WO2022266427A1

WO2022266427A1 - 4-(aryl-methyl-amino)-quinazoline derivatives and uses thereof

Info

Publication number: WO2022266427A1
Application number: PCT/US2022/033965
Authority: WO
Inventors: Iwona WRONA; Matthew C. Lucas; Stephane Ciblat; Luca Arista; Alexander Flohr
Original assignee: Black Diamond Therapeutics, Inc.
Priority date: 2021-06-17
Filing date: 2022-06-17
Publication date: 2022-12-22

Abstract

The present disclosure relates to compounds of Formula (I) 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).

Description

4-(ARYL-METHYL-AMINO)-QUINAZOLINE DERIVATIVES AND USES THEREOF RELATED APPLICATION [001] This application claims priority to, and the benefit of, U.S. Application No. 63/211,910, 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:

wherein * indicates attachment to Y; W¹ is =CR^W1– or =N–; R^W1 is H, halogen, C1-C6 alkyl, or -O(C1-C6 alkyl); W² is =CR^W2– or =N– R^W2 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); R¹ is C₃-C₈ cycloalkyl, –HC=CH₂, –HC=CHR^1a or –C≡C– CH₃; H₃)₂ or -CH₂-morpholinyl;

alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo, a C₃-C₈ cycloalkyl, or a 3- to 9-membered heterocycloalkyl; X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or –NH–; Y is a C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; each R^Y independently is oxo, halogen, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C3-C8 cycloalkyl), -O-(C6-C10 aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R^Y1; each R^Y1 independently is halogen, OH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl; Z is absent or 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R^Z ; each R^Z independently is OH, oxo, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl; wherein the C₁-C₆ alkyl is optionally substituted with one or more OH halogen. [004] In some aspects, the present disclosure provides a compound of Formula (I): (I); a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W¹ is =CR^W1– or =N–; R^W1 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); W² is =CR^W2– or =N– R^W2 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); R¹ is C₃-C₈ cycloalkyl, –HC=CH₂, –HC=CHR^1a or –C≡C– CH₃; R^1a is -CH₂-N(CH₃)₂ or -CH₂-morpholinyl; R² is H or C₁-C₆ alkyl;

alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo, a C₃-C₈ cycloalkyl, or a 3- to 9-membered heterocycloalkyl; X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or –NH–; Y is a C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9- membered heteroaryl, wherein the C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; each R^Y independently is oxo, halogen, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R^Y1; each R^Y1 independently is halogen, OH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl; Z is absent or 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more

each R^Z independently is OH, oxo, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl; wherein the C₁-C₆ alkyl is optionally substituted with one or more OH halogen. [005] 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 1-3). [006] In some aspects, the present disclosure provides an isotopic derivative of a compound described. [007] In some aspects, the present disclosure provides a method of preparing a compound described herein. [008] 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 1-18). [009] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. [010] 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. [011] 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. [012] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. [013] In some aspects, the present disclosure provides a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor. [014] 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. [015] 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. [016] 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. [017] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION [018] 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 [019] In some aspects, the present disclosure provides a compound of Formula (I’):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

wherein * indicates attachment to Y; W¹ is =CR^W1– or =N–; R^W1 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); W² is =CR^W2– or =N– R^W2 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); R¹ is C₃-C₈ cycloalkyl, –HC=CH₂, –HC=CHR^1a or –C≡C– CH₃; R^1a is -CH2-N(CH3)2 or -CH2-morpholinyl; R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo, a C3-C8 cycloalkyl, or a 3- to 9-membered heterocycloalkyl; X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or –NH–; Y is a C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; each ^Y independently is oxo, halogen, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R^Y1; each R^Y1 independently is halogen, OH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl; Z is absent or 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R^Z ; each R^Z independently is OH, oxo, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C3-C6 cycloalkyl; wherein the C1-C6 alkyl is optionally substituted with one or more OH halogen. [020] In some aspects, the present disclosure provides a compound of Formula (I):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W¹ is =CR^W1– or =N–; R^W1 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); W² is =CR^W2– or =N–; R^W2 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); R¹ is C₃-C₈ cycloalkyl, –HC=CH₂, –HC=CHR^1a or –C≡C– CH₃; R^1a is -CH2-N(CH3)2 or -CH2-morpholinyl; R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo, a C₃-C₈ cycloalkyl, or a 3- to 9-membered heterocycloalkyl; X¹ is absent,

X² is absent or –NH–; Y is a C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; each R^Y independently is oxo, halogen, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C3-C8 cycloalkyl), -O-(C6-C10 aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R

^Y1; each R^Y1 independently is halogen, OH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl; Z is absent or 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R^Z; and each R^Z independently is OH, oxo, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl; wherein the C₁-C₆ alkyl is optionally substituted with one or more OH or halogen. [021] In some embodiments, the compound is of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W¹ is =CR^W1– or =N–; R^W1 is H; W² is =CR^W2–; R^W2 is H or -O(C₁-C₆ alkyl); R¹ is –HC=CH₂; R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo or a C₃-C₈ cycloalkyl; X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or –NH–; Y is a C6-C10 aryl or 5- to 9-membered heteroaryl, wherein the C6-C10 aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R^Y; each R^Y independently is halogen, C₁-C₆ alkyl, or -O-(C₆-C₁₀ aryl); and Z is absent or 3- to 9-membered heterocycloalkyl. [022] It is understood that, for a compound of Formula (I), L, W¹, R^W1, W², R^W2, X¹, X², Y, R^Y, R^Y1, Z, R^Z, R¹, R^1a, R², R³, R^3a, R⁴, R^4a, and n can each be, where applicable, selected from the groups described herein, and any group described herein for any of L, W¹, R^W1, W², R^W2, X¹, X², Y, R^Y, R^Y1, Z, R^Z, R¹, R^1a, R², R³, R^3a, R⁴, R^4a, and n can be combined, where applicable, with any group described herein for one or more of the remainder of L, W¹, R^W1, W², R^W2, X¹, X², Y, R^Y, R^Y1, Z, R^Z, R¹, R^1a, R², R³, R^3a, R⁴, R^4a, and n. Variable L [023] In some embodiments,

C(R³R⁴)-O-*, wherein * indicates attachment to Y. [024] In some embodiments, L is -N(R²)-C(R³R⁴)-* or -C(R³R⁴)-N(R²)-*, wherein * indicates attachment to Y. [025] In some embodiments, L i , wherein * indicates attachment to Y. [026] In some embodiments, L i wherein * indicates attachment to Y. [027] In some embodiments, L i , wherein * indicates attachment to Y. [028] In some embodiments, L i wherein * indicates attachment to Y. [029] In some embodiments,

* or -C(R³R⁴)-O-*, wherein * indicates attachment to Y. [030] In some embodiments, L is -O-C(R³R⁴)-*, wherein * indicates attachment to Y. [031] In some embodiments, L is -C(R³R⁴)-O-*, wherein * indicates attachment to Y. Variables W¹, W², R^W1, and R^W2 [032] In some embodiments, W¹ is =CR^W1–. In some embodiments, W¹ is =CH–. [033] In some embodiments, W¹ is =N–. [034] In some embodiments, R^W1 is H, halogen, C₁-C₆ alkyl, or -O-(C₁-C₆ alkyl). [035] In some embodiments, R^W1 is H. [036] In some embodiments, W² is =CR^W2–. In some embodiments, W² is =CH–. In some embodiments, W² is =COMe–. [037] In some embodiments, R^W2 is H, halogen, C1-C6 alkyl, or -O-(C1-C6 alkyl). [038] In some embodiments, R^W2 is H. [039] In some embodiments, R^W2 is -OMe. [040] In some embodiments, W¹ is =CR^W1- and W² is =CR^W2-. [041] In some embodiments, W¹ is N and W² is =CR^W2-. [042] In some embodiments, W¹ is =CR^W1- and W² is N. [043] In some embodiments, W¹ is CH and W² is CH. [044] In some embodiments, W¹ is N and W² is CH. [045] In some embodiments, W¹ is CH and W² is N. Variables X¹, X², Z, and R^Z [046] In some embodiments, X¹ is absent, –NH–, –N(CH₃)– or –O–. [047] In some embodiments, X¹ is absent. In some embodiments, X¹ is–NH–. In some embodiments, X¹ is–N(CH₃)–. In some embodiments, X¹ is–O–. [048] In some embodiments, X² is absent or –NH–. [049] In some embodiments, X² is absent. [050] In some embodiments, X² is –NH–. [051] In some embodiments, Z is absent or 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R^Z. [052] In some embodiments, Z is absent. [053] 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 . [054] In some embodiments, Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9- membered heterocycloalkyl is substituted with one or more R^Z . [055] In some embodiments, Z is 3-membered heterocycloalkyl. In some embodiments, Z is 4- membered heterocycloalkyl. In some embodiments, Z is 5-membered heterocycloalkyl. In some embodiments, Z is 6-membered heterocycloalkyl. In some embodiments, Z is 7-membered heterocycloalkyl. In some embodiments, Z is 8-membered heterocycloalkyl. In some embodiments, Z is 9-membered heterocycloalkyl. [056] In some embodiments, Z is 3-membered heterocycloalkyl optionally substituted with one or more R^Z. In some embodiments, Z is 4-membered heterocycloalkyl optionally substituted with one or more R^Z. In some embodiments, Z is 5-membered heterocycloalkyl optionally substituted with one or more R^Z. In some embodiments, Z is 6-membered heterocycloalkyl optionally substituted with one or more R^Z. In some embodiments, Z is 7-membered heterocycloalkyl optionally substituted with one or more R^Z. In some embodiments, Z is 8-membered heterocycloalkyl optionally substituted with one or more R^Z. In some embodiments, Z is 9- membered heterocycloalkyl optionally substituted with one or more R^Z. [057] In some embodiments, Z is azetidinyl, pyrrolidinyl, piperidinyl, 2,5- diazabicyclo[2.2.1]heptyl, or 1,6-diazaspiro[3.3]heptyl. [058] In some embodiments, Z is azetidinyl, pyrrolidinyl, or piperidinyl. [059] In some embodiments, Z is 2,5-diazabicyclo[2.2.1]heptyl, or 1,6-diazaspiro[3.3]heptyl. [060] In some embodiments, Z is azetidinyl. In some embodiments, Z is pyrrolidinyl. In some embodiments, Z is piperidinyl. In some embodiments, Z is 2,5-diazabicyclo[2.2.1]heptyl. In some embodiments, Z is 1,6-diazaspiro[3.3]heptyl. [061] In some embodiments, Z is azetidinyl optionally substituted with one or more R^Z. In some embodiments, Z is pyrrolidinyl optionally substituted with one or more R^Z. In some embodiments, Z is piperidinyl optionally substituted with one or more R^Z. In some embodiments, Z is 2,5- diazabicyclo[2.2.1]heptyl optionally substituted with one or more R^Z. In some embodiments, Z is 1,6-diazaspiro[3.3]heptyl optionally substituted with one or more R^Z. [062] In some embodiments, R^Z is OH, oxo, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl; wherein the C₁-C₆ alkyl is optionally substituted with one or more OH or halogen. [063] In some embodiments, Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9- membered heterocycloalkyl contains at least one nitrogen atom. [064] In some embodiments, X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or

; and Z is absent or 3- to 9-membered heterocycloalkyl. Variables R¹, R^1a, R², R³, R^3a, R⁴, and R^4a [065] In some embodiments, R¹ is C₃-C₈ cycloalkyl, –HC=CH₂, –HC=CHR^1a or –C≡C–CH₃. [066] In some embodiments, R¹ is C3-C8 cycloalkyl. In some embodiments, R¹ is–HC=CH2. In some embodiments, R¹ is–HC=CHR^1a. In some embodiments, R¹ is –C≡C–CH₃. [067] In some embodiments, R^1a is -CH₂-N(Me)₂ or -CH₂-morpholinyl. [068] In some embodiments, R^1a is -CH₂-N(Me)₂. In some embodiments, R^1a is -CH₂- morpholinyl. [069] In some embodiments, R² is H or C₁-C₆ alkyl. In some embodiments, R² is H. In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is methyl. [070] In some embodiments, R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a. [071] In some embodiments, R³ is H. [072] In some embodiments, R³ is C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a. [073] In some embodiments, R³ is C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is substituted with one or more R^3a. [074] In some embodiments, R³ is C₁ alkyl optionally substituted with one or more R^3a. In some embodiments, R³ is C₂ alkyl optionally substituted with one or more R^3a. In some embodiments, R³ is C₃ alkyl optionally substituted with one or more R^3a. In some embodiments, R³ is C₄ alkyl optionally substituted with one or more R^3a. In some embodiments, R³ is C₅ alkyl optionally substituted with one or more R^3a. In some embodiments, R³ is C₆ alkyl optionally substituted with one or more R^3a. In some embodiments, R³ is methyl optionally substituted with one or more R^3a. [075] In some embodiments, R³ is C₁ alkyl. In some embodiments, R³ is C₂ alkyl. In some embodiments, R³ is C₃ alkyl. In some embodiments, R³ is C₄ alkyl. In some embodiments, R³ is C₅ alkyl. In some embodiments, R³ is C₆ alkyl. In some embodiments, R³ is methyl. [076] In some embodiments, R^3a is halogen, -OH, or -O(C₁-C₆ alkyl). [077] In some embodiments, R^3a is halogen. In some embodiments, R^3a is fluorine. In some embodiments, R^3a is chlorine. In some embodiments, R^3a is bromine. In some embodiments, R^3a is iodine. [078] In some embodiments, R^3a is -OH. [079] In some embodiments, R^3a is -O(C₁-C₆ alkyl). In some embodiments, R^3a is -O(C₁ alkyl). In some embodiments, R^3a is -O(C2 alkyl). In some embodiments, R^3a is -O(C3 alkyl). In some embodiments, R^3a is -O(C₄ alkyl). In some embodiments, R^3a is -O(C₅ alkyl). In some embodiments, R^3a is -O(C₆ alkyl). [080] In some embodiments, R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a. [081] In some embodiments, R⁴ is H. [082] In some embodiments, R⁴ is C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a. [083] In some embodiments, R⁴ is C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more R^4a. [084] In some embodiments, R⁴ is C₁ alkyl optionally substituted with one or more R^4a. In some embodiments, R⁴ is C₂ alkyl optionally substituted with one or more R^4a. In some embodiments, R⁴ is C₃ alkyl optionally substituted with one or more R^4a. In some embodiments, R⁴ is C₄ alkyl optionally substituted with one or more R^4a. In some embodiments, R⁴ is C₅ alkyl optionally substituted with one or more R^4a. In some embodiments, R⁴ is C₆ alkyl optionally substituted with one or more R^4a. In some embodiments, R⁴ is methyl optionally substituted with one or more R^4a. [085] In some embodiments, R⁴ is C₁ alkyl. In some embodiments, R⁴ is C₂ alkyl. In some embodiments, R⁴ is C₃ alkyl. In some embodiments, R⁴ is C₄ alkyl. In some embodiments, R⁴ is C₅ alkyl. In some embodiments, R⁴ is C₆ alkyl. In some embodiments, R⁴ is methyl. [086] In some embodiments, R^4a is halogen, -OH, or -O(C₁-C₆ alkyl). [087] In some embodiments, R^4a is halogen. In some embodiments, R^4a is fluorine. In some embodiments, R^4a is chlorine. In some embodiments, R^4a is bromine. In some embodiments, R^4a is iodine. [088] In some embodiments, R^4a is -OH. [089] In some embodiments, R^4a is -O(C₁-C₆ alkyl). In some embodiments, R^4a is -O(C₁ alkyl). In some embodiments, R^4a is -O(C₂ alkyl). In some embodiments, R^4a is -O(C₃ alkyl). In some embodiments, R^4a is -O(C₄ alkyl). In some embodiments, R^4a is -O(C₅ alkyl). In some embodiments, R^4a is -O(C₆ alkyl). [090] In some embodiments, R³ and R⁴ together with the carbon they are attached to form an oxo, a C3-C8 cycloalkyl, or a 3- to 9-membered heterocycloalkyl. [091] In some embodiments, R³ and R⁴ together with the carbon they are attached to form an oxo. [092] In some embodiments, R³ and R⁴ together with the carbon they are attached to form a C₃- C₈ cycloalkyl. In some embodiments, R³ and R⁴ together with the carbon they are attached to form a C₃ cycloalkyl. In some embodiments, R³ and R⁴ together with the carbon they are attached to form a C₄ cycloalkyl. In some embodiments, R³ and R⁴ together with the carbon they are attached to form a C₅ cycloalkyl. In some embodiments, R³ and R⁴ together with the carbon they are attached to form a C6 cycloalkyl. In some embodiments, R³ and R⁴ together with the carbon they are attached to form a C₇ cycloalkyl. In some embodiments, R³ and R⁴ together with the carbon they are attached to form a C₈ cycloalkyl. In some embodiments, R³ and R⁴ together with the carbon they are attached to form a cyclopropyl. [093] In some embodiments, at least one of R³ and R⁴ is not H. [094] In some embodiments, R¹ is –HC=CH₂; R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; and each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl). Variables Y, R^Y, and R^Y1 [095] In some embodiments, Y is a C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆- C₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y. [096] In some embodiments, Y is a C₃-C₈ cycloalkyl, optionally substituted with one or more R^Y. [097] In some embodiments, Y is a 3- to 8-membered heterocycloalkyl, optionally substituted with one or more R^Y. [098] In some embodiments, Y is a C₆-C₁₀ aryl optionally substituted with one or more R^Y. [099] In some embodiments, Y is a C₆-C₁₀ aryl substituted with one or more R^Y. [0100] In some embodiments, Y is a C₆-C₁₀ aryl. In some embodiments, Y is a C₆ aryl. In some embodiments, Y is a C7 aryl. In some embodiments, Y is a C8 aryl. In some embodiments, Y is a C₉ aryl. In some embodiments, Y is a C₁₀ aryl. In some embodiments, Y is phenyl. [0101] In some embodiments, Y is a C₆ aryl optionally substituted with one or more R^Y. In some embodiments, Y is a C₇ aryl optionally substituted with one or more R^Y. In some embodiments, Y is a C₈ aryl optionally substituted with one or more R^Y. In some embodiments, Y is a C₉ aryl optionally substituted with one or more R^Y. In some embodiments, Y is a C₁₀ aryl optionally substituted with one or more R^Y. In some embodiments, Y is phenyl optionally substituted with one or more R^Y. [0102] In some embodiments, Y is 5- to 9-membered heteroaryl optionally substituted with one or more R^Y. [0103] In some embodiments, Y is 5- to 9-membered heteroaryl substituted with one or more R^Y. [0104] In some embodiments, Y is 5- to 9-membered heteroaryl. In some embodiments, Y is 5- membered heteroaryl. In some embodiments, Y is 6-membered heteroaryl. In some embodiments, Y is 7-membered heteroaryl. In some embodiments, Y is 8-membered heteroaryl. In some embodiments, Y is 9-membered heteroaryl. In some embodiments, Y is pyridyl. [0105] In some embodiments, R^Y is oxo, halogen, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9- membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R^Y1. [0106] In some embodiments, R^Y is halogen, C₁-C₆ alkyl, or -O-(C₆-C₁₀ aryl), wherein the C₁-C₆ alkyl or -O-(C₆-C₁₀ aryl) is optionally substituted with one or more R^Y1. [0107] 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. [0108] In some embodiments, R^Y is C₁-C₆ alkyl optionally substituted with one or more R^Y1. [0109] In some embodiments, R^Y is C₁-C₆ alkyl substituted with one or more R^Y1. [0110] In some embodiments, R^Y is C1-C6 alkyl. In some embodiments, R^Y is C1 alkyl. In 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 C₆ alkyl. In some embodiments, R^Y is methyl. [0111] In some embodiments, R^Y is -O-(C₆-C₁₀ aryl) optionally substituted with one or more R^Y1. [0112] In some embodiments, R^Y is -O-(C₆-C₁₀ aryl) substituted with one or more R^Y1. [0113] In some embodiments, R^Y is -O-(C₆-C₁₀ aryl). In some embodiments, R^Y is -O-(C₆ aryl). In some embodiments, R^Y is -O-(C₇ aryl). In some embodiments, R^Y is -O-(C₈ aryl). In some embodiments, R^Y is -O-(C9 aryl). In some embodiments, R^Y is -O-(C10 aryl). In some embodiments, R^Y is -O-phenyl. [0114] In some embodiments, R^Y1 is halogen, OH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 3- to 9- membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl. [0115] In some embodiments, Y is C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C₆- C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; and each R^Y independently is halogen, C₁-C₆ alkyl, or -O-(C₆-C₁₀ aryl). [0116] In some embodiments, the compound is of formula (I-a), (I-b), or (I-c):

(I-c) or a pharmaceutically acceptable salt or stereoisomer thereof. [0117] In some embodiments, the compound is of formula (I-e) or (I-f):

wherein, m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or stereoisomer thereof. [0118] In some embodiments, the compound is of formula (I-d), (I-g), or (I-h):

(I-h) or a pharmaceutically acceptable salt or stereoisomer thereof. [0119] In some embodiments, the compound is selected from a compound described in Table I, or a pharmaceutically acceptable salt or stereoisomer thereof. [0120] In some embodiments, the compound is selected from a compound described in Table I, or a pharmaceutically acceptable salt thereof. [0121] In some embodiments, the compound is selected from a compound described in Table I.

Table I.

[0122] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of a compound disclosed herein. [0123] In some embodiments, the compound is an isotopic derivative of a compound described in Table I, or a pharmaceutically acceptable salt thereof. [0124] In some embodiments, the compound is an isotopic derivative of a compound described in Table I. [0125] 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. [0126] In some embodiments, the isotopic derivative is a deuterium labeled compound. [0127] In some embodiments, the isotopic derivative is a deuterium labeled compound of a compound of the Formulae disclosed herein. [0128] In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I, or a pharmaceutically acceptable salt thereof. [0129] In some embodiments, the compound is a deuterium labeled compound of a compound described in Table I. [0130] 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%. [0131] 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. [0132] 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. [0133] 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. [0134] 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. [0135] 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. [0136] 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. [0137] 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.” [0138] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents. [0139] 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). [0140] 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. [0141] 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. [0142] 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. [0143] 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. [0144] 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. [0145] 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. [0146] 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”. [0147] 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. [0148] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions. [0149] 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). [0150] 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. [0151] 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. [0152] 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. [0153] 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. [0154] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. [0155] 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. [0156] It is also to be understood that certain compounds of the present disclosure may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono- hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity. [0157] It is also to be understood that certain compounds of the present disclosure may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis. [0158] Compounds of the present disclosure may exist in a number of different tautomeric forms and references to compounds of the present disclosure include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

keto enol enolate [0159] 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. [0160] 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. [0161] 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. [0162] 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. [0163] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the present disclosure containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosforamidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1- ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include D-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0164] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0165] 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. [0166] 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 [0167] In some aspects, the present disclosure provides a method of preparing a compound disclosed herein. [0168] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein. [0169] 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. [0170] In some aspects, the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein. [0171] 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. [0172] 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. [0173] 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. [0174] 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. [0175] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. [0176] 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. [0177] 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. [0178] 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. [0179] The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art. [0180] The reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n- butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2- methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N- methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. [0181] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. [0182] 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. [0183] 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. [0184] 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). [0185] General routes for the preparation of a compound of the application are described in Schemes 1-3. Scheme 1

Scheme 2

Scheme 3

Biological Assays [0186] 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. [0187] 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. [0188] 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. [0189] In some embodiments, the biological assay is described in the Examples herein. [0190] In some embodiments, the biological assay is an assay measuring cell proliferation. [0191] 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. [0192] In some embodiments, the assay involves generation of EGFR mutant stable cell lines. In some embodiments, the cells (e.g., BaF3 cells) may be infected with supplemented viral supernatant and incubated. In some embodiments, the cells may be pelleted and the supernatant removed and the cells re-infected with supplemented viral supernatant, followed by incubation. In some embodiments, the cells may be maintained and then selected for retroviral infection. In some embodiments, the resistant populations may be washed and plated to select for selective growth (e.g., IL-3 independent growth). [0193] 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. [0194] 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 [0195] 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 [0196] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. [0197] 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. [0198] 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. [0199] 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. [0200] 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. [0201] 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. [0202] 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. [0203] 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. [0204] 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. [0205] 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. [0206] 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. [0207] 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. [0208] 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. [0209] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [0210] 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. [0211] 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). [0212] 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. [0213] 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 [0214] 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. [0215] 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. [0216] 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. [0217] 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. [0218] 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. [0219] 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. [0220] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a compound described herein. [0221] 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. [0222] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to the subject in need thereof a composition described herein. [0223] 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. [0224] 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. [0225] 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. [0226] 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. [0227] 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. [0228] 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. [0229] 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. [0230] 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. [0231] 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. [0232] 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. [0233] 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. [0234] 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. [0235] 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. [0236] 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. [0237] 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. [0238] 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. [0239] 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. [0240] 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. [0241] 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. [0242] 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. [0243] 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. [0244] 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. [0245] 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). [0246] 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). [0247] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. [0248] In some aspects, the present disclosure provides a compound described herein for use in the treatment of cancer. [0249] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer. [0250] In some aspects, the present disclosure provides a composition described herein for use in the treatment of cancer. [0251] 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. [0252] 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. [0253] 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. [0254] 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. [0255] 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. [0256] 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. [0257] 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. [0258] 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. [0259] 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). [0260] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer. [0261] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for treating cancer. [0262] 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. [0263] 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. [0264] 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. [0265] 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. [0266] 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. [0267] 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. [0268] 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. [0269] 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. [0270] 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). [0271] In some aspects, the present disclosure provides use of a compound described herein for preventing or treating cancer. [0272] In some aspects, the present disclosure provides use of a compound described herein in for treating cancer. [0273] 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. [0274] 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. [0275] 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. [0276] 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. [0277] 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. [0278] 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. [0279] 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. [0280] 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. [0281] In some embodiments, cancer is a solid tumor. [0282] 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. [0283] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof. [0284] In some embodiments, the cancer is glioblastoma. [0285] In some embodiments, the cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR). [0286] In some embodiments, the oncogenic variant is an oncogenic variant in an ErbB receptor. [0287] In some embodiments, the oncogenic variant in the ErbB receptor is an allosteric variant. [0288] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor. [0289] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR). [0290] In some embodiments, the ErbB receptor is a HER2 receptor. [0291] In some embodiments, the oncogenic variant is an oncogenic variant in an epidermal growth factor receptor (EGFR). [0292] In some embodiments, the oncogenic variant in the EGFR is an allosteric variant. [0293] In some embodiments, the oncogenic variant is an oncogenic variant of a HER2 receptor. [0294] In some embodiments, the oncogenic variant in the HER2 receptor is an allosteric variant. [0295] In some embodiments, the oncogenic variant in the EGFR is an EGFR variant III (EGFR- Viii) variant. [0296] 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. [0297] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, the oncogenic variant in the EGFR is a modification of a structure of the EGFR, wherein the oncogenic variant in the EGFR is capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor. In some embodiments, the modification of the structure of the EGFR comprises a modification of one or more of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a quaternary structure. In some embodiments, the modification of the structure of the EGFR occurs within a first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR. In some embodiments, the first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and/or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant in the EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant in the EGFR removes a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant in the EGFR results into one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant in the EGFR results into one or more free or unpaired Cysteine (C) residues at a site selected from the group consisting of C190-C199, C194C207, C215C223, C219-C231, C232C240, C236-C248, C251C260, C264C291, C295C307, C311C326, C329-C333, C506-C515, C510-C523, C526- C535, C539-C555, C558-C571, C562C579, C582C591, C595C617, C620-C628 and C624C636 according to SEQ ID NO: 1. In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of C190- C199, C194C207, C215C223, C219-C231, C232C240, C236-C248, C251C260, C264C291, C295C307, C311C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558- C571, C562C579, C582C591, C595C617, C620-C628 and C624C636 according to SEQ ID NO: 1. [0298] 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. [0299] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, wherein a nucleotide sequence encoding the EGFR having the oncogenic variant comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acid sequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitution of the amino acid sequence GYN for the DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertion of the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of the amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the amino acid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) an insertion of the amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the amino acid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequence GSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the amino acid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequence GNPHVC for the VC between positions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee) an insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGP for the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP for the NP between positions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) an insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) a substitution of the amino acid sequence STLASV for the SV between positions 768 and 769 of SEQ ID NO: 1. [0300] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, the EGFR having the oncogenic variant comprises EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR- R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR- A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR- G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR- C628Y, EGFR-C636Y, EGFR-G645C, EGFR-Δ660, EGFR- Δ768 or any combination thereof. [0301] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor. [0302] 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. [0303] 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. [0304] 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. [0305] 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. [0306] 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. [0307] 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. [0308] 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. [0309] 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. [0310] 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. [0311] 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. [0312] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, wherein a nucleotide sequence encoding the HER2 receptor having the oncogenic variant comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C- helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCV for the G between position 776 of SEQ ID NO: 2; (j) an insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) a substitution of the amino acid sequence PS for the LRE between positions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertion of the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for the AG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the amino acid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the amino acid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (r) an insertion of the amino acid G between positions G778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertion of the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u) an insertion of the amino acid sequence YAMA between positions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) a substitution of the amino acid sequence AVCGG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution of the amino acid sequence VVVG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the amino acid sequence AVGSGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the amino acid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution of the amino acid sequence HVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (ff) a substitution of the amino acid sequence VAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the amino acid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) a substitution of the amino acid sequence VPS for the VLRE between positions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the amino acid E between positions V777 and G778 of SEQ ID NO: 2; (ll) an insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S between positions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and (oo) an insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO: 2. [0313] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the HER2 receptor having the oncogenic variant comprises HER2-Δ16, HER2C311R, HER2-S310F, p95-HER2-M611 or any combination thereof. [0314] 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). [0315] 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. [0316] 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. [0317] 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. [0318] 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. [0319] 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. [0320] 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. [0321] 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. [0322] 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. [0323] 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. [0324] 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. [0325] 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. [0326] 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. [0327] In some embodiments, the therapeutically effective amount induces a period of remission. [0328] In some embodiments, the compound induces a period of remission. [0329] In some embodiments, the therapeutically effective amount improves a prognosis of the subject. [0330] In some embodiments, the compound improves a prognosis of the subject. [0331] 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. [0332] In some embodiments, the use comprises treating the subject with a Non-Type I inhibitor. [0333] In some embodiments, the composition comprises a Non-Type I inhibitor. [0334] 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 [0335] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [0336] 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. [0337] 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. [0338] As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C ₆ alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆ alkyl is intends to include C₁, C₂, C₃, C₄, C₅ and C₆ 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., C₁-C₆ for straight chain, C₃-C₆ for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. [0339] 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. [0340] 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., C₂-C₆ for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆” includes alkenyl groups containing two to six carbon atoms. The term “C₃-C₆” includes alkenyl groups containing three to six carbon atoms. [0341] 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. [0342] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In some embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆” includes alkynyl groups containing two to six carbon atoms. The term “

” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C₂, C₃, C₄, C₅ or C₆ chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C₂-C₆ alkenylene linker is intended to include C₂, C₃, C₄, C₅ and C₆ alkenylene linker groups. [0343] 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. [0344] 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. [0345] 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., C₃-C₁₂, C₃-C₁₀, or C₃-C₈). 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. [0346] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. 1¸, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H- spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2- azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2- azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa- azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl). [0347] 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. [0348] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NoO and S(O)_p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). [0349] 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. [0350] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). [0351] 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. [0352] 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. [0353] 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. [0354] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-. [0355] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. [0356] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. [0357] 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. [0358] 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. [0359] 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. [0360] 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. [0361] 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. [0362] 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. [0363] 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 [0364] 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. [0365] 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. [0366] 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. [0367] 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. [0368] 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. [0369] 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. [0370] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3^rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18^th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. [0371] 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. [0372] 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. [0373] 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. [0374] 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. [0375] 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. [0376] 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. [0377] 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. [0378] 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., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (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, LD₅₀/ED₅₀. 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. [0379] 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. [0380] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. In some embodiments, the appropriate formulation is dependent upon the route of administration chosen. [0381] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. [0382] 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. [0383] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [0384] 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. [0385] 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. [0386] 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. [0387] 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. [0388] 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. [0389] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. [0390] 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. [0391] 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. [0392] 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. [0393] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. [0394] 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. [0395] 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. [0396] 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. [0397] 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. [0398] 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. [0399] 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 [0400] A wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181 qnhlgscqkc dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc 241 tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv 301 vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls inatnikhfk 361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke itgflliqaw penrtdlhaf 421 enleiirgrt kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc yantinwkkl 481 fgtsgqktki isnrgensck atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkck 541 llegeprefv enseciqchp eclpqamnit ctgrgpdnci qcahyidgph cvktcpagvm 601 genntlvwky adaghvchlc hpnctygctg pglegcptng pkipsiatgm vgalllllvv 661 algiglfmrr rhivrkrtlr rllqerelve pltpsgeapn qallrilket efkkikvlgs 721 gafgtvykgl wipegekvki pvaikelrea tspkankeil deayvmasvd nphvcrllgi 781 cltstvqlit qlmpfgclld yvrehkdnig sqyllnwcvq iakgmnyled rrlvhrdlaa 841 rnvlvktpqh vkitdfglak llgaeekeyh aeggkvpikw malesilhri ythqsdvwsy 901 gvtvwelmtf gskpydgipa seissilekg erlpqppict idvymimvkc wmidadsrpk 961 freliiefsk mardpqrylv iqgdermhlp sptdsnfyra lmdeedmddv vdadeylipq 1021 qgffsspsts rtpllsslsa tsnnstvaci drnglqscpi kedsflqrys sdptgalted 1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps rdphyqdphs tavgnpeyln 1141 tvqptcvnst fdspahwaqk gshqisldnp dyqqdffpke akpngifkgs taenaeylrv 1201 apqssefiga (SEQ ID NO: 1, corresponding to epidermal growth factor receptor [Homo sapiens] and Genbank Accession No. CAA25240). [0401] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt lglepseeea prsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq rysedptvpl psetdgyvap ltcspqpeyv 1141 nqpdvrpqpp spregplpaa rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 1201 ggaapqphpp pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 2, corresponding to receptor tyrosine-protein kinase erbB-2 isoform a precursor [Homo sapiens] and GenBank Accession No. NP_004439). [0402] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 thscvdlddk gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl 661 lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv 721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql mpygclldhv 781 renrgrlgsq dllnwcmqia kgmsyledvr lvhrdlaarn vlvkspnhvk itdfglarll 841 dideteyhad ggkvpikwma lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger lpqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961 nedlgpaspl dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss 1021 strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqs lpthdpsplq 1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp spregplpaa rpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp pafspafdnl yywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv (SEQ ID NO: 3, corresponding to receptor tyrosine- protein kinase erbB-2 isoform b [Homo sapiens] and GenBank Accession No. NP_001005862). [0403] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mprgswkpqv ctgtdmklrl paspethldm lrhlyqgcqv vqgnleltyl ptnaslsflq 61 diqevqgyvl iahnqvrqvp lqrlrivrgt qlfednyala vldngdplnn ttpvtgaspg 121 glrelqlrsl teilkggvli qrnpqlcyqd tilwkdifhk nnqlaltlid tnrsrachpc 181 spmckgsrcw gessedcqsl trtvcaggca rckgplptdc cheqcaagct gpkhsdclac 241 lhfnhsgice lhcpalvtyn tdtfesmpnp egrytfgasc vtacpynyls tdvgsctlvc 301 plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa gckkifgsla 361 flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw pdslpdlsvf qnlqvirgri 421 lhngaysltl qglgiswlgl rslrelgsgl alihhnthlc fvhtvpwdql frnphqallh 481 tanrpedecv geglachqlc arghcwgpgp tqcvncsqfl rgqecveecr vlqglpreyv 541 narhclpchp ecqpqngsvt cfgpeadqcv acahykdppf cvarcpsgvk pdlsympiwk 601 fpdeegacqp cpincthscv dlddkgcpae qraspltsii savvgillvv vlgvvfgili 661 krrqqkirky tmrrllqete lvepltpsga mpnqaqmril ketelrkvkv lgsgafgtvy 721 kgiwipdgen vkipvaikvl rentspkank eildeayvma gvgspyvsrl lgicltstvq 781 lvtqlmpygc lldhvrenrg rlgsqdllnw cmqiakgmsy ledvrlvhrd laarnvlvks 841 pnhvkitdfg larlldidet eyhadggkvp ikwmalesil rrrfthqsdv wsygvtvwel 901 mtfgakpydg ipareipdll ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961 fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021 apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv fdgdlgmgaa 1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdv rpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe yltpqggaap qphpppafsp 1201 afdnlyywdq dppergapps tfkgtptaen peylgldvpv (SEQ ID NO: 4, corresponding to receptor tyrosine-protein kinase erbB-2 isoform c [Homo sapiens] and GenBank Accession No. NP_001276865). [0404] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 melaalcrwg lllallppga astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strnm (SEQ ID NO: 5, corresponding to receptor tyrosine-protein kinase erbB-2 isoform d precursor [Homo sapiens] and GenBank Accession No. NP_001276866). [0405] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of: 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 ths (SEQ ID NO: 6, corresponding to receptor tyrosine-protein kinase erbB-2 isoform e [Homo sapiens] and GenBank Accession No. NP_001276867). EXAMPLES [0406] 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: Acetonitrile tert-butyl carbamate diode array detector Dichloromethane Dimethylsulfoxide ethyl acetate electrospray ionisation high-performance liquid chromatography Isopropylalcohol liquid chromatography mass spectrometry nuclear magnetic resonance Pyridine retention time supercritical fluid chromatography trifluoroacetic acid Tetrahydrofuran thin layer chromatography

common intermediates and anilines: Intermediate A: Synthesis of tert-Butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (Int-A)

[0407] Step 1. Synthesis of 3-Amino-6-chloro-pyridine-2-carboxamide [0408] To a mixture of 6-chloro-3-nitro-pyridine-2-carbonitrile (25 g, 136 mmol) in ethanol (350 mL) was added tin(II) chloride dihydrate (123 g, 545 mmol), the reaction mixture was stirred at 85 °C for 2 hr. The reaction mixture was concentrated in vacuo to remove the solvent. The crude product was diluted with ethyl acetate (300 mL), adjusted to pH = 7~8 with saturated sodium carbonate and then extracted with ethyl acetate (2 L x 3). The combined organic layers were washed with brine (2 L x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-amino-6-chloro-pyridine-2-carboxamide (21 g, 0.12 mol, 89%) as a pink solid. m/z ES+ [M+H]⁺ 172.1. [0409] Step 2. Synthesis of 6-Chloropyrido[3,2-d]pyrimidin-4-ol [0410] A mixture of 3-amino-6-chloro-pyridine-2-carboxamide (21 g, 122 mmol) in triethyl orthoformate (400 mL) was stirred at 140 °C for 12 hr. The reaction mixture was filtered and the filter cake was dried in vacuo to give 6-chloropyrido[3,2-d]pyrimidin-4-ol (18 g, 99.4 mmol, 81%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.73 (s, 1H), 8.19 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H). [0411] Step 3. Synthesis of tert-Butyl (3S)-3-(4-hydroxypyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate [0412] To a mixture of 6-chloropyrido[3,2-d]pyrimidin-4-ol (13 g, 71.6 mmol) and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (26.8 g, 143 mmol) in dimethylsulfoxide (200 mL) was added potassium tert-butoxide (16.1 g, 143 mmol), the reaction mixture was stirred at 80 °C for 12 hr. The reaction mixture was quenched by formic acid to adjust pH = 7, and then water (500 mL) was added. The mixture was filtered and filter cake was dried in vacuo to give tert-butyl (3S)- 3-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate (14.3 g, 43.1 mmol, 60%) as a yellow solid. m/z ES+ [M-100+H]⁺ 233.0. [0413] Step 4. Synthesis of tert-Butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate [0414] To a mixture of tert-butyl (3S)-3-(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (14.3 g, 43.0 mmol) in toluene (300 mL) was added diisopropylethyl amine (27.8 g, 215 mmol), and then phosphorus oxychloride (8.58 g, 55.9 mmol) was added. The reaction mixture was stirred at 110 °C for 1 hr. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=100/1 to 1/1) to afford tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (12 g, 34.3 mmol, 79%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.35 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 5.71 (d, J = 13.6 Hz, 1H), 3.81 - 3.49 (m, 2H), 3.48 - 3.41(m, 1H), 2.52 - 2.20 (m, 2H), 1.39 (d, J = 6.4 Hz, 9H); m/z ES+ [M+H]⁺ 351.1. Intermediate B: Synthesis of 4,6-Dichloropyrido[3,2-d]pyrimidine (Int-B)

[0415] Step 1. Synthesis of 4,6-Dichloropyrido[3,2-d]pyrimidine [0416] To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (7 g, 38.6 mmol) in toluene (100 mL) was added phosphorus oxychloride (7.68 g, 50.1 mmol) and diisopropylethylamine (24.9 g, 192 mmol). The mixture was stirred at 110 °C for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=3:1 to 2:1) to give 4,6-dichloropyrido[3,2-d]pyrimidine (6.72 g, 33.6 mmol, 87%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H); m/z ES+ [M+H]⁺ 200.0. [0417] Intermediate C: Synthesis of tert-Butyl (3S)-3-[(4-chloropyrido[3,2-d]pyrimidin-6-yl)-methyl- amino]pyrrolidine-1-carboxylate (Int-C)

[0418] Step 1. Synthesis of tert-Butyl (3S)-3-[(6-cyano-5-nitro-2-pyridyl)-methyl- amino]pyrrolidine-1-carboxylate [0419] To a solution of 6-chloro-3-nitro-pyridine-2-carbonitrile (5.5 g, 29.9 mmol) and tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate (7.20 g, 35.9 mmol) in N-methyl pyrrolidone (100 mL) was added diisopropylethylamine (11.6 g, 89.9 mmol). The mixture was stirred at 100 °C for 1 hr. On completion, the reaction mixture was partitioned between water (200 mL) and ethyl acetate (700 mL). The organic phase was separated, washed with brine (250 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=20/1-0/1) to give tert-butyl (3S)-3-[(6-cyano-5-nitro-2-pyridyl)-methyl-amino]pyrrolidine-1-carboxylate (10 g, 28.8 mmol, 96%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J = 9.6 Hz, 1H), 6.75 (d, J = 9.6 Hz, 1H), 5.48 (br. s, 1H), 3.70 - 3.65(m, 2H), 3.48 - 3.39 (m, 2 H), 3.09 (s, 3H), 2.24 - 2.15 (m, 1H), 2.10 - 2.03 (m, 1H), 1.49 (s, 9H); m/z ES+ [M-56+H]⁺ 292.1. [0420] Step 2. Synthesis of tert-Butyl (3S)-3-[(5-amino-6-carbamoyl-2-pyridyl)-methyl- amino]pyrrolidine-1-carboxylate [0421] To a solution of tert-butyl (3S)-3-[(6-cyano-5-nitro-2-pyridyl)-methyl-amino]pyrrolidine- 1-carboxylate (5 g, 14.4 mmol) in ethanol (100 mL) and water (10 mL) was added calcium chloride (2.40 g, 21.6 mmol) and iron powder (8.04 g, 144 mmol).The mixture was stirred at 90 °C for 4 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[(5-amino-6-carbamoyl-2-pyridyl)-methyl-amino]pyrrolidine-1- carboxylate (4.8 g, crude) as a yellow solid. m/z ES+ [M-56+H]⁺ 336.2. [0422] Step 3. Synthesis of tert-Butyl (3S)-3-[(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-methyl- amino]pyrrolidine-1-carboxylate [0423] To a solution of tert-butyl (3S)-3-[(5-amino-6-carbamoyl-2-pyridyl)-methyl- amino]pyrrolidine-1-carboxylate (4.8 g, 14.31 mmol) in triethyl orthoformate (30 mL). The mixture was stirred at 140 °C for 12 hr. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[(4-hydroxypyrido[3,2-d]pyrimidin- 6-yl)-methyl-amino]pyrrolidine-1-carboxylate (5 g, crude) as a yellow solid. m/z ES+ [M+H]⁺ 346.2. [0424] Step 4. Synthesis of tert-Butyl (3S)-3-[(4-chloropyrido[3,2-d]pyrimidin-6-yl)-methyl- amino]pyrrolidine-1-carboxylate [0425] To a solution of tert-butyl (3S)-3-[(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-methyl- amino]pyrrolidine-1-carboxylate (3 g, 8.69 mmol) in toluene (50 mL) was added diisopropylethylamine (5.61 g, 43.4 mmol) and phosphorus oxychloride (1.73 g, 11.3 mmol). The mixture was stirred at 110 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=20/1 to 1/1) to give tert-butyl (3S)-3-[(4-chloropyrido[3,2-d]pyrimidin-6-yl)- methyl-amino]pyrrolidine-1-carboxylate (1 g, 2.47 mmol, 28%) as a yellow solid. m/z ES+ [M+H]⁺ 364.3. Aniline-1: Synthesis of 1-(3-Chloro-2-fluorophenyl)ethanamine (IA-1) Aniline-1p: Synthesis of N-(1-(3-Chloro-2-fluorophenyl) ethyl)-2-methylpropane-2-sulfinamide

[0426] Step 1. Synthesis of N-(1-(3-Chloro-2-fluorophenyl)ethylidene)-2-methylpropane-2- sulfinamide [0427] To a solution of 1-(3-chloro-2-fluoro-phenyl)ethanone (5 g, 29 mmol) in tetrahydrofuran (50 mL) was added tetraethoxytitanium (16.5 g, 72.4 mmol) and 2-methylpropane-2-sulfinamide (5.27 g, 43.5 mmol). The mixture was stirred at 70 °C for 12 hr. On completion, the mixture was cooled to 0 °C. Then ethyl acetate (5 mL), saturated sodium bicarbonate solution (1 mL) and brine (1 mL) were added sequentially into the mixture. The mixture was dried over anhydrous sodium sulphate, filtrated and concentrated in vacuo to give N-(1-(3-chloro-2-fluorophenyl)ethylidene)-2- methylpropane-2-sulfinamide (9 g, crude) as a yellow oil. m/z ES+ [ ⁺

275.8. [0428] Step 2. Synthesis of N-(1-(3-Chloro-2-fluorophenyl)ethyl)-2-methylpropane-2- sulfinamide [0429] To a solution of diisobutylaluminum hydride (1 M in toluene, 60.9 mL) in toluene (40 mL) was added a solution of N-[1-(3-chloro-2-fluoro-phenyl)ethylidene]-2-methyl-propane-2- sulfinamide (4.2 g, 15.2 mmol) in toluene (40 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hr. On completion, the mixture was carefully quenched by methanol (100 mL) at -78 °C. The mixture was then warmed to 15 °C and filtered. The filtrate was concentrated in vacuo to give N-(1-(3-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3.9 g, crude) as a yellow oil. m/z ES+ [M+H]⁺ 278.1. [0430] Step 3. Synthesis of 1-(3-Chloro-2-fluorophenyl)ethanamine [0431] To a solution of N-[1-(3-chloro-2-fluoro-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (0.25 g, 900 μmol) in methanol (3 mL) was added HCl/dioxane (4 M, 675 μL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA conditions) to give 1-(3-chloro-2- fluorophenyl)ethanamine (0.1 g, 450 μmol, 51%, FA salt) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.65 (s, 2H), 7.70 - 7.60 (m, 2H), 7.40 - 7.30 (m, 1H), 4.69 - 4.56 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H). Example 1. Synthesis of 1-((S)-3-((4-(((S)-1-(3-chloro-2 fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (Compound 2)

[0432] Step 1. Synthesis of (S)-1-(3-Chloro-2-fluorophenyl) ethanamine [0433] To a solution of N-[1-(3-chloro-2-fluoro-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (3.9 g, 14 mmol) in methanol (40 mL) was added hydrochloric acid in 1,4-dioxane (4 M, 10.5 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to give a crude product. The residue was purified by reversed-phase HPLC (NH₃ water conditions) and then separated by SFC (column: Daicel ChiralPak IG (250x30mm, 10 um); mobile phase: [0.1% NH₃water-MeOH]; B%: 15%-15%, 2.5; 410 min), which was further separated by SFC (column: DAICEL CHIRALPAK IG (250x30 mm, 10 um); mobile phase: [0.1% NH₃water methanol]; B%: 15%-15%, 2.6; 150 min) and SFC (column: Daicel ChiralPak IG (250x30 mm, 10 um); mobile phase: [0.1% NH₃water methanol]; B%: 15%-15%, 2.9; 80 min) to give (S)-1-(3-chloro- 2-fluorophenyl)ethanamine (120 mg, 0.69 mmol, 5%, Rt = 0.939 min) as a colorless oil and (R)- 1-(3-chloro-2-fluorophenyl) ethanamine (90 mg, 0.52 mmol, 4%, Rt = 1.031 min) as a colorless oil. m/z ES+ [M-14]⁺ 159.2; m/z ES+ [M-16]⁺ 157.1. [0434] Step 2. Synthesis of N-((S)-1-(3-Chloro-2-fluorophenyl) ethyl)-6-((S)-pyrrolidin-3- yloxy) pyrido [3,2-d]pyrimidin-4-amine [0435] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (0.18 g, 513 μmol) in acetonitrile (2 mL) was added (1S)-1-(3-chloro-2-fluoro- phenyl)ethanamine (107 mg, 616 μmol) and triethylamine (104 mg, 1.03 mmol). The mixture was stirred at 80 °C for 12 hr. The mixture was purified by reverse-phase HPLC (0.1% FA conditions) to give N-((S)-1-(3-chloro-2-fluorophenyl)ethyl)-6-((S)-pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (0.11 g, 0.23 mmol, 44%) as a yellow solid. m/z ES+ [M+H]⁺ 488.2. [0436] Step 3. Synthesis of N-((S)-1-(3-Chloro-2-fluorophenyl)ethyl)-6-((S)-pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0437] To a solution of tert-butyl (3S)-3-[4-[[(1S)-1-(3-chloro-2-fluoro- phenyl)ethyl]amino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (110 mg, 225 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.4 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to give

- chloro-2-fluorophenyl)ethyl)-6-((S)-pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (110 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H]⁺ 388.1. [0438] Step 4. Synthesis of 1-((S)-3-((4-(((S)-1-(3-Chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0439] To a solution of N-[(1S)-1-(3-chloro-2-fluoro-phenyl)ethyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (110 mg, 219 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (73.7 mg, 877 μmol) and prop-2-enoyl chloride (15.9 mg, 175 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a crude product. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mm, 5 um; mobile phase: [water (10 mM NH₄HCO₃)- acetonitrile]; B%: 39%-69%, 8 min) to give 1-((S)-3-((4-(((S)-1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (26.1 mg, 59.2 μmol, 27%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J = 2.0 Hz, 1H), 8.12 (t, J = 6.8 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.58 - 7.41 (m, 2H), 7.32 (dd, J = 2.8, 9.2 Hz, 1H), 7.20 (q, J = 7.6 Hz, 1H), 6.73 - 6.51 (m, 1H), 6.26 - 6.05 (m, 2H), 5.85 - 5.61 (m, 2H), 4.12 - 3.76 (m, 2H), 3.75 - 3.47 (m, 2H), 2.44 - 2.11 (m, 2H), 1.65 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H]⁺ 442.1. Example 2. Synthesis of 1-((S)-3-((4-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (Compound 1)

[0440] Step 1. Synthesis of (S)-tert-Butyl 3-((4-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0441] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (0.13 g, 371 μmol) in acetonitrile (2 mL) was added (1R)-1-(3-chloro-2-fluoro- phenyl)ethanamine (77.2 mg, 445 μmol) and triethylamine (75 mg, 741 μmol). The mixture was stirred at 80 °C for 12 hr. The mixture was purified by reverse-phase HPLC (0.1% FA conditions) to give (S)-tert-butyl 3-((4-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (90 mg, 0.18 mmol, 50%) as a yellow solid. m/z ES+ [M+H]⁺ 488.2. [0442] Step 2. Synthesis of N-((R)-1-(3-Chloro-2-fluorophenyl)ethyl)-6-((S)-pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0443] To a solution of (S)-tert-butyl 3-((4-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (86 mg, 176 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to give N-((R)- 1-(3-chloro-2-fluorophenyl)ethyl)-6-((S)-pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (90 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H]⁺ 388.1. [0444] Step 3. Synthesis of 1-((S)-3-((4-(((R)-1-(3-Chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy) pyrrolidin-1-yl)prop-2-en-1-one [0445] To a solution of N-[(1R)-1-(3-chloro-2-fluoro-phenyl)ethyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (88 mg, 175 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (58.9 mg, 701 μmol) and prop-2-enoyl chloride (12.7 mg, 140 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30 mm, 3 μm; mobile phase: [water (10 mM NH₄HCO₃)- acetonitrile]; B%: 30%-60%, 8 min) to give 1-((S)-3-((4-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (12.9 mg, 29.3 μmol, 17%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.18 - 8.09 (m, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (dd, J = 4.0, 9.2 Hz, 1H), 7.24 - 7.14 (m, 1H), 6.73 - 6.51 (m, 1H), 6.24 - 6.02 (m, 2H), 5.83 - 5.60 (m, 2H), 4.12 - 3.75 (m, 2H), 3.74 - 3.47 (m, 2H), 2.44 - 2.14 (m, 2H), 1.65 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]⁺ 442.1. Example 3. Preparation of 1-((3S)-3-((4-((1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (Compound 11)

[0446] Step 1. (3S)-tert-Butyl 3-((4-((1-(3-chloro-2-fluorophenyl)ethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0447] To a solution of tert-butyl (3S)-3-(4-chloropyrido [3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (0.15 g, 428 μmol) in acetonitrile (0.5 mL) was added 1-(3-chloro-2-fluoro- phenyl)ethanamine (93.9 mg, 428 μmol, formic acid salt). The mixture was stirred at 60 °C for 12 hr. The mixture was poured into water (30 mL) and then extracted with ethyl acetate (30 mL x 2). The organic layers were dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to give (3S)- tert-butyl 3-((4-((1-(3-chloro-2-fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (90 mg, 0.18 mmol, 30%) as a yellow solid. m/z ES+ [M+H]⁺ 488.1. [0448] Step 2. Synthesis of N-(1-(3-Chloro-2-fluorophenyl)ethyl)-6-((S)-pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0449] To a solution of (3S)-tert-butyl 3-((4-((1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (80 mg, 164 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.7 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to give N-(1-(3- chloro-2-fluorophenyl)ethyl)-6-((S)-pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (90 mg, crude, trifluoroacetic acid salt) as a yellow oil. m/z ES+ [M+H]⁺ 388.1. [0450] Step 3. Synthesis of 1-((3S)-3-((4-((1-(3-Chloro-2-fluorophenyl)ethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0451] To a solution of N-[1-(3-chloro-2-fluoro-phenyl)ethyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (80 mg, 159 μmol, trifluoroacetic acid) in tetrahydrofuran (1 mL) and water (1 mL) was added sodium bicarbonate (53.6 mg, 638 μmol) and prop-2-enoyl chloride (7.21 mg, 79.7 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875x30mm, 3 μm; mobile phase: [water (10 mM NH₄HCO₃)- acetonitrile]; B%: 30%-60%, 8 min) to give 1-((3S)-3-((4-((1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (20.9 mg, 47.4 μmol, 30%) as an off-white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.41 - 8.34 (m, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.49 - 7.33 (m, 2H), 7.30 (dd, J = 2.8, 9.2 Hz, 1H), 7.20 - 7.07 (m, 1H), 6.75 - 6.52 (m, 1H), 6.36 - 6.23 (m, 1H), 6.17 - 5.99 (m, 1H), 5.84 - 5.69 (m, 2H), 4.22 - 4.03 (m, 0.5H), 3.97 - 3.88 (m, 2H), 3.87 - 3.78 (m, 1H), 3.77 - 3.61 (m, 0.5H), 2.47 - 2.31 (m, 2H), 1.74 - 1.69 (m, 3H); m/z ES+ [M+H]⁺ 442.1. Example 4. Preparation of 1-((3S)-3-((4-((1-(3-chloro-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (Compound 9)

[0452] Step 1. Synthesis of 6-Chloro-N-[1-(3-chloro-2-fluoro-phenyl)ethyl]pyrido[3,2- d]pyrimidin-4-amine [0453] To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (0.6 g, 3.00 mmol) in acetonitrile (6 mL) was added triethylamine (607 mg, 6.00 mmol) and 1-(3-chloro-2-fluoro- phenyl)ethanamine (573 mg, 3.30 mmol). The mixture was stirred at 80 °C for 12 hr. The mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% NH₃•H₂O conditions) to afford 6-chloro-N-[1-(3-chloro-2-fluoro- phenyl)ethyl]pyrido[3,2-d]pyrimidin-4-amine (0.8 g, 2.25 mmol, 75%) as a black oil. m/z ES+ [M+H]⁺ 337.0. [0454] Step 2. Synthesis tert-Butyl N-[1-[4-[1-(3-chloro-2-fluoro- phenyl)ethylamino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]carbamate [0455] To a solution of 6-chloro-N-[1-(3-chloro-2-fluoro-phenyl)ethyl]pyrido[3,2-d]pyrimidin- 4- amine (200 mg, 0.60 mmol) and tert-butyl N-(azetidin-3-yl)carbamate (0.12 g, 0.6 mmol) in N-methyl pyrrolidone (2 mL) was added diisopropylethylamine (0.15 g, 1.19 mmol). The reaction mixture was stirred at 100 °C for 12 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 54%-84%, 9 min) to give tert-butyl N-[1-[4-[1-(3-chloro-2-fluoro- phenyl)ethylamino]pyrido[3,2-d]pyrimidin-6-yl]azetidin-3-yl]carbamate (80 mg, 0.17 mmol, 29%) as a white solid. m/z ES+ [M+H]⁺ 473.1. [0456] Step 3. Synthesis of 6-(3-Aminoazetidin-1-yl)-N-(1-(3-chloro-2- fluorophenyl)ethyl)pyrido[3,2-d]pyrimidin-4-amine [0457] To a solution of tert-butyl N-[1-[4-[1-(3-chloro-2-fluoro-phenyl)ethylamino]pyrido[3,2- d] pyrimidin-6-yl]azetidin-3-yl]carbamate (80 mg, 0.17 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated under reduced pressure to give 6-(3-aminoazetidin-1-yl)- N-(1-(3-chloro-2-fluorophenyl)ethyl)pyrido[3,2-d]pyrimidin-4-amine (80 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H]⁺ 373.1. [0458] Step 4. Synthesis of N-[1-[4-[1-(3-chloro-2-fluoro-phenyl) ethylamino]pyrido[3,2-d] pyrimidin-6-yl]azetidin-3-yl]prop-2-enamide [0459] To a solution of 6-(3-aminoazetidin-1-yl)-N-[1-(3-chloro-2-fluoro- phenyl)ethyl]pyrido[3,2-d] pyrimidin-4-amine (80 mg, 0.21 mmol) and sodium bicarbonate (54 mg, 0.64 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added prop-2-enoyl chloride (11.7 mg, 0.13 mmol). The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm, 5μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 36%-66%, 9 min) to give N-[1-[4-[1-(3-chloro-2-fluoro-phenyl) ethylamino]pyrido[3,2-d] pyrimidin-6-yl]azetidin-3-yl]prop-2-enamide (24.7 mg, 57.9 μmol, 26%) as a white solid ¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.15 - 7.07 (m, 1H), 7.01 (d, J = 9.2 Hz, 1H), 6.31 - 6.25 (m, 2H), 5.74 - 5.69 (m, 1H), 5.69 - 5.63 (m, 1H), 4.82 - 4.72 (m, 1H), 4.54 (dt, J = 3.6, 8.4 Hz, 2H), 4.08 (td, J = 4.8, 8.8 Hz, 2H), 1.68 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]⁺ 409.5. Example 5. Preparation of 1-[(3S)-3-[[4-[(2-methoxy-1-phenyl-ethyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-methyl -amino]pyrrolidin-1-yl]prop-2-en-1-one (Compound 26)

[0460] Step 1. Synthesis of tert-Butyl (3S)-3-[[4-[(2-methoxy-1-phenyl- ethyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-methyl-amino] pyrrolidine-1-carboxylate [0461] A solution of tert-butyl (3S)-3-[(4-chloropyrido[3,2-d]pyrimidin-6-yl)-methyl-amino] pyrrolidine-1-carboxylate (150 mg, 412 μmol), 2-methoxy-1-phenyl-ethanamine (93.5 mg, 618 μmol) in acetonitrile (2.0 mL) was stirred at 80 °C for 16 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (SiO₂, ethyl acetate:ethanol=10:1) to give tert-butyl (3S)-3-[[4-[(2-methoxy-1-phenyl- ethyl)amino]pyrido[3,2-d]pyrimidin-6-yl]-methyl-amino] pyrrolidine-1-carboxylate (130 mg, 0.27 mmol, 58%) as an off-white solid. m/z ES+ [M+H]⁺ 479.3. [0462] Step 2. Synthesis of N4-(2-methoxy-1-phenyl-ethyl)-N6-methyl-N6- [(3S)-pyrrolidin-3- yl]pyrido[3,2-d]pyrimidine-4,6-diamine [0463] A solution of tert-butyl (3S)-3-[[4-[(2-methoxy-1-phenyl-ethyl)amino]pyrido[3,2-d] pyrimidin-6-yl]-methyl-amino]pyrrolidine-1-carboxylate (100 mg, 209 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N4-(2-methoxy-1-phenyl-ethyl)-N6-methyl- N6-[(3S)-pyrrolidin-3-yl]pyrido[3,2-d]pyrimidine-4,6-diamine (100 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H]⁺ 379.3. [0464] Step 3. Synthesis of 1-[(3S)-3-[[4-[(2-methoxy-1-phenyl-ethyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-methyl -amino]pyrrolidin-1-yl]prop-2-en-1-one [0465] To a solution of N4-(2-methoxy-1-phenyl-ethyl)-N6-methyl-N6-[(3S)-pyrrolidin-3-yl] pyrido[3,2-d]pyrimidine-4,6-diamine (100 mg, 264 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (22.2 mg, 264.2 μmol). The mixture was added prop-2- enoyl chloride (23.9 mg, 264 μmol) and stirred at 0 °C for 1.5 hour. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150x25mm, 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 10 min) to give 1-[(3S)-3-[[4-[(2-methoxy-1-phenyl-ethyl)amino]pyrido[3,2- d]pyrimidin-6-yl]-methyl-amino]pyrrolidin-1-yl]prop-2-en-1-one (20.2 mg, 46.8 μmol, 18%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.73 (dd, J = 8.4, 10.8 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.36 - 7.28 (m, 2H), 7.28 - 7.21 (m, 1H), 6.64 (dt, J = 10.4, 16.8 Hz, 1H), 6.26 - 6.11 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 13.2 Hz, 1H), 5.58 - 5.47 (m, 1H), 5.46 - 5.28 (m, 1H), 4.00 - 3.82 (m, 2H), 3.80 - 3.54 (m, 3H), 3.47 - 3.40 (m, 1H), 3.32 - 3.28 (m, 3H), 3.10 (dd, J = 2.4, 6.8 Hz, 3H), 2.27 - 2.19 (m, 1H), 2.18 - 2.09 (m, 1H); m/z ES+ [M+H]⁺ 433.3. Example 6. Preparation of (S)-1-(3-((4-((3-chloro-2-fluorobenzyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0466] Step 1. tert-Butyl (S)-3-((4-((3-chloro-2-fluorobenzyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate [0467] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (150 mg, 427 μmol) and (3-chloro-2-fluoro-phenyl)methanamine (71.6 mg, 448 μmol) in acetonitrile (3.0 mL) was added diisopropylethylamine (276 mg, 2.14 mmol), the reaction mixture was stirred at 80 °C for 12 hr. On completion, the reaction mixture was partitioned between ethyl acetate (30.0 mL) and water (20.0 mL). The organic phase was separated, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 50/1) to give tert-butyl (3S)-3-[4-[(3-chloro-2-fluoro-phenyl)methylamino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate (120 mg, 253 μmol, 59%) as a yellow solid. m/z ES+[M+H]⁺ 474.3. [0468] Step 2. (S)-N-(3-Chloro-2-fluorobenzyl)-6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin- 4-amine [0469] To a mixture of tert-butyl (3S)-3-[4-[(3-chloro-2-fluoro- phenyl)methylamino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (120 mg, 253 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-[(3-chloro-2-fluoro-phenyl)methyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 214 μmol, 84%) as a yellow oil without purification. m/z ES+[M+H]⁺ 374.1. [0470] Step 3. (S)-1-(3-((4-((3-Chloro-2-fluorobenzyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0471] To a mixture of N-[(3-chloro-2-fluoro-phenyl)methyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (80.0 mg, 214 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (17.9 mg, 214 μmol) at 0 °C to pH = 7. Then prop-2-enoyl chloride (19.3 mg, 214 μmol) was added and the reaction mixture was stirred at 0 °C for 30 mins. On completion, the reaction mixture was partitioned between ethyl acetate (30.0 mL) and water (20.0 mL). The organic phase was separated, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25mm, 10 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 16% - 46%, 10 min) to give 1- [(3S)-3-[4-[(3-chloro-2-fluoro-phenyl)methylamino]pyrido[3,2-d]pyramidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (90.0 mg, 206 μmol, 96%) as a yellow solid. ¹H NMR (400 MHz, DMSO- d₆) δ 8.75 - 8.60 (m, 1H), 8.39 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.39 - 7.25 (m, 2H), 7.21 - 7.12 (m, 1H), 6.72 - 6.51 (m, 1H), 6.20 - 6.12 (m, 1H), 6.09 - 5.88 (m, 1H), 5.75 - 5.60 (m, 1H), 4.86 (br d, J = 6.4 Hz, 2H), 4.12 - 3.74 (m, 2H), 3.71 - 3.51 (m, 2H), 2.42 - 2.08 (m, 2H); m/z ES+[M+H]⁺ 428.0. Example 7. Preparation of 1-[(S)-3-((4-(((S)-1-phenylethyl)amino]pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0472] Step 1. tert-Butyl (S)-3-((4-(((S)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate [0473] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (200 mg, 570 μmol) in acetonitrile (3.0 mL) was added (1S)-1-phenylethanamine (69.1 mg, 570 μmol) and triethylamine (115 mg, 1.14 mmol). The mixture was stirred at 60 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (water : acetonitrile =20:1 to 1:1) to give tert-butyl (S)-3-((4-(((S)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (50 mg, 114 μmol, 20%) as a yellow solid. m/z ES+ [M+H]⁺ 436.3. [0474] Step 2. N-((S)-1-Phenylethyl)-6-(((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4- amine [0475] To a solution of tert-butyl (S)-3-((4-(((S)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)oxy)pyrrolidine-1-carboxylate (50 mg, 115 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated under reduced pressure to give N-((S)-1-phenylethyl)- 6-(((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (50 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H]⁺ 336.4. [0476] Step 3. 1-((S)-3-((4-(((S)-1-Phenylethyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0477] To a solution of 6-(3-aminoazetidin-1-yl)-N-(3-chloro-4-ethoxy-2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 298 μmol, TFA salt) in tetrahydrofuran (2 mL) and water (1 mL) was added potassium carbonate (41.2 mg, 298 μmol) and prop-2-enoyl chloride (27.0 mg, 298 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water(FA)- acetonitrile]; B%: 20%-50%, 10 min) to give 1-((S)-3-((4-(((S)-1-phenylethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (14.0 mg, 31.7 μmol, 10%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.09 – 7.96 (m, 2H), 7.49 – 7.47 (m, 2H), 7.36 – 7.33 (m, 3H), 7.31 (t, J = 3.2 Hz, 1H), 6.69 – 6.53 (m, 1H), 6.22 - 6.03 (m, 2H), 5.75 – 5.64 (m, 1H), 5.63 – 5.54 (m, 1H), 4.08 – 3.78 (m, 2H), 3.72 – 3.48 (m, 2H), 2.39 – 2.27 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]⁺ 390.0. Example 8. Preparation of 1-((S)-3-((4-(((R)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0478] Step 1. tert-Butyl (S)-3-((4-(((R)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate [0479] To a solution of tert-butyl (S)-3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (200 mg, 570 μmol) in acetonitrile (3 mL) was added (1R)-1-phenylethanamine (69.1 mg, 570 μmol) and triethylamine (115 mg, 1.14 mmol). The mixture was stirred at 60 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (water: acetonitrile =20:1 to 1:1) to give tert-butyl (S)-3-((4-(((R)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (90 mg, 205 μmol, 35%) as a yellow solid. m/z ES+ [M+H]⁺ 436.3. [0480] Step 2. N-((R)-1-phenylethyl)-6-(((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4- amine [0481] To a solution of tert-butyl (S)-3-((4-(((R)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)oxy)pyrrolidine-1-carboxylate (90 mg, 206 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated under reduced pressure to give N-((R)-1-phenylethyl)- 6-(((S)-pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (90 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H]⁺ 336.4. [0482] Step 3. 1-((S)-3-((4-(((R)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0483] To a solution of N-((R)-1-phenylethyl)-6-(((S)-pyrrolidin-3-yl)oxy)pyrido[3,2- d]pyrimidin-4-amine (90 mg, 200 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (27.7 mg, 200 μmol) and prop-2-enoyl chloride (18.1 mg, 200 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm, 3 um; mobile phase: [water(FA)- acetonitrile]; B%: 15%-45%, 10 min) to give 1-((S)-3-((4-(((R)-1-phenylethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one (31.1 mg, 79.2 μmol, 39%) as a yellow solid. ¹H NMR (400 MHz, DMSO- d₆) δ 8.37 (s, 1H), 8.08 - 7.98 (m, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.37 - 7.28 (m, 3H), 7.27 - 7.19 (m, 1H), 6.71 - 6.54 (m, 1H), 6.21 - 6.01 (m, 2H), 5.69 – 5.65 (m, 1H), 5.61 - 5.52 (m, 1H), 4.10 - 3.76 (m, 2H), 3.75 - 3.61 (m, 2H), 2.42 - 2.10 (m, 2H), 1.65 (d, J = 7.2 Hz, 3H); m/z ES+ [M+H]⁺ 390.0.

Example 9. Preparation of 1-((S)-3-((4-((S)-1-(3-chloro-2-fluorophenyl)ethoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0484] Step 1. 1-(3-Chloro-2-fluorophenyl)ethan-1-ol [0485] To a solution of 1-(3-chloro-2-fluoro-phenyl)ethanone (500 mg, 2.90 mmol) in methanol (15 mL) was added sodium borohydride (131 mg, 3.48 mmol). The mixture was stirred at 25 °C for 1 h. On completed, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried by sodium sulfate, filtered and concentrated in vacuo to give 1-(3-chloro-2-fluoro-phenyl)ethanol (430 mg, 2.46 mmol, 76%) as a white oil.¹H NMR (400 MHz, CDCl₃) δ 7.38 - 7.31 (m, 1H), 7.27 - 7.20 (m, 1H), 7.09 - 6.96 (m, 1H), 5.14 (q, J = 6.4 Hz, 1H), 1.45 (s, 3H). [0486] Step 2. tert-Butyl (3S)-3-((4-(1-(3-chloro-2-fluorophenyl)ethoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0487] To a solution of 1-(3-chloro-2-fluoro-phenyl) ethanol (388 mg, 2.22 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (205 mg, 5.13 mmol, 60% in mineral oil). The mixture was stirred at 0 °C for 0.5 hrs. Then tert-butyl (3S)-3-(4-chloropyrido [3, 2- d]pyrimidin-6-yl)oxypyrro lidine-1-carboxy late (600 mg, 1.71 mmol) was added, and the mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried by sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (3S)-3-[4-[1-(3-chloro-2-fluoro- phenyl)ethoxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (800 mg, 1.64 mmol, 85%) as a yellow solid. m/z ES+ [M+H]⁺ 489.2. [0488] Step 3. tert-Butyl (S)-3-((4-((S)-1-(3-chloro-2-fluorophenyl)ethoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate & tert-butyl (S)-3-((4-((R)-1-(3-chloro-2- fluorophenyl)ethoxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0489] tert-Butyl (3S)-3-[4-[1-(3-chloro-2-fluoro-phenyl)ethoxy]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (800 mg, 1.47 mmol) was separated by SFC ( column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 7%-7%, 2.5; 80min) to give tert-butyl (3S)-3-[4-[(1S)-1-(3-chloro-2-fluoro- phenyl)ethoxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (250 mg, 511 μmol, 29%) as a white solid ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.47 (d, J = 9.2 Hz, 1H), 7.32 - 7.16 (m, 1H), 6.67 (br. d, J = 6.4 Hz, 1H), 5.68 (s, 1H), 3.85 - 3.38 (m, 4H), 2.26 - 2.12 (m, 2H), 1.75 (d, J = 6.4 Hz, 3H), 1.47 - 1.32 (m, 9H); m/z ES+ [M+H]⁺ 489.3; and tert-butyl (S)-3-((4-((R)-1-(3-chloro-2- fluorophenyl)ethoxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (200 mg, 409 μmol, 23%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.47 (d, J = 9.2 Hz, 1H), 7.32 - 7.16 (m, 1H), 6.67 (br. d, J = 6.4 Hz, 1H), 5.68 (s, 1H), 3.85 - 3.38 (m, 4H), 2.26 - 2.12 (m, 2H), 1.75 (d, J = 6.4 Hz, 3H), 1.47 - 1.32 (m, 9H); m/z ES+ [M+H]⁺ 489.4. [0490] Step 4. 4-((S)-1-(3-chloro-2-fluorophenyl)ethoxy)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidine [0491] To a solution of tert-butyl (3S)-3-[4-[(1S)-1-(3-chloro-2-fluoro- phenyl)ethoxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 306 μmol) in dichloromethane (0.5 mL) was added zinc bromide (207 mg, 920 μmol). The mixture was stirred at 25 °C for 36 hrs. The mixture was poured into the water (10 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried by sodium sulfate, filtered and concentrated in vacuo to give 4-[(1S)-1-(3-chloro-2 -fluoro-phenyl)ethoxy]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidine (60.0 mg, crude) as a white solid. m/z ES+ [M+H]⁺ 389.2. [0492] Step 5. 1-((S)-3-((4-((S)-1-(3-chloro-2-fluorophenyl)ethoxy)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0493] To a solution of 4-[(1S)-1-(3-chloro-2-fluoro-phenyl)ethoxy]-6-[(3S)-pyrrolidin-3-yl] oxy-pyrido[3,2-d]pyrimidine (60.0 mg, 154 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (38.8 mg, 462 μmol) to adjusted pH = 8 at 0 C. Then prop- 2-enoyl chloride (20.9 mg, 231 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered, concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10 um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 22%-52%, 11 min) to give 1-[(3S)-3- [4-[(1S)-1-(3-chloro-2-fluoro-phenyl)ethoxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (3.49 mg, 7.88 μmol, 4.9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J = 5.6 Hz, 1H), 8.04 (dd, J = 1.2, 8.8 Hz, 1H), 7.64 - 7.51 (m, 2H), 7.36 - 7.23 (m, 2H), 6.71 - 6.47 (m, 1H), 6.23 - 6.10 (m, 2H), 5.81 - 5.60 (m, 2H), 4.04 - 3.72 (m, 2H), 3.69 - 3.46 (m, 2H), 2.28 - 2.19 (m, 2H), 1.87 (d, J = 7.6 Hz, 3H); m/z ES+ [M+H]⁺ 443.1. Example 10. Preparation of 1-((S)-3-((4-((R)-1-(3-chloro-2-fluorophenyl)ethoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0494] Step 1. 4-((R)-1-(3-Chloro-2-fluorophenyl)ethoxy)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidine [0495] To a solution of tert-butyl (3S)-3-[4-[(1R)-1-(3-chloro-2-fluoro-phenyl)ethoxy]pyrido [3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 306 μmol) in dichloromethane (0.5 mL) was added zinc bromide (207 mg, 920 μmol). The mixture was stirred at 25 °C for 36 hrs. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL). The organic layers were dried by sodium sulfate, filtered and concentrated in vacuo to give 4-[(1R)- 1-(3-chloro-2-fluoro-phenyl)ethoxy]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidine (40 mg, crude) as a white solid. m/z ES+ [M+H]⁺ 389.1 [0496] Step 2. 1-((S)-3-((4-((R)-1-(3-Chloro-2-fluorophenyl)ethoxy)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0497] To a solution of 4-[(1R)-1-(3-chloro-2-fluoro-phenyl)ethoxy]-6-[(3S)-pyrrolidin-3- yl]oxy- pyrido[3,2-d]pyrimidine (40.0 mg, 102 μmol) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (25.9 mg, 308 μmol) to adjust pH = 8 at 0 °C. Then prop-2- enoyl chloride (9.2 mg, 102 μmol) was added and the mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was filtered, concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( ammonium bicarbonate)- acetonitrile];B%: 22%-52%,11min) to give 1-[(3S)-3-[4-[(1R)- 1-(3-chloro-2-fluoro-phenyl)ethoxy]pyrido[3,2-d]pyrimidin-yl]oxypyrrolidin-1-yl]prop-2-en-1- one (2.05 mg, 4.63 μmol, 4.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J = 5.6 Hz, 1H), 8.04 (dd, J = 1.2, 8.8 Hz, 1H), 7.64 - 7.51 (m, 2H), 7.36 - 7.23 (m, 2H), 6.71 - 6.47 (m, 1H), 6.23 - 6.10 (m, 2H), 5.81 - 5.60 (m, 2H), 4.04 - 3.72 (m, 2H), 3.69 - 3.46 (m, 2H), 2.28 - 2.19 (m, 2H), 1.87 (d, J = 7.6 Hz, 3H); m/z ES+ [M+H]⁺ 443.1. Example 11. Preparation of 1-((S)-3-((4-((R)-1-(3-chloro-2-fluorophenyl)ethoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0498] Step 1. (S)-N-(3-Chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide [0499] To a solution of 3-chloro-2-fluoro-benzaldehyde (3.0 g, 18.9 mmol) in dichloromethane (30 mL) was added cesium carbonate (9.25 g, 28.4 mmol) and (S)-2-methylpropane-2- sulfinamide (2.29 g, 18.9 mmol). The mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 10/1) to give (S)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2- sulfinamide (4.40 g, 16.8 mmol, 88%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.95 (dt, J = 1.6, 7.2 Hz, 1H), 7.83 (dt, J = 1.6, 7.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 1.19 (s, 9H). [0500] Step 2. (S)-N-((R)-1-(3-Chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane- 2-sulfinamide [0501] To a solution of (S)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (2.00 g, 7.64 mmol) in N,N-dimethylformamide (20 mL) was added trimethyl(trifluoromethyl)silane (2.72 g, 19.1 mmol) and tetrabutylammonium acetate (2.30 g, 7.64 mmol). The mixture was stirred at 0 °C for 2 hrs. On completion, the reaction mixture was diluted with water 60 mL and extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (neutral condition; column: mobile phase; B%: 40%-70%, 11 min) to give (S)-N-((R)-1- (3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.63 mmol, 54%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.76 (t, J = 7.2 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.38 (dt, J = 0.8, 8.0 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 5.37 (quin, J = 8.4 Hz, 1H), 1.11 (s, 9H); m/z ES+ [M+H]⁺ 332.0. [0502] Step 3. (R)-1-(3-Chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-amine [0503] To a solution of (S)-N-((R)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-2- methylpropane-2-sulfinamide (400 mg, 1.21 mmol) in methanol (3.0 mL) was added hydrochloric acid /methanol (4 M, 1 mL). The mixture was stirred at 0 °C for 1 h. Then the reaction was stirred at 0 °C for 1 h. On completion, the reaction mixture was adjusted to pH = 8~9 with aqueous sodium bicarbonate, then diluted with water 10 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-1-(3-chloro-2-fluorophenyl)-2,2,2- trifluoroethanamine (300 mg, crude) as an orange oil. m/z ES+ [M+H]⁺ 228.0. [0504] Step 4. tert-Butyl (S)-3-((4-(((R)-1-(3-chloro-2-fluorophenyl)-2,2,2- trifluoroethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0505] To a solution of (S)-tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (150 mg, 428 μmol) in acetonitrile (1.0 mL) was added (R)-1-(3-chloro-2- fluorophenyl)-2,2,2-trifluoroethanamine (195 mg, 855 μmol). The mixture was stirred at 60 °C for 13 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% Formic acid condition, 85-90% acetonitrile, 3min) to give (S)-tert-butyl 3-((4-(((R)-1-(3-chloro-2-fluorophenyl)-2,2,2- trifluoroethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (170 mg, 251 μmol, 58%) as a yellow oil. m/z ES+ [M+H]⁺ 542.2. [0506] Step 5. N-((R)-1-(3-Chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [0507] A solution of (S)-tert-butyl 3-((4-(((R)-1-(3-chloro-2-fluorophenyl)-2,2,2- trifluoroethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (170 mg, 314 μmol) in dichloromethane (1.0 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give N-((R)-1-(3-chloro-2- fluorophenyl)-2,2,2-trifluoroethyl)-6-((S)-pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (138 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H]⁺ 442.1. [0508] Step 6. 1-((S)-3-((4-(((R)-1-(3-Chloro-2-fluorophenyl)-2,2,2- trifluoroethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0509] To a solution of N-((R)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-6-((S)- pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (138 mg, 312 μmol) in anhydrous tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (78.7 mg, 937 μmol). The mixture was added prop-2-enoyl chloride (28.8 mg, 312 μmol) and stirred at 0 °C for 10 min. Then the reaction was added prop-2-enoyl chloride (28.3 mg, 312 μmol) and stirred at 0 °C for another 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (Formic acid condition;column: Phenomenex Luna C18150 x 25 mm, 10 um; mobile phase: [water(FA)-ACN]; B%: 48%-78%, 10 min) to give 1-((S)-3-((4-(((R)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (39.4 mg, 79.4 μmol, 25%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.41 - 8.30 (m, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.03 (s, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.44 - 7.35 (m, 2H), 6.84 (t, J = 8.4 Hz, 1H), 6.70 - 6.45 (m, 1H), 6.22 - 6.06 (m, 2H), 5.74 - 5.59 (m, 1H), 4.11 - 3.77 (m, 2H), 3.75 - 3.49 (m, 2H), 2.43 - 2.16 (m, 2H); m/z ES+ [M+H]⁺ 495.9.

Example 12. Preparation of 1-((S)-3-((4-(((S)-1-(3-chloro-2-fluorophenyl)-2,2,2- trifluoroethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0510] Step 1. (R)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide [0511] To a solution of 3-chloro-2-fluoro-benzaldehyde (5.0 g, 31.5 mmol) in dichloromethane (50 mL) was added cesium carbonate (15.4 g, 47.3 mmol) and (R)-2-methylpropane-2- sulfinamide (3.82 g, 31.5 mmol). The mixture was stirred at 25 °C for 16 hrs. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1 to 5/1) to give (R)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (8.6 g, crude) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.99 - 7.92 (m, 1H), 7.84 (dt, J = 1.6, 7.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 1.19 (s, 9H). [0512] Step 2. (R)-N-((S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide [0513] To a solution of (R)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (2.70 g, 10.3 mmol) in N,N-dimethylformamide (15.0 mL) was added trimethyl(trifluoromethyl)silane (3.67 g, 25.8 mmol) and tetrabutylammonium acetate (3.11 g, 10.3 mmol). The mixture was stirred at 0 °C for 2 hrs. On completion, the reaction mixture was diluted with water 15 mL and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (neutral condition; column: Waters Xbridge C18150x 50 mm, 10 um; mobile phase: [water( ammonium bicarbonate)-acetonitrile] ;B%: 39%-69%, 11 min) to give (R)-N-((S)-1-(3- chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (430 mg, 1.30 mmol, 43%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 - 7.66 (m, 2H), 7.38 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 9.6 Hz, 1H), 5.37 (quin, J = 8.2 Hz, 1H), 1.12 (s, 9H). m/z ES+ [M+H]⁺ 332.1. [0514] Step 3. (S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethan-1-amine [0515] To a solution of (R)-N-((S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-2- methylpropane-2-sulfinamide (400 mg, 1.21 mmol) in methanol (3.0 mL) was added hydrochloric acid /methanol (4 M, 1 mL). The mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was adjusted to pH 8~9 with aqueous sodium bicarbonate, and then diluted with water 10 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethanamine (300 mg, crude) as a orange oil. m/z ES+ [M+H]⁺ 227.8. [0516] Step 4. tert-Butyl (S)-3-((4-(((S)-1-(3-chloro-2-fluorophenyl)-2,2,2- trifluoroethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0517] To a solution of (S)-tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (150 mg, 428 μmol) in acetonitrile (2.0 mL) was added (S)-1-(3-chloro-2- fluorophenyl)-2,2,2-trifluoroethanamine (146 mg, 641 μmol). The mixture was stirred at 60 °C for 1 h. Then the reaction was added (S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethanamine (146 mg, 641 μmol) and stirred at 60 °C for 2 hrs. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC ( 0.1% formic acid condition, 85%-90% acetonitrile, 3 min) to give (S)- tert-butyl 3-((4-(((S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 199 μmol, 46%) as a yellow oil. m/z ES+ [M+H]⁺ 541.9. [0518] Step 5. N-((S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [0519] A solution of (S)-tert-butyl 3-((4-(((S)-1-(3-chloro-2-fluorophenyl)-2,2,2- trifluoroethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 221 μmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1.0 mL) was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated in vacuo to give N-((S)-1-(3-chloro-2- fluorophenyl)-2,2,2-trifluoroethyl)-6-((S)-pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (98 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H]⁺ 442.0. [0520] Step 6. N-((S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [0521] To a solution of N-((S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)-6-((S)- pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (97.0 mg, 220 μmol) in anhydrous tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (55.3 mg, 659 μmol). The mixture was added prop-2-enoyl chloride (19.9 mg, 220 μmol) and stirred at 0 °C for 10 min. Then the reaction was added prop-2-enoyl chloride (9.94 mg, 110 μmol) and stirred at 0 °C for another 10 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)- acetonitrile];B%: 45%-75%,10min) to give 1-((S)-3-((4-(((S)-1-(3-chloro-2-fluorophenyl)-2,2,2-trifluoroethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (38.2 mg, 77.0 μmol, 35%) as an off- white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.37 (t, J = 10.4 Hz, 1H), 8.16 - 8.11 (m, 1H), 8.02 (s, 1H), 7.76 - 7.69 (m, 1H), 7.44 - 7.37 (m, 2H), 6.84 (quin, J = 8.4 Hz, 1H), 6.71 - 6.54 (m, 1H), 6.22 - 6.07 (m, 2H), 5.69 (ddd, J = 2.4, 10.4, 15.6 Hz, 1H), 4.10 - 3.77 (m, 2H), 3.75 - 3.47 (m, 2H), 2.42 - 2.10 (m, 2H); m/z ES+ [M+H]⁺ 495.9. Example 13. Preparation of (S)-1-(3-((4-((1-(3-chloro-2- fluorophenyl)cyclopropyl)amino)pyrido [3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0522] Step 1. tert-Butyl (S)-3-((4-((1-(3-chloro-2-fluorophenyl)cyclopropyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0523] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (200 mg, 570 μmol) in acetonitrile (3 mL) was added triethylamine (115 mg, 1.14 mmol) and 1-(3-chloro-2-fluoro-phenyl)cyclopropanamine (138 mg, 741 μmol). The mixture was stirred at 60 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (water: acetonitrile=20:1 to 1:1) to give tert-butyl (S)-3-((4-((1-(3-chloro-2-fluorophenyl)cyclopropyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (60 mg, 120 μmol, 21%) as a yellow solid. m/z ES+ [M+H]⁺ 500.2. [0524] Step 2. (S)-N-(1-(3-Chloro-2-fluorophenyl)cyclopropyl)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0525] To a solution of tert-butyl (S)-3-((4-((1-(3-chloro-2- fluorophenyl)cyclopropyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (60 mg, 120 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under reduced pressure to give (S)-N-(1-(3-chloro-2-fluorophenyl)cyclopropyl)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (60 mg, crude, TFA salt) as a yellow solid. m/z ES+ [M+H]⁺ 400.2. [0526] Step 3. (S)-N-(1-(3-Chloro-2-fluorophenyl)cyclopropyl)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0527] To a solution of (S)-N-(1-(3-chloro-2-fluorophenyl)cyclopropyl)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (60 mg, 117 μmol) in tetrahydrofuran (1 mL) and water (0.5 mL) was added potassium carbonate (16.1 mg, 116 μmol) and prop-2-enoyl chloride (10.6 mg, 116 μmol). The mixture was stirred at 0 °C for 0.2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10 um; mobile phase: [water(FA)-acetonitrile]; B%: 23%-53%, 10 min) to give (S)-1-(3-((4-((1-(3-chloro-2- fluorophenyl)cyclopropyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one (23.1 mg, 50.4 μmol, 43%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.47 - 8.37 (m, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.68 – 7.60 (m, 1H), 7.48 - 7.39 (m, 1H), 7.32 - 7.28 (m, 1H), 7.20 - 7.10 (m, 1H), 6.73 - 6.53 (m, 1H), 6.23 - 6.02 (m, 2H), 5.77 - 5.61 (m, 1H), 4.13 - 3.76 (m, 2H), 3.74 - 3.62 (m, 2H), 2.34 - 2.08 (m, 2H), 1.54 - 1.34 (m, 4H); m/z ES+ [M+H]⁺ 453.1. Example 14. Preparation of (S)-1-(3-((4-((2-(3-chloro-2-fluorophenyl)propan-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0528] Step 1. 2-(3-Chloro-2-fluorophenyl)propan-2-ol [0529] To a solution of ethyl 3-chloro-2-fluoro-benzoate (3.5 g, 17 mmol) in tetrahydrofuran (35 mL) was added methylmagnesium bromide (3 M in tetrahydrofuran, 29 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hrs. The mixture was quenched by aqueous ammonium chloride 10 mL. Then the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was concentrated in vacuo to give 2-(3-chloro-2- fluorophenyl)propan-2-ol (3.5 g, crude) as a colorless oil.¹H NMR (400 MHz, CD₃OD) δ 7.60 - 7.53 (m, 1H), 7.34 (ddd, J = 1.6, 6.4, 8.0 Hz, 1H), 7.12 (dt, J = 1.2, 8.0 Hz, 1H), 1.58 (d, J = 1.2 Hz, 6H). [0530] Step 2. 1-(2-Azidopropan-2-yl)-3-chloro-2-fluorobenzene [0531] To a solution of 2-(3-chloro-2-fluoro-phenyl)propan-2-ol (1 g, 5.3 mmol) in toluene (10 mL) was added azido(trimethyl)silane (1.2 g, 11 mmol) and boron trifluoride etherate (1.5 g, 11 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The mixture was quenched by aqueous ammonium chloride 30 mL. Then the mixture was poured into water 30 mL and extracted with ethyl acetate (60 mL x 2). The organic phase was concentrated in vacuo to give 1- (2-azidopropan-2-yl)-3-chloro-2-fluorobenzene (1 g, crude) as a colorless oil. [0532] Step 3. 2-(3-Chloro-2-fluorophenyl)propan-2-amine [0533] A solution of 1-(1-azido-1-methyl-ethyl)-3-chloro-2-fluoro-benzene (1 g, 4.7 mmol) in tetrahydrofuran (10 mL) was added dropwise into a mixture of lithium aluminum hydride (0.27 g, 7 mmol) in tetrahydrofuran (10 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The mixture was sequentially quenched by water (80 μL), 15% aqueous sodium hydroxide (80 μL) and water (0.24 mL). Then the mixture was directly dried by anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1 to dichloromethane/methanol=15:1) to give 2-(3-chloro-2-fluorophenyl)propan-2-amine (0.33 g, 1.76 mmol, 38%) as a colorless oil.¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 7.56 (ddd, J = 1.6, 7.2, 8.2 Hz, 1H), 7.41 (dt, J = 1.6, 7.6 Hz, 1H), 7.31 - 7.23 (m, 1H), 1.78 (s, 6H). [0534] Step 4. tert-Butyl (S)-3-((4-((2-(3-chloro-2-fluorophenyl)propan-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0535] A mixture of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1- carboxylate (0.1 g, 0.29 mmol) in acetonitrile (0.1 mL) was added 2-(3-chloro-2-fluoro- phenyl)propan-2-amine (64 mg, 0.34 mmol) and the mixture was stirred at 60 °C for 2 days. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in N,N- dimethylformamide (2.5 mL) and then filtered to remove the solid. The filtrate was purified by reversed-phase HPLC (0.1% formic acid condition) to give tert-butyl (S)-3-((4-((2-(3-chloro-2- fluorophenyl)propan-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (55 mg, 110 μmol, 38%) as a yellow solid. m/z ES+ [M+H]⁺ 502.2. [0536] Step 5. (S)-N-(2-(3-chloro-2-fluorophenyl)propan-2-yl)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine [0537] To a solution of tert-butyl (3S)-3-[4-[[1-(3-chloro-2-fluoro-phenyl)-1-methyl- ethyl]amino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (55 mg, 0.11 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.31 g, 2.7 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give (S)-N-(2-(3-chloro-2- fluorophenyl)propan-2-yl)-6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (60 mg, crude, TFA) as a yellow oil. m/z ES+ [M+H]⁺ 402.2. [0538] Step 6. (S)-1-(3-((4-((2-(3-chloro-2-fluorophenyl)propan-2-yl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0539] To a solution of N-[1-(3-chloro-2-fluoro-phenyl)-1-methyl-ethyl]-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (55 mg, 0.11 mmol) in tetrahydrofuran (0.25 mL) and water (0.25 mL) was added sodium bicarbonate (36 mg, 0.43 mmol) and prop-2-enoyl chloride (8.7 mg, 96 μmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 m, 5 um; mobile phase: [water ( ammonium bicarbonate)- acetonitrile]; B%: 46%-76%, 10 min) to give (S)-1-(3-((4-((2-(3-chloro-2-fluorophenyl)propan-2- yl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-pyrrolidin-1-yl)prop-2-en-1-one (16.7 mg, 36.5 μmol, 34%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.51 - 7.41 (m, 1H), 7.39 - 7.32 (m, 1H), 7.29 (dd, J = 1.6, 9.2 Hz, 1H), 7.18 - 7.05 (m, 1H), 6.75 - 6.56 (m, 1H), 6.37 - 6.24 (m, 1H), 6.01 - 5.87 (m, 1H), 5.77 (ddd, J = 1.6, 10.2, 12.4 Hz, 1H), 4.13 (dd, J = 4.4, 12.0 Hz, 1H), 4.01 - 3.90 (m, 2H), 3.89 - 3.78 (m, 1H), 3.68 (td, J = 8.8, 12.0 Hz, 1H), 2.51 - 2.42 (m, 1H), 2.41 - 2.34 (m, 1H), 2.00 (dd, J = 3.2, 9.2 Hz, 6H); m/z ES+ [M+H]⁺ 456.0. Example 15. Preparation of 1-((3S)-3-((4-((1-(3-chloro-2-fluorophenyl)-2- methoxyethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0540] Step 1. 2-Bromo-1-(3-chloro-2-fluorophenyl)ethan-1-one [0541] To a mixture of 1-(3-chloro-2-fluoro-phenyl)ethanone (3.50 g, 20.2 mmol) in dioxane (40 mL) was added bromine (3.89 g, 24.3 mmol) dropwise at 0 °C, and then the reaction mixture was stirred at 25 °C for 12 hr. On completion, the reaction mixture was partitioned between ethyl acetate (80 mL) and water (60 mL). The organic phase was separated, washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 2-bromo-1-(3-chloro-2-fluoro-phenyl)ethanone (5.00 g, 19.8 mmol, 98%) as a yellow oil without purification. ¹H NMR (400 MHz, CDCl₃) δ 7.88 - 7.75 (m, 1H), 7.70 - 7.58 (m, 1H), 7.26 - 7.18 (m, 1H), 4.50 (d, J = 2.4 Hz, 2H). [0542] Step 2. 1-(3-Chloro-2-fluorophenyl)-2-methoxyethan-1-one [0543] To a mixture of 2-bromo-1-(3-chloro-2-fluoro-phenyl)ethanone (5.00 g, 19.8 mmol) in methanol (100 mL) was added silver carbonate (6.03 g, 21.8 mmol) and boron trifluoride diethyl etherate (3.39 g, 23.8 mmol), the reaction mixture was stirred at 50 °C for 12 hr. On completion, the reaction mixture was partitioned between ethyl acetate (120 mL) and water (100 mL). The organic phase was separated, washed with brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=100/1 to 80/1) to give 1-(3-chloro-2-fluoro-phenyl)-2-methoxy-ethanone (2.50 g, 12.3 mmol, 62%) as a red oil.¹H NMR (400 MHz, CDCl₃) δ 7.92 - 7.81 (m, 1H), 7.67 - 7.57 (m, 1H), 7.22 (t, J = 7.6 Hz, 1H), 4.64 (d, J = 3.6 Hz, 2H), 3.52 (s, 3H). [0544] Step 3. 1-(3-Chloro-2-fluorophenyl)-2-methoxyethan-1-amine [0545] A solution of 1-(3-chloro-2-fluoro-phenyl)-2-methoxy-ethanone (500 mg, 2.47 mmol) and ammonium acetate (1.90 g, 24.6 mmol) in methanol (20 mL) was stirred at 25 °C for 0.5 hr, and then sodium cyanoborohydride (1.55 g, 24.6 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 1-(3-chloro-2-fluoro-phenyl)-2-methoxy-ethanamine (450 mg, 2.21 mmol, 89%) as a yellow oil without purification. m/z ES+[M+H]⁺ 204.1. [0546] Step 4. tert-Butyl (3S)-3-((4-((1-(3-chloro-2-fluorophenyl)-2- methoxyethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0547] A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1- carboxylate (387 mg, 1.10 mmol) and 1-(3-chloro-2-fluoro-phenyl)-2-methoxy-ethanamine (450 mg, 2.21 mmol) in acetonitrile (8.0 mL) was stirred at 80 °C for 12 hr. On completion, the reaction mixture was quenched by water (20 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether : ethyl acetate = 1:1) to give compound tert-butyl (3S)-3-[4-[[1-(3-chloro-2-fluoro-phenyl)-2-methoxy- ethyl]amino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (80.0 mg, 154 μmol, 13%) as a yellow solid. m/z ES+[M+H]⁺ 518.0. [0548] Step 5. N-(1-(3-chloro-2-fluorophenyl)-2-methoxyethyl)-6-(((S)-pyrrolidin-3- yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [0549] To a mixture of tert-butyl (3S)-3-[4-[[1-(3-chloro-2-fluoro-phenyl)-2-methoxy- ethyl]amin o]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (80.0 mg, 154 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol), the reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was concentrated in vacuo to give compound N-[1-(3-chloro-2-fluoro-phenyl)-2-methoxy-ethyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, crude) as a yellow oil. m/z ES+[M+H]⁺ 418.0. [0550] Step 6. 1-((3S)-3-((4-((1-(3-chloro-2-fluorophenyl)-2-methoxyethyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0551] To a mixture of N-[1-(3-chloro-2-fluoro-phenyl)-2-methoxy-ethyl]-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (50.0 mg, 119 μmol) in tetrahydrofuran (1.0 mL) and water (1.0 mL) was added sodium bicarbonate (10.0 mg, 119 μmol) at 0 °C to pH = 7~8, and then prop-2-enoyl chloride (10.8 mg, 119 μmol) was added. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water( NH₄HCO₃)-acetonitrile]; B%: 33%-63%, 9 min) to give compound1-[(3S)-3-[4-[[1-(3-chloro-2-fluoro-phenyl)-2-methoxy- ethyl]amino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (11.6 mg, 24.6 μmol, 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J = 2.8 Hz, 1H), 8.12 - 8.00 (m, 2H), 7.60 - 7.45 (m, 2H), 7.39 - 7.30 (m, 1H), 7.26 - 7.15 (m, 1H), 6.73 - 6.49 (m, 1H), 6.22 - 6.10 (m, 1H), 6.09 - 5.94 (m, 1H), 5.94 - 5.80 (m, 1H), 5.75 - 5.61 (m, 1H), 4.15 - 4.03 (m, 1H), 3.95 - 3.88 (m, 1H), 3.86 - 3.67 (m, 4H), 3.56 - 3.50 (m, 1H), 3.31 - 3.30 (m, 3H), 2.36 - 2.14 (m, 2H); m/z ES+[M+H]⁺ 471.9.

Example 16. Preparation of 1-((3S)-3-((4-((1-(3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one

[0552] Step 1. 1-(3-Chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)ethan-1-one [0553] To a solution of 1-(3-chloro-2-fluoro-4-hydroxy-phenyl)ethanone (500 mg, 2.65 mmol) in N,N-dimethylformamide (3.0 mL) was added potassium carbonate (1.10 g, 7.95 mmol) and bromomethylcyclopropane (715 mg, 5.30 mmol). The mixture was stirred at 80 °C for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo to give 1-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]ethanone (300 mg, 1.24 mmol, 40%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.89 - 7.72 (m, 1H), 6.77 (dd, J = 1.2, 9.2 Hz, 1H), 3.99 (d, J = 6.8 Hz, 2H), 2.63 (d, J = 5.6 Hz, 3H), 1.39 - 1.30 (m, 1H), 0.73 - 0.66 (m, 2H), 0.45 - 0.40 (m, 2H). [0554] Step 2. 1-(3-Chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)ethan-1-amine [0555] To a solution of 1-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]ethanone (300 mg, 1.24 mmol) in methanol (3.0 mL) was added ammoniom acetate (952 mg, 12.3 mmol) and sodium cyanoborohydride (93.2 mg, 1.48 mmol). The mixture was stirred at 25 °C for 4 hr. On completion, the mixture was purified by reversed-phase HPLC (0.1% formic acid condition) to give 1-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]ethanamine (200 mg, 0.82 mmol, 64%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.34 (br t, J = 8.4 Hz, 1H), 6.73 (br d, J = 8.8 Hz, 1H), 4.58 (br d, J = 6.8 Hz, 1H), 3.87 (br s, 2H), 1.60 (br d, J = 6.4 Hz, 3H), 1.38 - 1.21 (m, 1H), 0.72 - 0.62 (m, 2H), 0.40 (q, J = 4.8 Hz, 2H). [0556] Step 3. tert-Butyl (3S)-3-((4-((1-(3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0557] To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine- 1-carboxylate (143 mg, 410 μmol) in acetonitrile (1.0 mL) was added 1-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]ethanamine (100 mg, 410 μmol) and potassium carbonate (170 mg, 1.23 mmol). The mixture was stirred at 60 °C for 2 hr. On completion, the mixture was filtered and concentrated to give tert-butyl (3S)-3-[4-[1-[3-chloro-4- (cyclopropylmethoxy)-2-fluoro-phenyl]ethylamino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine- 1-carboxylate (120 mg, 0.22 mmol, 47%) as a yellow solid. m/z ES+ [M+H]⁺ 558.3. [0558] Step 4. N-(1-(3-chloro-4-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-6-(((S)- pyrrolidin-3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine [0559] To a solution of tert-butyl (3S)-3-[4-[1-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro- phenyl]ethylamino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (100 mg, 179 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated to give N- [1-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]ethyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (80 mg, crude) as a yellow solid. m/z ES+ [M+H]⁺ 458.2. [0560] Step 5. 1-((3S)-3-((4-((1-(3-chloro-4-(cyclopropylmethoxy)-2- fluorophenyl)ethyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0561] To a solution of N-[1-[3-chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]ethyl]-6-[(3S)- pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4-amine (60.0 mg, 131 μmol) in tetrahydrofuran (0.5 mL) was added sodium bicarbonate (11.0 mg, 131 μmol) and prop-2-enoyl chloride (11.8 mg, 131 μmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25mm, 10 um; mobile phase: [water(0.225%formic acid)-acetonitrile]; B%: 26%-56%, 10 min) to give 1-[(3S)-3-[4-[1-[3- chloro-4-(cyclopropylmethoxy)-2-fluoro-phenyl]ethylamino]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (30.0 mg, 58.6 μmol, 44%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 - 8.32 (m, 1H), 8.02 (d, J = 9.2 Hz, 2H), 7.41 (m, 1H), 7.31 (m, 1H), 6.99 - 6.90 (m, 1H), 6.71 - 6.50 (m, 1H), 6.21 - 6.11 (m, 1H), 6.10 - 6.02 (m, 1H), 5.76 - 5.60 (m, 2H), 3.90 (dd, J = 3.2, 6.8 Hz, 2H), 3.84 - 3.48 (m, 4H), 2.25 - 2.25 (m, 1H), 2.27 (m, 1H), 1.62 (m, 3H), 1.30 - 1.14 (m, 1H), 0.60 - 0.53 (m, 2H), 0.35 - 0.29 (m, 2H); m/z ES+ [M+H]⁺ 512.2. Example 17. Preparation of 1-((3S)-3-((4-((1-(3-chloro-2- fluorophenyl)propyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one

[0562] Step 1. N-(1-(3-chloro-2-fluorophenyl)propyl)-2-methylpropane-2-sulfinamide [0563] To a solution of (N)-N-[(3-chloro-2-fluoro-phenyl)methylene]-2-methyl-propane-2- sulfinamide (500 mg, 1.91 mmol) in tetrahydrofuran (20 mL) was added ethylmagnesium bromide (3 M in tetrahydrofuran, 1.27 mL). The mixture was stirred at 0 °C for 2 hr. The reaction mixture was diluted with ammonium chloride (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give N-[1-(3-chloro-2-fluoro- phenyl)propyl]-2-methyl-propane-2-sulfinamide (500 mg, crude) as a white solid. m/z ES+ [M+1]⁺ 292.0. [0564] Step 2. 1-(3-Chloro-2-fluorophenyl)propan-1-amine [0565] A mixture of N-[1-(3-chloro-2-fluoro-phenyl)propyl]-2-methyl-propane-2-sulfinamide (450 mg, 1.54 mmol) in hydrochloric acid/dioxane (2 mL) and methanol (10 mL) was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by perp-HPLC (column: Waters Xbridge C18150 x 50 mm, 10 um; mobile phase: [water(10mM-NH₄HCO₃)-acetonitrile]; B%: 27%-57%, 11 min) to give 1-(3- chloro-2-fluoro-phenyl)propan-1-amine (150 mg, 0.80 mmol, 52%) as a yellow solid. m/z ES+ [M+1]⁺ 188.0. [0566] Step 3. tert-Butyl (3S)-3-((4-((1-(3-chloro-2-fluorophenyl)propyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate [0567] A mixture of 1-(3-chloro-2-fluoro-phenyl)propan-1-amine (140 mg, 746 μmol), tert- butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate (261 mg, 746 μmol) in acetonitrile (10 mL) was stirred at 80 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water(10mM-NH₄HCO₃)- acetonitrile]; B%: 53%-83%, 9 min) to give tert-butyl (3S)-3-[4-[1-(3-chloro-2-fluoro- phenyl)propylamino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (80 mg, 0.16 mmol, 21.4%) as a white solid. m/z ES+ [M+1]⁺ 502.2. [0568] Step 4. N-(1-(3-chloro-2-fluorophenyl)propyl)-6-(((S)-pyrrolidin-3-yl)oxy)pyrido[3,2- d]pyrimidin-4-amine [0569] To a solution of tert-butyl (3S)-3-[4-[1-(3-chloro-2-fluoro- phenyl)propylamino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (75 mg, 149 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give N-[1-(3-chloro-2-fluoro-phenyl)propyl]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidin-4- amine (50 mg, crude) as a yellow solid. m/z ES+ [M+1]⁺ 402.0. [0570] Step 5. 1-((3S)-3-((4-((1-(3-chloro-2-fluorophenyl)propyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0571] To a solution of N-[1-(3-chloro-2-fluoro-phenyl)propyl]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidin-4-amine (45 mg, 111 μmol) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (9.41 mg, 111 μmol) and prop-2-enoyl chloride (10.13 mg, 111 μmol). The mixture was stirred at 0 °C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to give a residue. The residue was purified by perp-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water(10mM- NH₄HCO₃)-acetonitrile]; B%: 36%-66%, 9 min) to give 1-[(3S)-3-[4-[1-(3-chloro-2-fluoro- phenyl)propylamino]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (15.3 mg, 33.6 μmol, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 - 8.34 (m, 1H), 8.07 - 7.97 (m, 2H), 7.59 - 7.43 (m, 2H), 7.35 - 7.29 (m, 1H), 7.21 (q, J = 8.0 Hz, 1H), 6.71 - 6.51 (m, 1H), 6.21 - 6.03 (m, 2H), 5.74 - 5.62 (m, 1H), 5.59 - 5.31 (m, 1H), 4.13 - 3.76 (m, 2H), 3.74 - 3.49 (m, 2H), 2.41 - 2.15 (m, 2H), 2.12 - 1.92 (m, 2H), 1.03 - 0.94 (m, 3H); m/z ES+ [M+H]⁺ 456.0. Example 18. Synthesis and Characterization of Additional Exemplary Compounds [0572] Additional exemplary compounds were synthesized following the procedures described herein. Characterizations of the compounds are shown in Table A below.

Example 19. Biological Activity of Exemplary Compounds [0573] 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 100mm collagen coated plate (354450, Corning Life Sciences, Tewksbury, MA) (4 10⁵ per plate) and incubated overnight. The next day, retroviral plasmids (3 Pg of EGFR mutant, 1.0 Pg of pCMV-Gag-Pol and 0.5 Pg pCMV-VSV-G) were mixed in 500 Pl of Optimem (31985, Life Technologies). The mixture was incubated at room temperature for 5 min and then added to Optimem containing transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. Mixture was then added dropwise to HEK 293T cells. The next day the medium was replaced with fresh culture medium and retrovirus was harvested @ 24 and 48 hrs. [0574] Generation of EGFR mutant stable cell lines: BaF3 cells (1.5E5 cells) were infected with 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in a 37°C incubator overnight. Cells were then spun for 5 minutes to pellet the cells. Supernatant was removed and cells re-infected a fresh 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in 37°C incubator overnight. Cells were then maintained in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine containing 10 ng/ml IL-3. After 48 hours cells were selected for retroviral infection in 10 Pg/ml Blasticidin for one week. Blasticidin resistant populations were washed twice in phosphate buffered saline before plating in media lacking IL-3 to select for IL-3 independent growth. [0575] 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. [0576] Cellular protein analysis: Cell extracts were prepared by detergent lysis (RIPA, R0278, Sigma, St Louis, MO) containing 10 mM Iodoacetamide (786-228, G-Biosciences, St, Louis, MO), protease inhibitor (P8340, Sigma, St. Louis, MO) and phosphatase inhibitors (P5726, P0044, Sigma, St. Louis, MO) cocktails. The soluble protein concentration was determined by micro-BSA assay (Pierce, Rockford IL). Protein immunodetection was performed by electrophoretic transfer of SDS-PAGE separated proteins to nitrocellulose, incubation with antibody, and chemiluminescent second step detection. Nitrocellulose membranes were blocked with 5% nonfat dry milk in TBS and incubated overnight with primary antibody in 5% bovine serum albumin. The following primary antibodies from Cell Signaling Technology were used at 1:1000 dilution: phospho-EGFR[Y1173] and total EGFR. β-Actin antibody, used as a control for protein loading, was purchased from Sigma Chemicals. Horseradish peroxidase-conjugated secondary antibodies were obtained from Cell Signaling Technology and used at 1:5000 dilution. Horseradish peroxidase-conjugated secondary antibodies were incubated in nonfat dry milk for 1 hour. SuperSignal chemiluminescent reagent (Pierce Biotechnology) was used according to the manufacturer's directions and blots were imaged using the Alpha Innotech image analyzer and AlphaEaseFC software (Alpha Innotech, San Leandro CA). [0577] 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 <30 nM; B represents an IC₅₀ value ≥30 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

EQUIVALENTS [0578] 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. [0579] 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.

Claims

Claims 1. A compound of Formula (I’):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

wherein * indicates attachment to Y; W¹ is =CR^W1– or =N–; R^W1 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); W² is =CR^W2– or =N– R^W2 is H, halogen, C1-C6 alkyl, or -O(C1-C6 alkyl); R¹ is C₃-C₈ cycloalkyl, –HC=CH₂, –HC=CHR^1a or –C≡C– CH₃; R^1a is -CH₂-N(CH₃)₂ or -CH₂-morpholinyl; R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo, a C₃-C₈ cycloalkyl, or a 3- to 9-membered heterocycloalkyl; X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or –NH–; Y is a C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; each R^Y independently is oxo, halogen, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R^Y1; each R^Y1 independently is halogen, OH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl; Z is absent or 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R^Z ; each R^Z independently is OH, oxo, halogen, C1-C6 alkyl, C1-C6 alkoxyl, C3-C6 cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl; wherein the C₁-C₆ alkyl is optionally substituted with one or more OH halogen.

2. A compound of Formula (I):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W¹ is =CR^W1– or =N–; R^W1 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); W² is =CR^W2– or =N– R^W2 is H, halogen, C₁-C₆ alkyl, or -O(C₁-C₆ alkyl); R¹ is C₃-C₈ cycloalkyl, –HC=CH₂, –HC=CHR^1a or –C≡C– CH₃; R^1a is -CH₂-N(CH₃)₂ or -CH₂-morpholinyl; R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo, a C₃-C₈ cycloalkyl, or a 3- to 9-membered heterocycloalkyl; X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or –NH–; Y is a C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; each R^Y independently is oxo, halogen, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R^Y1; each R^Y1 independently is halogen, OH, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl; Z is absent or 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R^Z; and each R^Z independently is OH, oxo, halogen, CHF₂, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl; wherein the C₁-C₆ alkyl is optionally substituted with one or more OH.

3. The compound of claim 1 or claim 2, wherein: W¹ is =CR^W1– or =N–; R^W1 is H; W² is =CR^W2–; R^W2 is H or -O(C₁-C₆ alkyl); R¹ is –HC=CH₂; R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl); or R³ and R⁴ together with the carbon they are attached to form an oxo or a C₃-C₈ cycloalkyl; X¹ is absent, –NH–, –N(CH3)– or –O–; X² is absent or –NH–; Y is a C₆-C₁₀ aryl or 5- to 9-membered heteroaryl, wherein the C₆-C₁₀ aryl or 5- to 9- membered heteroaryl is optionally substituted with one or more R^Y; each R^Y independently is halogen, C₁-C₆ alkyl, or -O-(C₆-C₁₀ aryl); and Z is absent or 3- to 9-membered heterocycloalkyl.

4. The compound of any one of the preceding claims, wherein at least one of R³ and R⁴ is not H.

5. The compound of any one of the preceding claims, wherein W¹ is =CR^W1–.

6. The compound of any one of the preceding claims, wherein R^W1 is halogen, C₁-C₆ alkyl, or -O-(C₁-C₆ alkyl).

7. The compound of any one of the preceding claims, wherein W¹ is

or =N–.

8. The compound of any one of the preceding claims, wherein W² is =CR^W2–.

9. The compound of any one of the preceding claims, wherein R^W2 is halogen, C₁-C₆ alkyl, or -O-(C₁-C₆ alkyl).

10. The compound of any one of the preceding claims, wherein W² is =CH– or =N–.

11. The compound of any one of the preceding claims, wherein W¹ is =CH– and W² is CH–.

12. The compound of any one of the preceding claims, wherein W¹ is =N– and W² is =CH–.

13. The compound of any one of the preceding claims, wherein W¹ is =CH– and W² is =N–.

14. The compound of any one of the preceding claims, wherein W¹ is =N– and W² are =N–.

15. The compound of any one of the preceding claims, wherein X¹ is–NH–, –N(CH₃)– or –O– .

16. The compound of any one of the preceding claims, wherein X² is –NH–.

17. The compound of any one of the preceding claims, wherein Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl is optionally substituted with one or more R^Z.

18. The compound of any one of the preceding claims, wherein Z is 3- to 9-membered heterocycloalkyl, wherein the 3- to 9-membered heterocycloalkyl contains at least one nitrogen atom.

19. The compound of any one of the preceding claims, wherein Z is azetidinyl, pyrrolidinyl, piperidinyl, 2,5-diazabicyclo[2.2.1]heptyl, or 1,6-diazaspiro[3.3]heptyl, wherein the azetidinyl, pyrrolidinyl, piperidinyl, 2,5-diazabicyclo[2.2.1]heptyl, or 1,6-diazaspiro[3.3]heptyl is optionally substituted with one or more R^Z.

20. The compound of any one of the preceding claims, wherein Z is azetidinyl, pyrrolidinyl, piperidinyl, 2,5-diazabicyclo[2.2.1]heptyl, or 1,6-diazaspiro[3.3]heptyl.

21. The compound of any one of the preceding claims, wherein Z is azetidinyl, pyrrolidinyl, or piperidinyl.

22. The compound of any one of the preceding claims, wherein Z is 2,5- diazabicyclo[2.2.1]heptyl, or 1,6-diazaspiro[3.3]heptyl.

23. The compound of any one of the preceding claims, wherein R^Z is C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, or two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl; wherein the C₁-C₆ alkyl is substituted with one or more OH or halogen.

24. The compound of any one of the preceding claims, wherein R^Z is C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₆ cycloalkyl, or 3- to 9-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more OH or halogen.

25. The compound of any one of the preceding claims, wherein two R^Z together with the carbon they are attached to form a C₃-C₆ cycloalkyl.

26. The compound of any one of the preceding claims, wherein R^Z is OH, oxo, or halogen.

27. The compound of any one of the preceding claims, wherein X¹ is absent, –NH–, –N(CH₃)– or –O–; X² is absent or –NH–; and Z is absent or 3- to 9-membered heterocycloalkyl.

28. The compound of any one of the preceding claims, wherein R¹ is–HC=CH₂.

29. The compound of any one of the preceding claims, wherein R² is H.

30. The compound of any one of the preceding claims, wherein R² is C₁-C₆ alkyl.

31. The compound of any one of the preceding claims, wherein R²

32. The compound of any one of the preceding claims, wherein R³ is H.

33. The compound of any one of the preceding claims, wherein R³ is C₁-C₆ alkyl optionally substituted with one or more R^3a.

34. The compound of any one of the preceding claims, wherein R³ is C₁-C₆ alkyl substituted with one or more R^3a.

35. The compound of any one of the preceding claims, wherein R³ is C₁ alkyl substituted with one or more R^3a.

36. The compound of any one of the preceding claims, wherein R⁴ is H.

37. The compound of any one of the preceding claims, wherein R⁴ is C₁-C₆ alkyl optionally substituted with one or more R^4a.

38. The compound of any one of the preceding claims, wherein R⁴ is C₁-C₆ alkyl substituted with one or more R^4a.

39. The compound of any one of the preceding claims, wherein R⁴ is C₁ alkyl substituted with one or more R^4a.

40. The compound of any one of the preceding claims, wherein R^3a is halogen.

41. The compound of any one of the preceding claims, wherein R^3a is -OH or -O(C₁-C₆ alkyl).

42. The compound of any one of the preceding claims, wherein R^4a is halogen.

43. The compound of any one of the preceding claims, wherein R^4a is -OH or -O(C₁-C₆ alkyl).

44. The compound of any one of the preceding claims, wherein R³ and R⁴ together with the carbon they are attached to form C₃-C₈ cycloalkyl, or a 3- to 9-membered heterocycloalkyl.

45. The compound of any one of the preceding claims, wherein R³ and R⁴ together with the carbon they are attached to form C₃-C₈ cycloalkyl.

46. The compound of any one of the preceding claims, wherein R³ and R⁴ together with the carbon they are attached to form an oxo.

47. The compound of any one of the preceding claims, wherein R¹ is –HC=CH2; R² is H or C1- C₆ alkyl; R³ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^3a; each R^3a independently is halogen, -OH, or -O(C₁-C₆ alkyl); R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^4a; and each R^4a independently is halogen, -OH, or -O(C₁-C₆ alkyl).

48. The compound of any one of the preceding claims, wherein Y is a C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl, wherein the C₃-C₈ cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted with one or more R^Y.

49. The compound of any one of the preceding claims, wherein Y is a C₆-C₁₀ aryl or 5- to 9- membered heteroaryl, wherein the C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y.

50. The compound of any one of the preceding claims, wherein Y is a C₆-C₁₀ aryl or 5- to 9- membered heteroaryl.

51. The compound of any one of the preceding claims, wherein Y is phenyl.

52. The compound of any one of the preceding claims, wherein Y is pyridyl.

53. The compound of any one of the preceding claims, wherein R^Y is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆- C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9- membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆- C₁₀ aryl, 5- to 9-membered heteroaryl, -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9- membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is substituted with one or more R^Y1.

54. The compound of any one of the preceding claims, wherein R^Y is oxo, halogen, or OH.

55. The compound of any one of the preceding claims, wherein R^Y is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆- C₁₀ aryl, 5- to 9-membered heteroaryl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ alkoxyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 9-membered heteroaryl, is optionally substituted with one or more R^Y1.

56. The compound of any one of the preceding claims, wherein R^Y is -O-(C3-C8 cycloalkyl), - O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl), wherein the -O-(C₃-C₈ cycloalkyl), -O-(C₆-C₁₀ aryl), -O-(3- to 9-membered heterocycloalkyl), or O-(5- to 9-membered heteroaryl) is optionally substituted with one or more R^Y1.

57. The compound of any one of the preceding claims, wherein R^Y is -O-phenyl.

58. The compound of any one of the preceding claims, wherein R^Y is methyl.

59. The compound of any one of the preceding claims, wherein R^Y1 is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 3- to 9-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl.

60. The compound of any one of the preceding claims, wherein R^Y1 is halogen or OH.

61. The compound of any one of the preceding claims, wherein Y is C₆-C₁₀ aryl, or 5- to 9- membered heteroaryl, wherein the C₆-C₁₀ aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R^Y; and each R^Y independently is halogen, C₁-C₆ alkyl, or -O-(C₆- C₁₀ aryl).

62. The compound of any one of the preceding claims, being of formula (I-a), (I-b), or (I-c):

(I-c) or a pharmaceutically acceptable salt or stereoisomer thereof.

63. The compound of any one of the preceding claims, being of formula (I-e) or (I-f):

(I-f) wherein, m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or stereoisomer thereof.

64. The compound of any one of the preceding claims, being of formula (I-d), (I-g), or (I-h):

(I-h) or a pharmaceutically acceptable salt or stereoisomer thereof.

65. The compound of any one of the preceding claims, being selected from the compounds described in Table I and pharmaceutically acceptable salt or stereoisomer thereof.

66. An isotopic derivative of the compound of any one of the preceding claims.

67. A method of preparing the compound of any one of the preceding claims.

68. A pharmaceutical composition comprising the compound of any one of the preceding claims and one or more pharmaceutically acceptable carriers or excipients.

69. A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a compound of any one of the preceding claims.

70. A method of preventing or treating cancer, comprising administering the subject in need thereof a compound of any one of the preceding claims.

71. The compound of any one of the preceding claims for use in the prevention or treatment of cancer.

72. The compound of any one of the preceding claims for use in the inhibition of an oncogenic variant of an ErbB receptor.

73. The method or the compound of any one of the preceding claims, wherein the cancer is a solid tumor.

74. The method or the compound of any one of the preceding claims, wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.

75. The method or the compound of any one of the preceding claims, wherein the cancer is glioblastoma (GBM) or any subtype thereof.

76. The method or the compound of any one of the preceding claims, wherein the cancer is glioblastoma.

77. The method or the compound of any one of the preceding claims, wherein the cancer, or a tumor or a cell thereof, expresses an oncogenic variant of an ErbB receptor.

78. The method or the compound of any one of the preceding claims, wherein the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

79. The method or the compound of any one of the preceding claims, wherein the oncogenic variant of an ErbB receptor is an allosteric variant of the ErbB receptor.

80. The method or the compound of any one of the preceding claims, wherein the oncogenic variant or the oncogenic mutation is detected by a Food and Drug Administration (FDA)-approved diagnosis.