l- carboxylate (279 mg, 1.49 mmol) in dimethylsulfoxide (4 mL) was added potassium terZ-butoxide (223 mg, 1.98 mmol) in one portion. The mixture was then heated to 80 °C and stirred for 4 h. On completion, the reaction mixture was quenched by addition water 40 mL at 25 °C, and then diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=l/l) to give compound tert-butyl (3S)-3-[[8-[3- chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino] -7 -cyano- 1 ,5-naphthyridin-2- yl]oxy]pyrrolidine-l -carboxylate (100 mg, 157 μmol, 32%) as a yellow solid, m/z ES+ [M+H] ⁺ 554.3.

[0490] Step 22.. 4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(3S) -pyrrolidin-3- yl]oxy-l,5-naphthyridine-3-carbonitrile

[0491] A mixture of tert-butyl (3S)-3-[[8-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino ]-7- cyano-l,5-naphthyridin-2-yl]oxy]pyrrolidine-l -carboxylate (100 mg, 180.50 μmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound 4- [3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(3S)-p yrrolidin-3-yl]oxy-l,5- naphthyridine-3-carbonitrile (100 mg, 178 μmol, 99%) as a yellow oil. m/z ES+ [M+H] ⁺ 454.2.

[0492] Step 3. 4-[3-Chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(3S) -l-prop-2- enoylpyrrolidin-3-yl]oxy-l,5-naphthyridine-3-carbonitrile

[0493] To aa mixture of 4-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-anilino]-6-[(3S) - pyrrolidin-3-yl]oxy-l,5-naphthyridine-3-carbonitrile (100 mg, 220.31 pmol) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (17.9 mg, 198 μmol) and sodium bicarbonate (55.5 mg, 661 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex 018 75 x 30 mm, 3 um; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 7 min) to give compound 4-[3-chloro-4- (cyclopropyhnethoxy)-2-fluoro-anilino]-6-[(3S)- 1 -prop-2-enoylpyrrolidin-3 -yl]oxy- 1,5- naphthyridine-3-carbonitrile (13.5 mg, 26.6 μmol, 12%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-</ ₆ ) 8 9.64 (d, J= 0.8 Hz, 1H), 8.49 (d, J= 1.2 Hz, 1H), 8.21 (dd, J= 0.8, 9.2 Hz, 1H), 7.49 (dt, J= 6.0, 8.8 Hz, 1H), 7.35 (dd, J= 4.4, 9.2 Hz, 1H), 7.09 (d, J= 8.8 Hz, 1H), 6.72 - 6.51 (m, 1H), 6.26 - 6.09 (m, 2H), 5.68 (ddd, J= 2.4, 10.4, 18.0 Hz, 1H), 4.03 (d, J= 7.2 Hz, 2H), 3.83 - 3.69 (m, 2H), 3.66 - 3.54 (m, 2H), 2.36 - 2.21 (m, 2H), 1.33 - 1.27 (m, 1H), 0.64 - 0.59 (m, 2H), 0.42 - 0.37 (m, 2H); m/z ES+ [M+H] ⁺ 508.0.

Example 99.. Preparation of (S)-6-((l-acryloylpyrrolidin-3-yl)oxy)-4-((3-chloro-4- (difluoromethoxy)-2-fluorophenyl)amino)-7-fluoro-l 5-naphthyridine-3-carbonitrile

[0494] Step 1. Methyl (S)-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-3- (((dimethylamino)methylene)amino)-5-fluoropicolinate

[0495] To a solution of methyl (S)-3-amino-6-((l-(Zert-butoxycarbonyl)pyrrolidin-3-yl)oxy)- 5- fluoropicolinate (2.7 g, 7.6 mmol) in toluene (25 mL) was added N, A'-dimethylformamide dimethyl acetal (2.72 g, 22.8 mmol) and the mixture was stirred at 90 °C for 4 h. On completion, the mixture was concentrated in vvaaccuuoo to give compound methyl (S)-6-((l-(tert- butoxycarbonyl)pyrrolidin-3-yl)oxy)-3-(((dimethylamino)methy lene)amino)-5-fluoropicolinate (3.50 g, crude) as a yellow solid, m/z ES+ [M+H] ⁺ 410.9.

[0496] Step 2. tert-Butyl (S)-3-((7-cyano-3-fhioro-8 -hydroxy- 1, 5-naphthyridin-2 - yl)oxy)pyrrolidine- 1 -carboxylate

[0497] To a solution of acetonitrile (3.20 g, 10 eq) in tetrahydrofuran (30 mL) was added n- butyllithium (2.5 M in tetrahydrofuran, 9.36 mL, 23.4 mmol) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 30 min. Then methyl (S)-6-((l-(tert- butoxycarbonyl)pyrrolidin-3-yl)oxy)-3-(((dimethylamino)methy lene)amino)-5-fluoropicolinate (3.2 g, 7.80 mmol) dissolved in tetrahydrofuran (30 mL) was added dropwise at -78 °C. The mixture was slowly warmed to 25 °C and stirred at 25 °C for 12 h. On completion, the reaction mixture was quenched by addition acetic acid (50 mL) at 25 °C, and stirred for 30 min. The mixture was then diluted with water (200 mL), extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated, sodium bicarbonate (500 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give compound tert- butyl (S)-3-((7-cyano-3-fluoro-8-hydroxy- 1 ,5-naphthyridin-2-yl)oxy)pyrrolidine- 1 - carboxylate (800 mg, 2.05 mmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 7.86 (d, J- 10.0 Hz, 1H), 5.99 - 5.51 (m, 1H), 3.76 - 3.57 (m, 2H), 3.51 - 3.43 (m, 3H), 2.30 - 2.04 (m, 2H), 1.40 (d, J= 7.2 Hz, 9H); m/z ES+ [M-100] ⁺ 274.8.

[0498] Step 3. tert-Butyl (S)-3-((8-chloro-7-cyano-3-fluoro-l,5-naphthyridin-2- yl)oxy)pyrrolidine- 1 -carboxylate

[0499] To a solution of tert-butyl (S)-3-((7-cyano-3-fluoro-8-hydroxy-l,5-naphthyridin-2- yl)oxy)pyrrolidine- 1 -carboxylate (665 mg, 1.78 mmol) in toluene (10 mL) wwaass added diisopropylethylamine (1.38 g, 10.7 mmol) and phosphorus oxychloride (545 mg, 3.55 mmol), then the mixture was stirred at 110 °C for 16 h under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0—25% ethyl acetate/petroleum ethergradient @ 40 mL/min) to give compound tert-butyl (S)-3-((8-chloro-7- cyano-3-fluoro-l,5-naphthyridin-2-yl)oxy)pyrrolidine-l -carboxylate (500 mg, 698 μmol, 72%) as a yellow solid, m/z ES+ [M+H] ⁺ 393.1

[0500] Step 44.. (S)-4-((3-Chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-7 -fluoro-6- (pyrrolidin-3 -yloxy)- 1 ,5-naphthyridine-3 -carbonitrile

[0501] To a solution of tert-butyl (S)-3-((8-chloro-7-cyano-3-fluoro-l,5-naphthyridin-2- yl)oxy)pyrrolidine-l -carboxylate (100 mg, 255 ymol) and 3-chloro-4-(difluoromethoxy)-2- fluoroaniline (53.9 mg, 255 μmol) in isopropanol (1 mL) was added hydrochloric acid (1 M, 12.7 ummol) and the mixture was stirred at 80 °C for 16 h. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give compound (S)-4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-7 - fluoro-6-(pyrrolidin-3-yloxy)-l,5-naphthyridine-3 -carbonitrile (60.0 mg, 131 μmol, 41%, formic acid salt) as a light yellow solid, m/z ES+ [M+H] ⁺ 468.0.

[0502] Step 55.. (S)-6-((l-Acryloylpyrrolidin-3-yl)oxy)-4-((3-chloro-4-(diflu oromethoxy)-2- fluorophenyl)amino)-7 -fluoro- 1 ,5-naphthyridine-3 -carbonitrile [0503] To a solution of (S)-4-((3-chloro-4-(difluoromethoxy)-2-fluorophenyl)arnino)- 7-fluoro-6- (pyrrolidin-3-yloxy)-l,5-naphthyridine-3 -carbonitrile (60 mg, 106 μmol) and sodium bicarbonate (44.1 mg, 525 μmol) in anhydrous tetrahydrofuran (1 mL) and water (1 mL) was added prop-2 - enoyl chloride (9.51 mg, 106 μmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5 um; mobile phase: [water (NH4HCO3)- ACN]; B%: 37%-67%, 8 min) to give compound (8)-6-((l-acryloylpyrrolidin-3-yl)oxy)-4-((3- chloro-4-(difluoromethoxy)-2-fluorophenyl)amino)-7-fluoro-l, 5-naphthyridine-3-carbonitrile (21.7 mg, 54.8 mmol, 39%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.02 - 9.55 (m, 1H), 8.76 - 8.41 (m, 1H), 8.36 - 8.04 (m, 1H), 7.89 - 7.54 (m, 1H), 7.50 - 7.16 (m, 2H), 6.77 - 6.49 (m, 1H), 6.30 - 6.06 (m, 2H), 5.75 - 5.62 (m, 1H), 4.03 - 3.49 (m, 4H), 2.31 - 2.11 (m, 2H); m/z ES+ [M+H] ⁺ 521.9.

Example 10. Synthesis and Characterization of Additional Exemplary Compounds

[0504] Additional exemplary compounds were synthesized following the procedures described herein. Characterizations of the compounds are shown in Table A below.

Example 11. Biological Activity of Exemplary Compounds

[0505] Retroviral Production: EGFR mutants were subcloned into pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs, San Diego, CA). Retroviral expression vector retrovirus was produced by transient transfection of HEK 293T cells with the retroviral EGFR mutant expression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs), pCMV-Gag-Pol vector and pCMV-VSV-G- Envelope vector. Briefly, HEK 293T/17 cells were plated in 100 mm collagen coated plate (354450, Coming Life Sciences, Tewksbury, MA) (4 × 10 ⁵ per plate) and incubated overnight.

The next day, retroviral plasmids (3 μg of EGFR mutant, 1.0 μg of pCMV-Gag-Pol and 0.5 μg pCMV-VSV-G) were mixed in 500 μl of Optimem (31985, Life Technologies). The mixture was incubated at room temperature for 5 min and then added to Optimem containing transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. Mixture was then added dropwise to HEK 293T cells. The next day the medium was replaced with fresh culture medium and retrovirus was harvested @ 24 and 48 hrs.

[0506] Generation of EGFR mutant stable cell lines: BaF3 cells (1.5E5 cells) were infected with 1 ml of viral supernatant supplemented with 8 μg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in a 37°C incubator overnight. Cells were then spun for 5 minutes to pellet the cells. Supernatant was removed and cells re-infected a fresh 1 ml of viral supernatant supplemented with 8 μg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in 37 °C incubator overnight. Cells were then maintained in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine containing 10 ng/ml IL-3. After 48 hours cells were selected for retroviral infection in 10 E^/ml Blasticidin for one week. Blasticidin resistant populations were washed twice in phosphate buffered saline before plating in media lacking IL-3 to select for IL-3 independent growth.

[0507] Assay for cell proliferation: BaF3 cell lines were resuspended at 1.3E5 c/ml in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine and 1% Pen/Strep and dispensed in triplicate (17.5E4 c/well) into 96 well plates. To determine the effect of drug on cell proliferation, cells incubated for 3 days in the presence of vehicle control or test drug at varying concentrations. Inhibition of cell growth was determined by luminescent quantification of intracellular ATP content using CellTiterGlo (Promega), according to the protocol provided by the manufacturer. Comparison of cell number on day 0 versus 72 hours post drug treatment was used to plot dose-response curves. The number of viable cells was determined and normalized to vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls was expressed as a fraction of 1 and graphed using PRISM® software (Graphpad Software, San Diego, CA). EC50 values were determined with the same application.

[0508] Cellular protein analysis: Cell extracts were prepared by detergent lysis (RIP A, R0278, Sigma, St Louis, MO) containing 10 mM lodoacetamide (786-228, G-Biosciences, St, Louis, MO), protease inhibitor (P8340, Sigma, St. Louis, MO) and phosphatase inhibitors (P5726, P0044, Sigma, St. Louis, MO) cocktails. The soluble protein concentration was determined by micro-BSA assay (Pierce, Rockford IL). Protein immunodetection was performed by electrophoretic transfer of SDS-PAGE separated proteins to nitrocellulose, incubation with antibody, and chemiluminescent second step detection. Nitrocellulose membranes were blocked with 5% nonfat dry milk in TBS and incubated overnight with primary antibody in 5% bovine serum albumin. The following primary antibodies from Cell Signaling Technology were used at 1 : 1000 dilution: phospho-EGFR[Yl 173] and total EGFR. β-Actin antibody, used as a control for protein loading, was purchased from Sigma Chemicals. Horseradish peroxidase-conjugated secondary antibodies were obtained from Cell Signaling Technology and used at 1:5000 dilution. Horseradish peroxidase-conjugated secondary antibodies were incubated in nonfat dry milk for 1 hour. SuperSignal chemiluminescent reagent (Pierce Biotechnology) was used according to the manufacturer's directions and blots were imaged using the Alpha Innotech image analyzer and

AlphaEaseFC software (Alpha Innotech, San Leandro CA).

[0509] IC50 values were calculated using PRISM® software and are shown in Table B. Table B assigns each compound a potency code of A, B, C, D, or E. According to the code, A represents an IC50 value <20 nM; B represents an IC50 value >20 nM and <50 nM; C represents an IC50 value

>50 nM and <100 nM; and D represents an IC50 value >100 and <500 nM; and E represents an

IC50 value >500 nM.

Table B Comp. No. Baf3-HER2 BT 474 H292 EGFR A431 EGFR S310F HER2 WT WT WT

33 B B _ E

34 B B D D

EQUIVALENTS

[0510] 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.

[0511] 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.