Pyrimidine compounds, compositions thereof, and their pharmaceutical uses

Abstract

The present disclosure relates to a class of pyrimidine compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates. The present disclosure also relates to processes for preparing these pyrimidine compounds, pharmaceutical compositions containing them, and their pharmaceutical uses.

Description

[Background technology]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 108,185, filed October 30, 2020, U.S. Provisional Patent Application No. 63 / 236,194, filed August 23, 2021, and U.S. Provisional Patent Application No. 63 / 271,991, filed October 26, 2021, each of which is incorporated by reference herein in its entirety.

[0002] Lung cancer is the leading cause of cancer deaths, with approximately 85% of lung cancer cases being non-small cell lung cancer (NSCLC). The development of targeted therapies for lung cancer has primarily focused on tumors that exhibit mutations in specific oncogenic drivers, namely, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). While three generations of tyrosine kinase inhibitors (TKIs) have been developed for cancers with the most frequently observed EGFR mutations, other oncogenic drivers in the EGFR family of receptor tyrosine kinases have been less well researched and developed, including insertions in exon 20 of the EGFR gene, several of which currently have no approved therapeutics for treating those cancers.

[0003] Given that many patients with EGFR mutations do not experience clinical benefit from currently available therapies directed at these targets, there remains a significant unmet need in the development of novel therapies for the treatment of cancers associated with EGFR mutations. Summary of the Invention

[0004] In one aspect, Formula I: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is —NH— or —O—; R 1 is -(C(R4 )2) n R 5 and R 5 is unsubstituted or contains one R 5’ is replaced by n is 0, 1, 2, or 3; Each R 4 are independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl; R 5 is C 4~10 is cycloalkyl, aryl, or heteroaryl; Each R 5’ are independently deuterium, aryl, heteroaryl, alkyl, C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH2, -NHR 6 , -N(CH3)R6, -N(R 6 )2, -C(=O)NH2, -C(=O)NHR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 6 , -NHC(=O)R 6 , -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 NH2, -S(=O)2 NHR 6 , -S(=O)2N(R 6 )2, -S(=O)2 heteroaryl, alkoxy, or haloalkoxy; Each R 6 is independently alkyl, aminoalkyl, cycloalkyl, aryl, or heteroaryl; R 2 is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of at least one R 7 and 0, 1, or 2 R 8 is replaced by Each R 7 is, independently, [ka] and Y is -C(=O)-, -S(=O)-, or -S(=O)2; R 9 , R 9’ , and R 9’’ are independently hydrogen, deuterium, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl; R 10 is hydrogen, alkyl, haloalkyl, or cycloalkyl; Each R 8 are independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 11 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy; Each R 11 is independently alkyl, cycloalkyl, aryl, or heteroaryl; R 3 can contain 0, 1, 2, or 3 R 12 is heteroaryl substituted with Each R 12 are independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N(R 13 )2, -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl, or cycloalkyl, each of which aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is independently unsubstituted or contains 0, 1, or 2 R 14 is replaced by Each R 13 are independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl; Each R 14are independently deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 15 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy; Each R 15 is independently alkyl, cycloalkyl, aryl, or heteroaryl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0005] In some embodiments, X is —NH—.

[0006] In some embodiments, n is 0.

[0007] In some embodiments, R 5 is phenyl, naphthyl, anthracenyl, phenanthrenyl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl, or C-linked indolyl, where R 5 is zero or one R 5’ In some embodiments, R 5 is unsubstituted. In some embodiments, R 5 is one R 5’ is replaced by .

[0008] In some embodiments, each R 5’ are independently alkyl, haloalkyl, 3- to 8-membered heterocycloalkyl, halo, cyano, hydroxy, -N(R 6 )2, -N(CH3)R6, -C(=O)NHR 6 , -NHC(=O)R 6 , —S(═O)NH, alkoxy, or haloalkoxy. In some embodiments, each R 5’ are independently methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N(R 6)2, -C(=O)NHR 6 , -NHC(=O)R 6 , —S(═O)NH, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R 5’ is independently methyl, morpholinyl, fluoro, chloro, cyano, —C(═O)NHMe, —NHC(═O)Me, —S(═O)NH, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

[0009] In some embodiments, each R 6 is independently alkyl or aryl. In some embodiments, each R 6 is independently methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. 6 is independently methyl or phenyl.

[0010] In some embodiments, R 2 is monocyclic. In some embodiments, R 2 is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is phenyl, cyclohexyl, or pyrrolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is one R 7 is substituted with R 8 In some embodiments, R 2 is one R 7 and one R 8 In some embodiments, R 2 is one R 7 and two R 8 is replaced by .

[0011] In some embodiments, R 2 is one R 7 is replaced by .

[0012] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0013] In some embodiments, Y is -C(=O)-. In some embodiments, Y is -S(=O)-.

[0014] In some embodiments, R 9 , R 9 , and R 9’’ is independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocycloalkyl. In some embodiments, R 9 , R 9 , and R 9’’ is independently hydrogen, fluoro, chloro, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. 9 and R 9’ is independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocycloalkyl. In some embodiments, R 9 and R 9’ is independently hydrogen, fluoro, chloro, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl.

[0015] In some embodiments, R 10 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, or cyclopropyl. 10 is hydrogen or methyl.

[0016] In some embodiments, R 2 is R 8 In some embodiments, R 2 is one or two R 8 In some embodiments, R 2 is one R 8 In some embodiments, R 2 is two R8 In some embodiments, each R 8 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chloro, heteroalkyl, cyano, hydroxy, amino, -N(R 11 )2, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 8 are independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, -N(R 11 )2, hydroxyethyl, methoxyethyl, or cyano.

[0017] In some embodiments, each R 11 is independently alkyl or aryl. In some embodiments, each R 11 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl, or phenanthrenyl. 11 is independently methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. 11 is independently methyl or phenyl.

[0018] In some embodiments, R 3 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or naphthyridinyl, wherein R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3is imidazolyl, pyrazolyl, triazolyl, indolyl, indazolyl, thiazolyl, isothiazolyl, or pyridinyl, where R 3 can contain 0, 1, 2, or 3 R 12 is replaced by .

[0019] In some embodiments, R 3 teeth, [ka] where R 3 is 0 to 3 R 12 is replaced by .

[0020] In some embodiments, R 3 teeth, [ka] [ka] is.

[0021] In some embodiments, R 3 teeth, [ka] is.

[0022] In some embodiments, R 3 is unsubstituted. In some embodiments, R 3 is at least one R 12 In some embodiments, R 3 is at least two R 12 is replaced by .

[0023] In some embodiments, each R 12 are independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, heterocycloalkyl, -N(R 13)2, —S(═O)2NH2, or cycloalkyl. In some embodiments, each R 12 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluoro, chloro, cyano, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -N(R 13 )2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 12 is independently methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl, or cyclopropyl. 12 is independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chloro. In some embodiments, each R 12 is independently methyl or chloro.

[0024] In some embodiments, each R 13 is independently alkyl or cycloalkyl. In some embodiments, each R 13 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 13 is independently methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. 13 is independently methyl, cyclopropyl, or cyclohexyl.

[0025] In some embodiments, R 12The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl in R is unsubstituted. 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of 14 is replaced by .

[0026] In some embodiments, each R 14 are independently alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, -N(R 15 )2, or alkoxy. In some embodiments, each R 14 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, -N(R 15 )2, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 14 are independently methyl, ethyl, isopropyl, tert-butyl, pyrrolidinyl, piperidinyl, morpholinyl, fluoro, chloro, -N(R 15 )2, or methoxy.

[0027] In some embodiments, each R 15 is independently alkyl or cycloalkyl. In some embodiments, each R 15 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0028] In some embodiments, each R 13 is independently methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. 13is independently methyl, cyclopropyl, or cyclohexyl.

[0029] In some embodiments, X is —NH— or —O—; n is 0, R 5 is zero or one R 5’ is a phenyl substituted with R 2 is at least one R 7 and 0, 1, or 2 R 8 is a phenyl substituted with R 3 can contain 0, 1, 2, or 3 R 12 and pyrazolyl substituted with

[0030] In some embodiments, X is —NH—.

[0031] In some embodiments, R 5’ is fluoromethyl, difluoromethyl, or trifluoromethyl.

[0032] In some embodiments, R 7 teeth, [ka] and R 8 is a halo.

[0033] In some embodiments, R 8 is fluoro, Y is -C(=O)-, R 9 and R 9’ is hydrogen, R 10 is hydrogen.

[0034] In some embodiments, R 12 is alkyl.

[0035] In some embodiments, R 12 is methyl.

[0036] In some embodiments, the compound has formula IA, formula IB, formula IC, formula ID, formula IE, formula IF, or formula IG: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0037] In some embodiments, the compound has formula IA: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula IA: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0038] In some embodiments, the compound has formula IB: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of formula IB, R 1 is R 5 In some embodiments of the compound of formula IB, R 5 is zero or one R 5’ In some embodiments of the compound of formula IB, R 5 is unsubstituted. In some embodiments of the compound of formula IB, R 5 is one R 5’ is replaced by .

[0039] In some embodiments, the compound has formula IC: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of formula IB, R 1 is R 5 In some embodiments of the compound of formula IC, R 5 is zero or one R 5’ In some embodiments of the compound of formula IC, R 5 is unsubstituted. In some embodiments of the compound of formula IC, R 5 is one R 5’ is replaced by .

[0040] In some embodiments, the compound has formula ID: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula ID: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0041] In some embodiments, the compound has the formula IE: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IE: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0042] In some embodiments, the compound has the formula IF: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IF: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0043] In some embodiments, the compound has formula IG: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of formula IG, R 1 is R 5 In some embodiments of the compound of formula IG, R 5 is zero or one R 5’ In some embodiments of the compound of formula IG, R 5 is unsubstituted. In some embodiments of the compound of formula IG, R 5 is one R 5’ is replaced by .

[0044] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the compounds described herein are selective inhibitors of EGFR over HER2.

[0046] In some embodiments, the compounds described herein have an improved safety profile. In some embodiments, the compounds described herein have an improved toxicity profile. In some embodiments, the compounds described herein have an improved therapeutic index.

[0047] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0048] In another aspect, provided herein are methods of inhibiting an epidermal growth factor receptor (EGFR) family kinase mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the EGFR family kinase mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR family kinase mutant is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof.

[0049] In another aspect, provided herein are methods of inhibiting a mutant epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the mutant EGFR comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof.

[0050] In another aspect, provided herein are methods for inhibiting a drug-resistant epidermal growth factor receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the drug-resistant EGFR mutant is del19 / T790M EGFR or L858R / T790M EGFR.

[0051] In another aspect, provided herein is a method of inhibiting epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound exhibits stronger inhibition of EGFR mutants as compared to wild-type EGFR.

[0052] In some embodiments, the EGFR mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutant is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is del19 / T790M EGFR or L858R / T790M EGFR.

[0053] In another aspect, provided herein is a method for treating an epidermal growth factor receptor (EGFR) family kinase-associated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the EGFR mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof.

[0054] In some embodiments, the disease or disorder in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutation is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR.

[0055] In another aspect, provided herein is a method of treating one or more cancer cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0056] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0057] In some embodiments, the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, or non-small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, colorectal cancer, or glioblastoma.

[0058] In some embodiments, the cancer in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutation is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR.

[0059] In another aspect, the disclosure provides a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0060] In some embodiments, the inflammatory disease is psoriasis, eczema, or atherosclerosis.

[0061] In some embodiments, the inflammatory disease in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutation is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR.

[0062] In another aspect, the present disclosure provides a compound comprising: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0063] The present disclosure discloses processes for preparing compounds of formula I, or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, as well as pharmaceutical compositions containing them.

[0064] The compounds of the present disclosure may be useful in treating, preventing, or inhibiting diseases or disorders mediated by the epidermal growth factor receptor (EGFR).

[0065] These and other features, aspects, and advantages of the present disclosure will be better understood with reference to the following description. This description is provided to introduce selected concepts in a simplified form. It is not intended to identify key features or essential features of the subject matter, nor is it intended to be used to limit the scope of the subject matter.

[0066] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0067] definition In the structural formulas provided herein, and throughout this disclosure, the following terms have the indicated meanings unless otherwise indicated.

[0068] As used herein, the term "optionally substituted" means that the group in question is either unsubstituted or substituted with one or more of the specified substituents. In some embodiments where the group in question is substituted with two or more substituents, the substituents are the same. In some embodiments where the group in question is substituted with two or more substituents, the substituents are different. In some embodiments, the reference group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, —CN, —NH, —NH(alkyl), —N(alkyl), —OH, —COH, —COalkyl, —C(═O)NH, —C(═O)NH(alkyl), —C(═O)N(alkyl), —S(═O)NH, —S(═O)NH(alkyl), —S(═O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups.In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0069] As used herein, C1-C x For example, C1~C2, C1~C3...C1~C x and the like. By way of example only, a group designated "C1-C6" indicates that there is a group containing from 1 to 6 carbon atoms present in the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms present in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0070] The term "alkyl" refers to a branched or unbranched monoradical saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-hexyl, and the like.

[0071] The term "cycloalkyl," unless otherwise specified, refers to a carbocyclic group of 3 to 6 carbon atoms having a single ring or multiple condensed, spiro, or bridged rings. This definition encompasses rings that are saturated or partially unsaturated. Such cycloalkyl groups include, by way of example, single-ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0072] "Halo" or "halogen", alone or in combination with any other term, means halogen, for example, chloro (Cl), fluoro (F), bromo (Br), and iodo (I).

[0073] The term "aryl" refers to a radical derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. This definition includes monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, as well as fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise stated in this specification, the term "aryl" or the prefix "ar-" (e.g., in "aralkyl") is intended to include optionally substituted aryl radicals.

[0074] The term "phenyl" refers to an aromatic carbocyclic group of 6 carbon atoms having a single ring.

[0075] The term "phenylalkyl" refers to a branched or unbranched monoradical saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms substituted with an aromatic carbocyclic group of 6 carbon atoms having a single ring.

[0076] The term "heteroaryl" refers to an aromatic ring group having 5 or 6 carbon atoms and 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur in at least one ring. An "X-linked heteroaryl" refers to a heteroaryl that is linked to the rest of the molecule through an X atom. For example, [ka] is an N-linked imidazolyl, while [ka] is a C-linked imidazolyl.

[0077] The term "heterocycloalkyl," unless otherwise stated, refers to a saturated, partially unsaturated, or unsaturated group having a single ring or multiple fused, spiro, or bridged rings, having from 2 to 10 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen, sulfur, phosphorus, and / or oxygen within the ring.

[0078] The term "alkenyl" refers to an unsaturated aliphatic group having at least one double bond.

[0079] The term "alkynyl" refers to an unsaturated aliphatic group having at least one triple bond.

[0080] The term "amino" refers to the -NH2 radical.

[0081] The term "cyano" refers to the -CN radical.

[0082] The term "hydroxy" or "hydroxyl" refers to the --OH radical.

[0083] The term "heteroalkyl" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl has been replaced with an O, N, or S atom. Unless stated otherwise in the specification, a heteroalkyl group is optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCH2CHOMe, -OCH2CHOCH2CH2NH2, and -OCH2CHOCH2CH2OCH2CH2N(Me)2.

[0084] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is a C4-C 10 Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3- or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0085] The term "haloalkyl" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl has been replaced with a halogen atom. In some embodiments, the haloalkyl group is optionally substituted as described below. Representative haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl.

[0086] The term "aminoalkyl" refers to an alkyl group substituted with an amino (NH) group. In some embodiments, the aminoalkyl group is unsubstituted or has the nitrogen atom substituted with an alkyl.

[0087] The term "alkoxy" refers to the group RO-, where R is optionally substituted alkyl, or optionally substituted cycloalkyl, or optionally substituted alkenyl, or optionally substituted alkynyl, or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are as defined herein. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

[0088] The compounds described herein include isotopically labeled compounds that are identical to those listed in the various formulas and structures set forth herein, except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, the compounds of the present invention contain isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33 In one aspect, the isotopically labeled compounds described herein, e.g., 3 H and 14Incorporating a radioactive isotope such as C is useful for drug and / or substrate tissue distribution assays. In one aspect, substitution with an isotope such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, the compounds described herein exist as isotopic variants. In some embodiments, isotopic variants of the compounds described herein have one or more hydrogen atoms replaced with deuterium.

[0089] In some embodiments, the compounds described herein have one or more chiral centers and / or double bonds and therefore exist as stereoisomers, e.g., double bond isomers (i.e., geometric isomers), positional isomers, enantiomers, or diastereomers. Thus, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the compounds depicted or identified, including stereomerically pure (e.g., geometrically pure, enantiomerically pure, diastereomerically pure) forms as well as enantiomeric and stereoisomeric mixtures. In some embodiments, enantiomeric and stereoisomeric mixtures are separated into their enantiomeric or stereoisomeric components using separation or chiral synthesis techniques well known to those skilled in the art. In some embodiments, the compounds also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the compounds depicted or identified.

[0090] In some embodiments, the compounds disclosed herein are in the form of a free base, a salt, a hydrate, an isomer, a diastereomer, a prodrug (e.g., an ester), a metabolite, an ion-pair complex, or a chelate. In some embodiments, the compounds exist in solvated forms, including unsolvated and hydrated forms, and as N-oxides. In some embodiments, the compounds are hydrated, solvated, or N-oxides. Congeners, analogs, hydrolysates, metabolites, and precursors or prodrugs of the compounds are also intended to be within the scope of the present disclosure. Generally, unless otherwise specified, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.

[0091] "Pharmaceutically acceptable salts" include salts with pharmaceutically acceptable acids or bases. Pharmaceutically acceptable acids include both inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, and organic acids, such as citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides, and organic bases, such as alkylamines, arylalkylamines, and heterocyclic amines. In some embodiments, the compound is a pharmaceutically acceptable salt derived from an acid, including, but not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, or p-toluenesulfonic acid.

[0092] A "pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that constitute a carrier, as well as any product that results directly or indirectly from the combination, complex formation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present disclosure encompasses any composition containing a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0093] "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered. In some embodiments, such pharmaceutical carriers are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, including but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, water is the carrier when the pharmaceutical composition is administered orally. In some embodiments, saline and aqueous dextrose are exemplary carriers when the pharmaceutical composition is administered intravenously. In some embodiments, saline and aqueous dextrose and glycerol solutions are used as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene, glycol, water, ethanol, and the like. In some embodiments, the compositions contain minor amounts of wetting or emulsifying agents, or pH buffering agents. In some embodiments, these compositions take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, or the like. In some embodiments, the compositions are formulated as suppositories containing traditional binders and carriers such as triglycerides. In some embodiments, oral formulations include carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, or the like. Examples of suitable pharmaceutical carriers are described in E.W. Martin's "Remington's Pharmaceutical Sciences." Such compositions contain, for example, a therapeutically effective amount of the therapeutic agent in purified form, together with a suitable amount of carrier to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0094] "Combined" or "in combination" or "combination" should be understood as functional simultaneous administration, encompassing scenarios in which the compounds are administered separately, in different formulations, by different modes of administration (e.g., subcutaneous, intravenous, or oral), and at different times of administration. In some embodiments, the individual compounds of such combinations are administered sequentially in separate pharmaceutical compositions. In some embodiments, the individual compounds of such combinations are administered simultaneously in a combined pharmaceutical composition.

[0095] compound In one aspect, Formula I: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is —NH— or —O—; R 1 is -(C(R 4 )2) n R 5 and R 5 is zero or one R 5’ is replaced by n is 0, 1, 2, or 3; Each R 4 are independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl; R 5 is C 4~10 is a cycloalkyl, C-linked heterocycloalkyl, aryl, or heteroaryl; Each R 5’ are independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH, -NHR 6 , -N(R 6 )2, -C(=O)NH2, -C(=O)NHR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 6 , -NHC(=O)R 6, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 NH2, -S(=O)2 NHR 6 , -S(=O)2N(R 6 )2, -S(=O)2 heteroaryl, alkoxy, or haloalkoxy; Each R 6 is independently alkyl, cycloalkyl, aryl, or heteroaryl; R 2 is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of at least one R 7 and 0, 1, or 2 R 8 is replaced by Each R 7 is, independently, [ka] and Y is -C(=O)-, -S(=O)-, or -S(=O)2; R 9 and R 9’ are independently hydrogen, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl; R 10 is hydrogen, alkyl, haloalkyl, or cycloalkyl; Each R 8 are independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 11 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy; Each R 11 is independently alkyl, cycloalkyl, aryl, or heteroaryl; R 3 can contain 0, 1, 2, or 3 R 12 is heteroaryl substituted with Each R12 are independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N(R 13 )2, -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl, or cycloalkyl, each of the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl independently being selected from zero, one, or two R 14 is replaced by Each R 13 is independently alkyl, cycloalkyl, aryl, or heteroaryl; Each R 14 are independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 15 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy; Each R 15 is independently alkyl, cycloalkyl, aryl, or heteroaryl; However, when X is -O-, R 5 is not a C-linked heterocycloalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0096] In one aspect, Formula I: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is —NH— or —O—; R 1 is -(C(R 4 )2) n R 5 and R 5 is unsubstituted or contains one R 5’ is replaced by n is 0, 1, 2, or 3; Each R 4 are independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl; R 5 is C 4~10 is cycloalkyl, aryl, or heteroaryl; Each R 5’ are independently deuterium, aryl, heteroaryl, alkyl, C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH2, -NHR 6 , -N(CH3)R6, -N(R 6 )2, -C(=O)NH2, -C(=O)NHR 6 , -C(=O)N(R 6 )2, -NR 6 C(=O)R 6 , -NHC(=O)R 6 , -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 NH2, -S(=O)2 NHR 6 , -S(=O)2N(R 6 )2, -S(=O)2 heteroaryl, alkoxy, or haloalkoxy; Each R 6 is independently alkyl, aminoalkyl, cycloalkyl, aryl, or heteroaryl; R 2 is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is selected from the group consisting of at least one R 7 and 0, 1, or 2 R 8 is replaced by Each R 7 is, independently, [ka] and Y is -C(=O)-, -S(=O)-, or -S(=O)2; R 9 , R 9’ , and R9’’ are independently hydrogen, deuterium, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl; R 10 is hydrogen, alkyl, haloalkyl, or cycloalkyl; Each R 8 are independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 11 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy; Each R 11 is independently alkyl, cycloalkyl, aryl, or heteroaryl; R 3 can contain 0, 1, 2, or 3 R 12 is heteroaryl substituted with Each R 12 are independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N(R 13 )2, -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl, or cycloalkyl, each of which aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is independently unsubstituted or contains 0, 1, or 2 R 14 is replaced by Each R 13 are independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl; Each R 14 are independently deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 15 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy; Each R 15is independently alkyl, cycloalkyl, aryl, or heteroaryl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0097] For all embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, X is -NH-. In some embodiments, X is -O-.

[0098] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, 1, or 3. In some embodiments, n is 0, 2, or 3. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 0 or 2. In some embodiments, n is 0 or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0099] In some embodiments, R 5 is phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, pyrenyl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl, or C-linked indolyl, where R 5 is zero or one R 5’ In some embodiments, R 5 is phenyl, naphthyl, anthracenyl, phenanthrenyl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, or C-linked imidazolyl, where R 5 is zero or one R 5’ In some embodiments, R 5 is phenyl, wherein the phenyl is selected from the group consisting of zero or one R5’ In some embodiments, R 5 is naphthyl, wherein the naphthyl is selected from the group consisting of zero or one R 5’ In some embodiments, R 5 is an anthracenyl, wherein the anthracenyl is selected from the group consisting of zero or one R 5’ In some embodiments, R 5 is phenanthrenyl, wherein the phenanthrenyl is selected from the group consisting of zero or one R 5’ In some embodiments, R 5 is chrysenyl, wherein the chrysenyl is selected from the group consisting of 0 or 1 R 5’ In some embodiments, R 5 is pyrenyl, wherein the pyrenyl is selected from the group consisting of 0 or 1 R 5’ In some embodiments, R 5 is a C-linked pyridyl, wherein the C-linked pyridyl is selected from the group consisting of zero and one R 5’ In some embodiments, R 5 is a C-linked pyrimidinyl, wherein the C-linked pyrimidinyl is selected from the group consisting of zero or one R 5’ In some embodiments, R 5 is a C-linked pyrazolyl, wherein the C-linked pyrazolyl is selected from the group consisting of zero and one R 5’ In some embodiments, R 5 is a C-linked imidazolyl, wherein the C-linked imidazolyl is selected from the group consisting of zero or one R 5’ In some embodiments, R 5 is a C-linked indolyl, wherein the C-linked indolyl is selected from the group consisting of 0 or 1 R 5’ is replaced by .

[0100] In some embodiments, R 5 is zero or one R 5’ In some embodiments, R 5 is unsubstituted. In some embodiments, R 5is one R 5’ is replaced by .

[0101] In some embodiments, each R 4 is independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl. In some embodiments, each R 4 is independently hydrogen, alkyl, halo, haloalkyl, or alkoxy. In some embodiments, each R 4 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chloro, trifluoromethyl, trifluoroethyl, pentafluoroethyl, methoxy, ethoxy, or trifluoromethoxy. 4 is independently hydrogen, methyl, fluoro, trifluoromethyl, methoxy, or trifluoromethoxy. In some embodiments, each R 4 is hydrogen. In some embodiments, each R 4 is independently alkyl. In some embodiments, each R 4 is independently halo. In some embodiments, each R 4 is independently haloalkyl. In some embodiments, each R 4 is hydroxy. In some embodiments, each R 4 is independently alkoxy. In some embodiments, each R 4 is independently heteroalkyl. In some embodiments, each R 4 is methyl. In some embodiments, each R 4 is ethyl. In some embodiments, each R 4 is n-propyl. In some embodiments, each R 4 is isopropyl. In some embodiments, each R 4 is n-butyl. In some embodiments, each R 4 is isobutyl. In some embodiments, each R 4 is sec-butyl. In some embodiments, each R 4is tert-butyl. In some embodiments, each R 4 is fluoro. In some embodiments, each R 4 is chloro. In some embodiments, each R 4 is trifluoromethyl. In some embodiments, each R 4 is trifluoroethyl. In some embodiments, each R 4 is pentafluoroethyl. In some embodiments, each R 4 is methoxy. In some embodiments, each R 4 is ethoxy. In some embodiments, each R 4 is trifluoromethoxy.

[0102] In some embodiments, each R 5’ are independently alkyl, haloalkyl, heterocycloalkyl, halo, cyano, hydroxy, -N(R 6 )2, -C(=O)NHR 6 , -NHC(=O)R 6 , —S(═O)NH, alkoxy, or haloalkoxy. In some embodiments, each R 5’ are independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 6 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy. In some embodiments, each R 5’ are independently aryl, heteroaryl, alkyl, heterocycloalkyl, halo, cyano, hydroxy, -N(R 6 )2, or alkoxy. In some embodiments, each R 5’ is independently aryl. In some embodiments, each R 5’ is independently heteroaryl. In some embodiments, each R 5’ is independently alkyl. In some embodiments, each R 5’ is independently cycloalkyl. In some embodiments, each R 5’is independently heterocycloalkyl. In some embodiments, each R 5’ is independently halo. In some embodiments, each R 5’ is independently heteroalkyl. In some embodiments, each R 5’ is independently haloalkyl. In some embodiments, each R 5’ is cyano. In some embodiments, each R 5’ is hydroxy. In some embodiments, each R 5’ is amino. In some embodiments, each R 5’ are independently -N(R 6 )2. In some embodiments, each R 5’ is independently —S(═O) alkyl. In some embodiments, each R 5’ is independently —S(═O)aryl. In some embodiments, each R 5’ is independently —S(═O)2 heteroaryl. In some embodiments, each R 5’ is independently alkoxy. In some embodiments, each R 5’ are independently selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, pyrenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, naphthyridinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N(R 6 )2, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 5’are independently selected from phenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N(R 6 )2, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 5’ are independently methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N(R 6 )2, -C(=O)NHR 6 , -NHC(=O)R 6 , —S(═O)NH, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R 5’ is independently methyl, morpholinyl, fluoro, chloro, cyano, —C(═O)NHMe, —NHC(═O)Me, —S(═O)NH, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy. 5’ are independently selected from phenyl, imidazolyl, pyridinyl, methyl, tert-butyl, pyrrolidinyl, morpholinyl, fluoro, cyano, hydroxy, -N(R 6 )2, or methoxy. In some embodiments, each R 5’ is phenyl. In some embodiments, each R 5’ is naphthyl. In some embodiments, each R 5’ is anthracenyl. In some embodiments, each R 5’ is phenanthrenyl. In some embodiments, each R 5’ is chrysenyl. In some embodiments, each R 5’ is pyrenyl. In some embodiments, each R 5’ is pyrrolyl. In some embodiments, each R 5’is imidazolyl. In some embodiments, each R 5’ is pyrazolyl. In some embodiments, each R 5’ is triazolyl. In some embodiments, each R 5’ is tetrazolyl. In some embodiments, each R 5’ is indolyl. In some embodiments, each R 5’ is indazolyl. In some embodiments, each R 5’ is benzimidazolyl. In some embodiments, each R 5’ is azaindolyl. In some embodiments, each R 5’ is thiazolyl. In some embodiments, each R 5’ is isothiazolyl. In some embodiments, each R 5’ is oxazolyl. In some embodiments, each R 5’ is isoxazolyl. In some embodiments, each R 5’ is pyridinyl. In some embodiments, each R 5’ is pyrimidinyl. In some embodiments, each R 5’ is pyridazinyl. In some embodiments, each R 5’ is pyrazinyl. In some embodiments, each R 5’ is triazinyl. In some embodiments, each R 5’ is quinolinyl. In some embodiments, each R 5’ is isoquinolinyl. In some embodiments, each R 5’ is quinoxalinyl. In some embodiments, each R 5’ is quinazolinyl. In some embodiments, each R 5’ is cinnolinyl. In some embodiments, each R 5’ is naphthyridinyl. In some embodiments, each R 5’ is methyl. In some embodiments, each R 5’ is ethyl. In some embodiments, each R 5’ is n-propyl. In some embodiments, each R 5’is isopropyl. In some embodiments, each R 5’ is n-butyl. In some embodiments, each R 5’ is isobutyl. In some embodiments, each R 5’ is sec-butyl. In some embodiments, each R 5’ is tert-butyl. In some embodiments, each R 5’ is azetidinyl. In some embodiments, each R 5’ is oxetanyl. In some embodiments, each R 5’ is pyrrolidinyl. In some embodiments, each R 5’ is imidazolidinyl. In some embodiments, each R 5’ is tetrahydrofuranyl. In some embodiments, each R 5’ is piperidinyl. In some embodiments, each R 5’ is piperazinyl. In some embodiments, each R 5’ is tetrahydropyranyl. In some embodiments, each R 5’ is morpholinyl. In some embodiments, each R 5’ is fluoro. In some embodiments, each R 5’ is chloro. In some embodiments, each R 5’ is methoxy. In some embodiments, each R 5’ is ethoxy. In some embodiments, each R 5’ is trifluoromethoxy. In some embodiments, each R 5’ is —C(═O)NHMe. In some embodiments, each R 5’ is —NHC(═O)Me. In some embodiments, each R 5’ is —S(═O)NH. In some embodiments, each R 5’ is difluoromethoxy.

[0103] In some embodiments, each R 6 is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 6is independently alkyl or aryl. In some embodiments, each R 6 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, or pyrenyl. 6 is independently methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. 6 is independently methyl or phenyl. In some embodiments, each R 6 is methyl. In some embodiments, each R 6 is ethyl. In some embodiments, each R 6 is n-propyl. In some embodiments, each R 6 is isopropyl. In some embodiments, each R 6 is n-butyl. In some embodiments, each R 6 is isobutyl. In some embodiments, each R 6 is sec-butyl. In some embodiments, each R 6 is tert-butyl. In some embodiments, each R 6 is phenyl. In some embodiments, each R 6 is naphthyl. In some embodiments, each R 6 is anthracenyl. In some embodiments, each R 6 is phenanthrenyl. In some embodiments, each R 6 is chrysenyl. In some embodiments, each R 6 is pyrenyl.

[0104] In some embodiments, R 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2is aryl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is heteroaryl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cycloalkyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is heterocycloalkyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is monocyclic. In some embodiments, R 2 is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is phenyl, cyclohexyl, or pyrrolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is phenyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclopropyl, where R2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclobutyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclopentyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclohexyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyrrolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is imidazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyrazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is triazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is tetrazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R2 is thiazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is isothiazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is oxazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is isoxazolyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyridinyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyrimidinyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyridazinyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyrazinyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is triazinyl, where R 2 is at least one R 7 and 0, 1, or 2 R 8In some embodiments, R2 is substituted with at least one R 7 is substituted with R 8 In some embodiments, R2 is not substituted with at least one R 7 and one R 8 In some embodiments, R2 is substituted with at least two R 7 and one R 8 is replaced by .

[0105] In some embodiments, R 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is aryl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is heteroaryl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cycloalkyl, where R 2 is one R7 and 0, 1, or 2 R 8 In some embodiments, R 2 is heterocycloalkyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is monocyclic. In some embodiments, R 2is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is phenyl, cyclohexyl, or pyrrolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is phenyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclopropyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclobutyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclopentyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is cyclohexyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyrrolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R2 is imidazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyrazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is triazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is tetrazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is thiazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is isothiazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is oxazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is isoxazolyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyridinyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2is pyrimidinyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyridazinyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is pyrazinyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R 2 is triazinyl, where R 2 is one R 7 and 0, 1, or 2 R 8 In some embodiments, R2 is substituted with one R 7 is substituted with R 8 In some embodiments, R2 is not substituted with one R 7 and one R 8 In some embodiments, R2 is substituted with one R 7 and two R 8 is replaced by .

[0106] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0107] In some embodiments, Y is -C(=O)-. In some embodiments, Y is -S(=O)-. In some embodiments, Y is -S(=O)-.

[0108] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0109] In some embodiments, R 9 and R 9’ is independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocycloalkyl. In some embodiments, R 9 is hydrogen, halo, alkyl, cycloalkyl, or heteroalkyl. In some embodiments, R 9 is hydrogen, halo, or heteroalkyl. In some embodiments, R 9 and R 9’is independently hydrogen, fluoro, chloro, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. 9 is hydrogen, fluoro, chloro, hydroxyethyl, or methoxyethyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is fluoro. In some embodiments, R 9 is chloro. In some embodiments, R 9 is hydroxyethyl. In some embodiments, R 9 is methoxyethyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is methoxymethyl. In some embodiments, R 9 is dimethylaminomethyl. In some embodiments, R 9 is 1-piperidinylmethyl. In some embodiments, R 9 is 1-morpholinomethyl. In some embodiments, R 9 is fluoromethyl. In some embodiments, R 9’ is hydrogen. In some embodiments, R 9’ is fluoro. In some embodiments, R 9’ is chloro. In some embodiments, R 9’ is hydroxyethyl. In some embodiments, R 9’ is methoxyethyl. In some embodiments, R 9’ is methyl. In some embodiments, R 9’ is methoxymethyl. In some embodiments, R 9’ is dimethylaminomethyl. In some embodiments, R 9’ is 1-piperidinylmethyl. In some embodiments, R 9’ is 1-morpholinomethyl. In some embodiments, R 9’ is fluoromethyl.

[0110] In some embodiments, R 10 is hydrogen or alkyl. In some embodiments, R 10 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. 10 is hydrogen. In some embodiments, R 10 is methyl. In some embodiments, R 10 is ethyl. In some embodiments, R 10 is n-propyl. In some embodiments, R 10 is isopropyl. In some embodiments, R 10 is n-butyl. In some embodiments, R 10 is isobutyl. In some embodiments, R 10 is sec-butyl. In some embodiments, R 10 is tert-butyl.

[0111] In some embodiments, R 2 is R 8 In some embodiments, R 2 is one or two R 8 In some embodiments, R 2 is one R 8 In some embodiments, R 2 is two R 8 is replaced by .

[0112] In some embodiments, each R 8 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chloro, heteroalkyl, cyano, hydroxy, amino, -N(R 11 )2, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 8 are independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, -N(R11 )2, hydroxyethyl, methoxyethyl, or cyano. In some embodiments, each R 8 is methyl. In some embodiments, each R 8 is ethyl. In some embodiments, each R 8 is n-propyl. In some embodiments, each R 8 is isopropyl. In some embodiments, each R 8 is n-butyl. In some embodiments, each R 8 is isobutyl. In some embodiments, each R 8 is sec-butyl. In some embodiments, each R 8 is tert-butyl. In some embodiments, each R 8 is fluoro. In some embodiments, each R 8 is chloro. In some embodiments, each R 8 are independently -N(R 11 )2. In some embodiments, each R 8 is hydroxyethyl. In some embodiments, each R 8 is methoxyethyl. In some embodiments, each R 8 is cyano.

[0113] In some embodiments, each R 11 is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 11 is independently alkyl or aryl. In some embodiments, each R 11 is independently alkyl. In some embodiments, each R 11 is independently cycloalkyl. In some embodiments, each R 11 is independently aryl. In some embodiments, each R 11 is independently heteroaryl. In some embodiments, each R 11is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, or pyrenyl. 11 is independently methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. 11 is independently methyl or phenyl. In some embodiments, each R 11 is methyl. In some embodiments, each R 11 is ethyl. In some embodiments, each R 11 is n-propyl. In some embodiments, each R 11 is isopropyl. In some embodiments, each R 11 is n-butyl. In some embodiments, each R 11 is isobutyl. In some embodiments, each R 11 is sec-butyl. In some embodiments, each R 11 is tert-butyl. In some embodiments, each R 11 is phenyl. In some embodiments, each R 11 is naphthyl. In some embodiments, each R 11 is anthracenyl. In some embodiments, each R 11 is phenanthrenyl. In some embodiments, each R 11 is chrysenyl. In some embodiments, each R 11 is pyrenyl.

[0114] In some embodiments, R 3 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or naphthyridinyl, wherein R3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is imidazolyl, pyrazolyl, triazolyl, indolyl, indazolyl, thiazolyl, isothiazolyl, or pyridinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is pyrrolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is imidazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is pyrazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is triazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is tetrazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is indolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is indazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is benzimidazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is azaindolyl, where R 3 can contain 0, 1, 2, or 3 R12 In some embodiments, R 3 is thiazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is isothiazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is oxazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is isoxazolyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is pyridinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is pyrimidinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is pyridazinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is pyrazinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is triazinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is quinolinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is isoquinolinyl, where R 3can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is quinoxalinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is quinazolinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is cinnolinyl, where R 3 can contain 0, 1, 2, or 3 R 12 In some embodiments, R 3 is naphthyridinyl, where R 3 can contain 0, 1, 2, or 3 R 12 is replaced by .

[0115] In some embodiments, R 3 is unsubstituted. In some embodiments, R 3 is at least one R 12 In some embodiments, R 3 is at least two R 12 In some embodiments, R 3 is one R 12 In some embodiments, R 3 is two R 12 In some embodiments, R 3 is three R 12 is replaced by .

[0116] In some embodiments, R 3 teeth, [ka] where R 3 is 0 to 3 R 12 In some embodiments, R 3 teeth, [ka] where R 3 is one or two R 12 is replaced by .

[0117] In some embodiments, R 3 teeth, [ka] [ka] is.

[0118] In some embodiments, R 3 teeth, [ka] is.

[0119] In some embodiments, R 3 teeth, [ka] is.

[0120] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0121] In some embodiments, each R 12are independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N(R 13 )2, —S(═O)2NH2, —S(═O)2alkyl, —S(═O)2aryl, —S(═O)2heteroaryl, or cycloalkyl. In some embodiments, each R 12 are independently alkyl, heteroalkyl, haloalkyl, halo, cyano, heterocycloalkyl, -N(R 13 )2, or cycloalkyl. In some embodiments, each R 12 is independently aryl. In some embodiments, each R 12 is independently heteroaryl. In some embodiments, each R 12 is independently alkyl. In some embodiments, each R 12 is independently heteroalkyl. In some embodiments, each R 12 is independently haloalkyl. In some embodiments, each R 12 is independently halo. In some embodiments, each R 12 is cyano. In some embodiments, each R 12 is independently alkoxy. In some embodiments, each R 12 is independently heterocycloalkyl. In some embodiments, each R 12 are independently -N(R 13 )2. In some embodiments, each R 12 is independently —S(═O)NH. In some embodiments, each R 12 is independently —S(═O) alkyl. In some embodiments, each R 12 is independently —S(═O)aryl. In some embodiments, each R 12 is independently —S(═O)2 heteroaryl. In some embodiments, each R 12 is independently cycloalkyl. In some embodiments, each R 12are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluoro, chloro, cyano, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -N(R 13 )2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 12 is independently methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl, or cyclopropyl. 12 is independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chloro. In some embodiments, each R 12 is independently methyl or chloro. In some embodiments, each R 12 is methyl. In some embodiments, each R 12 is ethyl. In some embodiments, each R 12 is n-propyl. In some embodiments, each R 12 is isopropyl. In some embodiments, each R 12 is n-butyl. In some embodiments, each R 12 is isobutyl. In some embodiments, each R 12 is sec-butyl. In some embodiments, each R 12 is tert-butyl. In some embodiments, each R 12 is hydroxyethyl. In some embodiments, each R 12 is methoxyethyl. In some embodiments, each R 12 is trifluoromethyl. In some embodiments, each R 12 is trifluoroethyl. In some embodiments, each R 12is pentafluoroethyl. In some embodiments, each R 12 is fluoro. In some embodiments, each R 12 is chloro. In some embodiments, each R 12 is azetidinyl. In some embodiments, each R 12 is oxetanyl. In some embodiments, each R 12 is pyrrolidinyl. In some embodiments, each R 12 is imidazolidinyl. In some embodiments, each R 12 is tetrahydrofuranyl. In some embodiments, each R 12 is piperidinyl. In some embodiments, each R 12 is piperazinyl. In some embodiments, each R 12 is tetrahydropyranyl. In some embodiments, each R 12 is morpholinyl. In some embodiments, each R 12 is cyclopropyl. In some embodiments, each R 12 is cyclobutyl. In some embodiments, each R 12 is cyclopentyl. In some embodiments, each R 12 is cyclohexyl.

[0122] In some embodiments, each R 13 is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 13 is independently alkyl or cycloalkyl. In some embodiments, each R 13 is independently alkyl. In some embodiments, each R 13 is independently cycloalkyl. In some embodiments, each R 13 is independently aryl. In some embodiments, each R 13 is independently heteroaryl. In some embodiments, each R 13is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 13 is independently methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. 13 is independently methyl, cyclopropyl, or cyclohexyl. In some embodiments, each R 13 is methyl. In some embodiments, each R 13 is ethyl. In some embodiments, each R 13 is n-propyl. In some embodiments, each R 13 is isopropyl. In some embodiments, each R 13 is n-butyl. In some embodiments, each R 13 is isobutyl. In some embodiments, each R 13 is sec-butyl. In some embodiments, each R 13 is tert-butyl. In some embodiments, each R 13 is cyclopropyl. In some embodiments, each R 13 is cyclobutyl. In some embodiments, each R 13 is cyclopentyl. In some embodiments, each R 13 is cyclohexyl.

[0123] In some embodiments, R 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl in R is unsubstituted. 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of 14 In some embodiments, R 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of 14 In some embodiments, R12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of 14 is replaced by .

[0124] In some embodiments, each R 14 are independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N(R 15 )2, -S(=O)2 alkyl, -S(=O)2 aryl, -S(=O)2 heteroaryl, or alkoxy. In some embodiments, each R 14 are independently alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, -N(R 15 )2, or alkoxy. In some embodiments, each R 14 is independently aryl. In some embodiments, each R 14 is independently heteroaryl. In some embodiments, each R 14 is independently alkyl. In some embodiments, each R 14 is independently cycloalkyl. In some embodiments, each R 14 is independently heterocycloalkyl. In some embodiments, each R 14 is independently halo. In some embodiments, each R 14 is independently heteroalkyl. In some embodiments, each R 14 is independently haloalkyl. In some embodiments, each R 14 is cyano. In some embodiments, each R 14 is hydroxy. In some embodiments, each R 14 is amino. In some embodiments, each R 14 are independently -N(R 15 )2. In some embodiments, each R 14 is independently —S(═O) alkyl. In some embodiments, each R 14 is independently —S(═O)aryl. In some embodiments, each R 14is independently —S(═O)2 heteroaryl. In some embodiments, each R 14 is independently alkoxy. In some embodiments, each R 14 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, -N(R 15 )2, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 14 are independently methyl, ethyl, isopropyl, tert-butyl, pyrrolidinyl, piperidinyl, morpholinyl, fluoro, chloro, -N(R 15 )2, or methoxy. In some embodiments, each R 14 is methyl. In some embodiments, each R 14 is ethyl. In some embodiments, each R 14 is n-propyl. In some embodiments, each R 14 is isopropyl. In some embodiments, each R 14 is n-butyl. In some embodiments, each R 14 is isobutyl. In some embodiments, each R 14 is sec-butyl. In some embodiments, each R 14 is tert-butyl. In some embodiments, each R 14 is cyclopropyl. In some embodiments, each R 14 is cyclobutyl. In some embodiments, each R 14 is cyclopentyl. In some embodiments, each R 14 is cyclohexyl. In some embodiments, each R 14 is azetidinyl. In some embodiments, each R 14 is oxetanyl. In some embodiments, each R 14is pyrrolidinyl. In some embodiments, each R 14 is imidazolidinyl. In some embodiments, each R 14 is tetrahydrofuranyl. In some embodiments, each R 14 is piperidinyl. In some embodiments, each R 14 is piperazinyl. In some embodiments, each R 14 is tetrahydropyranyl. In some embodiments, each R 14 is morpholinyl. In some embodiments, each R 14 is fluoro. In some embodiments, each R 14 is chloro. In some embodiments, each R 14 is methoxy. In some embodiments, each R 14 is ethoxy. In some embodiments, each R 14 is trifluoromethoxy.

[0125] In some embodiments, each R 15 is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 15 is independently alkyl or cycloalkyl. In some embodiments, each R 15 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 15 is methyl. In some embodiments, each R 15 is ethyl. In some embodiments, each R 15 is n-propyl. In some embodiments, each R 15 is isopropyl. In some embodiments, each R 15 is n-butyl. In some embodiments, each R 15 is isobutyl. In some embodiments, each R 15 is sec-butyl. In some embodiments, each R 15is tert-butyl. In some embodiments, each R 15 is cyclopropyl. In some embodiments, each R 15 is cyclobutyl. In some embodiments, each R 15 is cyclopentyl. In some embodiments, each R 15 is cyclohexyl.

[0126] In some embodiments, X is —NH— or —O—; n is 0, R 5 is zero or one R 5’ is a phenyl substituted with R 2 is at least one R 7 and 0, 1, or 2 R 8 is a phenyl substituted with R 3 can contain 0, 1, 2, or 3 R 12 and pyrazolyl substituted with

[0127] In some embodiments, R 2 is one R 7 and 0, 1, or 2 R 8 is a phenyl substituted with

[0128] In some embodiments, X is —NH—.

[0129] In some embodiments, R 5’ is fluoromethyl, difluoromethyl, or trifluoromethyl.

[0130] In some embodiments, R 7 teeth, [ka] and R 8 is a halo.

[0131] In some embodiments, R 8 is fluoro, Y is -C(=O)-, R 9 and R 9’ is hydrogen, R 10 is hydrogen.

[0132] In some embodiments, R 12 is alkyl.

[0133] In some embodiments, R 12 is methyl.

[0134] In some embodiments, the compound has formula IA, formula IB, formula IC, formula ID, formula IE, formula IF, or formula IG: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0135] In some embodiments, the compound has formula IA: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula IA: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0136] In some embodiments, the compound has formula IB: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of formula IB, R 1 is R 5 In some embodiments of the compound of formula IB, R 5 is zero or one R 5’で In some embodiments of the compound of formula IB, R 5 is unsubstituted. In some embodiments of the compound of formula IB, R 5 is one R 5’ is replaced by .

[0137] In some embodiments, the compound has formula IC: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of formula IB, R 1 is R 5 In some embodiments of the compound of formula IC, R 5 is zero or one R 5’ In some embodiments of the compound of formula IC, R 5 is unsubstituted. In some embodiments of the compound of formula IC, R 5 is one R 5’ is replaced by .

[0138] In some embodiments, the compound has formula ID: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula ID: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0139] In some embodiments, the compound has the formula IE: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IE: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0140] In some embodiments, the compound has the formula IF: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IF: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0141] In some embodiments, the compound has formula IG: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of formula IG, R 1 is R 5 In some embodiments of the compound of formula IG, R 5 is zero or one R 5’ In some embodiments of the compound of formula IG, R 5 is unsubstituted. In some embodiments of the compound of formula IG, R 5 is one R 5’ is replaced by .

[0142] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0143] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0144] Particular embodiments of the present disclosure are compounds of Formula I selected from the group consisting of: or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof: N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 1), N-(3-((5-chloro-2-((6-oxo-1,6-dihydropyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 2), N-(3-((2-(4-amino-2-oxopyridin-1(2H)-yl)-5-chloropyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 3), (E)-N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 4), (E)-N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 5), (E)-N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-methoxybut-2-enamide (compound 6), (E)-N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-fluorobut-2-enamide (compound 7), N-(4-chloro-3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 8), (E)-N-(4-chloro-3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 9), N-(4-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-fluorophenyl)acrylamide (compound 10), (E)-N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)buta-2-enamide (compound 11), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)methacrylamide (compound 12), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide (compound 13), N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 14), N-(3-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 15), (E)-N-(3-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 16), (E)-4-(dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)buta-2-enamide (compound 17), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 18), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 19), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (compound 20), N-(3-((5-chloro-2-((5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 21), N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 22), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (compound 23), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)-2-fluoroacrylamide (compound 24), 1-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)-2-fluoroprop-2-en-1-one (compound 25), N-(3-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 26), (E)-N-(3-((5-chloro-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 27), N-(4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 28), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 29), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 30), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 31), N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 32), (E)-N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 33), 4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (compound 34), (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (compound 35), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 36), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 37), N-(4-fluoro-3-((2-((2-fluoropyridin-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 38), N-(4-fluoro-3-((2-((2-methoxyphenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 39), N-(3-((2-((2-chlorophenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 40), N-(3-((2-((5-chlorothiophen-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 41), N-(4-fluoro-3-((2-((1-methylpiperidin-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 42), N-(3-((2-((2-(dimethylamino)ethyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 43), N-(3-((2-((4-(dimethylamino)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 44), N-(3-((2-((4-((dimethylamino)methyl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 45), N-(4-fluoro-3-((2-(thiophen-3-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 46), N-(3-((5-(1-(N-benzylacetamido)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 47), N-(3-((5-((N-benzylacetamido)methyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 48), 4-((5-acrylamido-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (compound 49), N-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 50), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 51), (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-2-((2-methoxy-4-(piperidin-1-yl)phenyl)amino)-N-methyl-N-phenylpyrimidine-5-carboxamide (compound 52), (E)-N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 53), (E)-N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 54), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 55), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 56), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 57), N-(3-((5-(4-acetamidophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 58), N-(3-((5-(3-acetamidophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 59), 3-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-N-methylbenzamide (compound 60), N-(3-((5-(4-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 61), N-(3-((5-(4-cyanophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 62), N-(4-fluoro-3-((5-(4-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 63), 4-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-N-methylbenzamide (compound 64), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(2-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 65), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-methylpyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 66), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(5-methylpyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 67), N-(4-fluoro-3-((5-(2-methoxypyridin-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 68), N-(4-fluoro-3-((5-(5-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 69), N-(3-((5-(6-(difluoromethoxy)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 70), N-(3-((5-(2-(difluoromethoxy)pyridin-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 71), N-(3-((2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 72), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 73), N-(3-((5-(6-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 74), N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 75), N-(3-((5-(4-(tert-butyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 76), N-(4-fluoro-3-((5-(1-methyl-1H-indol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 77), N-(4-fluoro-3-((2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 78), N-(4-fluoro-3-((5-(2-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 79), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(2-methylpyridin-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 80), N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-1H-indol-4-yl)acrylamide (compound 81), N-(4-fluoro-3-((5-(2-fluoropyridin-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 82), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(2-(trifluoromethyl)pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 83), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(pyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 84), N-(4-fluoro-3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 85), N-(4-fluoro-3-((5-(6-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 86), N-(4-fluoro-3-((2-((3-fluoro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 87), N-(4-fluoro-3-((5-(3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 88), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(3-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 89), N-(4-fluoro-3-((5-(2-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 90), N-(4-fluoro-3-((5-(4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 91), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 92), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-phenylpyrimidin-4-yl)amino)phenyl)acrylamide (compound 93), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-morpholinophenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 94), N-(3-((5-(5-(difluoromethoxy)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 95), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 96), N-(3-((5-(1H-indol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 97), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 98), N-(3-((5-(4-(difluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 99), N-(4-fluoro-3-((5-(6-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 100), N-(3-((5-(6-chloropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 101), N-(3-((5-(5-chloropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 102), N-(3-((5-(4-(dimethylamino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 103), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 104), N-(3-((5-(4-(difluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 105), N-(3-((5-(6-(difluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 106), N-(3-((5-(6-(dimethylamino)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 107), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 108), N-(3-((5-(6-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 109), N-(3-((5-(5-(difluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 110), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 111), N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 112), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 113), N-(4-fluoro-3-((5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 114), N-(3-((5-(3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 115), N-(3-((5-(5-(dimethylamino)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 116), N-(3-((5-(2-chloropyridin-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 117), N-(3-((5-(6-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 118), N-(4-(dimethylamino)-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (Compound 119), N-(3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 120), N-(4-fluoro-3-((2-(phenylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 121), N-(4-fluoro-3-((2-((4-fluorophenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 122), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-2'-(trifluoromethyl)-[5,5'-bipyrimidin]-4-yl)amino)phenyl)acrylamide (compound 123), N-(3-((5-(3,6-dihydro-2H-pyran-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 124), N-(3-((5-(3-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 125), N-(4-fluoro-3-((5-(4-isopropylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 126), N-(3-((5-([1,1'-biphenyl]-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 127), N-(3-((5-(4-cyclopropylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 128), N-(3-((5-(2-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 129), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(2,2,2-trifluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 130), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(quinolin-7-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 131), N-(4-fluoro-3-((5-(imidazo[1,2-a]pyridin-7-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 132), N-(4-fluoro-3-((5-(imidazo[1,2-a]pyridin-6-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 133), N-(3-((5-(3-((dimethylamino)methyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 134), N-(3-((2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 135), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(naphthalen-1-yl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 136), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 137), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-sulfamoylphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 138), N-(4-fluoro-3-((2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 139), N-(3-((5-(4-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 140), N-(4-fluoro-3-((5-(5-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 141), N-(3-((5-(4-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 142), N-(3-((5-(3-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetic acid salt (compound 143), N-(3-((5-(5-(difluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 144), N-(3-((5-(3-(dimethylamino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 145), N-(4-fluoro-3-((2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 146), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-[5,5'-bipyrimidin]-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 147), N-(2-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 148), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(naphthalen-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetic acid salt (compound 149), N-(3-((5-(2-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide 2,2,2-trifluoroacetic acid salt (compound 150), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 151), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 152), N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)amino)-4-fluorophenyl)acrylamide (compound 153), N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 154), N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)acrylamide (compound 155), N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)acrylamide (compound 156), N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)acrylamide (compound 157), N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 158), N-(3-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4-fluorophenyl)acrylamide (compound 159), (E)-N-(3-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 160), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylethynyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 161), (E)-4-(dimethylamino)-N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylethynyl)pyrimidin-4-yl)amino)phenyl)buta-2-enamide (compound 162), 4-acrylamido-2-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-phenylbenzamide (compound 163), 4-acrylamido-2-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-phenylbenzamide (compound 164), N-(4-chloro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 165), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (compound 166), N-(3-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (compound 167), N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (compound 168), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-(trifluoromethyl)phenyl)acrylamide (compound 169), N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-methoxyphenyl)acrylamide (compound 170), N-(3-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-methoxyphenyl)acrylamide (compound 171), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-methoxyphenyl)acrylamide (compound 172), N-(2-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)-3-fluorophenyl)acrylamide (compound 173), (E)-N-(2-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)-3-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 174), N-(2-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)acrylamide (compound 175), (E)-4-(dimethylamino)-N-(2-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-[1,1′-biphenyl]-4-yl)but-2-enamide (compound 176), N-(2-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)acrylamide (compound 177), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-(phenylethynyl)phenyl)acrylamide (compound 178), (E)-N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-(phenylethynyl)phenyl)-4-(dimethylamino)but-2-enamide (compound 179), N-(3-((2-(cyclopropylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 180), N-(3-((2-(cyclobutylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 181), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide (compound 182), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(5-methylpyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 183), N-(3-((5-(5-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 184), N-(3-((5-(6-chloropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 185), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-methylpyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 186), N-(3-((5-(6-(difluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 187), N-(3-((5-(6-(difluoromethoxy)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 188), N-(3-((2-((2-chlorophenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 189), N-(3-((5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 190), N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 191), N-(3-((5-(3,6-dihydro-2H-pyran-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 192), N-(3-((2-((2-methoxyphenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 193), N-(3-((2-(cyclopropylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 194), N-(5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide (compound 195), N-(2-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-4-yl)acrylamide (compound 196), N-(6-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide (compound 197), N-(5-fluoro-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide (compound 198), N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 199), N-(4-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide (compound 200), N-(3-((5-(3-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 201), N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-fluorophenyl)acrylamide (compound 202), N-(3-((5-(4-bromophenyl)-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 203), N-(3-((5-(4-bromophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 204), N-(3-((5-(4-bromophenyl)-2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 205), N-(3-((5-(4-bromophenyl)-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 206), N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)acrylamide (compound 207), N-(3-((5-(4-bromophenyl)-2-((3-chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 208), N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)phenyl)acrylamide (compound 209), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyridin-4-yl)amino)phenyl)acrylamide (compound 210), N-(4-fluoro-3-((2-((3-methylisothiazol-5-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 211), N-(4-fluoro-3-((2-((5-methylisothiazol-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 212), N-(4-fluoro-3-((2-((4-methylthiazol-2-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 213), N-(4-fluoro-3-((2-((1-methyl-1H-imidazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 214), N-(4-fluoro-3-((2-(thiazol-2-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 215), N-(3-((2-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 216), N-(4-fluoro-3-((2-((5-methylthiophen-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 217), N-(3-((2-((3-((dimethylamino)methyl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 218), N-(4-fluoro-3-((2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 219), N-(4-fluoro-3-((2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 220), N-(3-((2-((3-chloro-1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 221), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-morpholinopyrimidin-4-yl)amino)phenyl)acrylamide (compound 222), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 223), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-6-(methylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 224), N-(4-fluoro-3-((2-(isoxazol-4-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 225), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 226), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(1-methylpyrrolidin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 227), N-(4-fluoro-3-(methyl(2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 228), N-(3-(methyl(2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 229), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(thiazol-5-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 230), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-6-(trifluoromethyl)quinazolin-4-yl)amino)phenyl)acrylamide (compound 231), N-(4-fluoro-3-((2-(pyridin-3-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 232), N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 233), N-(3-((2-((4-((dimethylamino)methyl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 234), N-(3-((2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 235), N-(3-((2-((2-(dimethylamino)ethyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 236), N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 237), N-(2-fluoro-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 238), N-(3-fluoro-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 239), N-(4-fluoro-3-((2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 240), N-(3-((2-((3-chloro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 241), N-(4-fluoro-3-((2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 242), N-(4-fluoro-3-((2-((1-(methyl- 13 C-d3)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 243), N-(3-((5-(cyclopropylethynyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 244), N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-5-fluorophenyl)acrylamide (compound 245), N-(3-((2-((1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 246), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide-3,3-d2 (compound 247), N-(4-fluoro-3-((2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide-3,3-d2 (compound 248), N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide-3,3-d2 (compound 249), N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide-3,3-d2 (compound 250), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)buta-2,3-dienamide (compound 251), 2-chloro-N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acetamide (compound 252), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)ethenesulfonamide (compound 253), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)propiolamide (compound 254), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 255), N-(3-((5-bromo-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 256), N 4 -(5-amino-2-fluorophenyl)-N 2 -(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (compound 257), N-(4-fluoro-3-((5-(2-isopropylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 258), N-(4-fluoro-3-((5-(2-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 259), N-(4-fluoro-3-((5-(1-methyl-1H-indol-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 260), N-(3-((5-(2,5-dihydrofuran-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 261), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(quinolin-5-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 262), N-(3-((5-([1,1'-biphenyl]-2-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 263), N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(2-fluorophenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 264), N-(3-((5-(1H-indol-7-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 265), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 266), N-(3-((5-(2-(dimethylamino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 267), N-(4-fluoro-3-((5-(isoquinolin-8-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 268), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(piperidin-1-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 269), N-(4-fluoro-3-((5-(1-methyl-1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 270), N-(3-((5-bromo-2-((1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 271), N-(3-((2-((1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)amino)-5-(2,5-dihydrofuran-3-yl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 272), N-(3-((5-bromo-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 273), N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 274), N-(3-((5-chloro-4-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (compound 275), N-(4-fluoro-3-((5-(4-((3-fluorobenzyl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 276), N-(3-((5-(1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 277), N-(3-((5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 278), N-(3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 279), N-(3-((5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 280), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenyl-4-d)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 281), N-(3-bromo-5-((5-(4-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 282), N-(3-bromo-5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 283), N-(3-((5-chloro-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 284), N-(4-fluoro-3-((5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 285), N-(3-((5-chloro-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 286), N-(3-((5-chloro-2-((4-((dimethylamino)methyl)phenyl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 287), N-(3-((5-chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 288), N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-(trifluoromethyl)phenyl)acrylamide (compound 289), N-(3-bromo-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 290), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-(trifluoromethyl)phenyl)acrylamide (compound 291), N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)acrylamide (compound 292), N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(2,2,2-trifluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 293), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 294), N-(3-fluoro-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(2,2,2-trifluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 295), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(perfluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 296), N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)acrylamide (compound 297), N-(3-((5-(5-chlorothiophen-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 298), N-(3-((5-(benzofuran-6-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 299), N-(4-fluoro-3-((5-(4-(3fluorophenoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 300), (E)-4-(dimethylamino)-N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(2,2,2-trifluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)buta-2-enamide (compound 301), N-(3-bromo-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(2,2,2-trifluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 302), (E)-4-fluoro-N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(2,2,2-trifluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)buta-2-enamide (compound 303), (E)-N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 304), and N-(4-fluoro-3-((5-(3-fluoro-5-methoxyphenyl)-2-(methyl(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 305).

[0145] Embodiments of the present disclosure relate to compounds of Formula I, or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, for treating diseases associated with epidermal growth factor receptor (EGFR) family kinases.

[0146] Another embodiment of the present disclosure relates to a compound of Formula I, or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, for treating cancer.

[0147] Another embodiment of the present disclosure relates to a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, for treating a disease or condition associated with non-small cell lung cancer or small cell lung cancer or prostate cancer or head and neck cancer or breast cancer or colorectal cancer.

[0148] The present disclosure relates to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

[0149] The present disclosure further relates to processes for preparing compounds of Formula I, or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof.

[0150] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0151] Purpose Some embodiments provided herein describe a class of compounds useful as epidermal growth factor receptor (EGFR) family kinase inhibitors. Some embodiments provided herein describe a class of compounds useful as EGFR inhibitors. Some embodiments provided herein describe a class of compounds useful as del19 / T790M EGFR inhibitors. Some embodiments provided herein describe a class of compounds useful as L858R / T790M EGFR inhibitors. In some embodiments, the compounds described herein have improved potency and / or a beneficial activity profile and / or a beneficial selectivity profile and / or increased efficacy and / or an improved safety profile (e.g., reduced side effects) and / or improved pharmacokinetic properties. In some embodiments, the compounds described herein are selective inhibitors of del19 / T790M EGFR over WT EGFR. In some embodiments, the compounds described herein are selective inhibitors of L858R / T790M EGFR over WT EGFR.

[0152] In some embodiments, the compounds described herein are selective inhibitors of EGFR over HER2.

[0153] In some embodiments, the compounds described herein have an improved safety profile. In some embodiments, the compounds described herein have an improved toxicity profile. In some embodiments, the compounds described herein have an improved therapeutic index.

[0154] In some embodiments, the compounds described herein are useful for treating, preventing, or ameliorating diseases or conditions exhibiting drug resistance associated with del19 / T790M EGFR activation. In some embodiments, the compounds described herein are useful for treating, preventing, or ameliorating diseases or conditions exhibiting drug resistance associated with L858R / T790M EGFR activation.

[0155] In some embodiments, EGFR family kinase mutants are detected using commercially available test kits. In some embodiments, EGFR family kinase mutants are detected by reverse transcription polymerase chain reaction (RT-PCR)-based methods. In some embodiments, EGFR family kinase mutants are detected by sequencing-based methods. In some embodiments, EGFR family kinase mutants are detected by mass spectrometry genotyping-based methods. In some embodiments, EGFR family kinase mutants are detected by immunohistochemistry-based methods. In some embodiments, EGFR family kinase mutants are detected by molecular diagnostic panels. In some embodiments, EGFR family kinase mutants are detected in tumor samples. In some embodiments, EGFR family kinase mutants are detected in circulating DNA. In some embodiments, EGFR family kinase mutants are detected in tumor cells.

[0156] In one aspect, provided herein is a method of inhibiting a mutant epidermal growth factor receptor (EGFR) family kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0157] In another aspect, provided herein are methods of inhibiting a human epidermal growth factor receptor 2 (HER2) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the HER2 mutant comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutant is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof. In some embodiments, the HER2 mutant is A775_G776insYVMA. In some embodiments, the HER2 mutant is A775_G776insSVMA. In some embodiments, the HER2 mutant is A775_G776insVVMA. In some embodiments, the HER2 mutant is G776del insVC. In some embodiments, the HER2 mutant is G776del insLC. In some embodiments, the HER2 mutant is G776del insAV. In some embodiments, the HER2 mutant is G776del insAVGC. In some embodiments, the HER2 mutant is S310F. In some embodiments, the HER2 mutant is S310Y. In some embodiments, the HER2 mutant is p95. In some embodiments, the HER2 mutant is V842I. In some embodiments, the HER2 mutant is P780_Y781insGSP.

[0158] In another aspect, provided herein is a method of inhibiting a mutant epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0159] In another aspect, provided herein are methods for inhibiting a drug-resistant epidermal growth factor receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the drug-resistant EGFR mutant is del19 / T790M EGFR or L858R / T790M EGFR.

[0160] In another aspect, provided herein are methods of inhibiting human epidermal growth factor receptor 2 (HER2) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound exhibits greater inhibition of HER2 mutants compared to wild-type EGFR. In some embodiments, the HER2 mutant comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutant is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof. In some embodiments, the HER2 mutant is A775_G776insYVMA. In some embodiments, the HER2 mutant is A775_G776insSVMA. In some embodiments, the HER2 mutant is A775_G776insVVMA. In some embodiments, the HER2 mutant is G776del insVC. In some embodiments, the HER2 mutant is G776del insLC. In some embodiments, the HER2 mutant is G776del insAV. In some embodiments, the HER2 mutant is G776del insAVGC. In some embodiments, the HER2 mutant is S310F. In some embodiments, the HER2 mutant is S310Y. In some embodiments, the HER2 mutant is p95. In some embodiments, the HER2 mutant is V842I. In some embodiments, the HER2 mutant is P780_Y781insGSP.

[0161] In another aspect, provided herein is a method of inhibiting epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound exhibits stronger inhibition of EGFR mutants as compared to wild-type EGFR.

[0162] In some embodiments, the EGFR mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutant is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutant is del19 / T790M EGFR. In some embodiments, the EGFR mutant is L858R / T790M EGFR.

[0163] In another aspect, provided herein is a method of treating an epidermal growth factor receptor (EGFR)-associated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0164] In some embodiments, the disease or disorder in the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and combinations thereof. In some embodiments, the HER2 mutation is A775_G776insYVMA. In some embodiments, the HER2 mutation is A775_G776insSVMA. In some embodiments, the HER2 mutation is A775_G776insVVMA. In some embodiments, the HER2 mutation is G776del insVC. In some embodiments, the HER2 mutation is G776del insLC. In some embodiments, the HER2 mutation is G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 mutation is S310F. In some embodiments, the HER2 mutation is S310Y. In some embodiments, the HER2 mutation is p95. In some embodiments, the HER2 mutation is V842I. In some embodiments, the HER2 mutation is P780_Y781insGSP.

[0165] In some embodiments, the disease or disorder in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutation is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutation is del19 / T790M EGFR. In some embodiments, the EGFR mutation is L858R / T790M EGFR.

[0166] In another aspect, provided herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the cancer exhibits drug resistance associated with del19 / T790M EGFR activation. In some embodiments, the cancer exhibits drug resistance associated with L858R / T790M EGFR activation. Other embodiments provided herein describe the use of the compounds described herein to treat cancer.

[0167] In some embodiments, the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, or non-small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, colorectal cancer, or glioblastoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is glioblastoma.

[0168] In some embodiments, the cancer in the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and combinations thereof. In some embodiments, the HER2 mutation is A775_G776insYVMA. In some embodiments, the HER2 mutation is A775_G776insSVMA. In some embodiments, the HER2 mutation is A775_G776insVVMA. In some embodiments, the HER2 mutation is G776del insVC. In some embodiments, the HER2 mutation is G776del insLC. In some embodiments, the HER2 mutation is G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 mutation is S310F. In some embodiments, the HER2 mutation is S310Y. In some embodiments, the HER2 mutation is p95. In some embodiments, the HER2 mutation is V842I. In some embodiments, the HER2 mutation is P780_Y781insGSP.

[0169] In some embodiments, the cancer in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutation is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutation is del19 / T790M EGFR. In some embodiments, the EGFR mutation is L858R / T790M EGFR.

[0170] In another aspect, provided herein is a method for treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. Also described herein is the use of the compounds described herein for treating inflammatory diseases associated with del19 / T790M EGFR activation. Also described herein is the use of the compounds described herein for treating inflammatory diseases associated with L858R / T790M EGFR activation.

[0171] In some embodiments, the inflammatory disease is psoriasis, eczema, or atherosclerosis. In some embodiments, the inflammatory disease is psoriasis. In some embodiments, the inflammatory disease is eczema. In some embodiments, the inflammatory disease is atherosclerosis.

[0172] In some embodiments, the inflammatory disease in the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof. In some embodiments, the HER2 mutation is A775_G776insYVMA. In some embodiments, the HER2 mutation is A775_G776insSVMA. In some embodiments, the HER2 mutation is A775_G776insVVMA. In some embodiments, the HER2 mutation is G776del insVC. In some embodiments, the HER2 mutation is G776del insLC. In some embodiments, the HER2 mutation is G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 mutation is S310F. In some embodiments, the HER2 mutation is S310Y. In some embodiments, the HER2 mutation is p95. In some embodiments, the HER2 mutation is V842I. In some embodiments, the HER2 mutation is P780_Y781insGSP.

[0173] In some embodiments, the inflammatory disease in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH In some embodiments, the EGFR mutation is selected from EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR. In some embodiments, the EGFR mutation is del19 / T790M EGFR. In some embodiments, the EGFR mutation is L858R / T790M EGFR.

[0174] Administration and Pharmaceutical Compositions In certain embodiments, the EGFR inhibitor compounds described herein are administered as pure chemicals. In other embodiments, the EGFR inhibitor compounds described herein are combined with a pharmaceutically suitable or pharmaceutically acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, such as that described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0175] Provided herein are pharmaceutical compositions comprising at least one EGFR inhibitor compound described herein, or its stereoisomer, pharmaceutically acceptable salt, or N-oxide, together with one or more pharmaceutically acceptable carriers. Carrier(s) (or excipient(s)) are acceptable or suitable if they are compatible with the other ingredients of the composition and not harmful to the recipient of the composition (i.e., subject or patient).

[0176] One embodiment provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0177] In certain embodiments, the EGFR inhibitor compounds disclosed herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0178] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of soft or hard gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0179] Dosages of compositions comprising at least one EGFR inhibitor compound described herein will vary depending on the patient's condition, ie, stage of disease, health status, age, and other factors.

[0180] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dosage and the suitable duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Usually, an appropriate dosage and treatment regimen provides a sufficient amount of the composition(s) to produce a therapeutic and / or prophylactic effect (e.g., improved clinical outcome) or a reduction in the severity of symptoms. The optimal dosage is usually determined using experimental models and / or clinical trials. The optimal dosage depends on the patient's size, weight, or blood volume.

[0181] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times daily or more. [Example]

[0182] Example 1: Synthetic Procedure Yields reported herein are for purified products (unless otherwise stated) and are not optimized. TLC analysis was performed on Merck aluminum-backed silica gel 60 F. 254 The chromatograms were run on plates. Compounds were visualized by ultraviolet light and / or stained with either iodine, potassium permanganate, or ninhydrin solution. Flash column chromatography was performed on silica gel (100-200 M) or flash chromatography. 1 H-NMR spectra were recorded on a Bruker Avance-400 MHz spectrometer equipped with BBO (Broad Band Observe) and BBFO (Broad Band Fluorine Observe) probes. Chemical shifts (δ) are expressed in parts per million (ppm) downfield relative to tetramethylsilane (TMS) as the internal standard. Splitting patterns are expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and bs (broad singlet). Coupling constants (J) are given in hertz (Hz). LC-MS analysis was performed on an Acquity BEH C-18 column (2.10 × 100 mm, 1.70 μm) or an Acquity HSS-T3 column (2.10 × 100 mm, 1.80 μm) using electrospray ionization (ESI) technology.

[0183] The following solvents, reagents, or scientific terms may be referred to by their abbreviations: TLC thin layer chromatography DCM dichloromethane THF tetrahydrofuran MeOH Methanol EtOH ethanol IPA Isopropyl Alcohol EtOAc ethyl acetate Et2O diethyl ether DMA N,N-dimethylacetamide DMF N,N-dimethylformamide TEA / Et3N Triethylamine DMSO dimethyl sulfoxide DIPEA Diisopropylethylamine (Hunig's base) MeI methyl iodide NBS N-Bromosuccinimide TBAB Tetrabutylammonium bromide TBAI Tetrabutylammonium Iodide DIBAL-H Diisobutylaluminum hydride TFA trifluoroacetic acid AcOH acetic acid Boc tert-butoxycarbonyl Cat catalyst mL milliliter mmol millimolar h hour or hours min minute or minutes g grams mg milligram μl microliter eq equivalent rt or RT room temperature, ambient temperature, approximately 27°C MS mass spectrometry Boc tert-butyloxycarbonyl m-CPBA metachloroperbenzoic acid T3P Propanephosphonic Anhydride BH3-DMS Borane dimethyl sulfide complex LiBH4 Lithium Aluminum Hydride NaBH4 Sodium borohydride H2 Hydrogen Pd / C Palladium Carbon 1,2-DCE 1,2-dichloroethane

[0184] General Procedure A: To an ice-cold solution of an arylamine (1.0 equiv.) in tetrahydrofuran was added sodium hydride (60% dispersion in mineral oil, 3.0 equiv.) in portions. The resulting reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of 2,4,5-trichloropyrimidine or 2,4-dichloro-5-bromopyrimidine (1.0 equiv.). The resulting reaction mixture was heated at 60° C. for 16 hours. Upon completion (TLC monitoring), the mixture was quenched with ice and extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with diethyl ether, filtered, and dried under reduced pressure to give the desired product.

[0185] General Procedure B: To a solution of arylhalo (1.0 equiv.) in 1,4-dioxane or toluene was added cesium carbonate (3.0 equiv.) and arylamine (1.2 equiv.). The resulting reaction mixture was degassed under nitrogen for 15 minutes, followed by the addition of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 0.1 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv.) under a nitrogen atmosphere. The resulting reaction mixture was again degassed for 15 minutes and then heated at 100°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled, diluted with water, and extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 4-8% methanol in dichloromethane as the eluent and the desired fractions were concentrated under reduced pressure to give the desired product.

[0186] General procedure C: To an ice-cold solution of a primary or secondary arylamine (1.0 equiv.) in dichloromethane, triethylamine (3.0 equiv.) and acetyl chloride (1.2 equiv.) were added dropwise. The resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash, eluting with 4-5% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give the desired product.

[0187] General Procedure D: To a solution of the aldehyde (1.0 equivalent) in methanol was added the corresponding amine (3.0 equivalents) and sodium acetate (5.0 equivalents). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice-cold water, and the resulting solid was filtered. The solid was dried under reduced pressure to obtain the desired product.

[0188] General Procedure E: To a solution of the product obtained by General Procedure D (1.0 equivalent) in methanol (2.5 volumes), acetic acid (1.0 volume) was added, followed by the addition of sodium borohydride (1.0 equivalent). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water, and the resulting solid was filtered and washed with water. The solid was dried under reduced pressure to obtain the desired product.

[0189] General Procedure F: To an ice-cold solution of the product obtained by General Procedure E (1.0 equivalent) in tetrahydrofuran, diisopropylethylamine (4.0 equivalents) was added, followed by triphosgene (0.4 equivalents). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), saturated sodium bicarbonate solution was added and extracted with dichloromethane (3 times). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was triturated with diethyl ether to give the desired product.

[0190] General Procedure G: To an ice-cold solution of the product obtained by General Procedure F (1.0 equivalent) in dichloromethane was added m-chloroperbenzoic acid (2.0 equivalents). The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction (monitored by TLC), saturated sodium bicarbonate solution was added to the reaction mixture, which was then extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was triturated with diethyl ether to give the desired product.

[0191] General Procedure H: To an ice-cold solution of the product obtained by General Procedure G (1.0 equivalent) in isopropanol was added the corresponding amine (1.2 equivalents) and trifluoroacetic acid (2.0 equivalents). The reaction mixture was heated at 110°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added, and extracted with dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude residue was triturated with diethyl ether to give the desired product, which was used directly in the next step.

[0192] General Procedure I: An ice-cold solution of the product obtained by General Procedure H (1.0 equiv.) in 20% trifluoroacetic acid in dichloromethane was stirred at room temperature for 3-16 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated. The reaction mass was diluted with saturated sodium bicarbonate solution and extracted with 5% methanol in dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was triturated with ether or purified by CombiFlash, eluting with 5-10% methanol in dichloromethane, to give the desired product.

[0193] General procedure J: To an ice-cold solution of the product obtained by General Procedure I (1.0 equiv.) in dichloromethane, triethylamine (3-5 equiv.) and the corresponding acid (1.1 equiv.) were added, followed by propylphosphonic anhydride (T3P, 50% in ethyl acetate, 2.5 equiv.). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mass was diluted with saturated sodium bicarbonate solution and extracted with 5% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash or preparative TLC or preparative HPLC purification to give the final compound.

[0194] General Procedure K: A solution of the product obtained by General Procedure I (1.0 equivalent) in dichloromethane:tetrahydrofuran (1:1) was cooled to -40°C, followed by the addition of triethylamine (3-5 equivalents) and acryloyl chloride (1.0 equivalent). The mixture was stirred at the same temperature for 2 hours. After completion of the reaction (monitored by TLC), water was added and extracted with dichloromethane (3 times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the final compound.

[0195] General Procedure K1: To a solution of the product (1.0 equivalent) obtained by General Procedure I in tetrahydrofuran and water (3:1) was added triethylamine (5 equivalents) and acryloyl chloride (1.0 equivalents) at -0°C. The reaction mixture was stirred at the same temperature for 2 hours. After completion of the reaction (monitored by TLC), water was added and extracted with ethyl acetate (3 times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the final compound.

[0196] General Procedure K2: To a solution of the product obtained by General Procedure I (1.0 equiv.) in tetrahydrofuran and water (3:1), triethylamine (5 equiv.) and 3-chloropropionyl chloride (1.2-1.5 equiv.) were added at -0°C. The reaction mixture was stirred at the same temperature for 20 minutes to 1 hour. After completion of the reaction (monitored by LCMS), water was added and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the final compound.

[0197] General procedure L: To an ice-cold solution of the nitro derivative (1.0 equiv.) in methanol:tetrahydrofuran:water (2:2:1) was added zinc or iron powder (5 equiv.) and ammonium chloride (5 equiv.). The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was passed through a Celite bed and washed with 5% methanol in dichloromethane. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the amino derivative.

[0198] General Procedure L1: To a solution of the nitro derivative (1.0 equivalent) in methanol or ethanol (10 volumes), 10% palladium on carbon (20% w / w) was added. The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and washed with methanol. The combined filtrate was concentrated under reduced pressure to give the amino derivative.

[0199] General Procedure M1: (Suzuki Coupling): To a solution of the halo derivative (1.0 equiv.) in acetonitrile, the corresponding boronate acid / boronic ester derivative (1.0 equiv.) was added, followed by an aqueous solution of potassium carbonate (2.0 equiv.) under argon purging. The resulting reaction mixture was degassed for 15 min. Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (0.1 equiv.) was added, and the reaction mixture was heated at 80 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice water and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by CombiFlash elution, eluting with 40–60% ethyl acetate in hexanes. The desired fractions were concentrated under reduced pressure to give the desired product.

[0200] General procedure M2: To a solution of a halo derivative (1.0 equiv.) and the corresponding boronic acid (1.1 equiv.) in toluene:ethanol (1:1), dimethylformamide, or dimethoxyethane and water (4:1) was added potassium carbonate (2.0 equiv.) or sodium bicarbonate (2.0 equiv.). The resulting reaction mixture was degassed with argon for 15 minutes, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.05 equiv.). The resulting reaction mixture was heated at 90°C for 5-16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash elution, eluting with 30-50% ethyl acetate in hexanes. The desired fractions were concentrated under reduced pressure to give the desired product.

[0201] General Procedure M3: To a solution of a halo derivative (1.0 equivalent) and the corresponding boronate acid / boronic ester derivative (1.1 equivalent) in N,N-dimethylformamide:water (4:1) was added sodium carbonate or sodium bicarbonate (2.0 equivalents). The resulting reaction mixture was degassed under an argon atmosphere for 15 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 equivalents). The resulting reaction mixture was heated at 90 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using CombiFlash, and the desired fractions were concentrated under reduced pressure to give the desired product.

[0202] General Procedure N: To an ice-cold solution of N-(3-(2-chloro-6-fluoroquinazolin-8-yl)phenyl)acrylamide (1.0 equiv.) in dimethylformamide, sodium hydride (60% dispersion in mineral oil, 10 equiv.) was added portionwise and stirred at room temperature for 30 minutes, followed by the addition of the corresponding amine (1.2 equiv.). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was diluted with ice-cold water and extracted with 5% methanol / dichloromethane (3 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash or preparative HPLC purification to give the desired product.

[0203] General Procedure: To a solution of a primary or secondary alcohol (1.0 equivalent) in dichloromethane, activated manganese dioxide (10 equivalents) was added at room temperature under a nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite bed and washed with dichloromethane (3 times). The combined filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired product.

[0204] Scheme 1: Synthesis of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (8): [ka] Step 1: Synthesis of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (2): An ice-cold solution of pyrimidine-2,4(1H,3H)-dione (1) (10 g, 89.21 mmol) and paraformaldehyde (9.63 g, 107.05 mmol) in aqueous potassium hydroxide (132 mL, 0.5 M, 66.74 mmol) was heated at 55° C. for 14 h. After completion of the starting material (TLC), the reaction mixture was cooled to 0° C., the pH was adjusted to 6 with 12 N hydrochloric acid, and the resulting white precipitate was filtered through a sintered funnel and washed with diethyl ether to give 2 as a white solid (6.3 g, 50% yield), which was used directly in the next step. 1 H-NMR (400 MHz, DMSO-d6): δ 10.98 (bs, 1H), 10.64 (bs, 1H), 7.24 (s, 1H), 4.78 (m, 1H), 4.12 (d, J = 12.8 Hz, 2H). LCMS: [M+H] + 143.04.

[0205] Step 2: Synthesis of 2,4-dichloro-5-(chloromethyl)pyrimidine (3): To an ice-cold solution of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (2) (10 g, 70.36 mmol) in toluene (25 mL) was added phosphoryl chloride (14 mL, 140.72 mmol), followed by N,N-diisopropylethylamine (37 mL, 211 mmol). The reaction mixture was heated at 120 °C for 16 h. After complete disappearance of the starting material by TLC, the reaction mixture was slowly quenched with sodium bicarbonate solution and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 3 as a brown solid (12 g, yield: 86%), which was used directly in the next step. 1 H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 4.64 (s, 2H). MS: [M+H] + 197.0.

[0206] Step 3: Synthesis of 2,4-dichloro-5-(iodomethyl)pyrimidine (4): To a solution of 2,4-dichloro-5-(chloromethyl)pyrimidine (3) (8.0 g, 40.51 mmol) in acetone (40 mL) was added sodium iodide (9.71 g, 64.82 mmol). The reaction mixture was stirred at room temperature for 30 minutes and heated to reflux for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature. The resulting white precipitate was filtered through a sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure to give 4 as a brown solid (10 g, yield: 85%), which was used directly in the next step. 1 H-NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 4.39 (s, 2H).

[0207] Step 4: Synthesis of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (6): To an ice-cold solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (4) (5.0 g, 17.30 mmol) in acetone (50 mL) was added potassium carbonate (5.26 g, 38.06 mmol) and aniline (5) (1.93 g, 20.76 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (as monitored by TLC), the resulting white precipitate was filtered through a sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (100-200 mesh) using 15% ethyl acetate / hexane as the eluent to give 6 as a brown solid (2.5 g, yield: 57%). 1 H-NMR (400 MHz, CDCl3): δ 8.61 (s, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.58 (m, 3H), 6.30 (bs, 1H), 4.33 (m, 2H). LCMS: [M+H] + 254.03.

[0208] Step 5: Synthesis of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (8): To an ice-cold solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (6) (500 mg, 1.96 mmol) in isopropanol (5 mL) were added N,N-diisopropylethylamine (1.47 mL, 8.42 mmol) and tert-butyl (3-aminophenyl)carbamate (7) (409 mg, 1.96 mmol). The resulting reaction mixture was heated at 100 °C in a sealed tube for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (100-200 mesh) using 30% ethyl acetate in hexane as the eluent to give 8 as a brown solid (500 mg, yield: 60%). 1 H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.96 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.25 (m, 2H), 7.12 (m, 3H), 6.61 (m, 3H), 6.14 (t, J = 7.2 Hz, 1H), 4.26 (m, 2H), 1.53 (s, 9H). LCMS: [M+H] + 426.14.

[0209] Scheme 2: Synthesis of 2-(4-amino-1H-pyrazol-1-yl)ethan-1-ol (11): [ka] Step 1: Synthesis of 2-(4-nitro-1H-pyrazol-1-yl)ethan-1-ol (10) To a stirred solution of 4-nitro-1H-pyrazole (9) (2.00 g, 17.7 mmol) in acetonitrile (20.0 mL) were added 2-bromoethan-1-ol (1.38 mL, 19.5 mmol), potassium carbonate (2.93 g, 21.2 mmol), and the reaction mixture was heated at 80° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL×4). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography using a CombiFlash purification system and eluted with 45% ethyl acetate in hexane to give the title compound (10) as a white solid (2.5 g, 90%). LCMS: [M+H] + 158.0.

[0210] Step 2: Synthesis of 2-(4-amino-1H-pyrazol-1-yl)ethan-1-ol (11) To a stirred solution of 2-(4-nitro-1H-pyrazol-1-yl)ethan-1-ol (10) (2.50 g, 15.9 mmol) in ethanol (20 mL) was purged with nitrogen for 5 minutes, palladium on carbon (0.25 g, 10% w / w) was added, and the reaction mixture was hydrogenated for 15 hours. The reaction mixture was filtered through Celite, and the filtrate was evaporated to give the title compound (11) as a brown liquid (2.0 g, crude). 1 H NMR (400 MHz, DMSO-d6): δ 7.00 (s, 1H), 6.87 (s, 1H), 4.78 (t, J = 4.8 Hz, 1H), 3.92 (t, J = 6.0 Hz, 2H), 3.73 (bs, 2H), 3.63-3.59 (m, 2H).

[0211] Scheme 3: Synthesis of N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 1): [ka] Step 1: Synthesis of 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (14): The title compound was prepared in a manner essentially similar to that described in General Procedure A. The crude product was triturated with diethyl ether, filtered, and dried under reduced pressure to give 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (14) as a pale yellow solid (10.0 g, 34% yield). 1 H-NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 8.48 (s, 1H), 8.40-8.43 (m, 1H), 8.22-8.26 (m, 1H), 7.65 (t, J = 9.2 Hz, 1H).

[0212] Step 2: Synthesis of 4-(4-((5-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexan-1-ol (16): The title compound was prepared in essentially the same manner as described in General Procedure H to give the desired product (16) as a pale yellow solid (0.75 g, 84.7% yield). MS: [M+H] + 448.21.

[0213] Step 3: Synthesis of 4-(4-((4-((5-amino-2-fluorophenyl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexan-1-ol (17): The title compound was prepared in a manner essentially similar to that described in General Procedure L to give the desired product (17) as a brown solid (0.55 g, yield: 78.57%). MS: [M+H] + 418.18.

[0214] Step 4: Synthesis of N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 1): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC purification to give Compound 1 (45 mg, yield: 13.27%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.32 (bs, 1H), 9.26 (bs, 1H), 8.86 (bs, 1H), 8.05 (s, 1H), 7.78-7.79 (m, 1H), 7.70 (s, 1H), 7.65 (bs, 1H), 7.31-7.34 (m, 1H), 7.08-7.13 (m, 2H), 6.38-6.45 (m, 1H), 6.24 (d, J = 17.2 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 4.62 (d, J = 4.4 Hz, 1H), 3.60-3.62 (m, 1H), 1.83 (d, J = 11.2 Hz, 2H), 1.23-1.63 (m, 6H). LCMS: [M+H] + 472.22.

[0215] Table 1: The following compounds were prepared using the above procedure. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0216] Scheme 4: N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 14): [ka] Step 1: 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (20) The title compound was prepared in essentially the same manner as described in General Procedure H to give the desired product (20) as a pale yellow solid (0.2 g, 23% yield). LCMS: [M+H] + 447.2.

[0217] Step 2: N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (21) To a stirred solution of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyrimidine-2,4-diamine (20) (0.2 g, 0.44 mmol) in methanol (30 mL), Raney nickel (0.07 g, 1.34 mmol) was added and stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through a Celite bed and distilled to give the title compound (21) as a yellow solid (0.16 g, 85%). LCMS [M+H] + 417.1.

[0218] Step 3: N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 14) The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC purification to give Compound 14 (17 mg, yield: 14%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.23 (s, 1H), 8.85 (s, 1H), 8.02 (s, 1H), 7.71 (d, J = 6.4 Hz, 2H), 7.30 (s, 1H), 7.10 (t, J = 15.2 Hz, 2H), 6.35-6.42 (m, 1H), 6.23 (d, J = 17.2 Hz, 1H), 5.74 (d, J = 10.0 Hz, 1H), 3.57 (s, 1H), 2.75 (d, J = 10.0 Hz, 2H), 2.16 (s, 3H). 1.93 (s, 2H), 1.63 (s, 4H). LCMS: [M+H] + 471.0.

[0219] Table 2: The following compounds were prepared using the above procedure. [Table 2]

[0220] Scheme 5: Synthesis of (E)-4-(dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)buta-2-enamide (compound 17): [ka] Step 1: Synthesis of tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (23): The title compound was prepared in a manner essentially similar to that described in General Procedure B. The crude product was purified by CombiFlash chromatography using 5% methanol in dichloromethane as the eluent, and the desired fractions were concentrated under reduced pressure to give tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (23) as a light brown solid (500 mg; yield: 87%). MS: [M+H] + 487.25.

[0221] Step 2: Synthesis of N4-(3-aminophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-((phenylamino)methyl)pyrimidine-2,4-diamine (24): The title compound was prepared in a manner essentially similar to that described in General Procedure I. The crude product was triturated with diethyl ether to give N4-(3-aminophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-((phenylamino)methyl)pyrimidine-2,4-diamine (24) as the TFA salt as a brown solid (0.50 g, 84% yield). MS: [M+H] + 387.25.

[0222] Step 3: Synthesis of (E)-4-(dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)buta-2-enamide (Compound 17) The title compound was prepared in a manner essentially similar to that described in General Procedure J. The resulting crude product was purified by CombiFlash, eluting with 8% methanol in dichloromethane. The title compound was further purified by preparative HPLC to give (E)-N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 17) as a white solid (66 mg; yield: 20.52%).1 H-NMR (400 MHz, DMSO-d6): δ 10.06 (bs, 1H), 8.91 (bs, 1H), 8.43 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.58-7.30 (m, 4H), 7.11-7.07 (m, 2H), 6.75-6.66 (m, 4H), 6.57 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 15.2 Hz, 1H), 5.99-5.97 (m, 1H), 4.17 (d, J = 4.0 Hz, 2H), 3.62 (s, 3H), 3.05 (d, J = 5.2 Hz, 2H), 2.16 (s, 6H). LCMS: [M+H] + 498.38 (96.05%).

[0223] Scheme 6: Synthesis of (E)-4-(dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)buta-2-enamide (compound 18): [ka] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (26): The title compound was prepared in a manner essentially similar to that described in General Procedure C. The crude product was purified by silica gel (100-200 mesh) eluting with 3-5% methanol in dichloromethane, and the desired fractions were concentrated to dryness to give tert-butyl (3-((2-chloro-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (26) as a light brown solid (300 mg, yield: 54.84%). MS: [M+H] + 468.06.

[0224] Step 2: Synthesis of tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (27): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified by silica gel (100-200 mesh) eluting with 6-8% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (27) as a light brown solid (290 mg, 85.5% yield). MS: [M+H] + 529.14.

[0225] Step 3: Synthesis of N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-phenylacetamide (28): The title compound was prepared in a manner essentially similar to that described in General Procedure I. The crude product was triturated with diethyl ether to give N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-phenylacetamide (28) as the TFA salt as a brown solid (130 mg, yield: 55.3%). MS: [M+H] + 429.25.

[0226] Step 4: Synthesis of N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 18): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC to give N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 18) as a white solid (22 mg; yield: 15.0%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.30 (s, 1H), 8.98 (s, 1H), 8.00-7.60 (m, 3H), 7.54 (d, J = 7.6 Hz, 1H), 7.47-7.32 (m, 6H), 7.20 (d, J = 7.6 Hz, 2H), 6.51-6.44 (q, J = 10.0 Hz, 1H), 6.28-6.23 (m, 1H), 5.77-5.74 (m, 1H), 4.74 (s, 2H), 3.66 (s, 3H), 1.84 (s, 3H). LCMS: [M+H] + 483.33.

[0227] Scheme 7: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 19): [ka] Step 1: Synthesis of tert-butyl (E)-(3-((2-(methylthio)-5-(((1-phenylethyl)imino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (31): The title compound was prepared in a manner essentially similar to that described in General Procedure D to give tert-butyl (E)-(3-((2-(methylthio)-5-(((1-phenylethyl)imino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (31) as a light brown solid (1.20 g, 93.70% yield). MS: [M+H] + 464.31.

[0228] Step 2: Synthesis of tert-butyl (3-((2-(methylthio)-5-(((1-phenylethyl)amino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (32): The title compound was prepared in a manner essentially similar to that described in General Procedure E to give tert-butyl (3-((2-(methylthio)-5-(((1-phenylethyl)amino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (32) as a pale yellow solid (1.0 g, 83% yield). MS: [M+H] + 466.25.

[0229] Step 3: Synthesis of tert-butyl (3-((2-(methylthio)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (33): The title compound was prepared in a manner essentially similar to that described in General Procedure C. The resulting crude product was purified by silica gel (100-200 mesh) eluting with 4-5% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give tert-butyl (3-((2-chloro-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (33) as a light brown solid (500 mg; yield: 41.66%). MS: [M+H] + 508.25.

[0230] Step 4: Synthesis of tert-butyl (3-((2-(methylsulfonyl)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (34): The title compound was prepared in a manner essentially similar to that described in General Procedure G to give tert-butyl (3-((2-(methylsulfonyl)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (34) as an off-white solid (400 mg; yield: 75%). MS: [M+H] + 540.15.

[0231] Step 5: Synthesis of tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (35): The title compound was prepared in a manner essentially similar to that described in General Procedure H to give tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (35) as a light brown solid (200 mg; yield: 48.54%). LCMS: [M+H] + 557.31.

[0232] Step 6: Synthesis of N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(1-phenylethyl)acetamide (36): The title compound was prepared in a manner substantially similar to that described in General Procedure I to give N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(1-phenylethyl)acetamide (36) as the TFA salt as a brown solid (150 mg; yield: 91.64%). MS: [M+H] + 457.25.

[0233] Step 7: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 19): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC to give N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 19) as a white solid (30 mg; yield: 15.0%). 1 H NMR (400 MHz, DMSO d6): δ 10.20 (s, 1H), 9.48 (s, 1H), 8.89 (s, 1H), 7.89 (s, 1H), 7.74-7.25 (m, 11H), 6.49-6.42 (m, 1H), 6.27-6.23 (m, 1H), 5-76-5.73 (m, 1H), 5.25-5.23 (m, 1H), 4.53-4.41 (m, 1H), 4.25-4.15 (m, 1H), 3.64 (bs, 3H), 2.15 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). LCMS: [M+H] + 511.37.

[0234] Scheme 8: Synthesis of N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (compound 20): [ka] Step 1: Synthesis of 2-fluoro-5-nitro-N-phenylaniline (38): The title compound was prepared in a manner essentially similar to that described in General Procedure B. The crude product was purified by CombiFlash chromatography using 10-20% ethyl acetate in hexane as the eluent, and the desired fractions were concentrated under reduced pressure to give 2-fluoro-5-nitro-N-phenylaniline (38) as a light brown solid (4.0 g; yield: 54.0%). MS: [MH] - 230.96.

[0235] Step 2: Synthesis of 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)-N-phenylpyrimidin-4-amine (39): To a solution of 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (38) (2.00 g, 8.61 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (2.40 g, 17.22 mmol) and 2,4,5-trichloropyrimidine (13) (1.60 g, 8.61 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled, diluted with ice-cold water, and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 5–10% ethyl acetate in hexane as the eluent, and the desired fractions were concentrated under reduced pressure to give 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)-N-phenylpyrimidin-4-amine (39) as a light brown solid (1.40 g; yield: 42.9%). 1 H-NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 7.97-7.94 (m, 1H), 7.72-7.68 (m, 1H), 7.49-7.42 (m, 1H), 7.38-7.29 (m, 2H), 7.19-7.17 (m, 2H), 7.14-7.03 (m, 1H).

[0236] Step 3: Synthesis of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (40): The title compound was prepared in a manner substantially similar to that described in General Procedure H to give 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (40) as a light brown solid (550 mg; yield: 94.8%). MS: [M+H] + 440.17.

[0237] Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (41): The title compound was prepared in a manner substantially similar to that described in General Procedure L to give N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (41) as a brown solid (450 mg; yield: 88%). MS: [M+H] + 410.01.

[0238] Step 5: Synthesis of N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (compound 20): The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude product was purified by preparative HPLC to give N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (Compound 20) as a white solid (95 mg, yield: 33.56%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.58 (s, 1H), 8.19 (s, 1H), 7.69-7.05 (m, 9H), 6.62 (bs, 1H), 6.36-6.18 (m, 2H), 5.74-5.71 (m, 1H), 3.47 (s, 3H). LCMS: [M+H] + 464.18.

[0239] Scheme 9: Synthesis of N-(3-((5-chloro-2-((5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 21): [ka] Step 1: Synthesis of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (43) The title compound was prepared in a manner substantially similar to that described in General Procedure H to give 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (43) as a light brown solid (500 mg; yield: 62.11%). LCMS: [M+H] + 407.97.

[0240] Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (44): To a solution of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (43) (250 mg, 0.61 mmol) in methanol (15 mL) was added Raney nickel (100 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite bed and washed with 10% methanol in dichloromethane (3 × 5 mL). The combined organic components were concentrated under reduced pressure to give N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (44) as a light brown solid (200 mg, yield: 86.58%). MS: [M+H] + 378.20.

[0241] Step 3: Synthesis of N-(3-((5-chloro-2-((5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 21): The title compound was prepared in a manner substantially similar to that described in General Procedure K. N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (44) and acryloyl chloride (18) gave N-(3-((5-chloro-2-((5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 21) as a white solid (45 mg, yield: 19.77%). 1 H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.46 (s, 1H), 8.89 (s, 1H), 8.06 (s, 1H), 7.76-7.68 (m, 2H), 7.28 (t, J = 9.4 Hz, 1H), 6.45-6.23 (m, 2H), 5.86-5.75 (m, 2H), 4.14 (s, 2H), 3.57 (s, 3H), 3.12 (s, 3H). LCMS: [M+H] + 432.17.

[0242] Scheme 10: Synthesis of N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 22): [ka] Step 1: Synthesis of N1-(2,5-dichloropyrimidin-4-yl)-6-fluorobenzene-1,3-diamine (46) The title compound was prepared in a manner substantially similar to that described in General Procedure I to give N1-(2,5-dichloropyrimidin-4-yl)-6-fluorobenzene-1,3-diamine (46) as the TFA salt as an off-white solid (2.0 g; yield: 62.11%). LCMS: [M+H] + 272.88.

[0243] Step 2: Synthesis of N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (47): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The resulting crude product was purified on silica gel (100-200 mesh) eluting with 3-5% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (47) as an off-white solid (800 mg, yield: 94.2%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 8.40 (s, 1H), 7.80-7.83 (m, 1H), 7.53-7.57 (m, 2H), 7.27-7.32 (m, 1H), 6.39-6.46 (m, 1H), 6.22-6.29 (m, 2H).

[0244] Step 3: Synthesis of N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 22): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified through silica gel (100-200 mesh) eluting with 4-6% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure. The resulting solid was purified again by preparative HPLC purification to give N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 22) as an off-white solid (30 mg, yield: 19.77%). 1H-NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.21 (s, 1H), 8.94 (s, 1H), 8.12-8.09 (m, 2H), 7.81-7.77 (m, 2H), 7.58-7.54 (m, 1H), 7.28 (t, J = 9.1 Hz, 1H), 6.50-6.37 (m, 2H), 6.27-6.22 (m, 1H), 5.77-5.54 (m, 1H), 3.73 (s, 3H). LCMS: [M+H] + 414.80.

[0245] Scheme 11: Synthesis of N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (compound 23): [ka] Step 1: Synthesis of N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (50): The title compound was prepared in a manner essentially similar to that described in General Procedure J. The resulting crude product was purified by CombiFlash, eluting with 10% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (50) as an off-white solid (350 mg; yield: 34%). MS: [M+H] + 345.18.

[0246] Step 2: Synthesis of N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (compound 23): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was further purified by preparative HPLC purification to give N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (Compound 23) as an off-white solid (55 mg, yield: 31.42%). 1 H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.25 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 7.85-7.74 (m, 2H), 7.37 (s, 1H), 7.11 (m, 1H), 6.98 (m, 1H), 5.78-5.65 (m, 1H), 5.47-5.42 (m, 1H), 3.52 (s, 3H). LCMS: [M+H] + 405.82.

[0247] Scheme 12: Synthesis of N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)-2-fluoroacrylamide (compound 24): [ka] Step 1: Synthesis of tert-butyl (3-aminocyclohexyl)carbamate (52): To an ice-cold solution of cyclohexane-1,3-diamine (51) (15.0 g, 131.57 mmol) in chloroform (300 mL) was added di-tert-butyl dicarbonate (14.93 mL, 65.78 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), water was added and the mixture was extracted with dichloromethane (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified through silica gel (100-200 mesh) eluting with 3-5% methanol in dichloromethane. The desired fractions were concentrated under reduced pressure to give tert-butyl (3-aminocyclohexyl)carbamate (52) as a white solid (21.0 g; yield: 75%). 1 H-NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 5.74 (s, 1H), 3.72 -3.76 (m, 2H), 3.01-3.20 (m, 4H), 1.40-1.84 (m, 4H), 1.36 (s, 9H).

[0248] Step 2: Synthesis of tert-butyl (3-((2,5-dichloropyrimidin-4-yl)amino)cyclohexyl)carbamate (53): To an ice-cold solution of tert-butyl (3-aminocyclohexyl)carbamate (52) (2.33 g, 10.9 mmol) in ethanol (20 mL) was added N,N-diisopropylethylamine (9.5 mL, 54.51 mmol) and 2,4,5-trichloropyrimidine (13) (2.0 g, 10.9 mmol). The resulting reaction mixture was heated at 90 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 100 mL). The combined organic components were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using flash chromatography using 30-50% ethyl acetate in hexane as the eluent, and the desired fractions were concentrated under reduced pressure to give tert-butyl (3-((2,5-dichloropyrimidin-4-yl)amino)cyclohexyl)carbamate (53) as a light brown solid (1.20 g; yield: 30.4%). MS: [M+H] + 360.97.

[0249] Step 3: Synthesis of tert-butyl (3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)carbamate (54): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified on silica gel (100-200 mesh) eluting with 2-4% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give tert-butyl (3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)carbamate (54) as a light brown solid (600 mg, 85.83% yield). MS: [M+H] + 422.38.

[0250] Step 4: Synthesis of N4-(3-aminocyclohexyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (55): The title compound was prepared in a manner substantially similar to that described in General Procedure I to give N4-(3-aminocyclohexyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (55) as the TFA salt as a light brown solid (400 mg; yield: 88%). MS: [M+H] + 322.25.

[0251] Step 5: Synthesis of N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (compound 24): The title compound was prepared in a manner essentially similar to that described in General Procedure J. The crude product was purified by preparative HPLC to give N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (Compound 24) as a white solid (35 mg; yield: 10%). 1 H-NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.90-7.75 (m, 2H), 7.36 (s, 1H), 6.78-6.76 (m, 1H), 5.57-5.73 (m, 1H), 5.25-5.20 (m, 1H), 4.03 (s, 1H), 3.83-3.76 (m, 4H), 2.01-1.23 (m, 8H). LCMS: [M+H] + 394.14.

[0252] Table 3: The following compounds were prepared using the above procedure. [Table 3]

[0253] Scheme 13: Synthesis of (E)-N-(3-((5-chloro-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 27): [ka] Step 1: Synthesis of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(3-methylisothiazol-5-yl)pyrimidine-2,4-diamine (57): The title compound was prepared in a manner essentially similar to that described in General Procedure B. The crude product was purified on silica gel (100-200 mesh) eluting with 3-5% methanol in dichloromethane, and the desired fractions were concentrated to dryness to give 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(3-methylisothiazol-5-yl)pyrimidine-2,4-diamine (57) as a light brown solid (500 mg; yield: 79.74%). MS: [M+H] + 381.13.

[0254] Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (58): The title compound was prepared in a manner substantially similar to that described in General Procedure L to give N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (58) as a brown solid (300 mg; yield: 65%). MS: [M+H] + 350.94.

[0255] Step 3: Synthesis of (E)-N-(3-((5-chloro-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 27): The title compound was prepared in a manner essentially similar to that described in General Procedure J. The crude product was purified by CombiFlash, eluting with 8% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure and purified again using preparative HPLC to afford (E)-N-(3-((5-chloro-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 27) as a white solid (20 mg, yield: 5.06%). 1 H-NMR (400 MHz, DMSO-d6): δ 11.05 (bs, 1H), 10.19 (bs 1H), 9.22 (bs, 1H), 8.24 (s, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 7.27 (t, J = 9.4 Hz, 1H), 6.69-6.76 (m, 1H), 6.49 (s, 1H), 6.25 (d, J = 15.4 Hz, 1H), 3.04-3.05 (m, 2H), 2.17 (m, 9H). LCMS: [M+H] + 462.13.

[0256] Scheme 14: Synthesis of N-(4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 28): [ka] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-nitropyridin-4-yl)amino)phenyl)carbamate (60): To an ice-cold solution of tert-butyl (3-aminophenyl)carbamate (7) (5.0 g, 26.04 mmol) in tetrahydrofuran (45 mL) was added N,N-diisopropylethylamine (9.3 mL, 52.082 mmol) and 2,4-dichloro-5-nitropyrimidine (59) (5.0 g, 26.04 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC), ice-cold water was added, and the resulting solid precipitate was filtered and dried under reduced pressure to give the desired product (60) as a pale yellow solid (8.1 g, yield: 85.23%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.16 (s, 1H), 9.03 (s, 1H), 7.95 (s, 1H), 7.23 (d, J = 15.2 Hz, 2H), 7.13 (s, 1H), 1.47 (s, 9H). LCMS: [M+H] + 366.09.

[0257] Step 2: Synthesis of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (61): The title compound was prepared in a manner essentially similar to that described in General Procedure L to give the desired product (61) as a brown solid (6.4 g, 85% yield). LCMS: [M+H] + 336.11.

[0258] Step 3: Synthesis of tert-butyl (3-((5-benzamido-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (63): To an ice-cold solution of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate 61 (1.0 g, 2.9 mmol) in tetrahydrofuran (20 mL) was added pyridine (0.9 mL, 11.9 mmol) and benzoyl chloride 62 (417.12 mg, 2.9 mmol) under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction mixture (monitored by TLC), the reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash eluting with 20% ethyl acetate in hexane to give the desired product 63 as a brown solid (1.1 g, yield: 84%). LCMS: [M+H] + 440.14.

[0259] Step 4: Synthesis of tert-butyl (3-((5-benzamido-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (64): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified by CombiFlash chromatography eluting with 4% methanol in dichloromethane to give the desired product (64) as a brown solid (720 mg; yield: 57%). LCMS: [M+H] + 501.23.

[0260] Step 5: Synthesis of N-(4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (65). The title compound was prepared in essentially the same manner as described in General Procedure I to give the desired product (65) as a brown solid (510 mg, yield: 91.01%). MS: [M+H] + 401.21.

[0261] Step 6: Synthesis of N-(4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (Compound 28). The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC to give the desired product, Compound 28, as an off-white color (65 mg, yield: 19.12%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.15 (bs, 1H), 9.59 (bs, 1H), 7.07 (bs, 1H), 8.72 (bs, 1H), 8.03-8.06 (m, 2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.51-7.59 (m, 4H), 7.31-7.43 (m, 4H), 6.40-6.47 (m, 1H), 6.21-6.26 (m, 1H), 5.73 (dd, J = 2.0 & 10.4 Hz, 1H), 3.64 (s, 3H). LCMS: [M+H] + 455.28.

[0262] Scheme 15: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 29): [ka] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)carbamate (67): To an ice-cold solution of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (61) (1.0 g, 2.98 mmol) in dichloromethane (15 mL) was added pyridine (0.69 mL, 11.98 mmol) and benzenesulfonyl chloride (66) (525 mg, 2.98 mmol) under nitrogen atmosphere at the same temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction mixture (monitored by TLC), it was diluted with water and extracted with dichloromethane (3 times). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired product (67) as a semi-solid (700 mg, yield: 50%). LCMS: [M+H] + 476.11.

[0263] Step 2: Synthesis of N-(4-((3-aminophenyl)amino)-2-chloropyrimidin-5-yl)benzenesulfonamide (68): The title compound was prepared in a manner essentially similar to that described in General Procedure I to give the desired product (68) as a brown solid (480 mg, 96% yield). LCMS: [M+H] + 376.11.

[0264] Step 3: Synthesis of N-(3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (69). The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by CombiFlash, eluting with 4% methanol in dichloromethane, to give the desired product (69) as a brown solid (340 mg, 67% yield). MS: [M+H] + 430.07.

[0265] Step 4: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 29): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified by preparative HPLC purification to give the desired product, Compound 29, as an off-white solid (10 mg, yield: 9%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.13 (bs, 1H), 9.25 (bs, 1H), 8.23 ​​(bs, 1H), 7.73-7.75 (m, 2H), 7.65 (s, 1H), 7.53-7.57 (m, 4H), 7.44-7.51 (m, 3H), 7.25 (s, 2H), 7.00-7.02 (m, 1H), 6.41-6.48 (m, 1H), 6.24 (d, J = 15.2 Hz, 1H), 5.74 (dd, J = 10.4 and 2.0 Hz, 1H), 3.59 (s, 3H). LCMS: [M+H] + 491.26.

[0266] Table 4: The following compounds were prepared using the above procedure. [Table 4]

[0267] Scheme 16: Synthesis of N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 32): [ka] Step 1: Synthesis of tert-butyl (3-((5-(benzylamino)-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (71): To an ice-cold solution of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (61) (1.5 g, 4.477 mmol) in dichloroethane (15 ml), benzaldehyde (70) (570 mg, 5.37 mmol) and sodium triacetoxyborohydride (2.8 g, 13.431 mmol) were added at the same temperature under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a CombiFlash purification system, eluting with 40% ethyl acetate in hexane to give the desired product (71) as a brown solid (1.1 g, yield: 57%). MS: [M+H] + 426.17.

[0268] Step 2: Synthesis of N-(3-aminophenyl)-N5-benzyl-2-chloropyrimidine-4,5-diamine (72): The title compound was prepared in essentially the same manner as described in General Procedure I to give the desired product (72) as an off-white solid (820 mg, 97% yield). MS: [M+H] + 326.17.

[0269] Step 3: Synthesis of N-(3-((5-(benzylamino)-2-chloropyrimidin-4-yl)amino)phenyl)acrylamide (73). The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by CombiFlash, eluting with 2% methanol in dichloromethane to give the desired product (73) as an off-white solid (260 mg; yield: 55.7%). MS: [M+H] + 380.13.

[0270] Step 4: Synthesis of N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 32) The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified by preparative HPLC purification to give the desired product, Compound 32, as a white solid (40 mg; yield: 14%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.12 (bs, 1H), 8.39 (bs, 2H), 7.91 (s, 1H), 7.67 (s, 1H), 7.53-7.54 (m, 1H), 7.43-7.44 (m, 3H), 7.34-7.37 (m, 3H), 7.24-7.27 (m, 3H), 6.42-6.49 (m, 1H), 6.23-6.27 (m, 1H), 5.74 (dd, J = 10.0 Hz and 1.6 Hz, 1H), 5.05-5.07 (m, 1H), 4.25 (d, J = 6.0 Hz, 2H), 3.65 (s, 3H). LCMS: [M+H] + 441.28.

[0271] Scheme 17: Synthesis of (E)-N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 33): [ka] Step 1: Synthesis of (E)-N-(3-((5-(benzylamino)-2-chloropyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (74) The title compound was prepared in a manner essentially similar to that described in General Procedure J to give the desired product (74) as an off-white solid (210 mg; yield: 40%). MS: [M+H] + 437.17.

[0272] Step 2: (E)-N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 33) The title compound was prepared in essentially the same manner as described in General Procedure H. The crude product was purified by preparative HPLC purification to give the desired product, Compound 33, as an off-white solid (35 mg; yield: 16%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.02 (bs, 1H), 8.40 (bs, 2H), 7.90 (s, 1H), 7.67 (s, 1H), 7.51-7.52 (m, 1H), 7.43-7.44 (m, 3H), 7.33-7.37 (m, 3H), 7.24-7.27 (m, 3H), 6.69-6.76 (m, 1H), 6.26 (d, J = 15.4 Hz, 1H), 5.04-5.06 (m, 1H), 4.25 (d, J = 5.6 Hz, 2H), 3.65 (s, 3H), 3.04 (d, J = 5.2 Hz, 2H), 2.17 (s, 6H). LCMS: [M+H] + 498.30.

[0273] Scheme 18: Synthesis of 4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (compound 34): [ka] Step 1: Synthesis of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylate (76): To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (75) (3.0 g, 13.56 mmol) in tetrahydrofuran (30 mL) was added N,N-diisopropylethylamine (4.82 mL, 27.02 mmol) and tert-butyl (3-aminophenyl)carbamate (7) (2.82 g, 13.56 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product (76) (4.5 g, yield: 84.42%). LCMS: [M+H] + 392.98.

[0274] Step 2: Synthesis of 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylic acid (77): To an ice-cold solution of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylate (76) (4.5 g, 4.82 mmol) in tetrahydrofuran (50 mL) was added sodium hydroxide (386 mg, 9.65 mmol) in water (10 mL). The resulting reaction mixture was heated at 50° C. for 8 hours. After completion of the reaction (monitored by TLC), the mixture was concentrated under reduced pressure. The crude product was diluted with ice-cold water (25 mL) and acidified with 1N hydrochloric acid (adjusted to pH ∼5). The resulting precipitate was filtered and dried under reduced pressure to give the desired product (77) as an off-white solid (2.6 g; yield: 63.14%). LCMS: [M+H] + 364.94.

[0275] Step 3: Synthesis of tert-butyl (3-((2-chloro-5-((1-phenylethyl)carbamoyl)pyrimidin-4-yl)amino)phenyl)carbamate (78): The title compound was prepared in a manner essentially similar to that described in General Procedure J to afford the desired product (78) as an off-white solid (800 mg; yield: 66.62%). MS: [M+H] + 468.17.

[0276] Step 4: Synthesis of tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((1-phenylethyl)carbamoyl)pyrimidin-4-yl)amino)phenyl)carbamate (79): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified by CombiFlash, eluting with 2% methanol in dichloromethane to give the desired product (79) as a semi-solid (600 mg; yield: 61.32%). LCMS: [M+H] + 529.16.

[0277] Step 5: Synthesis of 4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (80): The title compound was prepared in a manner essentially similar to that described in General Procedure I to afford the desired product (80) as an off-white solid (430 mg, yield: 88.21%). LCMS: [M+H] + 429.21.

[0278] Step 6: Synthesis of 4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (compound 34): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC purification to give the desired product, Compound 34, as an off-white solid (40 mg; yield: 14.21%). 1H NMR (400 MHz, DMSO-d6): δ 11.15 (bs, 1H), 10.19 (bs, 1H), 9.68 (bs, 1H), 8.73-8.84 (m, 2H), 7.47-7.93 (m, 4H), 7.39-7.41 (m, 2H), 7.29-7.35 (m, 3H), 7.21-7.24 (m, 2H), 6.39-6.46 (m, 1H), 6.22-6.26 (m, 1H), 5.74 (dd, J = 10.4 and 2.0 Hz, 1H), 5.12-5.19 (m, 1H) 3.61 (s, 3H), 1.47 (d, J = 2.2 Hz, 3H). LCMS: [M+H] + 483.28.

[0279] Scheme 19: Synthesis of (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (compound 35): [ka] The title compound was prepared in a manner essentially similar to that described in General Procedure J. The crude product was purified by preparative HPLC purification to give the desired product, Compound 35, as an off-white solid (48 mg; yield: 15.23%). 1 H-NMR (400 MHz, DMSO-d6): δ 11.14 (bs, 1H), 10.13 (bs, 1H), 9.67 (bs, 1H), 8.77-8.79 (m, 2H), 7.86-7.92 (m, 1H), 7.58-7.79 (m, 2H), 7.21-7.41 (m, 8H), 6.72 (s, 1H), 6.26 (s, 1H), 5.14-5.19 (m, 1H) 3.62 (s, 3H), 3.11-3.13 (m, 2H), 2.02 (s, 6H), 1.47 (d, J = 2.2Hz, 3H). LCMS: [M+H] + 540.40.

[0280] Scheme 20: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 36): [ka] Step 1: Synthesis of tert-butyl (4-fluoro-3-nitrophenyl)carbamate (82): To a solution of 4-fluoro-3-nitroaniline (81) (10 g, 64.102 mmol) in tert-butanol (50 mL) was added Boc anhydride (13.99 g, 64.102 mmol) at room temperature. The resulting reaction mixture was heated at 80° C. for 16 hours. After completion of the reaction (as monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with hexane and dried under reduced pressure to give the desired product (82) as a pale yellow solid (14 g; yield: 85.32%). 1 H NMR (400 MHz, DMSO-d6): δ 9.9 (s, 1H), 8.36 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.49-7.54 (m, 1H),1.49 (s, 9H).

[0281] Step 2: Synthesis of tert-butyl (3-amino-4-fluorophenyl)carbamate (83): To a solution of tert-butyl (4-fluoro-3-nitrophenyl)carbamate (82) (14 g, 54.68 mmol) in ethanol (50 mL) was added 10% palladium on carbon (1.4 g, 10% w / w). The resulting reaction was stirred under a hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and washed with ethyl acetate (200 mL). The combined filtrate was concentrated under reduced pressure to give the desired product (83) as an off-white solid (11 g; yield: 89.21%). 1H NMR (400 MHz, DMSO-d6): δ 9.01 (bs, 1H), 6.60-7.20 (m, 3H), 5.21 (s, 2H), 1.49 (s, 9H). LCMS: [M+1H] + 227.24.

[0282] Step 3: Synthesis of tert-butyl (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (85): The title compound was prepared in a manner essentially similar to that described in General Procedure A. The crude product was purified by CombiFlash, eluting with 70% ethyl acetate in hexane to give the desired product (85) (600 mg; yield: 21.42%). MS: [M+H] + 407.08.

[0283] Step 4: Synthesis of tert-butyl (4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)carbamate (86): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The crude product was purified by CombiFlash, eluting with 1% methanol in dichloromethane to give (86) (300 mg; yield: 43.47%). MS: [M+H] + 468.17.

[0284] Step 5: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (87): The title compound was prepared in a manner essentially similar to that described in General Procedure I to give the desired product (87) (150 mg; yield: 63.24%). MS: [M+H] + 368.15.

[0285] Step 6: N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 36): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC purification to afford compound 36 as an off-white solid (20 mg; yield: 12.62%). 1 H NMR (400 MHz, DMSO-d6): δ 10.30 (bs, 1H), 9.71 (bs, 1H), 8.82 (bs, 1H), 8.35 (s, 1H), 7.70-7.77 (m, 2H), 7.28-7.42 (m, 1H), 7.10 (s, 1H), 6.89 (s, 1H), 6.37-6.44 (m, 1H), 6.23-6.28 (m, 1H), 5.76 (d, J = 8.0 Hz, 1H), 3.50 (s, 3H). LCMS: [M+H] + 422.23.

[0286] Scheme 21: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 37): [ka] Step 1: Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (89): The title compound was prepared in essentially the same manner as described in General Procedure A. The crude product was purified by CombiFlash, eluting with 40% ethyl acetate in hexane to give (89) as a pale yellow solid (1.3 g, yield: 44.24%). MS: [M+H] + 346.97.

[0287] Step 2: Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine (91): The title compound was prepared in a manner essentially similar to that described in General Procedure M3. The crude product was purified by CombiFlash, eluting with 35% ethyl acetate in hexanes, to give the desired product (91) as a pale yellow solid (700 mg; yield: 50.12%). MS: [M+H] + 413.10.

[0288] Step 3: Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (92): The title compound was prepared in essentially the same manner as described in General Procedure H. The crude product was purified by CombiFlash, eluting with 1% methanol in dichloromethane to give the desired product (92) as a pale yellow solid (500 mg; yield: 70.24%). MS: [M+H] + 474.09.

[0289] Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (93): The title compound was prepared in a manner essentially similar to that described in General Procedure L to give (93) as a semi-solid (350 mg; yield: 74.78%). MS: [M+H] + 444.11.

[0290] Step 5: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 37): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC to afford compound 37 as an off-white solid (30 mg, yield: 13.33%). 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (bs, 1H), 9.24 (bs, 1H), 8.53 (bs, 1H), 7.99 (s, 1H), 7.71-7.81 (m, 5H), 7.57 (s, 1H), 7.08-7.16 (m, 3H), 6.37-6.44 (m, 1H), 6.21-6.26 (m, 1H), 5.74 (d, J = 8.4 Hz, 1H), 3.54 (s, 3H). LCMS: [M+H] + 498.35.

[0291] Table 5: The following compounds were prepared using the above procedure. [Table 5-1] [Table 5-2] [Table 5-3]

[0292] Scheme 22: Synthesis of N-(3-((5-(1-(N-benzylacetamido)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 47): [ka] Step 1: Preparation of tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (94) A solution of tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (29) (8.0 g, 22.22 mmol) in tetrahydrofuran (150 mL) was cooled at −78° C., followed by the addition of methylmagnesium bromide (3.0 M in diethyl ether, 22.22 mL, 66.66 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) eluting with 40-50% ethyl acetate in hexanes, and the desired fractions were concentrated to dryness to give tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (94) as an off-white solid (4.0 g; yield: 48%). MS: [M+H] + 377.43.

[0293] Step 2: Synthesis of tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (95): The title compound was prepared in a manner essentially similar to that described in General Procedure O to give tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (95) as a light brown solid (1.5 g; yield: 60%). MS: [M+H] + 375.42.

[0294] Step 3: Preparation of (E)-(3-((5-(1-(benzylimino)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)tert-butylcarbamate (97): The title compound was prepared in a manner essentially similar to that described in General Procedure D to give the desired product (97) as an off-white solid (1.0 g; yield: 58%). MS: [M+H] +464.25.

[0295] Step 4: Synthesis of tert-butyl (3-((5-(1-(benzylamino)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (98): The title compound was prepared in a manner essentially similar to that described in General Procedure E. The resulting crude product was purified by silica gel (100-200 mesh) eluting with 4-5% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give tert-butyl (3-((5-(1-(benzylamino)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (98) as a pale yellow solid (400 mg; yield: 40%). MS: [M+H] + 466.30.

[0296] Step 5: Synthesis of tert-butyl (3-((5-(1-(N-benzylacetamido)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (99): The title compound was prepared in a manner essentially similar to that described in General Procedure C. The crude product was purified through silica gel (100-200 mesh) eluting with 3% methanol in dichloromethane, and the desired fractions were concentrated under reduced pressure to give tert-butyl (3-((5-(1-(N-benzylacetamido)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (99) as a light brown solid (220 mg; yield: 50.45%). MS: [M+H] + 508.27.

[0297] Step 6: Synthesis of tert-butyl (3-((5-(1-(N-benzylacetamido)ethyl)-2-(methylsulfonyl)pyrimidin-4-yl)amino)phenyl)carbamate (100): The title compound was prepared in a manner essentially similar to that described in General Procedure G to give the desired product (100) as an off-white solid (130 mg; yield: 61%). MS: [M+H] + 540.06.

[0298] Step 7: Synthesis of tert-butyl (3-((5-(1-(N-benzylacetamido)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (101): The title compound was prepared in a manner substantially similar to that described in General Procedure H to give tert-butyl (3-((5-(1-(N-benzylacetamido)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (101) as a light brown solid (100 mg; 74.6%). MS: [M+H] + 557.41.

[0299] Step 8: Synthesis of N-(1-(4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethyl)-N-benzylacetamide (102): The title compound was prepared in a manner substantially similar to that described in General Procedure I to give N-(1-(4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethyl)-N-benzylacetamide (102) as the TFA salt as a light brown solid (100 mg; yield: 98%). MS: [MH] - 455.33.

[0300] Step 9: Synthesis of N-(3-((5-(1-(N-benzylacetamido)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 47) The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC purification to afford compound 47 as an off-white solid (6.0 mg, 6.7%). 1H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.61 (bs, 1H), 7.87-7.94 (m, 2H), 7.55-7.57 (m, 2H), 7.10-7.37 (m, 8H), 6.45-6.51 (m, 1H), 6.24 (d, J = 16.8 Hz, 1H), 5.96-6.01 (m, 1H), 5.76 (d, J = 10.4 Hz, 1H), 4.60 (s, 2H), 3.66 (s 3H), 2.53 (s, 1H), 2.02 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H). LCMS: [M+H] + 511.37.

[0301] Scheme 23: Synthesis of N-(3-((5-((N-benzylacetamido)methyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 48): [ka] Step 1: Synthesis of tert-butyl (3-((5-((N-benzylacetamido)methyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (104): The title compound was prepared in a manner essentially similar to that described in General Procedure C to give tert-butyl (3-((5-((N-benzylacetamido)methyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (104) as a brown solid (700 mg, quantitative yield). MS: [M+H] + 494.37.

[0302] Step 2: Synthesis of tert-butyl (3-((5-((N-benzylacetamido)methyl)-2-(methylsulfinyl)pyrimidin-4-yl)amino)phenyl)carbamate (105): The title compound was prepared in a manner essentially similar to that described in General Procedure G to give the desired product (105) as an off-white solid (650 mg; yield: 90%). MS: [M+H] + 510.34.

[0303] Step 3: Synthesis of tert-butyl (3-((5-((N-benzylacetamido)methyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (106) The title compound was prepared in essentially the same manner as described in General Procedure H to give the desired product (106) as an off-white solid (650 mg, 92% yield). MS: [M+H] + 543.18.

[0304] Step 4: Synthesis of N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-benzylacetamide (107): The title compound was prepared in a manner essentially similar to that described in General Procedure I to give the desired product (107) as an off-white solid (450 mg; yield: 94.9%). MS: [M+H] + 443.19.

[0305] Step 5: Preparation of N-(3-((5-((N-benzylacetamido)methyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 48): The title compound was prepared in a manner essentially similar to that described in General Procedure K. The final compound was purified by preparative HPLC to give N-(3-((5-((N-benzylacetamido)methyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 48) as an off-white solid (30 mg; yield: 15%). 1H-NMR (400 MHz, DMSO d6): δ 10.15 (bs, 1H), 9.50 (bs, 1H), 9.01 (bs, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.62 (s, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.40-7.36 (m, 4H), 7.31-7.27 (m, 3H), 7.24 (d, J = 7.6 Hz, 1H), 6.47 (d, J = 16.8 Hz, 1H), 6.23 (d, J = 1.6 Hz, 1H), 5.74 (d, J = 1.6 Hz, 1H), 4.62 (s, 2H), 4.37 (s, 2H), 3.68 (s, 3H), 2.12 (s, 3H). LCMS: [M+H] + 497.31.

[0306] Scheme 24: Synthesis of 4-((5-acrylamido-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (compound 49): [ka] Step 1: Synthesis of ethyl 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylate (108): The title compound was prepared in a manner essentially similar to that described in General Procedure A. The crude product was purified by silica gel column chromatography (100-200 mesh) using 20-25% ethyl acetate in hexane as the eluent to give ethyl 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylate (108) as a brown solid (1.6 g, yield: 15.78%). MS: [M+H] + 341.04.

[0307] Step 2: Synthesis of 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid (109): To an ice-cold solution of ethyl 2-chloro-4-[(2-fluoro-5-nitrophenyl)amino]pyrimidine-5-carboxylate (108) (800 mg, 2.35 mmol) in tetrahydrofuran (10 mL) and water (2.00 mL) was added lithium hydroxide monohydrate (246 mg, 5.87 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mass was concentrated under reduced pressure. The crude product was diluted with ice-cold water and adjusted to pH 4 using 1N hydrochloric acid. The resulting precipitate was filtered and dried under reduced pressure to give 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid (109) as an off-white solid (720 mg; yield: 98%). LCMS: [MH] - 311.26.

[0308] Step 3: Synthesis of 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)-N-methyl-N-phenylpyrimidine-5-carboxamide (111): The title compound was prepared in a manner essentially similar to that described in General Procedure J to give 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)-N-methyl-N-phenylpyrimidine-5-carboxamide (111) as an off-white solid (150 mg; yield: 20%). LCMS: [M+H] + 401.98.

[0309] Step 4: Synthesis of 4-((2-fluoro-5-nitrophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (112): The title compound was prepared in essentially the same manner as described in General Procedure H. The residue was purified by CombiFlash, eluting with 60% ethyl acetate in hexanes to give the desired product (112) as an off-white solid (300 mg, yield: 52.13%). LCMS: [M+H] + 463.27.

[0310] Step 5: Synthesis of 4-((5-amino-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (113): The title compound was prepared in a manner substantially similar to that described in General Procedure L to give 4-((5-amino-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (113) as a light green solid (220 mg; yield: 48.62%). MS: [M+H] + 433.20.

[0311] Step 6: Synthesis of 4-((5-acrylamido-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (compound 49): The title compound was prepared in a manner substantially similar to that described in General Procedure K. The residue was purified by preparative HPLC to give 4-((5-acrylamido-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide as an off-white solid (Compound 49) (10 mg, yield: 8%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.25 (bs, 1H), 9.61 (bs, 1H), 9.48 (s, 1H), 7.94 (bs, 1H), 7.68 (s, 1H), 7.58 (s, 1H), 7.35-7.39 (m, 2H), 7.31 (d, J = 6.8 Hz, 3H), 7.23 (d, J = 7.2 Hz, 2H), 7.15 (s, 1H), 6.43 (d, J = 16.4 Hz, 1H), 6.25 (d, J = 17.6 Hz, 1H), 5.77 (d, J = 11.6 Hz, 1H), 3.56 (s, 3H), 3.37 (s, 3H). LCMS: [M+H] + 487.35.

[0312] Scheme 25: Synthesis of N-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 50): [ka] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-nitropyridin-4-yl)amino)-4-fluorophenyl)carbamate (115): To an ice-cold solution of tert-butyl (3-amino-4-fluorophenyl)carbamate (83) (5.0 g, 22.12 mmol) in tetrahydrofuran (50 mL) was added N,N-diisopropylethylamine (7.82 mL, 44.24 mmol), followed by 2,4-dichloro-5-nitropyrimidine (114) (4.24 g, 22.12 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC, and upon completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic components were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3-((2-chloro-5-nitropyridin-4-yl)amino)-4-fluorophenyl)carbamate (115) (6.1 g, yield: 60.24%). MS: [M+H] + 384.12.

[0313] Step 2: Synthesis of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (116): The title compound was prepared in a manner essentially similar to that described in General Procedure L to give tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (116) (4.8 g, 85.40% yield). LCMS: [M+H] + 353.81.

[0314] Step 3: Synthesis of tert-butyl (3-((5-benzamido-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (117): To an ice-cold solution of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (116) (1.0 g, 2.831 mmol) in tetrahydrofuran (10 mL) was added pyridine (810 mg, 11.32 mmol) followed by benzoyl chloride (62) (400 mg, 2.831 mmol) under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash, eluting with 8% ethyl acetate in hexane to give tert-butyl (3-((5-benzamido-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (117) (800 mg, yield: 61.53%). MS: [M+H] + 458.23.

[0315] Step 4: Synthesis of tert-butyl (3-((5-benzamido-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (118): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The residue was purified by CombiFlash, eluting with 2% methanol in dichloromethane to give tert-butyl (3-((5-benzamido-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (118) (450 mg, yield: 49.61%). MS: [M+H] + 519.13.

[0316] Step 5: Synthesis of N-(4-((5-amino-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (119). The title compound was prepared in a manner substantially similar to that described in General Procedure I to give N-(4-((5-amino-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (119) (280 mg, 77.10% yield). MS: [M+H] + 419.24.

[0317] Step 6: Synthesis of N-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (Compound 50). The title compound was prepared in a manner essentially similar to that described in General Procedure K. The crude product was purified by preparative HPLC to give N-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (Compound 50) (17 mg, yield: 10.03%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.22 (bs, 1H), 9.68 (bs, 1H), 9.04 (bs, 1H), 8.63 (bs, 1H), 8.06-8.08 (m, 2H), 7.95 (s, 1H), 7.84-7.85 (m, 1H), 7.50-7.59 (m, 4H) 7.21-7.31 (m, 3H), 6.37-6.44 (m, 1H), 6.22 (d, J = 16.8 Hz, 1H), 5.74 (d, J = 11.2 Hz, 1H), 3.57 (s, 3H). LCMS: [M+H] + 473.35.

[0318] Scheme 26: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 51): [ka] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (120): To an ice-cold solution of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (116) (1.0 g, 2.83 mmol) in tetrahydrofuran (10 mL) was added pyridine (0.95 mL, 11.32 mmol), benzenesulfonyl chloride (66) (0.36 mL, 2.83 mmol), and a catalytic amount of N,N-dimethylaminopyridine under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash, eluting with 40% ethyl acetate in hexanes to give tert-butyl (3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (120) (600 mg, 42.85% yield). MS: [M+H] + 494.10.

[0319] Step 2: Synthesis of N-(4-((5-amino-2-fluorophenyl)amino)-2-chloropyrimidin-5-yl)benzenesulfonamide (121): The title compound was prepared in a manner essentially similar to that described in General Procedure I to give the desired product (121) (410 mg; yield: 54.14%). MS: [M+H] + 394.21.

[0320] Step 3: Synthesis of N-(3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (122): The title compound was prepared in a manner essentially similar to that described in General Procedure K to give the desired product (122) (330 mg; yield: 29.48%). MS: [M+H] + 448.11.

[0321] Step 4: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 51): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The final compound was purified by preparative HPLC to give the desired product, N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 51) (43 mg; yield: 19.14%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.17 (bs, 1H), 9.02 (bs, 1H), 8.24 (bs, 1H), 7.74-7.79 (m, 3H), 7.53-7.60 (m, 5H), 7.38 (s, 1H), 7.19-7.24 (m, 3H), 6.38-6.45 (m, 1H) 6.23-6.27 (m, 1H), 5.77 (d, J = 10.0 Hz, 1H), 3.56 (s, 3H). LCMS: [M+H] + 509.35.

[0322] Scheme 27: Synthesis of (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-2-((2-methoxy-4-(piperidin-1-yl)phenyl)amino)-N-methyl-N-phenylpyrimidine-5-carboxamide (compound 52): [ka] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(methyl(phenyl)carbamoyl)pyrimidin-4-yl)amino)phenyl)carbamate (124): The title compound was prepared in a manner essentially similar to that described in General Procedure J to give tert-butyl (3-((5-(methyl(phenyl)carbamoyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (124) (1.8 g, yield: 75.21%), MS: [M+H] + 466.21.

[0323] Step 2: Synthesis of 4-((3-aminophenyl)amino)-N-methyl-2-(methylthio)-N-phenylpyrimidine-5-carboxamide (125). The title compound was prepared in a manner substantially similar to that described in General Procedure I to give 4-((3-aminophenyl)amino)-N-methyl-2-(methylthio)-N-phenylpyrimidine-5-carboxamide (125) (1.1 g, 78.15% yield). MS: [M+H] + 366.18.

[0324] Step 3: Synthesis of (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-N-methyl-2-(methylthio)-N-phenylpyrimidine-5-carboxamide (126): The title compound was prepared in a manner essentially similar to that described in General Procedure J. The crude product was purified by CombiFlash, eluting with 2.5% methanol in dichloromethane to give (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-N-methyl-2-(methylthio)-N-phenylpyrimidine-5-carboxamide (126) (600 mg; yield: 46.15%). MS: [M+H] + 477.23.

[0325] Step 4: Synthesis of (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-N-methyl-2-(methylsulfonyl)-N-phenylpyrimidine-5-carboxamide (127): The title compound was prepared in a manner substantially similar to that described in General Procedure G to give (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-N-methyl-2-(methylsulfonyl)-N-phenylpyrimidine-5-carboxamide (127) (510 mg, 79.68% yield). MS: [M+H] + 509.19.

[0326] Step 5: Synthesis of (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-2-((2-methoxy-4-(piperidin-1-yl)phenyl)amino)-N-methyl-N-phenylpyrimidine-5-carboxamide (compound 52): The title compound was prepared in a manner essentially similar to that described in General Procedure H. The final compound was purified by preparative HPLC to afford compound 52 as an off-white solid (44 mg, yield: 7.06%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.01 (bs, 1H), 9.59 (bs, 1H), 7.84-7.86 (m, 2H), 7.62 (s, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.28-7.37 (m, 6H), 7.14-7.23 (m, 2H), 6.70-6.77 (m, 1H), 6.54 (s, 1H), 6.25-6.32 (m, 2H), 3.72 (s, 3H), 3.37 (s, 3H), 3.03-3.06 (m, 6H), 2.17 (s, 6H), 1.61 (s, 4H), 1.51-1.52 (m, 2H). LCMS: [M+H] + 635.18.

[0327] Scheme 28: Synthesis of (E)-N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 53): [ka] Step 1: Synthesis of tert-butyl (3-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (129): To a solution of tert-butyl (3-aminophenyl)carbamate (7) (5 g, 22.13 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (6.10 g, 44.26 mmol) and 5-bromo-2,4-dichloropyrimidine (88) (4.97 g, 22.13 mmol) at room temperature. The resulting reaction mixture was heated at 110° C. for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and ice-cold water (100 mL) was added. The resulting solid precipitate was filtered and dried under reduced pressure to give tert-butyl (3-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (129) (3.5 g; yield: 39.98%). LCMS: [M+H] + 399.48.

[0328] Step 2: Synthesis of tert-butyl (3-((2-chloro-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)carbamate (130): The title compound was prepared in a manner essentially similar to that described in General Procedure H to give the desired product (130) (1.4 g; yield: 35.12%). LCMS: [M+H] + 465.38.

[0329] Step 3: Synthesis of tert-butyl (3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)carbamate (132): The title compound was prepared in a manner essentially similar to that described in General Procedure H to give the desired product (132) (600 mg; yield: 37.54%). LCMS: [M+H] + 559.17.

[0330] Step 4: Synthesis of N4-(3-aminophenyl)-N2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (133): The title compound was prepared in a manner essentially similar to that described in General Procedure I to give the desired product (133) (320 mg, yield: 65.04%). MS: [M+H] + 460.48.

[0331] Step 5: Synthesis of (E)-N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 53): The title compound was prepared in a manner essentially similar to that described in General Procedure J. The final compound was purified by preparative HPLC purification to give the desired product, Compound 53, as a white solid (35 mg, yield: 18.86%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.25 (bs, 1H), 10.13 (bs, 1H), 8.46-8.50 (m, 2H), 7.98 (s, 1H), 7.78-7.80 (m, 3H), 7.68-7.70 (m, 2H), 7.39-7.41 (m, 1H), 7.22-7.32 (m, 2H) 6.70-6.77 (m, 1H), 6.42 (d, J = 15.2 Hz, 1H), 3.79 (s, 2H), 3.65 (s, 3H), 2.67 (s, 6H). LCMS: [M+H] + 571.12.

[0332] Scheme 29: Synthesis of (E)-N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 54): [ka] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)carbamate (134): To a solution of tert-butyl (3-aminophenyl)carbamate (84) (5.0 g, 24.038 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (6.63 g, 48.16 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (7) (5.16 g, 24.038 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with ice-cold water (200 mL). The resulting solid precipitate was filtered and dried under reduced pressure to give tert-butyl (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)carbamate (134) (4.4 g; yield: 48.88%). LCMS: [M+H] + 389.48.

[0333] Step 2: Synthesis of tert-butyl (3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)carbamate (135): The title compound was prepared in essentially the same manner as described in General Procedure H to give the desired product (135) (400 mg; yield: 32.25%). MS: [M+H] + 484.24.

[0334] Step 3: Synthesis of N4-(3-aminophenyl)-N2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (136): The title compound was prepared in a manner essentially similar to that described in General Procedure H to give the desired product (136) (310 mg; yield: 97.12%). LCMS: [M+H] + 384.11.

[0335] Step 4: Synthesis of (E)-N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (compound 54): The title compound was prepared in essentially the same manner as described in General Procedure J to afford the desired product, Compound 54, as an off-white solid after preparative HPLC purification (40 mg, yield: 15.56%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.22 (bs, 1H), 9.09 (bs, 1H), 8.84 (bs, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 7.55-7.57 (m, 1H), 7.32-7.34 (m, 1H), 7.09 (s, 1H) 6.70-6.77 (m, 1H), 6.32 (d, J = 14.8 Hz, 1H), 3.86-3.65 (m, 1H), 3.52 (s, 3H), 3.32-3.39 (m, 2H), 2.40 (s, 6H). LCMS: [M+H] + 495.16.

[0336] Scheme 30: Synthesis of N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-[6-(morpholin-4-yl)pyridin-3-yl]pyrimidin-4-yl}amino)phenyl]prop-2-enamide (compound 55): [ka] Step 1: Synthesis of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (137): The title compound was prepared in essentially the same manner as described in General Procedure H to give the desired product (137) as a pale yellow solid (yield: 70%). LCMS: [M+H] + 407.90.

[0337] Step 2: Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-[6-(morpholin-4-yl)pyridin-3-yl]pyrimidine-2,4-diamine (139) The title compound was prepared in a manner essentially similar to that described in General Procedure M3 to afford the desired product (139) as a reddish solid. LCMS: [M+H] + 492.50.

[0338] Step 3: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-[6-(morpholin-4-yl)pyridin-3-yl]pyrimidine-2,4-diamine (140) The title compound was prepared in essentially the same manner as described in General Procedure L to give the desired product (140) as a pale yellow solid. LCMS: [M+H] + 462.0.

[0339] Step 4: Synthesis of N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-[6-(morpholin-4-yl)pyridin-3-yl]pyrimidin-4-yl}amino)phenyl]prop-2-enamide (Compound 55) The title compound was prepared in a manner essentially similar to that described in General Procedure K to afford the desired product as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.08 (bs, 1H), 8.19 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.55 (bs, 1H), 7.25 (bs, 2H), 7.13-7.11 (m, 2H), 6.92 (d, J = 8.8 Hz, 1H), 6.42-6.36 (m, 1H), 6.24-6.20 (m, 1H), 5.74 (d, J = 11.6 Hz, 1H), 3.70 (s, 3H), 3.53-3.48 (m, 4H), 3.30 (4H, merged with DMSO-water peak). LCMS: [M+H] + 516.0.

[0340] Table 6: The following compounds were prepared using the above procedure. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8]

[0341] Scheme 31: Synthesis of N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenyl]prop-2-enamide (compound 89): [ka] Step 1: Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine (141) The title compound was prepared in a manner essentially similar to that described in general procedure M3 to give the desired product (141) as an off-white solid (0.4 g, 97% yield). LCMS: [M+H] + 474.1.

[0342] Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine (142) The title compound was prepared in a manner essentially similar to that described in General Procedure L1 to give the desired product (142) as a brown liquid (0.2 g, crude). LCMS: [M+H] + 444.2.

[0343] Step 3: Synthesis of N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenyl]prop-2-enamide (Compound 89) The title compound was prepared in a manner essentially similar to that described in General Procedure K and was obtained as an off-white solid (0.13 g, crude). 1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.40 (bs, 1H), 8.65 (bs, 1H), 7.96 (s, 1H), 7.77 (s, 2H), 7.68 (s, 2H), 7.55 (s, 2H), 7.28-7.10 (m, 3H), 6.40-6.35 (m, 1H), 6.24-6.20 (m, 1H), 5.74 (d, J = 10.0 Hz, 1H), 3.53 (s, 3H). LCMS: [M+H] + 498.3.

[0344] [Table 7-1] [Table 7-2]

[0345] Scheme 32: Synthesis of N-(4-fluoro-3-{[5-(1H-indol-5-yl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl]amino}phenyl)prop-2-enamide (compound 97): [ka] Step 1: Synthesis of tert-butyl 5-{4-[(2-fluoro-5-nitrophenyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-5-yl}-1H-indole-1-carboxylate (144) To a stirred solution of 5-bromo-N-(2-fluoro-5-nitrophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (137) (0.35 g, 0.85 mmol) in 1,4-dioxane (4.50 mL) and water (0.5 mL) was added cesium carbonate (0.83 g, 2.57 mmol) and {1-[(tert-butoxy)carbonyl]-1H-indol-5-yl}boronic acid (143) (0.269 g, 1.2 equiv., 1.03 mmol). The reaction mixture was then purged with nitrogen for 5 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.7 g, 0.085 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. The progress of the reaction was monitored by TLC / LCMS. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (25 mL x 2), brine (25 mL), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography using a CombiFlash purification system and eluted with 40-60% ethyl acetate in hexane to give the title compound (144) as a pale yellow solid. LCMS: [M+H] + 545.2.

[0346] Step 2: Synthesis of tert-butyl 5-{4-[(5-amino-2-fluorophenyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-5-yl}-1H-indole-1-carboxylate (145) The title compound was prepared in a manner essentially similar to that described in General Procedure L to give the desired product (145) as a brown solid (0.2 g, crude). LCMS: [M+H] + 515.2.

[0347] Step 3: Synthesis of tert-butyl 5-(4-{[2-fluoro-5-(prop-2-enamido)phenyl]amino}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-5-yl)-1H-indole-1-carboxylate (146) The title compound was prepared in essentially the same manner as described in General Procedure K to give the desired product (146) as a white solid (0.19 g). LCMS: [M+H] + 569.3.

[0348] Step 4: Synthesis of N-(4-fluoro-3-{[5-(1H-indol-5-yl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl]amino}phenyl)prop-2-enamide (Compound 97) To a stirred solution of tert-butyl 5-(4-{[2-fluoro-5-(prop-2-enamido)phenyl]amino}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-5-yl)-1H-indole-1-carboxylate (0.15 g, 0.264 mmol) in dichloromethane (10.0 mL), trifluoroacetic acid (1.00 mL) was added and stirred at room temperature for 2 hours. The progress of the reaction was monitored by LCMS / TLC. The reaction mixture was then concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound (0.05 g, 0.107 mmol) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 10.6 (s, 1H), 9.99 (s, 1H), 9.38 (s,1H), 7.88 (s, 2H), 7.77 (s, 1H), 7.67-7.43 (m, 2H), 7.33 (s, 1H), 7.27 (s, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.51 (s,1H), 6.42-6.24 (m, 1H), 6.21 (s, 1H), 5.76-5.73 (m, 1H), 3.53 (s, 3H). LCMS: [M+H] + 469.3.

[0349] Table 8: The following compounds were prepared using the procedure above. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10]

[0350] Scheme 33: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 137): [ka] Step 1: Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)pyrimidine-2,4-diamine (148) To a stirred solution of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (137) (300 mg, 0.73 mmol) in 1,4-dioxane (4.00 mL) and water (1.0 mL) was added cesium carbonate (599 mg, 1.84 mmol) and (pyridin-4-yl)boronic acid (147) (111 mg, 0.904 mmol). The reaction mixture was then purged with nitrogen for 5 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (60.0 mg, 0.073 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and evaporated. The crude compound was purified by CombiFlash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (155) (300 mg, 100%). LCMS: [M+H] + 407.0.

[0351] Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)pyrimidine-2,4-diamine (149) The title compound was prepared in a manner essentially similar to that described in general procedure L1 to give the desired product (149) as a brown solid (0.22 g, crude). LCMS: [M+H] + 377.

[0352] Step 3: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 137) The title compound was prepared in a manner essentially similar to that described in General Procedure K and was obtained as an off-white solid (0.028 g, 12.24%). 1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.30 (bs, 1H), 8.58-8.577 (m, 3H), 8.02 (s, 1H), 7.27 (s, 1H), 7.56-7.50 (m, 3H), 7.28 (bs, 2H), 7.13-7.05 (m, 2H), 6.42-6.35 (m, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.51 (s, 3H). LCMS: [M+H] + 431.2.

[0353] Table 9: The following compounds were prepared using the above procedure. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0354] Scheme 34: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 151): [ka] Step 1: Synthesis of 5-bromo-2-chloro-4-(3-nitrophenoxy)pyrimidine (151) To a stirred solution of 5-bromo-2,4-dichloropyrimidine (88) (20.0 g, 87.76 mmol) and 3-nitrophenol (150) (12.20 g, 87.76 mmol) in N,N-dimethylformamide (100.0 mL) was added potassium carbonate (14.53 g, 105.31 mmol), and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and diluted with ice-cold water (250 mL). The precipitated solid was filtered and washed with ice-cold water (2 × 100 mL). The solid was dried under reduced pressure to give the desired product (151) as an off-white solid (25 g, yield: 86%). 1 H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.28 (s, 1H), 8.21-8.23 (m, 1H), 7.78-7.830 (m, 2H). LCMS: [M+H] + 330.22.

[0355] Step 2: Synthesis of 5-bromo-N-(1-methyl-1H-pyrazol-4-yl)-4-(3-nitrophenoxy)pyrimidin-2-amine (152) The title compound was prepared in essentially the same manner as described in General Procedure H to give the desired compound as a yellow solid (5.0 g, 30% yield). LCMS: [M+H] + 391.27.

[0356] Step 3: Synthesis of N-(1-methyl-1H-pyrazol-4-yl)-4-(3-nitrophenoxy)-5-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (153): The title compound was prepared in a manner essentially similar to that described in General Procedure M3 to afford the desired compound as an off-white solid (0.2 g, 38% yield). LCMS: [M+H] + 457.13.

[0357] Step 4: Synthesis of 4-(3-aminophenoxy)-N-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (154): The title compound was prepared in a manner essentially similar to that described in General Procedure L to afford the desired compound as an off-white solid (0.12 g, 65% yield). LCMS: [M+H] + 427.07.

[0358] Step 5: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 151): The title compound was prepared in essentially the same manner as described in General Procedure K to afford the desired compound as an off-white solid after preparative HPLC purification (0.010 g, 15% yield). 1 H-NMR (400 MHz, DMSO-d6): δ 10.37 (bs, 1H), 9.78 (bs, 1H), 8.52 (s, 1H), 7.93-7.95 (m, 2H), 7.80-7.82 (m, 2H), 7.72 (s, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 7.11 (s, 1H), 7.03 (d, J = 6.4 Hz, 1H), 6.86 (s, 1H), 6.39-6.46 (m, 1H), 6.23-6.27 (m, 1H), 5.75 (d, J = 10.0 Hz, 1H), 3.51 (s, 3H). LCMS: [M+H] + 481.17.

[0359] Scheme 35: Synthesis of N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)amino)-4-fluorophenyl)acrylamide (compound 153): [ka] Step 1: Synthesis of tert-butyl (6-bromo-3-chloropyrazin-2-yl)carbamate (156): To a solution of 6-bromo-3-chloropyrazin-2-amine (155) (500 mg, 2.40 mmol) in dichloromethane (10.0 mL), triethylamine (170 mg, 1.68 mmol), N,N-dimethylpyridin-4-amine (29.3 mg, 0.240 mmol), and di-tert-butyl dicarbonate (1.05 g, 4.80 mmol) were added at room temperature. The resulting reaction mixture was stirred at the same temperature for 16 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was taken up in water (30 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by CombiFlash column chromatography eluting with 10-40% ethyl acetate in heptane to give tert-butyl (6-bromo-3-chloropyrazin-2-yl)carbamate (156) as a white solid (600 mg, yield: 81%). LCMS: [M-tBu+H] + 251.97.

[0360] Step 2: Synthesis of tert-butyl (3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)carbamate (157): To a solution of tert-butyl (6-bromo-3-chloropyrazin-2-yl)carbamate (156) (400 mg, 1.30 mmol) in 1,4-dioxane (10.0 mL) was added cesium carbonate (845 mg, 2.59 mmol). The reaction mixture was then purged with nitrogen for 15 minutes, and 1-methyl-1H-pyrazol-4-amine (22) (126 mg, 1.30 mmol), tris(dibenzylideneacetone)dipalladium(0) (119 mg, 0.130 mmol), and Xantphos (150 mg, 0.26 mmol) were added at room temperature. The resulting reaction mixture was heated at 120 °C for 16 hours. After completion of the reaction (as monitored by TLC), the reaction was cooled to room temperature, filtered through a Celite pad, and washed with ethyl acetate (3 × 30 mL). The combined filtrate was concentrated under reduced pressure to give tert-butyl (3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)carbamate (157) (800 mg, yield: 68.41%), which was used in the next step without further purification. MS: [M+H] + 325.16.

[0361] Step 3: Synthesis of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (158): The title compound was prepared in a manner substantially similar to that described in General Procedure H to give 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (158) as a green solid (150 mg, yield: 27.1%). LC-MS: [M+H] + 225.12.

[0362] Step 4: Synthesis of 3-chloro-N2-(2-fluoro-5-nitrophenyl)-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (160) To a stirred solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (158) (50.0 mg, 0.223 mmol) and 2-bromo-1-fluoro-4-nitrobenzene (159) (49.0 mg, 0.223 mmol) in 1,4-dioxane (2.0 mL) was added cesium carbonate (145 mg, 0.45 mmol) at room temperature. The reaction mass was purged with nitrogen for 15 minutes, and then tris(dibenzylideneacetone)dipalladium(0) (20.4 mg, 0.022 mmol) and [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (25.8 mg, 0.044 mmol) were added to the reaction mixture. The resulting reaction mixture was heated at 120 °C for 16 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature, poured into ice-cold water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-N2-(2-fluoro-5-nitrophenyl)-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (160) as a semi-solid (30.0 mg, yield: 13%). MS: [M+H] + 364.23.

[0363] Step 5: Synthesis of N2-(5-amino-2-fluorophenyl)-3-chloro-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (161): The title compound was prepared in a manner substantially similar to that described in General Procedure L to give N2-(5-amino-2-fluorophenyl)-3-chloro-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (161) (60.0 mg, 63% yield). MS: [M+H] + 334.09.

[0364] Step 6: Synthesis of N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)amino)-4-fluorophenyl)acrylamide (compound 153): The title compound was prepared in a manner substantially similar to that described in General Procedure J, using N2-(5-amino-2-fluorophenyl)-3-chloro-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (161) and acryloyl chloride (18) to give N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)amino)-4-fluorophenyl)acrylamide (Compound 153) as a white solid after preparative HPLC purification (8.0 mg, yield: 4.92%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.27 (s, 1H), 8.48 (s, 1H), 7.80-7.78 (m, 1H), 7.64-7.62 (m, 1H), 7.33 (t, J = 9.6 Hz, 1H), 7.25 (s, 1H), 7.15-7.14 (m, 2H), 6.38-6.45 (m, 1H), 6.23 (d, J = 15.6 Hz, 1H), 5.74 (d, J = 11.2 Hz, 1H), 3.54 (s, 3H). LCMS: [M+H] + 388.21.

[0365] Scheme 36: Synthesis of N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 218): [ka] Step 1: Synthesis of tert-butyl (3-((6-bromo-3-chloropyrazin-2-yl)oxy)phenyl)carbamate (164): To a stirred solution of tert-butyl (3-hydroxyphenyl)carbamate (163) (1.84 g, 8.81 mmol) in acetonitrile (10.0 mL) was added triethylamine (3.01 mL, 22.0 mmol) and 3,5-dibromo-2-chloropyrazine (162) (2.0 g, 7.34 mmol) at room temperature. The reaction mixture was stirred at 85 °C for 16 h. After consumption of the starting material (according to TLC monitoring), the reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (5-25% ethyl acetate in heptane) to give tert-butyl (3-((6-bromo-3-chloropyrazin-2-yl)oxy)phenyl)carbamate (164) as a yellow solid (1.90 g, yield: 64.57%). LCMS: [MH] - 397.97.

[0366] Step 2: Synthesis of tert-butyl (3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (165): To a stirred solution of 1-methyl-1H-pyrazol-4-amine (22) (654 mg, 6.74 mmol) in toluene (10.0 mL) was added cesium carbonate (2.20 g, 6.74 mmol) and tert-butyl (3-((6-bromo-3-chloropyrazin-2-yl)oxy)phenyl)carbamate (164) (900 mg, 2.25 mmol). The resulting reaction mixture was purged with nitrogen for 20 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (367 mg, 0.449 mmol) was added, and the resulting reaction mixture was stirred at 110 °C for 20 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude residue was taken up in water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (165) (1.30 g, yield: 28.75%) as a brown solid, which was used directly in the next step. MS: [M+H] + 417.28.

[0367] Step 3: Preparation of 6-(3-aminophenoxy)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (166): The title compound was prepared in a manner substantially similar to that described in General Procedure I using tert-butyl (3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (165) to give 6-(3-aminophenoxy)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (166) as a green solid (720 mg; yield: 72.89%). MS: [M+H] + 317.15.

[0368] Step 4: Synthesis of N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 154): The title compound was prepared in a manner substantially similar to that described in General Procedure J using 6-(3-aminophenoxy)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (166) and acryloyl chloride (18) to give N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (Compound 154) as a brown solid after preparative HPLC purification (64.0 mg, yield: 7.81%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.71 (s, 1H), 7.67-7.61 (m, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.09-6.98 (m, 2H), 6.39-6.45 (m, 1H), 6.23 (d, J = 16.0 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.53 (s, 3H). LCMS: [M+H] + 371.18.

[0369] Scheme 37: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)acrylamide (compound 155): [ka] Step 1: Synthesis of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (168): To a stirred solution of 3,5,6-trichloro-1,2,4-triazine (167) (1.40 g, 7.59 mmol) in dichloromethane (10 mL) was added triethylamine (1.54 g, 15.2 mmol) and tert-butyl (3-amino-4-fluorophenyl)carbamate (83) (2.06 g, 9.11 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (168) as a yellow solid (1.70 g, yield: 13.2%), which was used directly in the next step. MS: [M+H] + 374.04.

[0370] Step 2: Synthesis of tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (169): To a stirred solution of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (168) (1.10 g, 2.94 mmol) in isopropanol (3.0 mL) was added 1-methyl-1H-pyrazol-4-amine (22) (714 mg, 7.35 mmol) and camphorsulfonic acid (478 mg, 2.06 mmol). The reaction mixture was heated at 100° C. for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (169) as a viscous liquid (2.20 g, yield: 44.13%). MS: [M+H] + 435.53.

[0371] Step 3: Preparation of N5-(5-amino-2-fluorophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (170) The title compound was prepared in a manner substantially similar to that described in General Procedure I to afford N5-(5-amino-2-fluorophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (170) as a viscous liquid (700 mg; yield: 20.58%) with tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (169). MS: [M+H] + 335.12.

[0372] Step 4: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)acrylamide (Compound 155) The title compound was prepared in a manner substantially similar to that described in General Procedure K, using N5-(5-amino-2-fluorophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (170) and acryloyl chloride (18) to give N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)acrylamide (Compound 155) as a white solid after preparative HPLC purification (3.5 mg, yield: 5.29%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.81-9.58 (bs, 2H), 7.83 (s, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 7.20 (bs, 2H), 6.38-6.45 (m, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 11.6 Hz, 1H), 3.60 (s, 3H). LCMS: [M+H] + 389.21.

[0373] Scheme 38: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)acrylamide (compound 156): [ka] Step 1: Synthesis of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)carbamate (171): To a stirred solution of 3,5,6-trichloro-1,2,4-triazine (167) (3.0 g, 16.3 mmol) in dichloromethane (30.0 mL), triethylamine (3.29 g, 32.5 mmol) and tert-butyl (3-aminophenyl)carbamate (7) (2.37 g, 11.4 mmol) were added at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography (10-20% ethyl acetate in heptane) to give tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)carbamate (171) as a yellow solid (2.0 g, yield: 34.51%). LCMS: [M+H] + 356.09.

[0374] Step 2: Synthesis of tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)carbamate (172): To a stirred solution of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)carbamate (171) (1.50 g, 4.21 mmol) in propan-2-ol (5.0 mL) was added 1-methyl-1H-pyrazol-4-amine (22) (1.02 g, 10.5 mmol) and camphorsulfonic acid (685 mg, 2.95 mmol). The reaction mixture was stirred at 80° C. for 16 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by CombiFlash column chromatography, eluting with 10-20% ethyl acetate in heptane, to give tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)carbamate (172) as a yellow solid (700 mg, 1.68 mmol). [M+H] + 417.49.

[0375] Step 3: Synthesis of N5-(3-aminophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (173): The title compound was prepared in a manner substantially similar to that described in General Procedure I to afford N5-(3-aminophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (173) as a reddish solid (350 mg; yield: 76%) with tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)carbamate (172). + 317.17.

[0376] Step 4: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)acrylamide (compound 156): The title compound was prepared in a manner substantially similar to that described in General Procedure K, using N5-(3-aminophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (173) and acryloyl chloride (18) to give N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)acrylamide (Compound 156) as a white solid after preparative HPLC purification (15.0 mg, yield: 4.21%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.52 (bs, 2H), 7.88 (s, 1H), 7.59-7.57 (m, 1H), 7.42-7.30 (m, 4H), 6.42-6.48 (m, 1H), 6.23 (dd, J = 16.8 Hz, 2.0 Hz 1H), 5.75 (d, J = 10.4 Hz, 1H), 3.63 (bs, 3H). LCMS: [M+H] + 371.15.

[0377] Scheme 39: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)acrylamide (compound 157): [ka] Step 1: Synthesis of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (174): To a stirred solution of 3,5,6-trichloro-1,2,4-triazine (177) (2.0 g, 10.8 mmol) in dichloromethane (30 mL) was added triethylamine (1.44 g, 14.2 mmol) and tert-butyl (3-hydroxyphenyl)carbamate (163) (1.75 g, 8.34 mmol) at 0 °C, then the mixture was allowed to warm to room temperature and stirred at the same temperature for 16 h. After completion of the reaction (as monitored by TLC), water (50 mL) was added and extracted with dichloromethane (5 × 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by CombiFlash column chromatography, eluting with 5-10% ethyl acetate in heptane to give tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (174) as a white solid (1.90 g; yield: 63.76%). LCMS: [MH] - 355.11.

[0378] Step 2: Synthesis of tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (175): To a stirred solution of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (174) (500 mg, 1.40 mmol) and 1-methyl-1H-pyrazol-4-amine (22) (136 mg, 1.40 mmol) in toluene (3.0 mL) was added cesium carbonate (1.37 g, 4.20 mmol) at room temperature. The resulting reaction mixture was purged with nitrogen for 15 minutes, and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (229 mg, 0.28 mmol) was added. The resulting reaction mixture was heated at 110° C. for 16 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was taken up in water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (175) as a yellow gel (200 mg; yield: 34.19%). MS: [M+H] + 418.32.

[0379] Step 3: Synthesis of 5-(3-aminophenoxy)-6-chloro-N-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazin-3-amine (176): The title compound was prepared in a manner substantially similar to that described in General Procedure I using tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (175) to give 5-(3-aminophenoxy)-6-chloro-N-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazin-3-amine (176) as a brown solid (280 mg; yield: 28%). MS: [M+H] + 318.08.

[0380] Step 4: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)acrylamide (compound 157): The title compound was prepared in a manner substantially similar to that described in General Procedure K, using 5-(3-aminophenoxy)-6-chloro-N-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazin-3-amine (176) and acryloyl chloride (18) to give N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)acrylamide (Compound 157) as a white solid after preparative HPLC purification (20 mg, yield: 6.1%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.37-10.35 (m, 2H), 7.70 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.49-7.45 (m, 2H), 7.41 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.39-6.46 (m, 1H), 6.24 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.0 Hz, 1H), 3.64 (s, 3H). LCMS: [M+H] + 372.15.

[0381] Scheme 40: Synthesis of N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 158): [ka] Step 1: Synthesis of tert-butyl (3-((6-chloro-3-methylpyrazin-2-yl)oxy)phenyl)carbamate (178) To a solution of 3,5-dichloro-2-methylpyrazine (177) (1.00 g, 6.13 mmol) in dimethyl sulfoxide (10.0 mL) were added cesium fluoride (2.80 g, 18.4 mmol) and tert-butyl (3-hydroxyphenyl)carbamate (163) (1.28 g, 6.13 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography, eluting with 15-25% ethyl acetate in heptane, to give tert-butyl (3-((6-chloro-3-methylpyrazin-2-yl)oxy)phenyl)carbamate (178) as a white solid (1.90 g; yield: 82.08%). LCMS: [M+H] + 336.25.

[0382] Step 2: Synthesis of tert-butyl (3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (179) To a stirred solution of 1-methyl-1H-pyrazol-4-amine (22) (1.30 g, 3 equivalents, 13.4 mmol) in toluene (15.0 mL) was added cesium carbonate (4.37 g, 13.4 mmol) and tert-butyl (3-((6-chloro-3-methylpyrazin-2-yl)oxy)phenyl)carbamate (178) (1.50 g, 4.47 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 15 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.09 g, 1.34 mmol) was added at room temperature. The resulting reaction mixture was stirred at 110 °C for 16 hours. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature, ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (179) as a viscous liquid (1.00 g). MS: [M+H] + 397.32.

[0383] Step 3: Synthesis of 6-(3-aminophenoxy)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (180) The title compound was prepared in a manner substantially similar to that described in General Procedure I with tert-butyl (3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (179) to give 6-(3-aminophenoxy)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (180) as a brown liquid (1.40 g; yield: 28.95%). MS: [M+H] + 297.36.

[0384] Step 4: Synthesis of N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (Compound 158) The title compound was prepared in a manner substantially similar to that described in General Procedure K using 6-(3-aminophenoxy)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (180) and acryloyl chloride (18) to give N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (Compound 158) as a light brown solid after preparative HPLC purification (76.0 mg, yield: 5.09%). 1 H-NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 9.25 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.38-6.45 (m, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.76 (d, J = 11.6, 1H), 3.52 (s, 3H), 2.40 (s, 3H). LCMS: [M+H] + 351.18.

[0385] Scheme 41: Synthesis of N-(3-{5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-4-fluorophenyl)prop-2-enamide (compound 159): [ka] Step 1: Synthesis of 2,5-dichloro-4-(2-fluoro-5-nitrophenyl)pyrimidine (182) To a stirred solution of 2,4,5-trichloropyrimidine (13) (0.3 g, 1.64 mmol) in 1,4-dioxane (5.00 mL) and water (0.5 mL), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (181) (0.52 g, 1.96 mmol), sodium carbonate (0.34 g, 3.27 mmol), and the mixture was purged with nitrogen for 5 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.067 g, 0.081 mmol) was added and the mixture was stirred at 90 °C for 2 hours. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL × 2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by using a CombiFlash purification system, eluting with 1-5% ethyl acetate in hexane to give the title compound (182) as an off-white solid (0.5 g, 90%). LCMS: [M+H] + 288.0.

[0386] Step 2: Synthesis of 5-chloro-4-(2-fluoro-5-nitrophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (183) To a stirred solution of 2,5-dichloro-4-(2-fluoro-5-nitrophenyl)pyrimidine (182) (0.35 g, 1.22 mmol) in propan-2-ol (10.0 mL), 1-methyl-1H-pyrazol-4-amine (22) (0.118 g, 1.22 mmol) and N,N-diisopropylethylamine (0.43 mL, 2.43 mmol) were added and stirred in a sealed tube at 100 °C for 16 h. The reaction progress was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography, eluting with 5-7% methanol in dichloromethane, to give the title compound (183) (0.36 g, 84%). LCMS: [M+H] + 349.1.

[0387] Step 3: Synthesis of 4-(5-amino-2-fluorophenyl)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (184): To a stirred solution of 5-chloro-4-(2-fluoro-5-nitrophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (183) (0.36 g, 1.03 mmol) in tetrahydrofuran (10.0 mL), methanol (10.0 mL), and water (10.0 mL) was added zinc (0.34 g, 5.16 mmol) and ammonium chloride (0.27 g, 5.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by CombiFlash purification apparatus, eluting the product with 4-6% methanol in dichloromethane to give the title compound (184) as a reddish-brown sticky solid (0.2 g, 60.7%). 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.48 (s, 1H), 7.75 (s, 1H), 7.45 (s, 1H), 6.97-6.93 (m, 1H), 6.67-6.62 (m, 2H), 5.07 (s, 2H), 3.75 (s, 3H). LCMS [M+H] + 319.0.

[0388] Step 4: Synthesis of N-(3-{5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-4-fluorophenyl)prop-2-enamide (Compound 159) To a stirred solution of 4-(5-amino-2-fluorophenyl)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (184) (0.1 g, 0.314 mmol) in dichloromethane (10.0 mL) was added triethylamine (0.088 mL, 0.63 mmol) and prop-2-enoyl chloride (0.031 g, 0.35 mmol) in dichloromethane (2 mL) at −30° C. The reaction progress was immediately monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (5 mL) at −30° C. and extracted with ethyl acetate (50 mL × 2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography, eluting with 2–4% methanol in dichloromethane to give the crude product. The crude product was purified by preparative HPLC to give the title compound as an off-yellow solid (0.038 g, 33.1%). 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.55 (s, 1H), 7.94 (s, 2H), 7.82 (s, 1H), 7.73 (s, 1H), 7.45 (s, 1H), 7.35-7.31 (m, 1H), 6.43-6.36 (m, 1H), 6.27-6.23 (d, J = 16.0 Hz, 1H), 5.77-5.75 (d, J = 11.6 Hz, 1H), 3.76 (s, 3H). LCMS: [M+H] + 372.9.

[0389] Scheme 42: Synthesis of (E)-N-(3-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 160): [ka] The title compound was prepared as a yellow solid (0.016 g; yield: 12%) in a manner essentially similar to that described in General Procedure J. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.85 (s, 1H), 9.65 (s, 1H), 8.56 (s, 1H), 7.94-7.75 (m, 3H), 7.46 (s, 1H), 7.35 (s, 1H), 6.71 (s, 1H), 6.43-6.39 (d, J = 15.2 Hz, 1H), 3.93 (s, 2H), 3.76 (s, 3H), 2.78 (s, 6H). LCMS: [M+H] + 430.2.

[0390] Scheme 46: N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]prop-2-enamide TFA salt (compound 161): [ka] Step 1: Synthesis of tert-butyl (3-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (185) To a microwave vial was added 5-bromo-2,4-dichloropyrimidine (88) (1.00 g, 4.39 mmol), tert-butyl N-(3-amino-4-fluorophenyl)carbamate (83) (0.993 g, 4.39 mmol), N,N-dimethylformamide (10.0 mL), and dipotassium carbonate (1.21 g, 8.78 mmol). The reaction mixture was heated to 100 °C in a microwave for 1 hour. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with cold water (25 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), water (20 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude residue was purified by CombiFlash purification using 50% ethyl acetate in hexane to give the title compound (185) as a pale yellow solid (1.1 g, crude). LCMS: [M+H] + 417.0.

[0391] Step 2: Synthesis of tert-butyl N-[3-({5-bromo-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-4-fluorophenyl]carbamate (186) To a stirred solution of tert-butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-4-fluorophenyl}carbamate (185) (1.00 g, 2.39 mmol), 1-methyl-1H-pyrazol-4-amine (22) (0.233 g, 2.39 mmol) in propan-2-ol (10.0 mL) was added trifluoroacetic acid (0.1 mL). The reaction mixture was heated to 90° C. in a microwave for 30 minutes. The reaction mixture was evaporated under reduced pressure. The crude product was purified by CombiFlash purification using 50% ethyl acetate in hexane as the eluent to give the title compound (186) as a brown solid (0.75 g, 65%). LCMS: [M+H] + 478.1.

[0392] Step 3: Synthesis of tert-butyl N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]carbamate (188) To a sealed tube was added tert-butyl N-[3-({5-bromo-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-4-fluorophenyl]carbamate (186) (0.6 g, 1.25 mmol), N,N-dimethylformamide (10.0 mL), and triethylamine (0.35 mL, 2.51 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, and copper iodide (0.048 g, 0.25 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.088 g, 0.125 mmol), and ethynylbenzene (197) (0.19 g, 1.88 mmol) were added. The reaction mixture was heated at 85 °C for 9 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography using a silica column and 60% ethyl acetate in hexane as the eluent to give the title compound (188) as a yellow solid (0.4 g, crude). LCMS: [M+H] + 500.3.

[0393] Step 4: Synthesis of 2,2,2-trifluoro-N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]acetamide (189) To a stirred solution of tert-butyl N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]carbamate (188) (0.375 g, 0.75 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.4 mL) dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether (20 mL) and dried to give 2,2,2-trifluoro-N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]acetamide (189) as a brown solid (0.1 g, crude). LCMS: [M+H] + 400.2.

[0394] Step 5: Synthesis of N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]prop-2-enamide TFA salt (Compound 161) To a stirred solution of 2,2,2-trifluoro-N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]acetamide (189) (0.1 g, 0.2 mmol) in dichloromethane (5 mL) was added triethylamine (0.08 mL, 0.60 mmol), cooled to −40° C., and stirred for 10 min. After 10 min, prop-2-enoyl chloride (18) (0.02 g, 0.2 mmol) was added and stirred at −40° C. for 20 min. The reaction mixture was quenched with water (5 mL) and extracted into dichloromethane (2×5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by CombiFlash purification using 5% methanol in dichloromethane as the eluent, which was further purified by preparative HPLC to give the title compound (compound 161) as a white solid (0.02 g, 22%). 1H NMR (400 MHz, DMSO d6) δ 10.3 (s, 1H), 9.72 (s, 1H), 9.15 (s, 1H), 8.24 (s, 1H), 7.87 (bs, 2H), 7.63-7.62 (m, 3H), 7.41-7.39 (m, 4H), 7.17-7.11 (m, 2H), 6.44-6.38 (m, 1H), 6.27-6.23 (m, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.56 (s, 3H). LCMS: [M+H] + 454.5.

[0395] Scheme 43: Synthesis of (2E)-4-(dimethylamino)-N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]but-2-enamide (compound 162): [ka] The title compound (Compound 162) was prepared as a white solid (0.035 g, 28%) in a manner essentially similar to that described in General Procedure J. 1 H NMR (400 MHz, DMSO d6) δ 10.20 (s, 1H), 9.47 (s, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.65 - 7.60 (m, 3H), 7.40- 7.35 (m, 4H), 7.14 - 7.10 (m, 2H), 6.76 - 6.69 (m, 1H), 6.26 - 6.22 (m, 1H), 3.52 (s, 3H), 3.04 (d, J = 5.2 Hz, 2H), 2.15 (s, 6H). LCMS: [M+H] + 511.5.

[0396] Scheme 48: Synthesis of 2-({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-N-phenyl-4-(prop-2-enamido)benzamide (compound 163): [ka] Step 1: Synthesis of 2-amino-4-nitro-N-phenylbenzamide (191) To a stirred solution of 2-amino-4-nitrobenzoic acid (190) (2.00 g, 11.0 mmol) in dichloromethane (30.0 mL) was added 1H-1,2,3-benzotriazol-1-ol hydrate (1.68 g, 11.0 mmol), (3-{[(ethylimino)methylidene]amino}propyl)dimethylamine (1.70 g, 11.0 mmol), followed by N,N-diisopropylethylamine (2.13 g, 16.5 mmol) and aniline (1.12 g, 12.1 mmol) at 25 °C and stirred at 25 °C for 6 h. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography eluting with 12-20% ethyl acetate in hexane to give 191 (1.70 g, 60%). LCMS: [M+H] + 258.1.

[0397] Step 2: Synthesis of 2-[(2,5-dichloropyrimidin-4-yl)amino]-4-nitro-N-phenylbenzamide (192) To a stirred solution of 2-amino-4-nitro-N-phenylbenzamide (191) (1.00 g, 3.89 mmol) in N,N-dimethylformamide (10.0 mL) was added sodium hydride (0.187 g, 7.77 mmol) followed by 2,4,5-trichloropyrimidine (1.07 g, 5.83 mmol) at 25° C. and stirred at 25° C. for 3 hours. The reaction mixture was then quenched with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sulfate, and evaporated under reduced pressure to give 192 (0.55 g, 35%). LCMS: [M+H] + 404.0.

[0398] Step 3: Synthesis of 2-({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-4-nitro-N-phenylbenzamide (193) To a stirred solution of 2-[(2,5-dichloropyrimidin-4-yl)amino]-4-nitro-N-phenylbenzamide (194) (0.5 g, 1.24 mmol) in propan-2-ol (7.00 mL) was added 1-methyl-1H-pyrazol-4-amine (22) (0.12 g, 1.24 mmol), trifluoroacetic acid (0.141 g, 1.24 mmol), and the reaction mixture was heated at 100° C. for 12 hours. The reaction mixture was diluted with isopropanol (4 mL) and filtered. The resulting solid was dried to give 193 (0.550 g, 95%). LCMS: [M+H] + 464.1.

[0399] Step 4: Synthesis of 4-amino-2-({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-N-phenylbenzamide (194) The title compound was prepared in a manner essentially similar to that described in General Procedure L to give the desired compound 194 as a brown solid (0.15 g, yield: 53%). LCMS: [M+H] + 435.1.

[0400] Step 5: Synthesis of 2-({5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-N-phenyl-4-(prop-2-enam...

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R １ is -(C(R ４ ) ２ ) ｎ R ５ and X is —NH; n is 0, R ５ is 0 or 1 R ５’ is a phenyl substituted with R ２ is at least one R ７ and 0, 1, or 2 R ８ is a phenyl substituted with R ３ is 0, 1, 2, or 3 R １２ is a pyrazolyl substituted with Each R ５’ is independently alkyl, haloalkyl, heterocycloalkyl, halo, hydroxy, or alkoxy; R ７ teeth, 【Chemistry 2】 and R ８ is fluoro, Y is —C(═O)—; R ９ , R ９’ , and R ９’’ is hydrogen, R １０ is hydrogen, Each R １２ are independently methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl, or cyclopropyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. Each R ５’ is independently methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, hydroxy, methoxy, ethoxy, fluoromethyl, difluoromethyl, or trifluoromethyl.

3. Each R ５’ The compound of claim 2, wherein is independently methyl, morpholinyl, fluoro, chloro, methoxy, fluoromethyl, difluoromethyl, or trifluoromethyl.

4. R ２ But one or two R ８ The compound of any one of claims 1 to 3, substituted with

5. R ２ The compound of any one of claims 1 to 3, wherein is substituted with 0 R 8 .

6. R ３ The compound of any one of claims 1 to 5, wherein is unsubstituted.

7. R ３ but at least one R １２ The compound of any one of claims 1 to 5, substituted with

8. R ３ However, there are at least two R １２ 8. The compound of claim 7 , substituted with:

9. Each R １２ The compound of claim 8 , wherein is independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chloro.

10. Each R １２ The compound of claim 9 , wherein is independently methyl or chloro.

11. R ５’ The compound of any one of claims 1 to 10, wherein is fluoromethyl, difluoromethyl, or trifluoromethyl.

12. R １２ The compound according to any one of claims 1 to 11, wherein is methyl.

13. 1. The compound of formula IA, formula IB, formula IC, formula ID, formula IE, formula IF, or formula IG: 【Chemistry 3-1】 【Chemistry 3-2】 13. The compound of any one of claims 1 to 12, which is: or a pharmaceutically acceptable salt or stereoisomer thereof.

14. The compound is Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 10. The compound of claim 1 selected from: or a pharmaceutically acceptable salt of any of the foregoing.

15. The compound is 【Chemistry 4】 15. The compound of claim 14, which is: or a pharmaceutically acceptable salt or stereoisomer thereof.

16. A pharmaceutical composition comprising the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

17. 16. A pharmaceutical composition for use in the treatment of cancer, comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. 18. The pharmaceutical composition of claim 17, wherein the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, or non-small cell lung cancer.

19. 19. The pharmaceutical composition of claim 18, wherein the cancer in the subject comprises an EGFR mutation comprising a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.

20. The EGFR mutations are del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH 20. The pharmaceutical composition of claim 19, wherein the EGFR is selected from EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof.

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