Pyrimidine compounds, compositions and medical uses thereof

Abstract

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

Description

[0001] Cross-references

[0002] 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 herein by reference in its entirety. Background of the Invention

[0004] Lung cancer accounts for the largest number of cancer deaths, and approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). The development of targeted therapies for lung cancer has primarily focused on tumors exhibiting specific oncogenic drivers, namely mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Third-generation tyrosine kinase inhibitors (TKIs) have been developed for cancers with the most frequently observed EGFR mutations; however, other oncogenic drivers within the EGFR family of receptor tyrosine kinases have received less research and development attention, and several oncogenic drivers, including insertions in exon 20 of the EGFR gene, currently lack approved therapeutic agents for treating their associated cancers.

[0005] Given that many patients with mutations in EGFR do not receive clinical benefit from currently available therapies targeting these targets, there remains a significant unmet need to develop novel therapies for treating cancers associated with EGFR mutations. Summary of the Invention

[0006] In one respect, this paper provides a compound of formula I:

[0007]

[0008] Or its pharmaceutically acceptable salt or stereoisomer, wherein:

[0009] X is -NH- or -O-;

[0010] R 1 -(C(R) 4 )2) n R 5 , where R 5 Not replaced or replaced by 1 R 5 'replace;

[0011] n is 0, 1, 2, or 3;

[0012] Each R 4 It is independently hydrogen, alkyl, halogroup, haloalkyl, hydroxyl, alkoxy, or heteroalkyl;

[0013] R 5 C 4-10 cycloalkyl, aryl, or heteroaryl;

[0014] Each R 5 Independently, it can be deuterium, aryl, heteroaryl, alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, oxo, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, 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)2alkyl, -S(=O)2aryl, -S(=O)2NH2, -S(=O)2NHR 6 -S(=O)2N(R) 6 )2、-S(=O)2 heteroaryl, alkoxy, or haloalkoxy;

[0015] Each R 6 It is independently an alkyl, aminoalkyl, cycloalkyl, aryl, or heteroaryl group;

[0016] R 2 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is formed by at least one R 7 And 0, 1 or 2 R 8 replace;

[0017] Each R 7 Independently

[0018] Y is -C(=O)-, -S(=O)-, or -S(=O)2-;

[0019] R 9 R 9 'and R 9 "Independently hydrogen, deuterium, halogen, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl;

[0020] R 10 It is hydrogen, alkyl, haloalkyl, or cycloalkyl;

[0021] Each R 8 Independently, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 11)2、-S(=O)2alkyl、-S(=O)2aryl、-S(=O)2heteroaryl or alkoxy;

[0022] Each R 11 It can be independently alkyl, cycloalkyl, aryl, or heteroaryl;

[0023] R 3 For 0, 1, 2 or 3 R 12 Substituted heteroaryl groups;

[0024] Each R 12 Independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halogen, cyano, alkoxy, heterocyclic alkyl, -N(R) 13 2. -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl or cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl or cycloalkyl group is independently unsubstituted or surrounded by 0, 1 or 2 R groups. 14 replace;

[0025] Each R 13 It can be independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl;

[0026] Each R 14 Independently, it is deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 15 )2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl or alkoxy; and

[0027] Each R 15 It can be alkyl, cycloalkyl, aryl or heteroaryl independently.

[0028] In some implementations, X is -NH-.

[0029] In some implementations, n is 0.

[0030] In some implementation schemes, R 5 It is phenyl, naphthyl, anthraceneyl, phenanthrene, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl, or C-linked indoleyl; wherein R 5 By 0 or 1 R 5 'Replace.' In some implementations, R 5 It has not been replaced. In some implementations, R 5 By 1 R 5 'replace.

[0031] In some implementations, each R 5'Independently alkyl, haloalkyl, 3-8 membered heterocyclic alkyl, halogen, cyano, hydroxyl, -N(R) 6 )2、-N(CH3)R6、-C(=O)NHR 6 -NHC(=O)R 6 -S(=O)₂NH₂, alkoxy, or haloalkoxy. In some embodiments, each R 5 Independently, it is methyl, ethyl, tert-butyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, fluorine, chlorine, cyano, hydroxyl, -N(R) 6 )2、-C(=O)NHR 6 -NHC(=O)R 6 -S(=O)2NH2, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R 5 Independently, it is methyl, morpholino, fluorine, chlorine, cyano, -C(=O)NHMe, -NHC(=O)Me, -S(=O)2NH2, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

[0032] In some implementations, each R 6 Independently alkyl or aryl. In some embodiments, each R 6 Independently, it is methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R... 6 It can be methyl or phenyl on its own.

[0033] In some implementation schemes, R 2 It is a single-ring structure. In some implementations, R 2 It is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrazinyl, or triazinyl; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is phenyl, cyclohexyl or pyrrole; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is determined by one R. 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 By 1 R7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 By 1 R 7 Replaced and not by R 8 Replacement. In some implementations, R 2 By 1 R 7 And 1 R 8 Replacement. In some implementations, R 2 By 1 R 7 and 2 R 8 replace.

[0034] In some implementation schemes, R 2 By 1 R 7 replace.

[0035] In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for

[0036] In some implementations, Y is -C (=O)-. In some implementations, Y is -S (=O)2-.

[0037] In some implementation schemes, R 9 R 9 and R 9 "Independently hydrogen, halogroup, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocyclic alkyl. In some embodiments, R..." 9 R 9 and R 9 "Independently hydrogen, fluorine, chlorine, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. In some embodiments, R..." 9 and R 9 'Independently hydrogen, halogroup, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocyclic alkyl. In some embodiments, R 9 and R 9 'Independently hydrogen, fluorine, chlorine, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl or fluoromethyl.

[0038] In some implementation schemes, R 10It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, or cyclopropyl. In some embodiments, R 10 It can be hydrogen or methyl.

[0039] In some implementation schemes, R 2 Not R 8 Replacement. In some implementations, R 2 By 1 or 2 R 8 Replacement. In some implementations, R 2 By 1 R 8 Replacement. In some implementations, R 2 By 2 R 8 Replacement. In some implementations, each R 8 Independently, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, chlorine, heteroalkyl, cyano, hydroxyl, amino, -N(R) 11 2. Methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 8 Independently methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine, -N(R) 11 2. Hydroxyethyl, methoxyethyl, or cyano.

[0040] In some implementations, each R 11 Independently alkyl or aryl. In some embodiments, each R 11 Independently, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthraceneyl, or phenanthryl. In some embodiments, each R 11 Independently, it is methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R... 11 It can be methyl or phenyl on its own.

[0041] In some implementation schemes, R 3 It is pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, indoleyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cenolinyl, or naphthidyl; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is imidazole, pyrazol, triazol, indole, indazole, thiazolyl, isothiazol, or pyridinyl; wherein R 3 By 0, 1, 2 or 3 R 12 replace.

[0042] In some implementation schemes, R 3 for:

[0043]

[0044] Where R 3 By 0 to 3 R 12 replace.

[0045] In some implementation schemes, R 3 for:

[0046]

[0047]

[0048] In some implementation schemes, R 3 for:

[0049]

[0050]

[0051] In some implementation schemes, R 3 It has not been replaced. In some implementations, R 3 At least 1 R 12 Replacement. In some implementations, R 3 At least 2 Rs 12 replace.

[0052] In some implementations, each R 12 Independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halogen, cyano, heterocyclic alkyl, -N(R) 13 )2, -S(=O)2NH2 or cycloalkyl. In some embodiments, each R 12 Independently, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluorine, chlorine, cyano, azacyclic butyl, oxacyclic butyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -N(R) 13 2. Cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 12 Independently, it is methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholino, or cyclopropyl. In some embodiments, each R 12 Independently, it is methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chlorinated. In some embodiments, each R... 12 It can be methyl or chlorine on its own.

[0053] In some implementations, each R 13 Independently alkyl or cycloalkyl. In some embodiments, each R 13 Independently, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 13 Independently, it is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, each R... 13 It can be methyl, cyclopropyl, or cyclohexyl independently.

[0054] In some implementation schemes, R 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl groups are not substituted. In some embodiments, R 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl groups are bound by one or two R groups. 14 replace.

[0055] In some implementations, each R 14 Independently alkyl, cycloalkyl, heterocycloalkyl, halogen, cyano, -N(R) 15 )2 or alkoxy. In some embodiments, each R 14 Independently, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidine, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluorine, chlorine, cyano, -N(R) 15 2. Methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 14 Independently, methyl, ethyl, isopropyl, tert-butyl, pyrrolyl, piperidinyl, morpholinyl, fluorine, chlorine, -N(R) 15 )2 or methoxy.

[0056] In some implementations, each R 15 Independently alkyl or cycloalkyl. In some embodiments, each R 15 It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0057] In some implementations, each R 13 Independently, it is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, each R... 13 It can be methyl, cyclopropyl, or cyclohexyl independently.

[0058] In some implementation schemes:

[0059] X is -NH- or -O-;

[0060] n is 0;

[0061] R 5 For 0 or 1 R 5 'Substituted phenyl;

[0062] R 2 For being at least one R 7 And 0, 1 or 2 R 8 Substituted phenyl; and

[0063] R 3 For 0, 1, 2 or 3 R 12 Substituted pyrazol group.

[0064] In some implementations, X is -NH-.

[0065] In some implementation schemes, R 5 It can be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0066] In some implementation schemes:

[0067] R 7 for and

[0068] R 8 It is a halogen group.

[0069] In some implementation schemes:

[0070] R 8 It is fluorine;

[0071] Y is -C(=O)-;

[0072] R 9 and R 9 'For hydrogen; and

[0073] R 10 It is hydrogen.

[0074] In some implementation schemes, R 12 It is an alkyl group.

[0075] In some implementation schemes, R 12 It is a methyl group.

[0076] In some embodiments, the compound has the formula IA, IB, IC, ID, IE, IF, or IG:

[0077]

[0078]

[0079]

[0080] Or its pharmaceutically acceptable salts or stereoisomers.

[0081] In some embodiments, the compound has the formula IA: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IA: Or its pharmaceutically acceptable salts or stereoisomers.

[0082] In some embodiments, the compound has the formula IB: Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments of the compound of formula IB, wherein R... 1 For R 5 In some embodiments of the IB compound, R 5 By 0 or 1 R 5 'Replacement.' In some embodiments of the compound of formula IB, R 5 Not replaced. In some embodiments of the formula IB compound, R 5 By 1 R 5 'replace.

[0083] In some embodiments, the compound has the formula IC: Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments of the compound of formula IB, wherein R... 1 For R 5 In some embodiments of the IC compound, R 5 By 0 or 1 R 5 'Replacement.' In some embodiments of the formula IC compound, R 5 Not replaced. In some embodiments of the IC compound, R 5 By 1 R 5 'replace.

[0084] In some embodiments, the compound has formula ID: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula ID: Or its pharmaceutically acceptable salts or stereoisomers.

[0085] In some embodiments, the compound has the formula IE: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IE: Or its pharmaceutically acceptable salts or stereoisomers.

[0086] In some embodiments, the compound has the formula IF: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IF: Or its pharmaceutically acceptable salts or stereoisomers.

[0087] In some embodiments, the compound has the formula IG: Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments of the formula IG compound, R... 1 For R 5 In some embodiments of the IG compound, R 5 By 0 or 1 R 5 'Replacement.' In some embodiments of the formula IG compound, R 5 Not replaced. In some embodiments of the formula IG compound, R 5 By 1 R 5 'replace.

[0088] In some embodiments, the compound is:

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] Or its pharmaceutically acceptable salt.

[0102] In some implementations, the compounds described herein are selective inhibitors of EGFR rather than HER2.

[0103] 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.

[0104] In another respect, this article provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

[0105] On the other hand, this document provides a method for inhibiting epidermal growth factor receptor (EGFR) family kinase mutants in a subject of need, 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. 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 mutants are selected from del19 / T790MEGFR, 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, 772insNPEGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASVEGFR, 773insAH EGFR, M766_A767insAI EGFR and any combination thereof.

[0106] On the other hand, this document provides a method for inhibiting epidermal growth factor receptor (EGFR) mutants in a subject of need, 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. 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 selected from del19 / T790M EGFR, L858R / T790M EGFR, L858REGFR, 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, 773insHEGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR and any combination thereof.

[0107] On the other hand, this document provides a method for inhibiting a drug-resistant epidermal growth factor receptor (EGFR) mutant in a subject of need, 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. In some embodiments, the drug-resistant EGFR mutant is del19 / T790MEGFR or L858R / T790M EGFR.

[0108] On the other hand, this article provides a method for inhibiting epidermal growth factor receptor (EGFR) in a subject in need, 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, wherein the compound exhibits higher inhibition of EGFR mutants relative to wild-type EGFR.

[0109] In some embodiments, the EGFR mutant includes 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 selected from del19 / T790M EGFR, L858R / T790M EGFR, L858REGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPGEGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. 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.

[0110] On the other hand, this document provides a method for treating a disease or condition associated with epidermal growth factor receptor (EGFR) family kinases in a subject of need, 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. 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 selected from del19 / T790MEGFR, L858R / T790MEGFR, 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, 772insNPEGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASVEGFR, 773insAH EGFR, M766_A767insAI EGFR and any combination thereof.

[0111] In some embodiments, the subject's disease or condition includes an EGFR mutation. In some embodiments, the EGFR mutation includes 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 implementations, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEAEGFR, 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, 773insNPHEGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. 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.

[0112] On the other hand, this article provides a method for treating one or more cancer cells in a subject in need, 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.

[0113] On the other hand, this article provides a method for treating cancer in a subject in need, 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.

[0114] 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.

[0115] In some embodiments, the subject's cancer contains an EGFR mutation. In some embodiments, the EGFR mutation includes 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 implementations, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVDEGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. EGFR, EGFRvii, EGFRviii, A767_dupASVEGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19 / T790M EGFR or L858R / T790M EGFR.

[0116] In another aspect, this disclosure provides a method for treating an inflammatory disease in a subject in need, 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.

[0117] In some implementations, the inflammatory disease is psoriasis, eczema, or atherosclerosis.

[0118] In some embodiments, the subject's inflammatory disease includes an EGFR mutation. In some embodiments, the EGFR mutation includes 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 implementations, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEAEGFR, 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, 773insNPHEGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. 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.

[0119] In another aspect, this disclosure provides a compound, wherein the compound is:

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] Or its pharmaceutically acceptable salts or stereoisomers.

[0127] This disclosure discloses a method for preparing a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, stereoisomer, solvate, and hydrate thereof, and relates to pharmaceutical compositions containing the thereof.

[0128] The disclosed compounds are applicable for the treatment, prevention, or inhibition of diseases and conditions mediated by epidermal growth factor receptor (EGFR).

[0129] These and other features, aspects, and advantages of this disclosure will be better understood with reference to the following description. This description is provided to introduce some concepts in a simplified form. This description is not intended to identify key or fundamental features of the subject matter, nor is it intended to limit the scope of the subject matter.

[0130] By incorporating references

[0131] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is expressly and individually indicated to be incorporated by reference. Detailed Implementation

[0132] definition

[0133] Unless otherwise specified, the following terms have specific meanings in the structures given herein and throughout this disclosure.

[0134] 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, when the group in question is substituted with more than one substituent, the substituents are identical. In some embodiments, when the group in question is substituted with more than one substituent, the substituents are different. In some embodiments, the reference group is optionally substituted individually and independently with one or more additional groups selected from the following: halogen, -CN, -NH2, -NH (alkyl), -N (alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH (alkyl), -C(=O)N (alkyl)2, -S(=O)2NH2, -S(=O)2NH (alkyl), -S(=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, the optional substituents are independently selected from: halogens, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituents are independently selected from halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, the substituted group is replaced by one or both of the preceding groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic) include oxo groups (=O).

[0135] As used in this article, C1-C x Including C1-C2, C1-C3…C1-C x For example only, a group designated as "C1-C6" indicates that the group contains one to six carbon atoms, that is, a group containing one, two, three, or four carbon atoms. Therefore, for example only, "C1-C4 alkyl" indicates that the alkyl group contains one to four carbon atoms, meaning the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0136] The term "alkyl" refers to a single-group branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of this term include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, etc.

[0137] Unless otherwise specified, the term "cycloalkyl" refers to a carbocyclic group having 3 to 6 carbon atoms, consisting of a single ring or multiple fused, spiro, or bridging rings. This definition covers saturated or partially unsaturated rings. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, etc.

[0138] "Halogen" or "halogen" alone or in combination with any other term means halogen, such as chlorine (Cl), fluorine (F), bromine (Br), and iodine (I).

[0139] The term "aryl" refers to a group derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. This definition covers monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, as well as fused or bridged ring systems. Aryl groups include (but are not limited to) aryl groups derived from hydrocarbon ring systems of ethyleneanthracene, ethylenenaphthalene, ethylenephenanthrene, anthracene, azulene, benzene, chrysene, fluorene, as-indacene, s-indacene, indame, indene, naphthalene, phenalene, pleiadene, pyrene, and benzo[a]phenanthrene. Unless otherwise specifically stated in this specification, the term "aryl" or the prefix "aromatic-" (e.g., in "arylalkyl") is intended to include optionally substituted aryl groups.

[0140] The term "phenyl" refers to an aromatic carbocyclic group with 6 carbon atoms, which has a single ring.

[0141] The term "phenylalkyl" refers to a single-group branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms, which is substituted with an aromatic carbocyclic group having 6 carbon atoms, said aromatic carbocyclic group having a single ring.

[0142] The term "heteroaryl" refers to an aromatic cyclic group having 5 or 6 carbon atoms and 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur within at least one ring. "X-linked heteroaryl" refers to a heteroaryl group linked to the remainder of the molecule via an X atom. For example, It is an N-bonded imidazole group, and It is C-linked with an imidazole group.

[0143] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated, partially unsaturated or unsaturated group having a monocyclic or multiple fused or spirocyclic or bridging rings, having 2 to 10 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, sulfur, phosphorus and / or oxygen in the ring.

[0144] The term "alkenyl" refers to an unsaturated aliphatic group having at least one double bond.

[0145] The term "alkynyl" refers to an unsaturated aliphatic group having at least one triple bond.

[0146] The term "amino" refers to the -NH2 group.

[0147] The term "cyano" refers to the -CN group.

[0148] The term "hydroxyl" (or "hydroxyl") refers to the -OH group.

[0149] The term "heteroalkyl" refers to an alkyl group as described above, wherein one or more carbon atoms of the alkyl group are replaced by O, N, or S atoms. Unless otherwise specifically stated in this specification, heteroalkyl groups are optionally substituted as described below. Representative heteroalkyl groups include (but are not limited to) -OCH2CH2OMe, -OCH2CH2OCH2CH2NH2 and -OCH2CH2OCH2CH2OCH2CH2N(Me)2.

[0150] "Heterocyclic alkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group is fused with an aryl or heteroaryl group. In some embodiments, the heterocyclic alkyl group is oxazolidinone, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, piperidin-2-one, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-diketone, pyrrolidine-2,5-dione, pyrrolidine-ketone, imidazoalkyl, imidazoalkyl-2-one, or thiazoalkyl-2-one. In one aspect, the heterocyclic alkyl group is C2-C 10 Heterocyclic alkyl groups. On the other hand, heterocyclic alkyl groups are C4-C. 10 Heterocyclic alkyl groups. In some embodiments, the heterocyclic alkyl group is monocyclic or bicyclic. In some embodiments, the heterocyclic alkyl group is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, the heterocyclic alkyl group is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, the heterocyclic alkyl group is monocyclic and is a 3 or 4-membered ring. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms, 0-2 oxygen atoms, and 0-1 sulfur atoms in the ring.

[0151] The term "haloalkyl" refers to an alkyl group as described above, wherein one or more carbon atoms of the alkyl group are replaced by halogen atoms. In some embodiments, the haloalkyl group may optionally be substituted as described below. Representative haloalkyl groups include (but are not limited to) fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl.

[0152] The term "aminoalkyl" refers to an alkyl group substituted with an amino (NH2) group. In some embodiments, the aminoalkyl group is unsubstituted or substituted with an alkyl group on the nitrogen atom.

[0153] The term "alkoxy" refers to the group RO-, where R is an optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, wherein 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, etc.

[0154] The compounds described herein include isotopically labeled compounds that are identical to those listed in the polyforms and structures presented herein, but in practice, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. In some embodiments, the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, for example... 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 P. In one aspect, isotopically labeled compounds described herein (e.g., those containing, for example, 3 H and 14Compounds containing radioactive isotopes of C are suitable for drug and / or substrate tissue distribution assays. In one aspect, substitution with an isotope such as deuterium yields certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirement. In some embodiments, the compounds described herein are present in the form of isotopic variants. In some embodiments, the isotopic variants of the compounds described herein have one or more deuterium-substituted hydrogen atoms.

[0155] In some embodiments, the compounds described herein contain one or more chiral centers and / or double bonds, and are therefore present as stereoisomers such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers, or diastereomers. Therefore, the chemical structures depicted herein cover all possible enantiomers and stereoisomers of the illustrated or identified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and mixtures of enantiomers and stereoisomers. In some embodiments, mixtures of enantiomers and stereoisomers are resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. In some embodiments, the compounds are also present in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Therefore, the chemical structures depicted herein cover all possible tautomeric forms of the illustrated or identified compounds.

[0156] In some embodiments, the compounds disclosed herein are in the form of free bases, salts, hydrates, isomers, diastereomers, prodrugs (e.g., esters), metabolites, ion-pair complexes, or chelates. In some embodiments, the compounds are present in both unsolvated and solvated forms (including hydrated forms and as N-oxide forms). In some embodiments, the compounds are hydrated, solvated, or N-oxides. The scope of this disclosure also covers analogues, hydrolysis products, metabolites, and prodrugs or precursors of the compounds. Generally, unless otherwise specified, all physical forms are equivalent for the uses covered herein and are intended to fall within the scope of this disclosure.

[0157] "Pharmaceutically acceptable salts" include salts formed with pharmaceutically acceptable acids or bases. Pharmaceutically acceptable acids include 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, or 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, aralkylamines, and heterocyclic amines. In some embodiments, the compound is a pharmaceutically acceptable salt derived from an acid including (but not limited to) the following: acetic acid, alginate, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, glucuronic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, or p-toluenesulfonic acid.

[0158] "Pharmaceutical composition" means one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly produced by the combination, compounding, or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions disclosed herein cover any composition comprising the compounds of this disclosure and a pharmaceutically acceptable carrier.

[0159] "Carrier" refers to a diluent, adjuvant, excipient, or medium that is administered with a therapeutic agent. In some embodiments, such drug carriers are sterile liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, including (but not limited to) peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, water is used as a carrier when the drug composition is administered orally. In some embodiments, saline and aqueous dextran are exemplary carriers when the drug composition is administered intravenously. In some embodiments, saline solution, aqueous dextran solution, and glycerol solution are used as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, etc. In some embodiments, the composition contains a small amount of wetting agent or emulsifier, or pH buffer. In some embodiments, these pharmaceutical compositions are in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. In some embodiments, the compositions are formulated as suppositories having a conventional binder and a carrier such as triglycerides. In some embodiments, oral formulations contain carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in EW Martin's "Remington's Pharmaceutical Sciences". Such compositions will contain a therapeutically effective amount, for example, a purified form of the therapeutic agent, and a suitable amount of carrier to provide a form appropriate for administration to the patient. The formulation should conform to the requirements of the administration method.

[0160] The terms "combined," "in combination," or "combined" should be understood as co-administered, encompassing situations where compounds are administered separately in different formulations, 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 the combined pharmaceutical composition.

[0161] compound

[0162] In one respect, this paper provides a compound of formula I:

[0163]

[0164] Or its pharmaceutically acceptable salt or stereoisomer, wherein:

[0165] X is -NH- or -O-;

[0166] R 1 -(C(R)4 )2) n R 5 , where R 5 By 0 or 1 R 5 'replace;

[0167] n is 0, 1, 2, or 3;

[0168] Each R 4 It is independently hydrogen, alkyl, halogen, haloalkyl, hydroxy, alkoxy, or heteroalkyl;

[0169] R 5 C 4-10 Cycloalkyl, C-linked heterocycloalkyl, aryl or heteroaryl;

[0170] Each R 5 'Independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, oxo, halogen, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH2, -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)2alkyl, -S(=O)2aryl, -S(=O)2NH2, -S(=O)2NHR 6 -S(=O)2N(R) 6 )2、-S(=O)2 heteroaryl, alkoxy, or haloalkoxy;

[0171] Each R 6 It can be independently alkyl, cycloalkyl, aryl, or heteroaryl;

[0172] R 2 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is formed by at least one R 7 And 0, 1 or 2 R 8 replace;

[0173] Each R 7 Independently

[0174] Y is -C(=O)-, -S(=O)-, or -S(=O)2-;

[0175] R 9 and R 9'Independently hydrogen, halogroup, alkyl, haloalkyl, cycloalkyl, heteroalkyl or (alkyl)heterocycloalkyl;

[0176] R 10 It is hydrogen, alkyl, haloalkyl, or cycloalkyl;

[0177] Each R 8 Independently, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 11 )2、-S(=O)2alkyl、-S(=O)2aryl、-S(=O)2heteroaryl or alkoxy;

[0178] Each R 11 It can be independently alkyl, cycloalkyl, aryl, or heteroaryl;

[0179] R 3 For 0, 1, 2 or 3 R 12 Substituted heteroaryl groups;

[0180] Each R 12 Independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halogen, cyano, alkoxy, heterocyclic alkyl, -N(R) 13 2. -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl or cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl or cycloalkyl group is independently unsubstituted or surrounded by 0, 1 or 2 R groups. 14 replace;

[0181] Each R 13 It can be independently alkyl, cycloalkyl, aryl, or heteroaryl;

[0182] Each R 14 Independently, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 15 )2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl or alkoxy; and

[0183] Each R 15 It can be independently alkyl, cycloalkyl, aryl, or heteroaryl;

[0184] The condition is that when X is -O-, R 5 It is not a C-bonded heterocyclic alkyl group.

[0185] In one respect, this paper provides a compound of formula I:

[0186]

[0187] Or its pharmaceutically acceptable salt or stereoisomer, wherein:

[0188] X is -NH- or -O-;

[0189] R 1 -(C(R) 4 )2) n R 5 , where R 5 Not replaced or replaced by 1 R 5 'replace;

[0190] n is 0, 1, 2, or 3;

[0191] Each R 4 It is independently hydrogen, alkyl, halogen, haloalkyl, hydroxy, alkoxy, or heteroalkyl;

[0192] R 5 C 4-10 cycloalkyl, aryl, or heteroaryl;

[0193] Each R 5 Independently, it can be deuterium, aryl, heteroaryl, alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, oxo, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, 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)2alkyl, -S(=O)2aryl, -S(=O)2NH2, -S(=O)2NHR 6 -S(=O)2N(R) 6 )2、-S(=O)2 heteroaryl, alkoxy, or haloalkoxy;

[0194] Each R 6 It is independently an alkyl, aminoalkyl, cycloalkyl, aryl, or heteroaryl group;

[0195] R 2 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is formed by at least one R 7 And 0, 1 or 2 R 8 replace;

[0196] Each R 7 Independently

[0197] Y is -C(=O)-, -S(=O)-, or -S(=O)2-;

[0198] R 9 R 9 'and R 9 "Independently hydrogen, deuterium, halogen, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl;

[0199] R 10 It is hydrogen, alkyl, haloalkyl, or cycloalkyl;

[0200] Each R 8 Independently, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 11 )2、-S(=O)2alkyl、-S(=O)2aryl、-S(=O)2heteroaryl or alkoxy;

[0201] Each R 11 It can be independently alkyl, cycloalkyl, aryl, or heteroaryl;

[0202] R 3 For 0, 1, 2 or 3 R 12 Substituted heteroaryl groups;

[0203] Each R 12 Independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halogen, cyano, alkoxy, heterocyclic alkyl, -N(R) 13 2. -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl or cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl or cycloalkyl group is independently unsubstituted or surrounded by 0, 1 or 2 R groups. 14 replace;

[0204] Each R 13 It can be independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl;

[0205] Each R 14 Independently, it is deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 15 )2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl or alkoxy; and

[0206] Each R 15 It can be alkyl, cycloalkyl, aryl or heteroaryl independently.

[0207] For any and all embodiments, the substituent is selected from a subset of the listed alternatives. For example, in some embodiments, X is -NH-. In some embodiments, X is -O-.

[0208] In some implementations, n is 0, 1, 2, or 3. (This is repeated four times in the original text.)

[0209] In some implementation schemes, R 5 It is phenyl, naphthyl, anthraceneyl, phenanthryl, trefyl, pyrene, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl, or C-linked indoleyl; wherein R 5 By 0 or 1 R 5 'Replace.' In some implementations, R 5 It is phenyl, naphthyl, anthraceneyl, phenanthryl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, or C-linked imidazoleyl; wherein R 5 By 0 or 1 R 5 'Replace.' In some implementations, R 5 It is a phenyl group; wherein the phenyl group is 0 or 1 R 5 'Replace.' In some implementations, R 5 It is a naphthyl group; wherein the naphthyl group is separated by 0 or 1 R 5 'Replace.' In some implementations, R 5 It is an anthracene group; wherein the anthracene group is separated by 0 or 1 R 5 'Replace.' In some implementations, R 5 For phenekers; wherein the pheneker is defined by 0 or 1 R 5 'Replace.' In some implementations, R 5 For a flexure; wherein the flexure is formed by 0 or 1 R 5 'Replace.' In some implementations, R 5 It is a pyrene group; wherein the pyrene group is divided by 0 or 1 R 5 'Replace.' In some implementations, R 5 It is a C-linked pyridinyl group; wherein the C-linked pyridinyl group is separated by 0 or 1 R 5 'Replace.' In some implementations, R 5It is a C-linked pyrimidine group; wherein the C-linked pyrimidine group is separated by 0 or 1 R 5 'Replace.' In some implementations, R 5 It is a C-linked pyrazol group; wherein the C-linked pyrazol group is separated by 0 or 1 R 5 'Replace.' In some implementations, R 5 It is a C-linked imidazole group; wherein the C-linked imidazole group is separated by 0 or 1 R 5 'Replace.' In some implementations, R 5 It is a C-linked indole group; wherein the C-linked indole group is separated by 0 or 1 R 5 'replace.

[0210] In some implementation schemes, R 5 By 0 or 1 R 5 'Replace.' In some implementations, R 5 It has not been replaced. In some implementations, R 5 By 1 R 5 'replace.

[0211] In some implementations, each R 4 Independently, it is hydrogen, alkyl, halogroup, haloalkyl, hydroxyl, alkoxy, or heteroalkyl. In some embodiments, each R... 4 Independently hydrogen, alkyl, halogroup, haloalkyl, or alkoxy. In some embodiments, each R... 4 Independently, it is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, chlorine, trifluoromethyl, trifluoroethyl, pentafluoroethyl, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 4 Independently, it is hydrogen, methyl, fluorine, trifluoromethyl, methoxy, or trifluoromethoxy. In some embodiments, each R... 4 It is hydrogen. In some implementations, each R... 4 Independently alkyl. In some embodiments, each R 4 Independently a halogen group. In some implementations, each R... 4 Independently, it is a haloalkyl group. In some embodiments, each R... 4 For hydroxyl groups. In some embodiments, each R... 4 Independently alkoxy. In some embodiments, each R 4 Independently, it is a heteroalkyl group. In some embodiments, each R... 4 For methyl. In some embodiments, each R 4 For ethyl. In some embodiments, each R 4 It is n-propyl. In some embodiments, each R 4 It is isopropyl. In some embodiments, each R...4 It is n-butyl. In some implementations, each R 4 It is isobutyl. In some implementations, each R 4 It is sec-butyl. In some implementations, each R 4 It is tert-butyl. In some implementations, each R 4 For fluorine. In some implementations, each R 4 For chlorine. In some implementations, each R 4 It is trifluoromethyl. In some embodiments, each R 4 It is trifluoroethyl. In some embodiments, each R 4 It is pentafluoroethyl. In some embodiments, each R 4 It is methoxylated. In some embodiments, each R 4 It is ethoxylated. In some embodiments, each R 4 It is trifluoromethoxy.

[0212] In some implementations, each R 5 'Independently alkyl, haloalkyl, heterocyclic alkyl, halogen, cyano, hydroxyl, -N(R) 6 )2、-C(=O)NHR 6 -NHC(=O)R 6 -S(=O)₂NH₂, alkoxy, or haloalkoxy. In some embodiments, each R 5 'Independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 6 )2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl, or alkoxy. In some embodiments, each R 5 Independently aryl, heteroaryl, alkyl, heterocyclic alkyl, halogen, cyano, hydroxyl, -N(R) 6 )2 or alkoxy. In some embodiments, each R 5 'Independently aryl. In some implementations, each R...' 5 'Independently heteroaryl. In some embodiments, each R...' 5 'Independently alkyl. In some embodiments, each R...' 5 'Independently cycloalkyl. In some embodiments, each R...' 5 'Independently heterocyclic alkyl. In some embodiments, each R...' 5 'Independently a halogen group. In some implementations, each R...' 5 'Independently heteroalkyl. In some embodiments, each R...' 5 'Independently a haloalkyl group. In some embodiments, each R...'5 'It is cyano.' In some embodiments, each R 5 ' is a hydroxyl group. In some embodiments, each R... 5 'Amino.' In some embodiments, each R 5 Independently for -N(R) 6 2. In some implementations, each R 5 'Independently -S(=O)2 alkyl. In some embodiments, each R 5 'Independently -S(=O)2 aryl. In some embodiments, each R 5 'Independently -S(=O)2 heteroaryl. In some embodiments, each R 5 'Independently alkoxy. In some embodiments, each R...' 5 Independently, it can be phenyl, naphthyl, anthraceneyl, phenanthryl, treyl, pyrene, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, indoleyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cenolinyl, naphthidinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, azacyclobutane, oxacyclobutane, pyrrolyl, imidazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluorine, chlorine, cyano, hydroxyl, -N(R) 6 2. Methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 5 Independently, it is phenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, methyl, ethyl, tert-butyl, pyrrolylalkyl, piperidinyl, piperazine, morpholinyl, fluorine, chlorine, cyano, hydroxyl, -N(R) 6 2. Methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 5 Independently, it is methyl, ethyl, tert-butyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, fluorine, chlorine, cyano, hydroxyl, -N(R) 6 )2、-C(=O)NHR 6 -NHC(=O)R 6 -S(=O)2NH2, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R 5 'Independently methyl, morpholino, fluorine, chloro, cyano, -C(=O)NHMe, -NHC(=O)Me, -S(=O)2NH2, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R5 Independently, it is phenyl, imidazolyl, pyridinyl, methyl, tert-butyl, pyrrolyl, morpholinyl, fluorine, cyano, hydroxyl, -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 'For anthracene.' In some embodiments, each R 5 'For Fiki. In some implementations, each R 5 'For the base.' In some implementations, each R 5 'For pyrene.' In some implementations, each R 5 'is pyrrole.' In some embodiments, each R 5 'Imidazolyl group.' In some embodiments, each R 5 'is pyrazolyl.' In some embodiments, each R 5 'is triazole.' In some embodiments, each R 5 'is tetrazolium.' In some embodiments, each R 5 'For indole.' In some embodiments, each R 5 'is indazole group.' In some embodiments, each R 5 'is benzimidazole group.' In some embodiments, each R 5 'It is an azaindolyl group.' In some embodiments, each R 5 'For thiazolyl.' In some embodiments, each R 5 'isothiazolyl.' In some embodiments, each R 5 'For oxazolyl.' In some embodiments, each R 5 'isoxazolyl.' In some embodiments, each R 5 'is pyridyl.' In some embodiments, each R 5 ' is pyrimidinyl.' In some embodiments, each R 5 'It is pyridazinyl.' In some embodiments, each R 5 'is pyrazinyl.' In some embodiments, each R 5 ' is triazine-based.' In some embodiments, each R... 5 'is quinolinyl.' In some embodiments, each R 5 'is isoquinolinyl.' In some embodiments, each R 5 'For quinoxalinyl.' In some embodiments, each R 5 'is quinazolinyl.' In some embodiments, each R 5 'For senolinyl.' In some embodiments, each R 5'is naphthidyl.' In some embodiments, each R 5 ' is methyl.' In some embodiments, each R 5 'For ethyl.' In some embodiments, each R 5 'is n-propyl.' In some embodiments, each R... 5 'Isopropyl.' In some embodiments, each R 5 'is n-butyl.' In some implementations, each R 5 'Isobutyl.' In some implementations, each R 5 'For sec-butyl.' In some implementations, each R... 5 'For tert-butyl.' In some implementations, each R... 5 'It is a nitrogen-containing heterocyclic butyl group.' In some embodiments, each R 5 'It is an oxetane.' In some embodiments, each R... 5 'is pyrroleyl.' In some embodiments, each R 5 'Imidazolyl.' In some embodiments, each R 5 'It is tetrahydrofuranyl.' In some embodiments, each R 5 'is piperidinyl.' In some embodiments, each R 5 'is piperazine-based.' In some embodiments, each R 5 'It is tetrahydropyranyl.' In some embodiments, each R 5 'For morpholino. In some embodiments, each R 5 'For fluorine.' In some implementations, each R... 5 'For chlorine.' In some implementations, each R 5 'It is methoxylated.' In some embodiments, each R 5 'It is ethoxylated.' In some embodiments, each R 5 ' is trifluoromethoxy. In some embodiments, each R 5 'For -C(=O)NHMe.' In some implementations, each R 5 'For -NHC(=O)Me.' In some implementations, each R 5 'For -S(=O)2NH2.' In some implementations, each R 5 ' is difluoromethoxy.

[0213] In some implementations, each R 6 Independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 6 Independently alkyl or aryl. In some embodiments, each R 6Independently, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthraceneyl, phenanthryl, trefyl, or pyrene. In some embodiments, each R 6 Independently, it is methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R... 6 Independently methyl or phenyl. In some embodiments, each R 6 For methyl. In some embodiments, each R 6 For ethyl. In some embodiments, each R 6 It is n-propyl. In some embodiments, each R 6 It is isopropyl. In some embodiments, each R... 6 It is n-butyl. In some implementations, each R 6 It is isobutyl. In some implementations, each R 6 It is sec-butyl. In some implementations, each R 6 It is tert-butyl. In some implementations, each R 6 It is phenyl. In some embodiments, each R 6 It is naphthyl. In some embodiments, each R 6 For anthracene. In some embodiments, each R 6 For Fiki. In some implementations, each R 6 For the base. In some implementations, each R 6 It is a pyrene group.

[0214] In some implementation schemes, R 2 It is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is aryl, where R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a heteroaryl group; in which R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a cycloalkyl group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a heterocyclic alkyl group; wherein R 2 By at least one R 7And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a single-ring structure. In some implementations, R 2 It is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrazinyl, or triazinyl; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is phenyl, cyclohexyl or pyrrole; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a phenyl group; where R is a phenyl group. 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclopropyl; where R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclobutyl; where R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclopentyl; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclohexyl; where R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyrrole; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an imidazole group; where R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a pyrazolyl group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8Replacement. In some implementations, R 2 It is a triazole group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a tetrazolium group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a thiazolyl group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an isothiazolyl group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an oxazolyl group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an isoxazolyl group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyridinyl; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a pyrimidinyl group; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyridazinyl; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyrazinyl; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is triazine; wherein R 2 By at least one R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R2 is replaced by at least one R. 7 Replaced and not by R8 Replacement. In some implementations, R2 is replaced by at least one R. 7 Replaced and by 1 R 8 Replacement. In some implementations, R2 is replaced by at least one R. 7 Replaced and by 2 R 8 replace.

[0215] In some implementation schemes, R 2 It is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is aryl, where R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a heteroaryl group; in which R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a cycloalkyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a heterocyclic alkyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a single-ring structure. In some implementations, R 2 It is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrazinyl, or triazinyl; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is phenyl, cyclohexyl or pyrrole; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a phenyl group; where R is a phenyl group. 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclopropyl; where R 2 By 1 R7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclobutyl; where R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclopentyl; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is cyclohexyl; where R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyrrole; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an imidazole group; where R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a pyrazolyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a triazole group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a tetrazolium group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a thiazolyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an isothiazolyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is an oxazolyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2It is an isoxazolyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyridinyl; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is a pyrimidinyl group; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyridazinyl; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is pyrazinyl; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R 2 It is triazine; wherein R 2 By 1 R 7 And 0, 1 or 2 R 8 Replacement. In some implementations, R2 is replaced by 1 R 7 Replaced and not by R 8 Replacement. In some implementations, R2 is replaced by 1 R 7 Replaced and by 1 R 8 Replacement. In some implementations, R2 is replaced by 1 R 7 Replaced and by 2 R 8 replace.

[0216] In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for

[0217] In some implementations, Y is -C (=O)-. In some implementations, Y is -S (=O)-. In some implementations, Y is -S (=O)2-.

[0218] In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for In some implementation schemes, R 7 for

[0219] In some implementation schemes, R 9 and R 9 'Independently hydrogen, halogroup, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocyclic alkyl. In some embodiments, R 9 It can be hydrogen, halogenated, alkyl, cycloalkyl, or heteroalkyl. In some embodiments, R9 It is hydrogen, halogroup, or heteroalkyl. In some embodiments, R 9 and R 9 'Independently hydrogen, fluorine, chlorine, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. In some embodiments, R 9 It can be hydrogen, fluorine, chlorine, hydroxyethyl, or methoxyethyl. In some embodiments, R 9 It is hydrogen. In some implementations, R 9 It is fluorine. In some implementations, R 9 It is chlorine. In some implementations, R 9 It is hydroxyethyl. In some embodiments, R 9 It is methoxyethyl. In some embodiments, R 9 It is methyl. In some embodiments, R 9 It is a methoxymethyl group. In some embodiments, R... 9 It is dimethylaminomethyl. In some embodiments, R 9 It is 1-piperidinylmethyl. In some embodiments, R 9 It is 1-morpholinylmethyl. In some embodiments, R 9 It is a fluoromethyl group. In some embodiments, R 9 'For hydrogen.' In some implementations, R 9 'For fluorine.' In some implementations, R 9 'For chlorine.' In some implementations, 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-morpholinylmethyl.' In some embodiments, R 9 ' is fluoromethyl.

[0220] In some implementation schemes, R 10 It is hydrogen or alkyl. In some embodiments, R 10 It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 10 It is hydrogen. In some implementations, R 10 It is methyl. In some embodiments, R 10 It is ethyl. In some embodiments, R10 It is n-propyl. In some embodiments, R 10 It is isopropyl. In some embodiments, R 10 It is n-butyl. In some implementations, R 10 It is isobutyl. In some embodiments, R 10 It is sec-butyl. In some implementations, R 10 It is tert-butyl.

[0221] In some implementation schemes, R 2 Not R 8 Replacement. In some implementations, R 2 By 1 or 2 R 8 Replacement. In some implementations, R 2 By 1 R 8 Replacement. In some implementations, R 2 By 2 R 8 replace.

[0222] In some implementations, each R 8 Independently, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, chlorine, heteroalkyl, cyano, hydroxyl, amino, -N(R) 11 2. Methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 8 Independently methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine, -N(R) 11 2. Hydroxyethyl, methoxyethyl, or cyano. In some embodiments, each R 8 For methyl. In some embodiments, each R 8 For ethyl. In some embodiments, each R 8 It is n-propyl. In some embodiments, each R 8 It is isopropyl. In some embodiments, each R... 8 It is n-butyl. In some implementations, each R 8 It is isobutyl. In some implementations, each R 8 It is sec-butyl. In some implementations, each R 8 It is tert-butyl. In some implementations, each R 8 For fluorine. In some implementations, each R 8 For chlorine. In some implementations, each R 8 Independently for -N(R) 11 2. In some implementations, each R 8 It is hydroxyethyl. In some embodiments, each R 8 It is methoxyethyl. In some embodiments, each R 8It is a cyano group.

[0223] In some implementations, each R 11 Independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 11 Independently alkyl or aryl. In some embodiments, each R 11 Independently alkyl. In some embodiments, each R 11 Independently cycloalkyl. In some embodiments, each R 11 Independently aryl. In some implementations, each R 11 Independently, it is a heteroaryl group. In some embodiments, each R... 11 Independently, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthraceneyl, phenanthryl, trefyl, or pyrene. In some embodiments, each R 11 Independently, it is methyl, ethyl, isopropyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R... 11 Independently methyl or phenyl. In some embodiments, each R 11 For methyl. In some embodiments, each R 11 For ethyl. In some embodiments, each R 11 It is n-propyl. In some embodiments, each R 11 It is isopropyl. In some embodiments, each R... 11 It is n-butyl. In some implementations, each R 11 It is isobutyl. In some implementations, each R 11 It is sec-butyl. In some implementations, each R 11 It is tert-butyl. In some implementations, each R 11 It is phenyl. In some embodiments, each R 11 It is naphthyl. In some embodiments, each R 11 For anthracene. In some embodiments, each R 11 For Fiki. In some implementations, each R 11 For the base. In some implementations, each R 11 It is a pyrene group.

[0224] In some implementation schemes, R 3 It is pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, indoleyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cenolinyl, or naphthidyl; wherein R 3 By 0, 1, 2 or 3 R12 Replacement. In some implementations, R 3 It is imidazole, pyrazol, triazol, indole, indazole, thiazolyl, isothiazol, or pyridinyl; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is pyrrole; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is an imidazole group; where R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is a pyrazolyl group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is a triazole group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is a tetrazolium group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is an indole group; where R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is an indazole group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is benzimidazole group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is an azaindolyl; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is a thiazolyl group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is an isothiazolyl group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is an oxazolyl group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is an isoxazolyl group; wherein R 3By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is pyridinyl; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is a pyrimidinyl group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is pyridazinyl; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is pyrazinyl; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is triazine; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is quinolinyl; where R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is isoquinolinyl; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is quinoxalinyl; where R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is a quinazolinyl group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is a terpinen group; wherein R 3 By 0, 1, 2 or 3 R 12 Replacement. In some implementations, R 3 It is naphthidyl; wherein R 3 By 0, 1, 2 or 3 R 12 replace.

[0225] In some implementation schemes, R 3 It has not been replaced. In some implementations, R 3 At least 1 R 12 Replacement. In some implementations, R 3 At least 2 Rs 12 Replacement. In some implementations, R 3 By 1 R 12 Replacement. In some implementations, R3 By 2 R 12 Replacement. In some implementations, R 3 3 Rs 12 replace.

[0226] In some implementation schemes, R 3 for Where R 3 By 0 to 3 R 12 Replacement. In some implementations, R 3 for

[0227] Where R 3 By 1 or 2 R 12 replace.

[0228] In some implementation schemes, R 3 for:

[0229]

[0230]

[0231] In some implementation schemes, R 3 for:

[0232]

[0233] In some implementation schemes, R 3 for:

[0234]

[0235] In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for In some implementation schemes, R 3 for

[0236] In some implementations, each R 12 Independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halogen, cyano, alkoxy, heterocyclic alkyl, -N(R) 13 )2, -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl or cycloalkyl. In some embodiments, each R 12 Independently alkyl, heteroalkyl, haloalkyl, halogen, cyano, heterocyclic alkyl, -N(R) 13 )2 or cycloalkyl. In some embodiments, each R 12 Independently aryl. In some implementations, each R 12 Independently, it is a heteroaryl group. In some embodiments, each R... 12 Independently alkyl. In some embodiments, each R 12 Independently, it is a heteroalkyl group. In some embodiments, each R... 12Independently, it is a haloalkyl group. In some embodiments, each R... 12 Independently a halogen group. In some implementations, each R... 12 It is cyano. In some embodiments, each R 12 Independently alkoxy. In some embodiments, each R 12 Independently, it is a heterocyclic alkyl group. In some embodiments, each R... 12 Independently for -N(R) 13 2. In some implementations, each R 12 Independently -S(=O)2NH2. In some implementations, each R 12 Independently, it is a -S(=O)2 alkyl group. In some embodiments, each R 12 Independently -S(=O)2 aryl. In some embodiments, each R 12 Independently -S(=O)2 heteroaryl. In some embodiments, each R 12 Independently cycloalkyl. In some embodiments, each R 12 Independently, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluorine, chlorine, cyano, azacyclic butyl, oxacyclic butyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -N(R) 13 2. Cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 12 Independently, it is methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholino, or cyclopropyl. In some embodiments, each R 12 Independently, it is methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chlorinated. In some embodiments, each R... 12 Independently methyl or chlorine. In some embodiments, each R 12 For methyl. In some embodiments, each R 12 For ethyl. In some embodiments, each R 12 It is n-propyl. In some embodiments, each R 12 It is isopropyl. In some embodiments, each R... 12 It is n-butyl. In some implementations, each R 12 It is isobutyl. In some implementations, each R 12 It is sec-butyl. In some implementations, each R 12 It is tert-butyl. In some implementations, each R 12 It is hydroxyethyl. In some embodiments, each R 12It is methoxyethyl. In some embodiments, each R 12 It is trifluoromethyl. In some embodiments, each R 12 It is trifluoroethyl. In some embodiments, each R 12 It is pentafluoroethyl. In some embodiments, each R 12 For fluorine. In some implementations, each R 12 For chlorine. In some implementations, each R 12 It is a nitrogen-containing heterocyclic butyl group. In some embodiments, each R 12 It is an oxetane-butane. In some embodiments, each R 12 It is a pyrroleyl group. In some embodiments, each R 12 It is an imidazolyl group. In some embodiments, each R 12 It is tetrahydrofuranyl. In some embodiments, each R 12 It is piperidinyl. In some embodiments, each R 12 Piperazine group. In some embodiments, each R 12 It is a tetrahydropyranyl group. In some embodiments, each R 12 For morpholino. In some embodiments, each R 12 Cyclopropyl. In some embodiments, each R 12 It is cyclobutyl. In some implementations, each R 12 It is cyclopentyl. In some embodiments, each R 12 It is a cyclohexyl group.

[0237] In some implementations, each R 13 Independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 13 Independently alkyl or cycloalkyl. In some embodiments, each R 13 Independently alkyl. In some embodiments, each R 13 Independently cycloalkyl. In some embodiments, each R 13 Independently aryl. In some implementations, each R 13 Independently, it is a heteroaryl group. In some embodiments, each R... 13 Independently, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 13 Independently, it is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, each R... 13 Independently methyl, cyclopropyl, or cyclohexyl. In some embodiments, each R... 13For methyl. In some embodiments, each R 13 For ethyl. In some embodiments, each R 13 It is n-propyl. In some embodiments, each R 13 It is isopropyl. In some embodiments, each R... 13 It is n-butyl. In some implementations, each R 13 It is isobutyl. In some implementations, each R 13 It is sec-butyl. In some implementations, each R 13 It is tert-butyl. In some implementations, each R 13 Cyclopropyl. In some embodiments, each R 13 It is cyclobutyl. In some implementations, each R 13 It is cyclopentyl. In some embodiments, each R 13 It is a cyclohexyl group.

[0238] In some implementation schemes, R 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl groups are not substituted. In some embodiments, R 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl groups are bound by one or two R groups. 14 Replacement. In some implementations, R 12 The aryl, heteroaryl, heterocycloalkyl or cycloalkyl group is marked with one R 14 Replacement. In some implementations, R 12 The aryl, heteroaryl, heterocycloalkyl, or cycloalkyl groups are bound by two R groups. 14 replace.

[0239] In some implementations, each R 14 Independently, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halogen, heteroalkyl, haloalkyl, cyano, hydroxyl, amino, -N(R) 15 )2, -S(=O)2alkyl, -S(=O)2aryl, -S(=O)2heteroaryl, or alkoxy. In some embodiments, each R 14 Independently alkyl, cycloalkyl, heterocycloalkyl, halogen, cyano, -N(R) 15 )2 or alkoxy. In some embodiments, each R 14 Independently aryl. In some implementations, each R 14 Independently, it is a heteroaryl group. In some embodiments, each R... 14 Independently alkyl. In some embodiments, each R 14 Independently cycloalkyl. In some embodiments, each R 14 Independently, it is a heterocyclic alkyl group. In some embodiments, each R... 14Independently a halogen group. In some implementations, each R... 14 Independently, it is a heteroalkyl group. In some embodiments, each R... 14 Independently, it is a haloalkyl group. In some embodiments, each R... 14 It is cyano. In some embodiments, each R 14 For hydroxyl groups. In some embodiments, each R... 14 It is an amino group. In some embodiments, each R... 14 Independently for -N(R) 15 2. In some implementations, each R 14 Independently, it is a -S(=O)2 alkyl group. In some embodiments, each R 14 Independently -S(=O)2 aryl. In some embodiments, each R 14 Independently -S(=O)2 heteroaryl. In some embodiments, each R 14 Independently alkoxy. In some embodiments, each R 14 Independently, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidine, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluorine, chlorine, cyano, -N(R) 15 2. Methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R 14 Independently, methyl, ethyl, isopropyl, tert-butyl, pyrrolyl, piperidinyl, morpholinyl, fluorine, chlorine, -N(R) 15 )2 or methoxy. In some embodiments, each R 14 For methyl. In some embodiments, each R 14 For ethyl. In some embodiments, each R 14 It is n-propyl. In some embodiments, each R 14 It is isopropyl. In some embodiments, each R... 14 It is n-butyl. In some implementations, each R 14 It is isobutyl. In some implementations, each R 14 It is sec-butyl. In some implementations, each R 14 It is tert-butyl. In some implementations, each R 14 Cyclopropyl. In some embodiments, each R 14 It is cyclobutyl. In some implementations, each R 14 It is cyclopentyl. In some embodiments, each R 14 It is cyclohexyl. In some implementations, each R... 14It is a nitrogen-containing heterocyclic butyl group. In some embodiments, each R 14 It is an oxetane-butane. In some embodiments, each R 14 It is a pyrroleyl group. In some embodiments, each R 14 It is an imidazolyl group. In some embodiments, each R 14 It is tetrahydrofuranyl. In some embodiments, each R 14 It is piperidinyl. In some embodiments, each R 14 Piperazine group. In some embodiments, each R 14 It is a tetrahydropyranyl group. In some embodiments, each R 14 For morpholino. In some embodiments, each R 14 For fluorine. In some implementations, each R 14 For chlorine. In some implementations, each R 14 It is methoxylated. In some embodiments, each R 14 It is ethoxylated. In some embodiments, each R 14 It is trifluoromethoxy.

[0240] In some implementations, each R 15 Independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R 15 Independently alkyl or cycloalkyl. In some embodiments, each R 15 It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 15 For methyl. In some embodiments, each R 15 For ethyl. In some embodiments, each R 15 It is n-propyl. In some embodiments, each R 15 It is isopropyl. In some embodiments, each R... 15 It is n-butyl. In some implementations, each R 15 It is isobutyl. In some implementations, each R 15 It is sec-butyl. In some implementations, each R 15 It is tert-butyl. In some implementations, each R 15 Cyclopropyl. In some embodiments, each R 15 It is cyclobutyl. In some implementations, each R 15 It is cyclopentyl. In some embodiments, each R 15 It is a cyclohexyl group.

[0241] In some implementation schemes:

[0242] X is -NH- or -O-;

[0243] n is 0;

[0244] R 5 For 0 or 1 R 5 'Substituted phenyl;

[0245] R 2 For being at least one R 7 And 0, 1 or 2 R 8 Substituted phenyl; and

[0246] R 3 For 0, 1, 2 or 3 R 12 Substituted pyrazol group.

[0247] In some implementation schemes, R 2 For 1 R 7 And 0, 1 or 2 R 8 Substituted phenyl groups.

[0248] In some implementations, X is -NH-.

[0249] In some implementation schemes, R 5 It can be fluoromethyl, difluoromethyl, or trifluoromethyl.

[0250] In some implementation schemes:

[0251] R 7 for and

[0252] R 8 It is a halogen group.

[0253] In some implementation schemes:

[0254] R 8 It is fluorine;

[0255] Y is -C(=O)-;

[0256] R 9 and R 9 'For hydrogen; and

[0257] R 10 It is hydrogen.

[0258] In some implementation schemes, R 12 It is an alkyl group.

[0259] In some implementation schemes, R 12 It is a methyl group.

[0260] In some embodiments, the compound has the formula IA, IB, IC, ID, IE, IF, or IG:

[0261]

[0262]

[0263] Or its pharmaceutically acceptable salts or stereoisomers.

[0264] In some embodiments, the compound has the formula IA: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IA: Or its pharmaceutically acceptable salts or stereoisomers.

[0265] In some embodiments, the compound has the formula IB: Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments of the compound of formula IB, wherein R... 1 For R 5 In some embodiments of the IB compound, R 5 By 0 or 1 R 5 'Replacement.' In some embodiments of the compound of formula IB, R 5 Not replaced. In some embodiments of the formula IB compound, R 5 By 1 R 5 'replace.

[0266] In some embodiments, the compound has the formula IC: Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments of the compound of formula IB, wherein R... 1 For R 5 In some embodiments of the IC compound, R 5 By 0 or 1 R 5 'Replacement.' In some embodiments of the formula IC compound, R 5 Not replaced. In some embodiments of the IC compound, R 5 By 1 R 5 'replace.

[0267] In some embodiments, the compound has formula ID: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula ID: Or its pharmaceutically acceptable salts or stereoisomers.

[0268] In some embodiments, the compound has the formula IE: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IE: Or its pharmaceutically acceptable salts or stereoisomers.

[0269] In some embodiments, the compound has the formula IF: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula IF: Or its pharmaceutically acceptable salts or stereoisomers.

[0270] In some embodiments, the compound has the formula IG: Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments of the formula IG compound, R... 1 For R 5 In some embodiments of the IG compound, R 5 By 0 or 1 R 5 'Replacement.' In some embodiments of the formula IG compound, R 5 Not replaced. In some embodiments of the formula IG compound, R 5 By 1 R 5 'replace.

[0271] In some embodiments, the compound of formula I is:

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284] Or its pharmaceutically acceptable salt.

[0285] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0286] Specific embodiments of this disclosure are compounds of formula I or thereof, stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates selected from the group consisting of:

[0287] N-(3-((5-chloro-2-((1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 1),

[0288] N-(3-((5-chloro-2-((6-oxo-1,6-dihydropyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 2),

[0289] N-(3-((2-(4-amino-2-oxopyridin-1(2H)-yl)-5-chloropyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 3),

[0290] (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),

[0291] (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),

[0292] (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)

[0293] (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),

[0294] N-(4-chloro-3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 8),

[0295] (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),

[0296] N-(4-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-fluorophenyl)acrylamide (compound 10),

[0297] (E)-N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)but-2-enamide (compound 11),

[0298] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)methacrylamide (compound 12),

[0299] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide (compound 13),

[0300] N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 14),

[0301] N-(3-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 15),

[0302] (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),

[0303] (E)-4-(dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)but-2-enamide (compound 17),

[0304] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 18),

[0305] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 19),

[0306] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (compound 20),

[0307] N-(3-((5-chloro-2-((5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 21),

[0308] N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 22),

[0309] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (compound 23),

[0310] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)-2-fluoroacrylamide (compound 24),

[0311] 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),

[0312] N-(3-((5-chloro-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 26),

[0313] (E)-N-(3-((5-chloro-2-((3-methylisothiazo-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 27),

[0314] N-(4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 28)

[0315] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 29),

[0316] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 30),

[0317] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 31),

[0318] N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 32),

[0319] (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),

[0320] 4-((3-Acrylamidophenyl)amino)-2-((1-Methyl-1H-pyrazol-4-yl)amino)-N-(1-Phenylacetyl)pyrimidin-5-carboxamide (Compound 34),

[0321] (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidin-5-carboxamide (compound 35)

[0322] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 36),

[0323] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 37),

[0324] N-(4-fluoro-3-((2-((2-fluoropyridin-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 38),

[0325] N-(4-fluoro-3-((2-((2-methoxyphenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 39), N-(3-((2-((2-chlorophenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 40)

[0326] N-(3-((2-((5-chlorothiophen-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 41)

[0327] N-(4-fluoro-3-((2-((1-methylpiperidin-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 42)

[0328] N-(3-((2-((2-(dimethylamino)ethyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 43)

[0329] N-(3-((2-((4-(dimethylamino)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 44)

[0330] N-(3-((2-((4-((dimethylamino)methyl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 45)

[0331] N-(4-fluoro-3-((2-(thiophen-3-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 46)

[0332] N-(3-((5-(1-(N-benzylacetamido)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 47),

[0333] N-(3-((5-((N-benzylacetamido)methyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 48),

[0334] 4-((5-acrylamido-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (compound 49),

[0335] N-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 50)

[0336] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 51),

[0337] (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),

[0338] (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),

[0339] (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),

[0340] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-(N-morpholinyl)pyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 55)

[0341] 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),

[0342] 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),

[0343] N-(3-((5-(4-acetamidophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 58),

[0344] N-(3-((5-(3-acetamidophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 59),

[0345] 3-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-N-methylbenzamide (compound 60),

[0346] N-(3-((5-(4-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 61),

[0347] N-(3-((5-(4-cyanophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 62),

[0348] N-(4-fluoro-3-((5-(4-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 63),

[0349] 4-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-N-methylbenzamide (compound 64),

[0350] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(2-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 65),

[0351] 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)

[0352] 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),

[0353] 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)

[0354] 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)

[0355] 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),

[0356] 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),

[0357] N-(3-((2-((1-(2-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 72)

[0358] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 73),

[0359] N-(3-((5-(6-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 74),

[0360] N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 75)

[0361] N-(3-((5-(4-(tert-butyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 76)

[0362] 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 trifluoroacetate (compound 77)

[0363] 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),

[0364] 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)

[0365] 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)

[0366] N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)-1H-indol-4-yl)acrylamide (compound 81),

[0367] 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)

[0368] 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),

[0369] N-(4-fluoro-3-((2-(((1-methyl-1H-pyrazol-4-yl)amino)-5-(pyridin-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 84),

[0370] 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),

[0371] 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),

[0372] 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),

[0373] N-(4-fluoro-3-((5-(3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 88)

[0374] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(3-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 89),

[0375] N-(4-fluoro-3-((5-(2-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 90)

[0376] N-(4-fluoro-3-((5-(4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 91),

[0377] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 92)

[0378] N-(4-fluoro-3-((2-(((1-methyl-1H-pyrazol-4-yl)amino)-5-phenylpyrimidin-4-yl)amino)phenyl)acrylamide (compound 93),

[0379] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(N-morpholinyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 94),

[0380] 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),

[0381] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 96)

[0382] N-(3-((5-(1H-indol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 97),

[0383] 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)

[0384] N-(3-((5-(4-(difluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 99),

[0385] 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),

[0386] N-(3-((5-(6-chloropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 101),

[0387] N-(3-((5-(5-chloropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 102),

[0388] N-(3-((5-(4-(dimethylamino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 103),

[0389] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 104),

[0390] N-(3-((5-(4-(difluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 105),

[0391] 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),

[0392] 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),

[0393] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 108),

[0394] N-(3-((5-(6-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 109),

[0395] 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),

[0396] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 111),

[0397] N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 112)

[0398] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 113)

[0399] 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),

[0400] N-(3-((5-(3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 115)

[0401] N-(3-((5-(5-(dimethylamino)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 116)

[0402] N-(3-((5-(2-chloropyridin-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 117),

[0403] N-(3-((5-(6-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 118)

[0404] N-(4-(dimethylamino)-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 119)

[0405] N-(3-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 120)

[0406] N-(4-fluoro-3-((2-(phenylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 121),

[0407] N-(4-fluoro-3-((2-((4-fluorophenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 122)

[0408] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-2'-(trifluoromethyl)-[5,5'-diamyrimidin]-4-yl)amino)phenyl)acrylamide (compound 123),

[0409] 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),

[0410] 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),

[0411] N-(4-fluoro-3-((5-(4-isopropylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 126)

[0412] 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),

[0413] N-(3-((5-(4-cyclopropylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 128)

[0414] N-(3-((5-(2-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 129)

[0415] 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 trifluoroacetate (compound 130)

[0416] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(quinolin-7-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 131),

[0417] 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),

[0418] 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 trifluoroacetate (compound 133)

[0419] N-(3-((5-(3-((dimethylamino)methyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 134),

[0420] N-(3-((2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 135)

[0421] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(naphth-1-yl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 136)

[0422] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 137),

[0423] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-aminosulfonylphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 138),

[0424] N-(4-fluoro-3-((2-((1-(oxecyclobutan-3-yl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 139),

[0425] N-(3-((5-(4-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 140),

[0426] 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),

[0427] N-(3-((5-(4-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 142)

[0428] N-(3-((5-(3-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (compound 143)

[0429] N-(3-((5-(5-(difluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 144)

[0430] N-(3-((5-(3-(dimethylamino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 145),

[0431] N-(4-fluoro-3-((2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 146), N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-[5,5'-dipyrimidin]-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 147)

[0432] N-(2-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 148)

[0433] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(naphth-2-yl)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (compound 149)

[0434] N-(3-((5-(2-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide 2,2,2-trifluoroacetate (compound 150)

[0435] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 151),

[0436] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 152),

[0437] N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)amino)-4-fluorophenyl)acrylamide (compound 153),

[0438] N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 154),

[0439] N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)-4-fluorophenyl)acrylamide (compound 155),

[0440] N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)phenyl)acrylamide (compound 156),

[0441] N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)oxy)phenyl)acrylamide (compound 157),

[0442] N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 158),

[0443] N-(3-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4-fluorophenyl)acrylamide (compound 159),

[0444] (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),

[0445] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylethynyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 161),

[0446] (E)-4-(dimethylamino)-N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylethynyl)pyrimidin-4-yl)amino)phenyl)but-2-enamide (compound 162)

[0447] 4-Acrylamido-2-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-phenylbenzamide (compound 163),

[0448] 4-Acrylamido-2-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-N-phenylbenzamide (Compound 164),

[0449] N-(4-chloro-3-((2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 165),

[0450] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (compound 166),

[0451] N-(3-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (compound 167),

[0452] N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (compound 168),

[0453] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-(trifluoromethyl)phenyl)acrylamide (compound 169),

[0454] N-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-methoxyphenyl)acrylamide (compound 170),

[0455] N-(3-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-methoxyphenyl)acrylamide (compound 171),

[0456] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-methoxyphenyl)acrylamide (compound 172),

[0457] N-(2-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)-3-fluorophenyl)acrylamide (compound 173),

[0458] (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),

[0459] N-(2-((2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)acrylamide (compound 175),

[0460] (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),

[0461] N-(2-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)acrylamide (compound 177),

[0462] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-(phenylethynyl)phenyl)acrylamide (compound 178),

[0463] (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),

[0464] N-(3-((2-(cyclopropylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 180),

[0465] N-(3-((2-(cyclobutanamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 181),

[0466] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide (compound 182),

[0467] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(5-methylpyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 183),

[0468] N-(3-((5-(5-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 184),

[0469] N-(3-((5-(6-chloropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 185),

[0470] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(6-methylpyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 186),

[0471] N-(3-((5-(6-(difluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 187),

[0472] N-(3-((5-(6-(difluoromethoxy)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 188),

[0473] N-(3-((2-((2-chlorophenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 189),

[0474] 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),

[0475] N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 191),

[0476] 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),

[0477] N-(3-((2-((2-methoxyphenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 193),

[0478] N-(3-((2-(cyclopropylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 194),

[0479] N-(5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide (compound 195),

[0480] N-(2-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-4-yl)acrylamide (compound 196),

[0481] N-(6-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide (compound 197),

[0482] 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),

[0483] 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),

[0484] N-(4-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide (compound 200),

[0485] N-(3-((5-(3-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 201),

[0486] N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-fluorophenyl)acrylamide (compound 202),

[0487] N-(3-((5-(4-bromophenyl)-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 203),

[0488] N-(3-((5-(4-bromophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 204),

[0489] N-(3-((5-(4-bromophenyl)-2-((1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 205),

[0490] N-(3-((5-(4-bromophenyl)-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 206),

[0491] N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)acrylamide (compound 207),

[0492] 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),

[0493] N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)phenyl)acrylamide (compound 209),

[0494] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyridin-4-yl)amino)phenyl)acrylamide (compound 210),

[0495] N-(4-fluoro-3-((2-((3-methylisothiazo-5-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 211),

[0496] N-(4-fluoro-3-((2-((5-methylisothiazo-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 212),

[0497] N-(4-fluoro-3-((2-((4-methylthiazolyl-2-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 213),

[0498] N-(4-fluoro-3-((2-((1-methyl-1H-imidazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 214),

[0499] N-(4-fluoro-3-((2-(thiazolyl-2-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 215),

[0500] 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),

[0501] N-(4-fluoro-3-((2-((5-methylthiophen-3-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 217),

[0502] N-(3-((2-((3-((dimethylamino)methyl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 218),

[0503] 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),

[0504] 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),

[0505] 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),

[0506] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(N-morpholinyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 222),

[0507] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 223),

[0508] N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-6-(methylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 224),

[0509] N-(4-Fluoro-3-((2-(isoxazo-4-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 225),

[0510] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(1-methyl-2,5-dihydro-1H-pyrrolo-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 226),

[0511] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(1-methylpyrrolid-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 227),

[0512] 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),

[0513] N-(3-(methyl(2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 229),

[0514] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(thiazo-5-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 230),

[0515] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-6-(trifluoromethyl)quinazolin-4-yl)amino)phenyl)acrylamide (compound 231),

[0516] N-(4-fluoro-3-((2-(pyridin-3-ylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 232),

[0517] N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 233),

[0518] N-(3-((2-((4-((dimethylamino)methyl)phenyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 234),

[0519] N-(3-((2-((1-(2-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 235),

[0520] N-(3-((2-((2-(dimethylamino)ethyl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 236),

[0521] 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),

[0522] N-(2-fluoro-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 238),

[0523] N-(3-fluoro-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 239),

[0524] 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),

[0525] 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),

[0526] N-(4-Fluoro-3-((2-((1-(methyl- 13 C-d3)-1H-pyrazole-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 243),

[0527] N-(3-((5-(cyclopropylethynyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 244),

[0528] 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),

[0529] N-(3-((2-((1-(2-cyanopropyl-2-yl)-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 246),

[0530] 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),

[0531] 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),

[0532] 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),

[0533] 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),

[0534] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)but-2,3-dieneamide (compound 251)

[0535] 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),

[0536] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)ethylenesulfonamide (compound 253),

[0537] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)propynamide (compound 254),

[0538] 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),

[0539] N-(3-((5-bromo-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 256),

[0540] N 4 -(5-amino-2-fluorophenyl)-N 2 -(1-Methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidin-2,4-diamine (compound 257)

[0541] N-(4-fluoro-3-((5-(2-isopropylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 258),

[0542] N-(4-fluoro-3-((5-(2-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 259),

[0543] 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),

[0544] 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),

[0545] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(quinolin-5-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 262),

[0546] 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),

[0547] N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(2-fluorophenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 264),

[0548] N-(3-((5-(1H-indol-7-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 265),

[0549] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(tetrahydrofuran-3-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 266),

[0550] N-(3-((5-(2-(dimethylamino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 267),

[0551] N-(4-fluoro-3-((5-(isoquinoline-8-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 268),

[0552] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(piperidin-1-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 269),

[0553] 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),

[0554] N-(3-((5-bromo-2-((1-(2-cyanopropyl-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 271),

[0555] N-(3-((2-((1-(2-cyanopropyl-2-yl)-1H-pyrazol-4-yl)amino)-5-(2,5-dihydrofuran-3-yl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 272),

[0556] N-(3-((5-bromo-2-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 273),

[0557] N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 274),

[0558] N-(3-((5-chloro-4-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (compound 275),

[0559] 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),

[0560] N-(3-((5-(1H-indazol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 277),

[0561] 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),

[0562] 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),

[0563] N-(3-((5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 280),

[0564] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenyl-4-d)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 281),

[0565] N-(3-bromo-5-((5-(4-(difluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 282),

[0566] N-(3-bromo-5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 283),

[0567] N-(3-((5-chloro-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 284),

[0568] N-(4-fluoro-3-((5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 285),

[0569] N-(3-((5-chloro-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 286),

[0570] N-(3-((5-chloro-2-((4-(((dimethylamino)methyl)phenyl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 287),

[0571] N-(3-((5-chloro-2-((4-(((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 288),

[0572] N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-(trifluoromethyl)phenyl)acrylamide (compound 289),

[0573] N-(3-bromo-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 290),

[0574] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-(trifluoromethyl)phenyl)acrylamide (compound 291),

[0575] N-(3-((5-(4-bromophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)acrylamide (compound 292),

[0576] 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),

[0577] 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),

[0578] 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),

[0579] N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(perfluoroethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 296),

[0580] N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)naphthyl-1-yl)acrylamide (compound 297),

[0581] N-(3-((5-(5-chlorothiophen-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 298),

[0582] N-(3-((5-(benzofuran-6-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 299),

[0583] N-(4-fluoro-3-((5-(4-(3-fluorophenoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 300)

[0584] (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)but-2-enamide (compound 301)

[0585] 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),

[0586] (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)but-2-enamide (compound 303),

[0587] (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

[0588] 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).

[0589] One embodiment of this disclosure relates to a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, stereoisomer, solvate, and hydrate thereof for the treatment of diseases associated with epidermal growth factor receptor (EGFR) family kinases.

[0590] Another embodiment of this disclosure relates to a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof for the treatment of cancer.

[0591] Another embodiment of this disclosure relates to a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof for the treatment of diseases or disorders associated with non-small cell or small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, or colorectal cancer.

[0592] This disclosure relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

[0593] This disclosure further relates to methods for preparing compounds of formula I or their stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates.

[0594] In another respect, this disclosure provides compounds selected from the following:

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601] Or its pharmaceutically acceptable salts or stereoisomers.

[0602] use

[0603] The embodiments provided herein describe a class of compounds suitable as inhibitors of the epidermal growth factor receptor (EGFR) family of kinases. Some embodiments provided herein describe a class of compounds suitable as EGFR inhibitors. Some embodiments provided herein describe a class of compounds suitable as inhibitors of EGFR del19 / T790M. Some embodiments provided herein describe a class of compounds suitable as inhibitors of EGFR L858R / T790M. In some embodiments, the compounds described herein have improved potency and / or beneficial activity profile and / or beneficial selectivity profile and / or increased efficacy and / or improved safety profile (e.g., reduced side effects) and / or improved pharmacokinetic properties. In some embodiments, the compounds described herein are selective inhibitors of EGFR del19 / T790M rather than WT EGFR. In some embodiments, the compounds described herein are selective inhibitors of EGFR L858R / T790M rather than WT EGFR.

[0604] In some implementations, the compounds described herein are selective inhibitors of EGFR rather than HER2.

[0605] 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.

[0606] In some embodiments, the compounds described herein are suitable for treating, preventing, or improving diseases or conditions exhibiting resistance associated with EGFR del19 / T790M activation. In some embodiments, the compounds described herein are suitable for treating, preventing, or improving diseases or conditions exhibiting resistance associated with EGFR L858R / T790M activation.

[0607] In some embodiments, commercially available test kits are used to detect EGFR family kinase mutants. In some embodiments, reverse transcription polymerase chain reaction (RT-PCR) based methods are used to detect EGFR family kinase mutants. In some embodiments, sequencing-based methods are used to detect EGFR family kinase mutants. In some embodiments, mass spectrometry-based genotyping methods are used to detect EGFR family kinase mutants. In some embodiments, immunohistochemistry-based methods are used to detect EGFR family kinase mutants. In some embodiments, molecular diagnostics are used to detect EGFR family kinase mutants. In some embodiments, EGFR family kinase mutants are detected from tumor samples. In some embodiments, EGFR family kinase mutants are detected from circulating DNA. In some embodiments, EGFR family kinase mutants are detected from tumor cells.

[0608] In one aspect, this article provides a method for inhibiting epidermal growth factor receptor (EGFR) family kinase mutants in a subject in need, 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.

[0609] On the other hand, this document provides a method for inhibiting a human epidermal growth factor receptor 2 (HER2) mutant in a subject of need, 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. 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 G776delinsAVGC. 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.

[0610] On the other hand, this article provides a method for inhibiting epidermal growth factor receptor (EGFR) mutants in a subject in need, 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.

[0611] On the other hand, this document provides a method for inhibiting a drug-resistant epidermal growth factor receptor (EGFR) mutant in a subject of need, 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. In some embodiments, the drug-resistant EGFR mutant is del19 / T790MEGFR or L858R / T790M EGFR.

[0612] On the other hand, this document provides a method for inhibiting human epidermal growth factor receptor 2 (HER2) in a subject of need, 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, wherein the compound exhibits higher inhibition of a HER2 mutant relative 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.

[0613] On the other hand, this article provides a method for inhibiting epidermal growth factor receptor (EGFR) in a subject in need, 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, wherein the compound exhibits higher inhibition of EGFR mutants relative to wild-type EGFR.

[0614] In some embodiments, the EGFR mutant includes 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 selected from del19 / T790M EGFR, L858R / T790M EGFR, L858REGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPGEGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. 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.

[0615] On the other hand, this article provides a method for treating epidermal growth factor receptor (EGFR)-related diseases or conditions in subjects in need, 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.

[0616] In some embodiments, the subject's disease or condition includes a HER2 mutation. In some embodiments, the HER2 mutation includes insertions in exon 20, in-frame deletions and insertions in exon 20, substitutions in the extracellular domain, extracellular truncations, or substitutions 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.

[0617] In some embodiments, the subject's disease or condition includes an EGFR mutation. In some embodiments, the EGFR mutation includes 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 implementations, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEAEGFR, 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, 773insNPHEGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. 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.

[0618] On the other hand, this document provides a method for treating cancer in a subject of need, 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. In some embodiments, the cancer exhibits resistance associated with EGFR del19 / T790M activation. In some embodiments, the cancer exhibits resistance associated with EGFR L858R / T790M activation. Other embodiments provided herein describe the use of the compounds described herein for the treatment of cancer.

[0619] 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.

[0620] In some embodiments, the subject's cancer 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.

[0621] In some embodiments, the subject's cancer contains an EGFR mutation. In some embodiments, the EGFR mutation includes 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 implementations, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVDEGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. EGFR, EGFRvii, EGFRviii, A767_dupASVEGFR, 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.

[0622] On the other hand, this document provides a method for treating inflammatory diseases in a subject of need, 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. This document also describes the use of the compounds described herein for treating inflammatory diseases associated with EGFR del19 / T790M activation. This document further describes the use of the compounds described herein for treating inflammatory diseases associated with EGFR L858R / T790M activation.

[0623] 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.

[0624] In some embodiments, the subject's inflammatory disease 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.

[0625] In some embodiments, the subject's inflammatory disease includes an EGFR mutation. In some embodiments, the EGFR mutation includes 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 implementations, the EGFR mutation is selected from del19 / T790M EGFR, L858R / T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEAEGFR, 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, 773insNPHEGFR (or H773insNPH EGFR), 773insH EGFR, and 773insPH EGFR. 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.

[0626] Application and pharmaceutical composition

[0627] In some embodiments, the EGFR-inhibiting compound described herein is administered in the form of a pure chemical. In other embodiments, the EGFR-inhibiting compound described herein is combined with a pharmaceutically suitable or acceptable vehicle (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) vehicle) selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)).

[0628] This document provides a pharmaceutical composition comprising at least one EGFR inhibitory compound or its stereoisomer as described herein, a pharmaceutically acceptable salt or N-oxide, and one or more pharmaceutically acceptable carriers. A carrier is acceptable or suitable if it is compatible with the other components of the composition and harmless to the recipient of the composition (i.e., the subject or patient).

[0629] 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.

[0630] In some embodiments, the EGFR inhibitory compounds disclosed herein are substantially pure because they contain less than about 5%, less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated in one or more steps of the synthetic method.

[0631] Suitable oral dosage forms include tablets, pills, capsules, or sachets, such as hard or soft gelatin, methylcellulose, or another suitable material that is readily soluble in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical-grade 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)).

[0632] The dosage of a composition containing at least one EGFR inhibitory compound as described herein varies depending on the patient’s condition (i.e., the stage of the disease), general health status, age and other factors.

[0633] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and suitable duration and frequency of administration will be determined by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dose and treatment regimen are to provide the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes) or to reduce the severity of symptoms. Optimal doses are typically determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[0634] Oral dosage is usually in the range of about 1.0 mg to about 1000 mg, once to four or more times a day.

[0635] Example

[0636] Example 1: Synthesis Procedure

[0637] The yields reported in this article refer to purified products (unless otherwise specified) and are not optimized. (Mercck silica gel 60F) 254 Analytical TLC was performed on aluminum-backed plates. Compounds were visualized by UV light and / or staining with iodine, potassium permanganate, or ninhydrin solutions. Rapid column chromatography was performed using silica gel (100-200 M) or a rapid chromatography method. Recordings were obtained on a Bruker Avance-400 MHz spectrometer equipped with BBO (broadband observation) and BBFO (broadband fluorine observation) probes. 1 1H-NMR spectra. Chemical shift (δ) of tetramethylsilane (TMS), used as an internal standard, is expressed in parts per million (ppm) at the low field. Splitting patterns are represented as s (singleton), d (doublet), t (triplet), q (quartet), m (multiplex), and bs (broad singlet). Coupling constants (J) are given in Hertz (Hz). LC-MS analysis was performed using electroinjection ionization (ESI) 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).

[0638] The following solvents, reagents, or scientific terms may be referred to by their abbreviations:

[0639] TLC (Thin Layer Chromatography)

[0640] DCM dichloromethane

[0641] THF Tetrahydrofuran

[0642] MeOH (methanol)

[0643] EtOH (ethanol)

[0644] IPA isopropanol

[0645] EtOAc (ethyl acetate)

[0646] Et2O diethyl ether

[0647] DMA N,N-dimethylacetamide

[0648] DMF N,N-dimethylformamide

[0649] TEA / Et3N Triethylamine

[0650] DMSO (dimethylformamide)

[0651] DIPEA (Diisopropylethylamine, Hunig's base)

[0652] MeI methyl iodine

[0653] NBS N-bromosuccinimide

[0654] TBAB Tetrabutylammonium Bromide

[0655] TBAI Tetrabutylammonium Iodide

[0656] DIBAL-H diisobutylaluminum hydride

[0657] TFA (trifluoroacetic acid)

[0658] AcOH (acetic acid)

[0659] Boc tert-butoxycarbonyl

[0660] Cat catalysis

[0661] mL

[0662] mmol millimole

[0663] h hours

[0664] min minutes

[0665] g gram

[0666] mg

[0667] μl

[0668] eq equivalent

[0669] rt or RT refers to room temperature, approximately 27°C.

[0670] MS mass spectrometry

[0671] Boc tert-butoxycarbonyl

[0672] m-CPBA (m-chloroperoxybenzoic acid)

[0673] T3P propanephosphonic anhydride

[0674] BH3-DMS Borane dimethyl sulfide complex

[0675] LiBH4 lithium aluminum hydride

[0676] NaBH4 sodium borohydride

[0677] H2 hydrogen

[0678] Pd / C Palladium / Charcoal

[0679] 1,2-DCE 1,2-Dichloroethane

[0680] General Program A:

[0681] Sodium hydride (60% dispersion in mineral oil, 3.0 eq) was added fractionally to an ice-cold solution of arylamine (1.0 eq) in tetrahydrofuran. 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 eq). The resulting reaction mixture was heated at 60 °C for 16 hours. After completion (monitored by TLC), the mixture was quenched with ice and extracted with ethyl acetate (3 times). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was wet-milled with diethyl ether, filtered, and dried under vacuum to obtain the desired product.

[0682] General Program B:

[0683] Cesium carbonate (3.0 eq) and an arylamine (1.2 eq) were added to a solution of an aryl halide (1.0 eq) in 1,4-dioxane or toluene. The resulting reaction mixture was degassed under nitrogen for 15 min, followed by the addition of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 0.1 eq) and tris(diphenylmethyleneacetone)dipalladium(0)(0.1 eq) under nitrogen atmosphere. The resulting reaction mixture was again degassed for 15 min and then heated at 100 °C for 16 h. After the reaction was complete (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 rapid chromatography using dichloromethane containing 4-8% methanol as eluent, and the eluent was concentrated under reduced pressure to obtain the desired product.

[0684] General Program C:

[0685] Triethylamine (3.0 eq) and acetyl chloride (1.2 eq) were added dropwise to an ice-cold solution of a primary or secondary aryl amine (1.0 eq). The resulting reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (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 substance was purified by combiflash, eluted with dichloromethane containing 4-5% methanol, and the eluent was concentrated under reduced pressure to obtain the desired product.

[0686] General Program D:

[0687] A solution of aldehyde (1.0 eq) in methanol was added with the corresponding amine (3.0 eq) and sodium acetate (5.0 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was poured into ice-cold water and the resulting solid was filtered. The solid was dried under vacuum to give the desired product.

[0688] General Program E:

[0689] Acetic acid (1.0 v / v) was added to a solution of the product obtained from general procedure D in methanol (2.5 v / v), followed by sodium borohydride (1.0 v / v). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold water and the resulting solid was filtered off and washed with water. The solid was dried under vacuum to give the desired product.

[0690] General Program F:

[0691] Diisopropylethylamine (4.0 eq) was added to an ice-cold solution of the product obtained from general procedure E in tetrahydrofuran, followed by triphosgene (0.4 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), a saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3 times). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude material was wet-milled with diethyl ether to give the desired product.

[0692] General program G:

[0693] 2.0 eq of m-chloroperbenzoic acid was added to an ice-cold solution of the product obtained from general procedure F in dichloromethane. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), a saturated sodium bicarbonate solution was added to the reaction mixture and extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The product was then wet-milled with diethyl ether to obtain the desired product.

[0694] General program H:

[0695] The product (1.0 eq) obtained from general procedure G was added to an ice-cold solution of isopropanol with the corresponding amine (1.2 eq) and trifluoroacetic acid (2.0 eq). The reaction mixture was heated at 110 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was coarsely ground with diethyl ether to give the desired product, which was used directly in the next step.

[0696] General Program I:

[0697] The product (1.0 eq) obtained from general procedure H was stirred at room temperature in an ice-cold solution of dichloromethane containing 20% ​​trifluoroacetic acid for 3–16 hours. After the reaction was complete (monitored by TLC), the solvent was evaporated. The reactants were diluted with saturated sodium bicarbonate solution and extracted (three times) with dichloromethane containing 5% methanol. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was wet-milled with diethyl ether or purified by combiflash, and eluted with dichloromethane containing 5%–10% methanol to obtain the desired product.

[0698] General Program J:

[0699] Triethylamine (3–5 eq) and the corresponding acid (1.1 eq) were added to an ice-cold solution of the product obtained from General Procedure I (1.0 eq) in dichloromethane, followed by the addition of propylphosphonic anhydride (T3P, 50% in ethyl acetate, 2.5 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reactants were diluted with saturated sodium bicarbonate solution and extracted with dichloromethane containing 5% methanol. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by combiflash, preparative TLC, or preparative HPLC to give the final compound.

[0700] General program K:

[0701] The product obtained from General Procedure I (1.0 eq) in dichloromethane:tetrahydrofuran (1:1) was cooled to -40 °C, followed by the addition of triethylamine (3-5 eq) and acryloyl chloride (1.0 eq). The mixture was stirred at the same temperature for 2 hours. After the reaction was complete (monitored by TLC), water was added and the mixture was 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 substance was purified by preparative HPLC to obtain the final compound.

[0702] General Program K1:

[0703] At -0 °C, triethylamine (5 eq) and acryloyl chloride (1.0 eq) were added to a solution of the product obtained from General Procedure I (1.0 eq) in tetrahydrofuran and water (3:1). The reaction mixture was stirred at the same temperature for 2 hours. After the reaction was complete (monitored by TLC), water was added and the mixture was extracted (3 times) with ethyl acetate. 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.

[0704] General Program K2:

[0705] At -0 °C, triethylamine (5 eq) and 3-chloropropionyl chloride (1.2 to 1.5 eq) were added to a solution of the product obtained from General Procedure I (1.0 eq) in tetrahydrofuran and water (3:1). The reaction mixture was stirred at the same temperature for 20 min to 1 h. After the reaction (monitored by LCMS) was complete, water was added and the mixture was extracted (3 times) with ethyl acetate. 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.

[0706] General Program L:

[0707] Zinc or iron powder (5 eq) and ammonium chloride (5 eq) were added to an ice-cold solution of the nitro derivative (1.0 eq) in methanol:tetrahydrofuran:water (2:2:1). The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was passed through a diatomaceous earth bed and washed with dichloromethane containing 5% methanol. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the amino derivative.

[0708] General Program L1:

[0709] A solution of the nitro derivative (1.0 eq) in methanol or ethanol (10 volumes) was added with 10% palladium / carbon (20% w / w). The reaction mixture was stirred for 16 hours under a hydrogen atmosphere. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and washed with methanol. The combined filtrates were concentrated under reduced pressure to give the amino derivative.

[0710] General Program M1: (Suzuki Coupler):

[0711] Under argon purging, a solution of the halogen derivative (1.0 eq) in acetonitrile was added with the corresponding boric acid / ester derivative (1.0 eq), followed by an aqueous solution of potassium carbonate (2.0 eq). The resulting reaction mixture was degassed for 15 min, then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (0.1 eq) was added, and the reaction mixture was heated at 80 °C for 16 h. After the reaction was complete (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 material was purified by combiflash, eluted with hexane containing 40-60% ethyl acetate, and the eluent was concentrated under reduced pressure to obtain the desired product.

[0712] General Program M2:

[0713] Potassium carbonate (2.0 eq) or sodium bicarbonate (2.0 eq) was added to a solution of the halogen derivative (1.0 eq) and the corresponding boronic acids (1.1 eq) in toluene:ethanol (1:1) or dimethylformamide or dimethoxyethane and water (4:1). The resulting reaction mixture was degassed with argon for 15 min, followed by the addition of the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.05 eq). The reaction mixture was heated at 90 °C for 5–16 h. After the reaction was complete (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 material was purified by combiflash, eluted with hexane containing 30–50% ethyl acetate, and the eluent was concentrated under reduced pressure to obtain the desired product.

[0714] General Program M3:

[0715] Sodium carbonate or sodium bicarbonate (2.0 eq) was added to a solution of the halogen derivative (1.0 eq) and the corresponding boric acid / ester derivative (1.1 eq) in N,N-dimethylformamide:water (4:1). The resulting reaction mixture was degassed under an argon atmosphere for 15 min, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 eq). The resulting reaction mixture was heated at 90 °C for 16 h. After the reaction was complete (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, and the eluent was concentrated under reduced pressure to obtain the desired product.

[0716] General Program N:

[0717] Sodium hydride (60% dispersion in mineral oil, 10 eq) was added fractionally to an ice-cold solution of N-(3-(2-chloro-6-fluoroquinazoline-8-yl)phenyl)acrylamide (1.0 eq) in dimethylformamide, and the mixture was stirred at room temperature for 30 min, followed by the addition of the corresponding amine (1.2 eq). The resulting reaction mixture was stirred at room temperature for 16 h. After the reaction was complete (according to TLC monitoring), the reaction mixture was diluted with ice-cold water and extracted (three times) with dichloromethane containing 5% methanol. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by combiflash or preparative HPLC to obtain the desired product.

[0718] General Program O:

[0719] Activated manganese dioxide (10 eq) was added to a solution of primary or secondary alcohol (1.0 eq) in dichloromethane at room temperature under a nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and washed with dichloromethane (3 times). The combined filtrates were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired product.

[0720] Scheme 1: Synthesis of tert-butyl 3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (8):

[0721]

[0722] Step 1: Synthesis of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (2):

[0723] The pyrimidine 2,4-(1H,3H)-dione (1) (10 g, 89.21 mmol) and paraformaldehyde (9.63 g, 107.05 mmol) in an ice-cold solution of potassium hydroxide aqueous solution (132 mL, 0.5 M, 66.74 mmol) were heated at 55 °C for 14 hours. After the starting material was completely dissolved (TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 6 with 12 N hydrochloric acid. The resulting white precipitate was filtered through a sintered funnel and washed with diethyl ether to give 2 (6.3 g, yield: 50%) as a white solid, which was used directly in the next step. 1 H-NMR (400MHz, DMSO-d6): δ10.98 (bs, 1H), 10.64 (bs, 1H), 7.24 (s, 1H), 4.78 (m, 1H), 4.12 (d, J = 12.8Hz, 2H). LCMS:[M+H] + 143.04.

[0724] Step 2: Synthesis of 2,4-dichloro-5-(chloromethyl)pyrimidine (3):

[0725] A solution of 10 g (70.36 mmol) of 5-(hydroxymethyl)pyrimidine-2,4-(1H,3H)-dione (2) in toluene (25 mL) was dissolved in ice-cold water and phosphoryl chloride (14 mL, 140.72 mmol) was added, followed by N,N-diisopropylethylamine (37 mL, 211 mmol). The reaction mixture was heated at 120 °C for 16 h. After the starting material had completely disappeared on 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 (12 g, yield: 86%) as a brown solid, which was used directly in the next step. 1 H NMR (400MHz, CDCl3): δ8.66 (s, 1H), 4.64 (s, 2H). MS:[M+H] + 197.0.

[0726] Step 3: Synthesis of 2,4-dichloro-5-(iodomethyl)pyrimidine (4):

[0727] Sodium iodide (9.71 g, 64.82 mmol) was added to a solution of 2,4-dichloro-5-(chloromethyl)pyrimidine (3) (8.0 g, 40.51 mmol) in acetone (40 mL). The reaction mixture was stirred at room temperature for 30 min and heated to reflux for 2 h. After the reaction was complete (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 (10 g, yield: 85%) as a brown solid, which was used directly in the next step. 1 H-NMR (400MHz, CDCl3): δ8.60 (s, 1H), 4.39 (s, 2H).

[0728] Step 4: Synthesis of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (6):

[0729] Potassium carbonate (5.26 g, 38.06 mmol) and aniline (5) (1.93 g, 20.76 mmol) were added to an ice-cold solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (4) (5.0 g, 17.30 mmol) in acetone (50 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (according to TLC monitoring), the resulting white precipitate was filtered through a sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100-200 mesh) using 15% ethyl acetate-hexane as eluent to give 6 (2.5 g, yield: 57%) as a brown solid. 1H-NMR (400MHz, CDCl3): δ8.61 (s, 1H), 7.07 (t, J = 7.6Hz, 2H), 6.58 (m, 3H), 6.30 (bs, 1H), 4.33 (m, 2H). LCMS:[M+H] + 254.03.

[0730] Step 5: Synthesis of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (8):

[0731] N,N-diisopropylethylamine (1.47 mL, 8.42 mmol) and tert-butyl (3-aminophenyl)carbamate (7) (409 mg, 1.96 mmol) were added to an ice-cold solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (6) (500 mg, 1.96 mmol) in isopropanol (5 mL). The resulting reaction mixture was heated at 100 °C in a sealed tube for 16 hours. After the reaction was complete (monitored by TLC), the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (100-200 mesh) using hexane containing 30% ethyl acetate as eluent to give 8 (500 mg, yield: 60%) as a brown solid. 1 H-NMR (400MHz, DMSO-d6): δ9.41(s,1H),8.96(s,1H),8.10(s,1H),7.73(s,1H),7.2 5(m,2H),7.12(m,3H),6.61(m,3H),6.14(t,J=7.2Hz,1H),4.26(m,2H),1.53(s,9H). LCMS:[M+H] + 426.14.

[0732] Scheme 2: Synthesis of 2-(4-amino-1H-pyrazol-1-yl)ethanol (11):

[0733]

[0734] Step 1: Synthesis of 2-(4-nitro-1H-pyrazole-1-yl)ethanol (10)

[0735] 2-Bromoethane-1-ol (1.38 mL, 19.5 mmol) and potassium carbonate (2.93 g, 21.2 mmol) were added to a stirred solution of 4-nitro-1-pyrazole (9) (2.00 g, 17.7 mmol) in acetonitrile (20.0 mL), 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 purifier and eluted with hexane containing 45% ethyl acetate to give the title compound (10) (2.5 g, 90%) as a white solid. LCMS: [M+H] + 158.0.

[0736] Step 2: Synthesis of 2-(4-amino-1H-pyrazol-1-yl)ethanol (11)

[0737] A stirred solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanol-1-ol (10) (2.50 g, 15.9 mmol) in ethanol (20 mL) and nitrogen was purged for 5 min. Palladium / carbon (0.25 g, 10% w / w) was added, and the reaction mixture was hydrogenated for 15 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to give the title compound (11) (2.0 g, crude substance) as a brown liquid. 1 H NMR (400MHz, DMSO-d6): δ7.00 (s, 1H), 6.87 (s, 1H), 4.78 (t, J = 4.8Hz, 1H), 3.92 (t, J = 6.0Hz, 2H), 3.73 (bs, 2H), 3.63-3.59 (m, 2H).

[0738] 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):

[0739]

[0740] Step 1: Synthesis of 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)pyrimidine-4-amine (14):

[0741] The title compound was prepared in a manner substantially similar to that described in General Procedure A. The crude material was wet-milled with diethyl ether, filtered, and dried under vacuum to give 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)pyrimidine-4-amine (14) (10.0 g, 34% yield) as a pale yellow solid. 1H-NMR (400MHz, CDCl3): δ9.87 (s, 1H), 8.48 (s, 1H), 8.40-8.43 (m, 1H), 8.22-8.26 (m, 1H), 7.65 (t, J = 9.2Hz, 1H).

[0742] Step 2: Synthesis of 4-(4-((5-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl-1-ol (16):

[0743] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (16) (0.75 g, yield: 84.7%) as a pale yellow solid, MS: [M+H]. + 448.21.

[0744] Step 3: Synthesis of 4-(4-((4-((5-amino-2-fluorophenyl)amino)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclohexyl-1-ol (17):

[0745] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding the desired product (17) as a brown solid (0.55 g, yield: 78.57%). MS: [M+H] + 418.18.

[0746] 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):

[0747] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give compound 1 (45 mg, yield: 13.27%). 1 H-NMR (400MHz, DMSO-d6): δ10.32(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),7.08-7.1 3(m,2H),6.38-6.45(m,1H),6.24(d,J=17.2Hz,1H),5.75(d,J=10.4Hz,1H),4.6 2(d,J=4.4Hz,1H),3.60-3.62(m,1H),1.83(d,J=11.2Hz,2H),1.23-1.63(m,6H). LCMS:[M+H]+ 472.22.

[0748] Table 1: Preparation of the following compounds using the procedure described above:

[0749]

[0750]

[0751]

[0752] 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):

[0753]

[0754] Step 1: 5-Chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (20)

[0755] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (20) (0.2 g, yield: 23%) as a pale yellow solid, LCMS: [M+H]. + 447.2.

[0756] Step 2: N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (21)

[0757] Raney nickel (0.07 g, 1.34 mmol) was added to a stirred solution of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-[1-(1-methylpiperidinyl-4-yl)-1H-pyrazol-4-yl]pyrimidin-2,4-diamine (20) (0.2 g, 0.44 mmol) in methanol (30 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a diatomaceous earth bed and distilled to give the title compound (21) (0.16 g, 85%) as a yellow solid. LCMS [M+H] + 417.1.

[0758] 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)

[0759] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give compound 14 (17 mg, yield: 14%). 1 H-NMR (400MHz, DMSO-d6): δ10.26(s,1H),9.23(s,1H),8.85(s,1H),8.02(s,1H),7.71(d,J=6.4Hz,2H),7.30(s,1H),7.10(t,J=1 5.2Hz,2H),6.35-6.42(m,1H),6.23(d,J=17.2Hz,1H),5.74(d,J=10.0Hz,1H),3.57(s,1H),2.75(d,J=10.0Hz,2H),2.16(s,3H). 1.93(s,2H),1.63(s,4H). LCMS:[M+H] + 471.0.

[0760] Table 2: Preparation of the following compounds using the procedure described above:

[0761]

[0762] 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)but-2-enamide (compound 17):

[0763]

[0764] 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):

[0765] The title compound was prepared in a manner substantially similar to that described in General Procedure B. The crude substance was purified by combiflash chromatography using dichloromethane containing 5% methanol as eluent. The eluent was 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.

[0766] Step 2: Synthesis of N4-(3-aminophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-((phenylamino)methyl)pyrimidine-2,4-diamine (24):

[0767] The title compound was prepared in a manner substantially similar to that described in General Procedure I. The crude compound was wet-milled with diethyl ether to give N4-(3-aminophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-((phenylamino)methyl)pyrimidine-2,4-diamine (24), a brown solid. (0.50 g, yield: 84%) It was given as a TFA salt. MS: [M+H] + 387.25.

[0768] 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)but-2-enamide (compound 17)

[0769] The title compound was prepared in a manner substantially similar to that described in General Procedure J. The crude product obtained was purified by combiflash, eluting with dichloromethane containing 8% methanol. 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) (66 mg; yield: 20.52%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.06(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=7.2Hz,1H),6.27(d,J=15.2Hz,1H),5.99-5.97(m,1H) ,4.17(d,J=4.0Hz,2H),3.62(s,3H),3.05(d,J=5.2Hz,2H),2.16(s,6H). LCMS:[M+H] + 498.38 (96.05%).

[0770] 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)but-2-enamide (compound 18):

[0771]

[0772] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (26)

[0773] The title compound was prepared in a manner substantially similar to that described in General Procedure C. The crude material was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 3-5% methanol, and the desired eluent was 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.

[0774] 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):

[0775] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude material was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 6-8% methanol, and the eluent was 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) (290 mg, yield: 85.5%) as a light brown solid. MS: [M+H] + 529.14.

[0776] Step 3: Synthesis of N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-phenylacetamide (28):

[0777] The title compound was prepared in a manner substantially similar to that described in General Procedure I. The crude compound was wet-milled 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), a brown solid (130 mg, yield: 55.3%), as a TFA salt. MS: [M+H] + 429.25.

[0778] 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):

[0779] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance 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) (22 mg; yield: 15.0%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.27(s,1H),9.30(s,1H),8.98(s,1H),8.00-7.60(m,3H),7.54(d,J=7.6Hz,1H),7.47-7.32(m,6H), 7.20(d,J=7.6Hz,2H),6.51-6.44(q,J=10.0Hz,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

[0780] 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):

[0781]

[0782] Step 1: Synthesis of (E)-(3-((2-(methylthio)-5-(((1-phenylethyl)imino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate tert-butyl ester (31):

[0783] The title compound was prepared in a manner substantially similar to that described in General Procedure D, yielding (E)-(3-((2-(methylthio)-5-(((1-phenylethyl)imino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate tert-butyl ester (31), a light brown solid. (1.20 g, yield: 93.70%). MS: [M+H] + 464.31.

[0784] Step 2: Synthesis of tert-butyl (3-((2-(methylthio)-5-(((1-phenylethyl)amino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (32):

[0785] The title compound was prepared in a manner substantially similar to that described in General Procedure E, yielding 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, yield: 83%). MS: [M+H] + 466.25.

[0786] Step 3: Synthesis of tert-butyl (3-((2-(methylthio)-5-((N-(1-phenylethyl)acetamyl)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (33):

[0787] The title compound was prepared in a manner substantially similar to that described in General Procedure C. The crude product obtained was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 4-5% methanol, and the desired eluent was concentrated under reduced pressure to give tert-butyl (3-((2-chloro-5-((N-phenylacetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (33%) as a pale brown solid. (500 mg; yield: 41.66%). MS: [M+H] + 508.25.

[0788] Step 4: Synthesis of tert-butyl (3-((2-(methanesulfonyl)-5-((N-(1-phenylethyl)acetamyl)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (34):

[0789] The title compound was prepared in a manner substantially similar to that described in General Procedure G, yielding tert-butyl (3-((2-(methanesulfonyl)-5-((N-(1-phenylethyl)acetamyl)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (34) as a grayish-white solid (400 mg; yield: 75%). MS: [M+H + 540.15.

[0790] Step 5: Synthesis of tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamyl)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (35):

[0791] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding tert-butyl (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((1-phenethyl)acetamido)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (35) (200 mg; yield: 48.54%) as a light brown solid, LCMS: [M+H] + 557.31.

[0792] 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):

[0793] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(1-phenylethyl)acetamide (36), a brown solid (150 mg; yield: 91.64%) as a TFA salt, MS: [M+H]. + 457.25.

[0794] 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):

[0795] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((N-(1-phenylethyl)acetamyl)methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 19) (30 mg; yield: 15.0%) as a white solid. 1 H NMR(400MHz,DMSO d6): δ10.20(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),5-7 6-5.73(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=6.8Hz,3H). LCMS:[M+H] + 511.37.

[0796] 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):

[0797]

[0798] Step 1: Synthesis of 2-fluoro-5-nitro-N-phenylaniline (38):

[0799] The title compound was prepared in a manner substantially similar to that described in General Procedure B. The crude substance was purified by combiflash chromatography using hexane containing 10-20% ethyl acetate as eluent. The eluent was concentrated under reduced pressure to give 2-fluoro-5-nitro-N-phenylaniline (38) (4.0 g; yield: 54.0%) as a light brown solid. MS: [MH] - 230.96.

[0800] Step 2: Synthesis of 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)-N-phenylpyrimidine-4-amine (39):

[0801] Potassium carbonate (2.40 g, 17.22 mmol) and 2,4,5-trichloropyrimidine (13) (1.60 g, 8.61 mmol) were added to a solution of 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)pyrimidine-4-amine (38) (2.00 g, 8.61 mmol) in N,N-dimethylformamide (20 mL). The resulting reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled, diluted with ice-cold water, 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 substance was purified by rapid chromatography using hexane containing 5-10% ethyl acetate as the eluent. The eluent was concentrated under reduced pressure to obtain 2,5-dichloro-N-(2-fluoro-5-nitrophenyl)-N-phenylpyrimidine-4-amine (39) (1.40 g; yield: 42.9%), which is a light brown solid. 1 H-NMR (400MHz, DMSO-d6): δ8.48(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).

[0802] Step 3: Synthesis of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (40):

[0803] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (40) (550 mg; yield: 94.8%) as a light brown solid, MS: [M+H]. + 440.17.

[0804] Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (41):

[0805] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding 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.

[0806] 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):

[0807] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(phenyl)amino)-4-fluorophenyl)acrylamide (compound 20) (95 mg, yield: 33.56%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.25(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.

[0808] 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):

[0809]

[0810] 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)

[0811] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding 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.

[0812] Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-phenylpyrimidine-2,4-diamine (44):

[0813] Raney nickel (100 mg) was added 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). The resulting reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and washed with dichloromethane (3 × 5 mL) containing 10% methanol. The combined organic compounds 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.

[0814] 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):

[0815] The title compound was prepared in a manner substantially similar to that described in the general procedure K, N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (44) and acryloyl chloride (18) to give N-(3-((5-chloro-2-((5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 21) (45 mg, yield: 19.77%) as a white solid.1 H NMR (400MHz, DMSO-d6): δ10.26(s,1H),9.46(s,1H),8.89(s,1H),8.06(s,1H),7.76-7.68(m,2H),7 .28(t,J=9.4Hz,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.

[0816] Scheme 10: Synthesis of N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 22):

[0817]

[0818] Step 1: Synthesis of N1-(2,5-dichloropyrimidin-4-yl)-6-fluorobenzene-1,3-diamine (46)

[0819] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding N1-(2,5-dichloropyrimidin-4-yl)-6-fluorobenzene-1,3-diamine (46) (2.0 g; yield: 62.11%) as a grayish-white solid, LCMS: [M+H] + 272.88.

[0820] Step 2: Synthesis of N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (47):

[0821] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude material obtained was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 3-5% methanol, and the eluent was concentrated under reduced pressure to give N-(3-(((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (47) (800 mg, yield: 94.2%) as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.39(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).

[0822] Step 3: Synthesis of N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 22):

[0823] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude material was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 4-6% methanol, and the eluent was concentrated under reduced pressure. The resulting solid was purified again by preparative HPLC to give N-(3-((5-chloro-2-((6-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (compound 22) (30 mg, yield: 19.77%) as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.22(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=9.1Hz,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.

[0824] 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):

[0825]

[0826] Step 1: Synthesis of N-(3-((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (50):

[0827] The title compound was prepared in a manner substantially similar to that described in General Procedure J. The crude product obtained was purified by combiflash, eluted with dichloromethane containing 10% methanol, and the eluent was concentrated under reduced pressure to give N-(3-(((2,5-dichloropyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (50) (350 mg; yield: 34%) as a grayish-white solid. MS: [M+H] + 345.18

[0828] 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):

[0829] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude substance was further purified by preparative HPLC to give N-(3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (compound 23) (55 mg, yield: 31.42%) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.46(s,1H),9.25(s,1H),8.95(s,1H),8.05(s,1H),7.85-7.74(m,2 H),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.

[0830] 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):

[0831]

[0832] Step 1: Synthesis of tert-butyl (3-aminocyclohexyl)carbamate (52):

[0833] Di-tert-butyl dicarbonate (14.93 mL, 65.78 mmol) was added dropwise to an ice-cold solution of cyclohexane-1,3-diamine (51) (15.0 g, 131.57 mmol) in chloroform (300 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (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 crude material obtained by purification with silica gel (100-200 mesh) was eluted with dichloromethane containing 3-5% methanol, and the eluent was concentrated under reduced pressure to give tert-butyl (3-aminocyclohexyl)carbamate (52) (21.0 g; yield: 75%) as a white solid. 1H-NMR (400MHz, DMSO-d6): δ8.29(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).

[0834] Step 2: Synthesis of tert-butyl (3-((2,5-dichloropyrimidin-4-yl)amino)cyclohexyl)carbamate (53):

[0835] N,N-diisopropylethylamine (9.5 mL, 54.51 mmol) and 2,4,5-trichloropyrimidine (13) (2.0 g, 10.9 mmol) were added to an ice-cold solution of (3-aminocyclohexyl)carbamate (52) in ethanol (20 mL). The resulting reaction mixture was heated at 90 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic matter was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude substance was purified by rapid chromatography using hexane containing 30-50% ethyl acetate as the eluent. The eluent was concentrated under reduced pressure to give tert-butyl (3-((2,5-dichloropyrimidin-4-yl)amino)cyclohexyl)carbamate (53) (1.20 g; yield: 30.4%) as a light brown solid. MS: [M+H] + 360.97.

[0836] Step 3: Synthesis of tert-butyl (3-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)carbamate (54):

[0837] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude compound was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 2-4% methanol, and the eluent was 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) (600 mg, yield: 85.83%) as a light brown solid. MS: [M+H] + 422.38.

[0838] Step 4: Synthesis of N4-(3-aminocyclohexyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (55):

[0839] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding N4-(3-aminocyclohexyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (55) as a TFA salt in the form of a light brown solid (400 mg; yield: 88%). MS: [M+H] + 322.25.

[0840] 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):

[0841] The title compound was prepared in a manner substantially similar to that described in General Procedure J. The crude substance 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) (35 mg; yield: 10%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ9.05 (s, 1H), 8.47 (d, J = 8.0Hz, 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.

[0842] Table 3: Preparation of the following compounds using the procedure described above:

[0843]

[0844] Scheme 13: Synthesis of (E)-N-(3-((5-chloro-2-((3-methylisothiazo-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 27):

[0845]

[0846] Step 1: Synthesis of 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(3-methylisothiazo-5-yl)pyrimidine-2,4-diamine (57):

[0847] The title compound was prepared in a manner substantially similar to that described in General Procedure B. The crude compound was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 3-5% methanol, and the desired eluent was concentrated to dryness to give 5-chloro-N4-(2-fluoro-5-nitrophenyl)-N2-(3-methylisothiazo-5-yl)pyrimidine-2,4-diamine (57) (500 mg; yield: 79.74%) as a light brown solid. MS: [M+H] + 381.13.

[0848] Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (58):

[0849] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding 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.

[0850] Step 3: Synthesis of (E)-N-(3-((5-chloro-2-((3-methylisothiazo-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 27):

[0851] The title compound was prepared in a manner substantially similar to that described in General Procedure J. The crude product was purified by combiflash, eluted with dichloromethane containing 8% methanol, concentrated under reduced pressure, and purified again by preparative HPLC to give (E)-N-(3-((5-chloro-2-((3-methylisothiazo-5-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (compound 27) (20 mg, yield: 5.06%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ11.05(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=9.4Hz,1H),6.6 9-6.76(m,1H),6.49(s,1H),6.25(d,J=15.4Hz,1H),3.04-3.05(m,2H),2.17(m,9H). LCMS:[M+H] + 462.13.

[0852] Scheme 14: Synthesis of N-(4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 28):

[0853]

[0854] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-nitropyrimidin-4-yl)amino)phenyl)carbamate (60):

[0855] N,N-diisopropylethylamine (9.3 mL, 52.082 mmol) and 2,4-dichloro-5-nitropyrimidine (59) (5.0 g, 26.04 mmol) were added to an ice-cold solution of tert-butyl (3-aminophenyl)carbamate (7) (5.0 g, 26.04 mmol) in tetrahydrofuran (45 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), ice-cold water was added, the resulting solid precipitate was filtered, and dried under vacuum to give the desired product (60) (8.1 g, yield: 85.23%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ10.25(s,1H),9.16(s,1H),9.03(s,1H),7.95(s,1H),7.23(d,J=15.2Hz,2H),7.13(s,1H),1.47(s,9H). LCMS:[M+H] + 366.09.

[0856] Step 2: Synthesis of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (61):

[0857] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding the desired product (61) (6.4 g, yield: 85%) as a brown solid. LCMS: [M+H] + 336.11.

[0858] Step 3: Synthesis of tert-butyl (3-((5-benzamido-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (63):

[0859] Pyridine (0.9 mL, 11.9 mmol) and benzoyl chloride (62) (417.12 mg, 2.9 mmol) were added to an ice-cold solution of (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (61) in tetrahydrofuran (20 mL) under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 30 minutes. After the reaction mixture (monitored by TLC) was complete, 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 and eluted with hexane containing 20% ​​ethyl acetate to give the desired product (63) (1.1 g, yield: 84%) as a brown solid. LCMS: [M+H] + 440.14.

[0860] Step 4: Synthesis of tert-butyl (3-((5-benzamido-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (64):

[0861] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude substance was purified by combiflash chromatography, eluting with dichloromethane containing 4% methanol, to give the desired product (64) (720 mg; yield: 57%) as a brown solid. LCMS: [M+H] + 501.23.

[0862] Step 5: Synthesize N-(4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (65).

[0863] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (65) as a brown solid (510 mg, yield: 91.01%). MS: [M+H] + 401.21.

[0864] Step 6: Synthesize N-(4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 28).

[0865] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude material was purified by preparative HPLC to give the desired product compound 28 (65 mg, yield: 19.12%), which was grayish-white. 1H-NMR (400MHz, DMSO-d6): δ10.15(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&10.4Hz,1H),3.64(s,3H). LCMS:[M+H] + 455.28.

[0866] Scheme 15: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 29):

[0867]

[0868] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)carbamate (67):

[0869] Pyridine (0.69 mL, 11.98 mmol) and benzenesulfonyl chloride (66) (525 mg, 2.98 mmol) were added to an ice-cold solution of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (61) in dichloromethane (15 mL) under a nitrogen atmosphere and at the same temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction mixture (monitored by TLC) was complete, the reactants were diluted with water and extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired product (67) (700 mg, yield: 50%) as a semi-solid. LCMS: [M+H] + 476.11.

[0870] Step 2: Synthesis of N-(4-((3-aminophenyl)amino)-2-chloropyrimidin-5-yl)benzenesulfonamide (68):

[0871] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (68) as a brown solid (480 mg, yield: 96%). LCMS: [M+H] + 376.11.

[0872] Step 3: Synthesize N-(3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (69).

[0873] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by combiflash, eluted with dichloromethane containing 4% methanol, to give the desired product (69) as a brown solid (340 mg, yield: 67%). MS: [M+H] + 430.07

[0874] Step 4: Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(phenylsulfonamido)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 29):

[0875] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude substance was purified by preparative HPLC to give the desired product compound 29 (10 mg, yield: 9%) as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.13(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=15.2Hz,1H),5.74(dd,J=10.4&2.0Hz,1H),3.59(s,3H). LCMS:[M+H] + 491.26.

[0876] Table 4: Preparation of the following compounds using the procedure described above:

[0877]

[0878]

[0879] Scheme 16: Synthesis of N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 32):

[0880]

[0881] Step 1: Synthesis of tert-butyl (3-((5-(phenylmethylamino)-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (71):

[0882] Benzaldehyde (70) (570 mg, 5.37 mmol) and sodium triacetoxyborohydride (2.8 g, 13.431 mmol) were added to an ice-cold solution of (3-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (61) (1.5 g, 4.477 mmol) in dichloroethane (15 mL) under a nitrogen atmosphere and at the same temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, 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 by a combiflash purifier and eluted with hexane containing 40% ethyl acetate to give the desired product (71) (1.1 g, yield: 57%) as a brown solid. MS: [M+H] + 426.17.

[0883] Step 2: Synthesis of N-(3-aminophenyl)-N5-benzyl-2-chloropyrimidine-4,5-diamine (72):

[0884] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (72) as a grayish-white solid (820 mg, yield: 97%). MS: [M+H] + 326.17.

[0885] Step 3: Synthesize N-(3-((5-(phenylmethylamino)-2-chloropyrimidin-4-yl)amino)phenyl)acrylamide (73).

[0886] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude product was purified by combiflash, eluted with dichloromethane containing 2% methanol, to give the desired product (73) (260 mg; yield: 55.7%) as a grayish-white solid. MS: [M+H] + 380.13

[0887] Step 4: Synthesis of N-(3-((5-(benzylamino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 32)

[0888] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude substance was purified by preparative HPLC to give the desired product compound 32 (40 mg; yield: 14%) as a white solid. 1H-NMR (400MHz, DMSO-d6): δ10.12(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. 0Hz&1.6Hz,1H),5.05-5.07(m,1H),4.25(d,J=6.0Hz,2H),3.65(s,3H). LCMS:[M+H] + 441.28.

[0889] 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):

[0890]

[0891] Step 1: Synthesis of (E)-N-(3-((5-(phenylmethylamino)-2-chloropyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (74)

[0892] The title compound was prepared in a manner substantially similar to that described in General Procedure J, yielding the desired product (74) as a grayish-white solid (210 mg; yield: 40%). MS: [M+H] + 437.17.

[0893] 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)

[0894] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude substance was purified by preparative HPLC to give the desired product compound 33 (35 mg; yield: 16%) as a grayish-white solid. 1H-NMR (400MHz, DMSO-d6): δ10.02(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=15.4Hz,1H),5.04-5.06(m,1H ), 4.25 (d, J = 5.6Hz, 2H), 3.65 (s, 3H), 3.04 (d, J = 5.2Hz, 2H), 2.17 (s, 6H). LCMS:[M+H] + 498.30.

[0895] Scheme 18: Synthesis of 4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidin-5-carboxamide (compound 34):

[0896]

[0897] Step 1: Synthesis of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylate (76):

[0898] N,N-diisopropylethylamine (4.82 mL, 27.02 mmol) and tert-butyl (3-aminophenyl)carbamate (7) (2.82 g, 13.56 mmol) were added to a solution of ethyl 2,4-dichloropyrimidin-5-carboxylate (75) in tetrahydrofuran (30 mL) at room temperature. The resulting reaction mixture was heated at 100 °C for 4 hours. After the reaction was complete (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, 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.

[0899] Step 2: Synthesis of 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylic acid (77):

[0900] To an ice-cold solution of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidin-5-carboxylate (76) (4.5 g, 4.82 mmol) in tetrahydrofuran (50 mL), 10 mL of water containing sodium hydroxide (386 mg, 9.65 mmol) was added. The resulting reaction mixture was heated at 50 °C for 8 hours. After the reaction was complete (monitored by TLC), the mixture was concentrated under reduced pressure. The crude product was diluted with ice-cold water (25 mL) and acidified with 1 N hydrochloric acid (adjusting the pH to approximately 5). The precipitate was filtered and dried under vacuum to give the desired product (77) (2.6 g; yield: 63.14%) as a grayish-white solid. LCMS: [M+H] + 364.94.

[0901] Step 3: Synthesis of tert-butyl (3-((2-chloro-5-((1-phenylethyl)carbamoyl)pyrimidin-4-yl)amino)phenyl)carbamate (78):

[0902] The title compound was prepared in a manner substantially similar to that described in General Procedure J, yielding the desired product (78) as a grayish-white solid (800 mg; yield: 66.62%). MS: [M+H] + 468.17.

[0903] Step 4: Synthesis of tert-butyl carbamate (3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-((1-phenylethyl)carbamoyl)pyrimidin-4-yl)amino)phenyl)carbamate (79):

[0904] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude compound was purified by combiflash and eluted with dichloromethane containing 2% methanol to give the desired product (79) as a semi-solid (600 mg; yield: 61.32%). LCMS: [M+H] + 529.16.

[0905] Step 5: Synthesis of 4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazole-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (80):

[0906] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (80) as a grayish-white solid (430 mg, yield: 88.21%). LCMS: [M+H] + 429.21.

[0907] Step 6: Synthesis of 4-((3-acrylamidophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-(1-phenylethyl)pyrimidine-5-carboxamide (compound 34):

[0908] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give the desired product compound 34 (40 mg; yield: 14.21%) as a grayish-white solid. 1 HNMR (400MHz, DMSO-d6): δ11.15(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,3 H),7.21-7.24(m,2H),6.39-6.46(m,1H),6.22-6.26(m,1H),5.74(dd,J =10.4&2.0Hz,1H),5.12-5.19(m,1H)3.61(s,3H),1.47(d,J=2.2Hz,3H). LCMS:[M+H] + 483.28.

[0909] 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):

[0910]

[0911] The title compound was prepared in a manner substantially similar to that described in General Procedure J. The crude substance was purified by preparative HPLC to give the desired product compound 35 (48 mg; yield: 15.23%) as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ11.14(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.

[0912] 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):

[0913]

[0914] Step 1: Synthesis of tert-butyl (4-fluoro-3-nitrophenyl)carbamate (82):

[0915] Boc anhydride (13.99 g, 64.102 mmol) was added to a solution of 4-fluoro-3-nitroaniline (81) (10 g, 64.102 mmol) in tert-butanol (50 mL) at room temperature. The resulting reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (according to TLC monitoring), the mixture was concentrated under reduced pressure. The residue was washed with hexane and dried under vacuum to give the desired product (82) (14 g; yield: 85.32%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ9.9 (s, 1H), 8.36 (s, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.49-7.54 (m, 1H), 1.49 (s, 9H).

[0916] Step 2: Synthesis of tert-butyl (3-amino-4-fluorophenyl)carbamate (83):

[0917] A solution of tert-butyl (4-fluoro-3-nitrophenyl)carbamate (82) (14 g, 54.68 mmol) in ethanol (50 mL) was added with 10% palladium / carbon (1.4 g, 10% w / w). The resulting reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered and washed with ethyl acetate (200 mL). The combined filtrates were concentrated under reduced pressure to give the desired product (83) (11 g; yield: 89.21%) as a grayish-white solid. 1 HNMR (400MHz, DMSO-d6): δ9.01 (bs, 1H), 6.60-7.20 (m, 3H), 5.21 (s, 2H), 1.49 (s, 9H). LCMS:[M+1H] + 227.24.

[0918] Step 3: Synthesis of tert-butyl (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (85):

[0919] The title compound was prepared in a manner substantially similar to that described in General Procedure A. The crude compound was purified by combiflash and eluted with hexane containing 70% ethyl acetate to give the desired product (85) (600 mg; yield: 21.42%). MS: [M+H] + 407.08.

[0920] 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):

[0921] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude compound was purified by combiflash, eluted with dichloromethane containing 1% methanol, to give (86) (300 mg; yield: 43.47%). MS: [M+H] + 468.17

[0922] Step 5: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (87):

[0923] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (87) (150 mg; yield: 63.24%). MS: [M+H] + 368.15

[0924] Step 6: N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (compound 36):

[0925] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give compound 36 (20 mg; yield: 12.62%) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.30(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=8.0Hz,1H),3.50(s,3H). LCMS:[M+H] + 422.23.

[0926] 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):

[0927]

[0928] Step 1: Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidine-4-amine (89):

[0929] The title compound was prepared in a manner substantially similar to that described in General Procedure A. The crude compound was purified by combiflash, eluted with hexane containing 40% ethyl acetate, to give (89) (1.3 g, yield: 44.24%) as a pale yellow solid. MS: [M+H] + 346.97.

[0930] Step 2: Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-4-amine (91):

[0931] The title compound was prepared in a manner substantially similar to that described in General Procedure M3. The crude substance was purified by combiflash, eluted with hexane containing 35% ethyl acetate, to give the desired product (91) (700 mg; yield: 50.12%) as a pale yellow solid. MS: [M+H] + 413.10

[0932] 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):

[0933] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The crude substance was purified by combiflash, eluted with dichloromethane containing 1% methanol, to give the desired product (92) (500 mg; yield: 70.24%) as a pale yellow solid. MS: [M+H] + 474.09

[0934] 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):

[0935] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding (93) (350 mg; yield: 74.78%) as a semi-solid. MS: [M+H]+ 444.11

[0936] 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):

[0937] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give compound 37 (30 mg, yield: 13.33%) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.21(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=8.4Hz,1H),3.54(s,3H). LCMS:[M+H] + 498.35.

[0938] Table 5: Preparation of the following compounds using the procedure described above:

[0939]

[0940]

[0941]

[0942] 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):

[0943]

[0944] Step 1: Preparation of tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (94)

[0945] 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 the reaction was complete (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 substance was purified by silica gel (100-200 mesh), eluted with hexane containing 40-50% ethyl acetate, and the desired eluent was concentrated to dryness to give tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (94) (4.0 g; yield: 48%), a grayish-white solid. MS: [M+H] + 377.43.

[0946] Step 2: Synthesis of tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (95):

[0947] The title compound was prepared in a manner substantially similar to that described in General Procedure O, yielding tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (95 g) (1.5 g; yield: 60%) as a light brown solid. MS: [M+H] + 375.42.

[0948] Step 3: Preparation of (E)-(3-((5-(1-(benzylimino)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate tert-butyl ester (97):

[0949] The title compound was prepared in a manner substantially similar to that described in General Procedure D, yielding the desired product (97) (1.0 g; yield: 58%) as a grayish-white solid. MS: [M+H] + 464.25.

[0950] Step 4: Synthesis of tert-butyl (3-((5-(1-(benzylamino)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (98):

[0951] The title compound was prepared in a manner substantially similar to that described in General Procedure E. The crude product obtained was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 4-5% methanol, and the eluent was concentrated under reduced pressure to give tert-butyl (3-((5-(1-(phenylmethylamino)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (98) (400 mg; yield: 40%) as a pale yellow solid. MS: [M+H] + 466.30.

[0952] Step 5: Synthesis of tert-butyl (3-((5-(1-(N-benzylacetamyl)ethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (99):

[0953] The title compound was prepared in a manner substantially similar to that described in General Procedure C. The crude compound was purified by silica gel (100-200 mesh), eluted with dichloromethane containing 3% methanol, and the eluent was 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.

[0954] Step 6: Synthesis of tert-butyl (3-((5-(1-(N-benzylacetamyl)ethyl)-2-(methanesulfonyl)pyrimidin-4-yl)amino)phenyl)carbamate (100):

[0955] The title compound was prepared in a manner substantially similar to that described in General Procedure G, yielding the desired product (100) (130 mg; yield: 61%) as a grayish-white solid. MS: [M+H] + 540.06.

[0956] Step 7: Synthesis of tert-butyl carbamate (3-((5-(1-(N-benzylacetamyl)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (101):

[0957] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding tert-butyl (3-((5-(1-(N-benzylacetamido)ethyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (101) (100 mg; 74.6%) as a light brown solid. MS: [M+H] + 557.41.

[0958] 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):

[0959] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding N-(1-(4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethyl)-N-benzylacetamide (102) as a light brown solid in the form of a TFA salt. (100 mg; yield: 98%). MS: [MH] - 455.33.

[0960] 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)

[0961] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give compound 47 (6.0 mg, 6.7%) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.27(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=16.8Hz,1H),5.96-6.01(m,1H),5.76(d,J=10.4Hz,1H),4.60(s,2H),3.66(s 3H), 2.53 (s, 1H), 2.02 (s, 3H), 1.50 (d, J = 6.8Hz, 3H). LCMS:[M+H] + 511.37.

[0962] 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):

[0963]

[0964] Step 1: Synthesis of tert-butyl (3-((5-((N-benzylacetamyl)methyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (104):

[0965] The title compound was prepared in a manner substantially similar to that described in General Procedure C, yielding tert-butyl (3-((5-(((N-benzylacetamyl)methyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (104) as a brown solid (700 mg, quantitative yield). MS: [M+H] + 494.37.

[0966] Step 2: Synthesis of tert-butyl (3-((5-((N-benzylacetamyl)methyl)-2-(methylsulfinyl)pyrimidin-4-yl)amino)phenyl)carbamate (105):

[0967] The title compound was prepared in a manner substantially similar to that described in General Procedure G, yielding the desired product (105) as a grayish-white solid (650 mg; yield: 90%). MS: [M+H] + 510.34.

[0968] Step 3: Synthesis of tert-butyl carbamate (3-((5-((benzylacetamyl)methyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (106)

[0969] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (106) as a grayish-white solid (650 mg, yield: 92%). MS: [M+H] + 543.18.

[0970] Step 4: Synthesis of N-((4-((3-aminophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-benzylacetamide (107):

[0971] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (107) as a grayish-white solid (450 mg; yield: 94.9%). MS: [M+H] + 443.19

[0972] 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):

[0973] The title compound was prepared in a manner substantially 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) (30 mg; yield: 15%) as a grayish-white solid. 1 H-NMR(400MHz,DMSO d6): δ10.15(bs,1H),9.50(bs,1H),9.01(bs,1H),7.87(s,1H),7.65(s,1 H),7.62(s,1H),7.53(d,J=7.2Hz,1H),7.40-7.36(m,4H),7.31-7.27(m,3 H),7.24(d,J=7.6Hz,1H),6.47(d,J=16.8Hz,1H),6.23(d,J=1.6Hz,1H),5 .74(d,J=1.6Hz,1H),4.62(s,2H),4.37(s,2H),3.68(s,3H),2.12(s,3H). LCMS:[M+H] + 497.31.

[0974] 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):

[0975]

[0976] Step 1: Synthesis of ethyl 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylate (108):

[0977] The title compound was prepared in a manner substantially similar to that described in General Procedure A. The crude substance was purified by silica gel column chromatography (100-200 mesh) using hexane containing 20-25% ethyl acetate as eluent to give ethyl 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylate (108) (1.6 g, yield: 15.78%) as a brown solid. MS: [M+H] + 341.04.

[0978] Step 2: Synthesis of 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid (109):

[0979] Lithium hydroxide monohydrate (246 mg, 5.87 mmol) was added to an ice-cold solution of ethyl 2-chloro-4-[(2-fluoro-5-nitrophenyl)amino]pyrimidine-5-carboxylic acid (108) (800 mg, 2.35 mmol) in tetrahydrofuran (10 mL) and water (2.00 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude mixture was diluted with ice-cold water and the pH was adjusted to approximately 4 using 1 N hydrochloric acid. The precipitate was filtered and dried under vacuum to give 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid (109) (720 mg; yield: 98%) as a grayish-white solid. LCMS: [MH] - 311.26.

[0980] Step 3: Synthesis of 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)-N-methyl-N-phenylpyrimidine-5-carboxamide (111):

[0981] The title compound was prepared in a manner substantially similar to that described in General Procedure J, yielding 2-chloro-4-((2-fluoro-5-nitrophenyl)amino)-N-methyl-N-phenylpyrimidine-5-carboxamide (111) as a grayish-white solid (150 mg; yield: 20%). LCMS: [M+H] + 401.98.

[0982] 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):

[0983] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The residue was purified by combiflash, eluting with hexane containing 60% ethyl acetate to give the desired product (112) as a grayish-white solid. (300 mg, yield: 52.13%). LCMS: [M+H] + 463.27.

[0984] 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):

[0985] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding 4-((5-amino-2-fluorophenyl)amino)-N-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-N-phenylpyrimidine-5-carboxamide (113) (220 mg; yield: 48.62%) as a light green solid. MS: [M+H] + 433.20.

[0986] 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):

[0987] 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 (compound 49) (10 mg, yield: 8%) as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.25(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. 8Hz, 3H), 7.23 (d, J = 7.2Hz, 2H), 7.15 (s, 1H), 6.43 (d, J = 16.4Hz, 1H), 6.25 (d, J = 17.6Hz, 1H), 5.77 (d, J = 11.6Hz, 1H), 3.56 (s, 3H), 3.37 (s, 3H). LCMS:[M+H] + 487.35.

[0988] 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):

[0989]

[0990] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-nitropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (115):

[0991] N,N-diisopropylethylamine (7.82 mL, 44.24 mmol) was added to an ice-cold solution of (3-amino-4-fluorophenyl)carbamate (83) (5.0 g, 22.12 mmol) in tetrahydrofuran (50 mL), 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. After the reaction was complete, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic matter was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-((2-chloro-5-nitropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (115) (6.1 g, yield: 60.24%), MS: [M+H). + 384.12.

[0992] Step 2: Synthesis of tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (116):

[0993] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding tert-butyl (3-((5-amino-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (116) (4.8 g, yield: 85.40%), LCMS: [M+H] + 353.81.

[0994] Step 3: Synthesis of tert-butyl (3-((5-benzamido-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (117):

[0995] Pyridine (810 mg, 11.32 mmol) was added 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) under a nitrogen atmosphere, followed by the addition of benzoyl chloride (62) (400 mg, 2.831 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was diluted 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 material was purified by combiflash and eluted with hexane containing 8% ethyl acetate 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.

[0996] 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):

[0997] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The residue was purified by combiflash, eluting with dichloromethane containing 2% methanol 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.

[0998] Step 5: Synthesize N-(4-((5-amino-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (119).

[0999] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding N-(4-((5-amino-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (119) (280 mg, yield: 77.10%), MS: [M+H + 419.24

[1000] Step 6: Synthesize N-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide (compound 50).

[1001] The title compound was prepared in a manner substantially similar to that described in General Procedure K. The crude substance was purified by preparative HPLC to give 50 (17 mg, yield: 10.03%) of N-(4-((5-acrylamido-2-fluorophenyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzamide compound. 1H-NMR (400MHz, DMSO-d6): δ10.22(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=16.8Hz,1H),5.74(d,J=11.2Hz,1H),3.57(s,3H),LCMS:[M+H] + 473.35.

[1002] 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):

[1003]

[1004] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (120):

[1005] Under a nitrogen atmosphere, pyridine (0.95 mL, 11.32 mmol), benzenesulfonyl chloride (66) (0.36 mL, 2.83 mmol), and a catalytic amount of N,N-dimethylaminopyridine were added to an ice-cold solution of (3-((5-amino-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (116) (1.0 g, 2.83 mmol) in tetrahydrofuran (10 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, 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 material was purified by combiflash and eluted with hexane containing 40% ethyl acetate to give tert-butyl (3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (120) (600 mg, yield 42.85%). MS: [M+H + 494.10.

[1006] Step 2: Synthesis of N-(4-((5-amino-2-fluorophenyl)amino)-2-chloropyrimidin-5-yl)benzenesulfonamide (121):

[1007] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (121) (410 mg; yield: 54.14%). MS: [M+H] + 394.21

[1008] Step 3: Synthesis of N-(3-((2-chloro-5-(phenylsulfonamido)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (122):

[1009] The title compound was prepared in a manner substantially similar to that described in General Procedure K, yielding the desired product (122) (330 mg; yield: 29.48%). MS: [M+H] + 448.11

[1010] 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):

[1011] The title compound was prepared in a manner substantially 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 (400MHz, DMSO-d6): δ10.17(bs,1H),9.02(bs,1H),8.24(bs,1H),7.74-7.79(m,3H),7.53-7.60(m,5H),7.3 8(s,1H),7.19-7.24(m,3H),6.38-6.45(m,1H)6.23-6.27(m,1H),5.77(d,J=10.0Hz,1H),3.56(s,3H),LCMS:[M+H] + 509.35.

[1012] 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):

[1013]

[1014] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(methyl(phenyl)carbamoyl)pyrimidin-4-yl)amino)phenyl)carbamate (124):

[1015] The title compound was prepared in a manner substantially similar to that described in General Procedure J, yielding 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.

[1016] Step 2: Synthesize 4-((3-aminophenyl)amino)-N-methyl-2-(methylthio)-N-phenylpyrimidine-5-carboxamide (125).

[1017] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding 4-((3-aminophenyl)amino)-N-methyl-2-(methylthio)-N-phenylpyrimidine-5-carboxamide (125) (1.1 g, yield: 78.15%), MS: [M+H + 366.18

[1018] Step 3: Synthesis of (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-N-methyl-2-(methylthio)-N-phenylpyrimidine-5-carboxamide (126):

[1019] The title compound was prepared in a manner substantially similar to that described in General Procedure J. The crude compound was purified by combiflash and eluted with dichloromethane containing 2.5% methanol 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

[1020] Step 4: Synthesis of (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-N-methyl-2-(methanesulfonyl)-N-phenylpyrimidine-5-carboxamide (127):

[1021] The title compound was prepared in a manner substantially similar to that described in General Procedure G, yielding (E)-4-((3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-N-methyl-2-(methanesulfonyl)-N-phenylpyrimidine-5-carboxamide (127) (510 mg, yield: 79.68%), MS: [M+H + 509.19.

[1022] 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):

[1023] The title compound was prepared in a manner substantially similar to that described in General Procedure H. The final compound was purified by preparative HPLC to give compound 52 (44 mg, yield: 7.06%) as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.01(bs,1H),9.59(bs,1H),7.84-7.86(m,2H),7.62(s,1H),7.47(d,J=6.4Hz,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),3.3 7(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.

[1024] 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):

[1025]

[1026] Step 1: Synthesis of tert-butyl (3-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (129):

[1027] Potassium carbonate (6.10 g, 44.26 mmol) and 5-bromo-2,4-dichloropyrimidine (88) (4.97 g, 22.13 mmol) were added to a solution of tert-butyl (3-aminophenyl)carbamate (7) (5 g, 22.13 mmol) in N,N-dimethylformamide (50 mL) at room temperature. The resulting reaction mixture was heated at 110 °C for 16 h. After the reaction was complete (monitored by TLC), 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 vacuum to give tert-butyl (3-((5-bromo-2-chloropyrimidine-4-yl)amino)phenyl)carbamate (129) (3.5 g; yield: 39.98%), LCMS: [M+H].+ 399.48.

[1028] Step 2: Synthesis of tert-butyl (3-((2-chloro-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)carbamate (130):

[1029] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (130) (1.4 g; yield: 35.12%). LCMS: [M+H] + 465.38.

[1030] 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):

[1031] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (132) (600 mg; yield: 37.54%). LCMS: [M+H] + 559.17.

[1032] 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):

[1033] The title compound was prepared in a manner substantially similar to that described in General Procedure I, yielding the desired product (133) (320 mg, yield: 65.04%). MS: [M+H] + 460.48.

[1034] 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):

[1035] The title compound was prepared in a manner substantially similar to that described in General Procedure J. The final compound was purified by preparative HPLC to give the desired product compound 53 (35 mg, yield: 18.86%) as a white solid. 1H-NMR (400MHz, DMSO-d6): δ10.25(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=15.2Hz,1H),3.79(s,2H),3.65(s,3H),2.67(s,6H). LCMS:[M+H] + 571.12.

[1036] 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):

[1037]

[1038] Step 1: Synthesis of tert-butyl (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)carbamate (134):

[1039] Potassium carbonate (6.63 g, 48.16 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (7) (5.16 g, 24.038 mmol) were added to a solution of tert-butyl (3-aminophenyl)carbamate (84) (5.0 g, 24.038 mmol) in N,N-dimethylformamide (50 mL) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with ice-cold water (200 mL). The resulting solid precipitate was filtered and dried under vacuum 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.

[1040] 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):

[1041] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (135) (400 mg; yield: 32.25%), MS: [M+H]. + 484.24.

[1042] Step 3: Synthesis of N4-(3-aminophenyl)-N2-(3-chloro-1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (136):

[1043] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (136) (310 mg; yield: 97.12%), LCMS: [M+H]. + 384.11.

[1044] 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):

[1045] The title compound was prepared in a manner substantially similar to that described in General Procedure J, and after preparative HPLC purification, the desired product compound 54 (40 mg, yield: 15.56%) was obtained as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.22(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=14.8Hz,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.

[1046] 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):

[1047]

[1048] Step 1: Synthesis of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (137):

[1049] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired product (137) as a pale yellow solid (yield: 70%), LCMS: [M+H].+ 407.90.

[1050] 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)

[1051] The title compound was prepared in a manner substantially similar to that described in general procedure M3, yielding the desired product (139) as a red solid. LCMS: [M+H] + 492.50

[1052] 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)

[1053] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding the desired product (140) as a pale yellow solid. LCMS: [M+H] + 462.0

[1054] 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)

[1055] The title compound was prepared in a manner substantially similar to that described in General Procedure K, yielding the desired product as a grayish-white solid. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.19 (s, 1H), 9.08 (bs, 1H), 8.19 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 5.6Hz, 1H), 7.63 (d, J = 6.8Hz, 1H), 7.55 (bs, 1H), 7.25 (bs, 2H), 7.13–7.11 (m, 2H), 6.92 (d, J = 8.8Hz, 1H), 6.42–6.36 (m, 1H), 6.24–6.20 (m, 1H), 5.74 (d, J = 11.6Hz, 1H), 3.70 (s, 3H), 3.53–3.48 (m, 4H), 3.30 (4H, merged with DMSO water peak). LCMS: [M+H] + 516.0.

[1056] Table 6: Preparation of the following compounds using the procedure described above:

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065] 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):

[1066]

[1067] 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)

[1068] The title compound was prepared in a manner substantially similar to that described in general procedure M3, yielding the desired product (141) as a grayish-white solid (0.4 g, 97% yield). LCMS: [M+H] + 474.1.

[1069] 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)

[1070] The title compound was prepared in a manner substantially similar to that described in General Procedure L1, yielding the desired product (142) (0.2 g, crude substance) as a brown liquid. LCMS: [M+H] + 444.2.

[1071] 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)

[1072] The title compound was prepared in a manner substantially similar to that described in General Procedure K, yielding a grayish-white solid (0.13 g, crude material). 1 H NMR (400MHz, DMSO-d6): δ10.22(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=10.0Hz,1H),3.53(s,3H). LCMS:[M+H] + 498.3.

[1073] Table 7: Preparation of the following compounds using the procedure described above:

[1074]

[1075]

[1076] 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):

[1077]

[1078] 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-carboxylic acid (144)

[1079] 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 eq., 1.03 mmol) were added to a stirred solution of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (137) (0.35 g, 0.85 mmol) in 1,4-dioxane (4.50 mL) and water (0.5 mL). The reaction mixture was then purged with nitrogen for 5 min, and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (0.7 g, 0.085 mmol) was added. The reaction mixture was heated at 100 °C for 16 h. The reaction progress was monitored by TLC / LCMS. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with water (25 mL × 2) and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography using a combiflash purifier and eluted with hexane containing 40–60% ethyl acetate to give the title compound (144) as a pale yellow solid. LCMS: [M + H] + 545.2.

[1080] 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-carboxylic acid (145)

[1081] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding the desired product (145) (0.2 g, crude matter) as a brown solid. LCMS: [M+H] + 515.2.

[1082] 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-carboxylic acid (146)

[1083] The title compound was prepared in a manner substantially similar to that described in General Procedure K, yielding the desired product (146) (0.19 g) as a white solid. LCMS: [M+H] + 569.3.

[1084] 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)

[1085] Trifluoroacetic acid (1.00 mL) was added to a stirred solution of 5-(4-{[2-fluoro-5-(prop-2-enamido)phenyl]amino}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-5-yl)-1H-indole-1-carboxylic acid tert-butyl ester (0.15 g, 0.264 mmol) in dichloromethane (10.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction progress 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 (400MHz, DMSO-d6): δ11.24(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=8.0Hz,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.

[1086] Table 8: Preparation of the following compounds using the procedure described above:

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096] 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):

[1097]

[1098] 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)

[1099] Cesium carbonate (599 mg, 1.84 mmol) and (pyridin-4-yl)boronic acid (147) (111 mg, 0.904 mmol) were added to a stirred solution of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (137) (300 mg, 0.73 mmol) in 1,4-dioxane (4.00 mL) and water (1.0 mL). The reaction mixture was then purged with nitrogen for 5 min, and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride (60.0 mg, 0.073 mmol) was added. The reaction mixture was heated at 100 °C for 16 h. The reaction progress 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) and brine (20 mL), dried over anhydrous sodium sulfate, and evaporated. The crude compound was purified by combiflash column chromatography using hexane containing 20% ​​ethyl acetate as eluent to give the title compound (155) (300 mg, 100%). LCMS: [M+H] + 407.0

[1100] 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)

[1101] The title compound was prepared in a manner substantially similar to that described in General Procedure L1, yielding the desired product (149) (0.22 g, crude matter) as a brown solid. LCMS: [M+H] + 377.

[1102] 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)

[1103] The title compound was prepared in a manner substantially similar to that described in General Procedure K, yielding a grayish-white solid (0.028 g, 12.24%). 1H NMR (400MHz, DMSO-d6): δ10.21(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,3 H),7.28(bs,2H),7.13-7.05(m,2H),6.42-6.35(m,1H),6.23(d,J=16.8Hz,1H),5.73(d,J=10.0Hz,1H),3.51(s,3H). LCMS:[M+H] + 431.2

[1104] Table 9: Preparation of the following compounds using the procedure described above:

[1105]

[1106]

[1107]

[1108]

[1109] Scheme 34: 4 Synthesis of N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (compound 151):

[1110]

[1111] Step 1: Synthesis of 5-bromo-2-chloro-4-(3-nitrophenoxy)pyrimidine (151)

[1112] Potassium carbonate (14.53 g, 105.31 mmol) was added 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), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and diluted with ice-cold water (250 mL). The precipitated solid was filtered off and washed with ice-cold water (2 × 100 mL). The solid was dried under vacuum to give the desired product (151) (25 g, yield: 86%) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6): δ8.94(s,1H),8.28(s,1H),8.21-8.23(m,1H),7.78-7.830(m,2H). LCMS:[M+H]+ 330.22.

[1113] Step 2: Synthesis of 5-bromo-N-(1-methyl-1H-pyrazol-4-yl)-4-(3-nitrophenoxy)pyrimidine-2-amine (152)

[1114] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding the desired compound as a yellow solid (5.0 g, yield: 30%). LCMS: [M+H] + 391.27.

[1115] Step 3: Synthesis of N-(1-methyl-1H-pyrazol-4-yl)-4-(3-nitrophenoxy)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2-amine (153):

[1116] The title compound was prepared in a manner substantially similar to that described in General Procedure M3, yielding the desired compound as a grayish-white solid (0.2 g, yield: 38%). LCMS: [M+H] + 457.13

[1117] Step 4: Synthesis of 4-(3-aminophenoxy)-N-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2-amine (154):

[1118] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding the desired compound as a grayish-white solid (0.12 g, yield: 65%). LCMS: [M+H] + 427.07

[1119] 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):

[1120] The title compound was prepared in a manner substantially similar to that described in General Procedure K, and after preparative HPLC purification, the desired compound (0.010 g, yield: 15%) was obtained as a grayish-white solid. 1H-NMR (400MHz, DMSO-d6): δ10.37(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=6.4Hz,1H),6.86(s,1H),6.39-6.46(m,1H),6.23-6.27(m,1H),5.75(d,J=10.0Hz,1H),3.51(s,3H). LCMS:[M+H] + 481.17

[1121] 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):

[1122]

[1123] Step 1: Synthesis of (6-bromo-3-chloropyrazine-2-yl) tert-butyl carbamate (156):

[1124] 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 to a solution of 6-bromo-3-chloropyrazine-2-amine (155) (500 mg, 2.40 mmol) in dichloromethane (10.0 mL) at room temperature. The resulting reaction mixture was stirred at the same temperature for 16 hours. After the reaction was complete (according to TLC monitoring), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (30 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by combiflash column chromatography, eluting with heptane containing 10-40% ethyl acetate to give tert-butyl (6-bromo-3-chloropyrazine-2-yl)carbamate (156) as a white solid (600 mg, yield: 81%). LCMS: [M-tBu+H] + 251.97.

[1125] Step 2: Synthesis of tert-butyl (3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)carbamate (157):

[1126] Cesium carbonate (845 mg, 2.59 mmol) was added to a solution of (6-bromo-3-chloropyrazin-2-yl)carbamate (156) (400 mg, 1.30 mmol) in 1,4-dioxane (10.0 mL). The reaction mixture was then purged with nitrogen for 15 min. 1-Methyl-1H-pyrazole-4-amine (22) (126 mg, 1.30 mmol), tris(diphenylmethyleneacetone)dipalladium (0) (119 mg, 0.130 mmol), and xanthphos (150 mg, 0.26 mmol) were added at room temperature. The resulting reaction mixture was heated at 120 °C for 16 h. After the reaction was complete (as monitored by TLC), the reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and washed with ethyl acetate (3 × 30 mL). The combined filtrates were 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.

[1127] Step 3: Synthesis of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (158):

[1128] The title compound was prepared in a manner substantially similar to that described in General Procedure H, yielding 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.

[1129] Step 4: Synthesis of 3-chloro-N2-(2-fluoro-5-nitrophenyl)-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (160)

[1130] Cesium carbonate (145 mg, 0.45 mmol) was added to a stirred solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrazin-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). The reactants were purged with nitrogen for 15 min, followed by the addition of tris(diphenylmethyleneacetone)dipalladium (0) (20.4 mg, 0.022 mmol) and [5-(diphenylphosphine)-9,9-dimethyl-9H-dibenzopyran-4-yl]diphenyl phosphate (25.8 mg, 0.044 mmol). The resulting reaction mixture was heated at 120 °C for 16 h. After the reaction was complete (according to TLC monitoring), the reaction solution was cooled to room temperature, poured into ice-cold water (50 mL), and extracted with ethyl acetate (2 × 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)pyrazin-2,6-diamine (160) (30.0 mg, yield: 13%) as a semi-solid. MS: [M+H] + 364.23.

[1131] Step 5: Synthesis of N2-(5-amino-2-fluorophenyl)-3-chloro-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (161):

[1132] The title compound was prepared in a manner substantially similar to that described in General Procedure L, yielding N2-(5-amino-2-fluorophenyl)-3-chloro-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (161) (60.0 mg, yield: 63%). MS: [M+H + 334.09.

[1133] 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):

[1134] The title compound was prepared by N2-(5-amino-2-fluorophenyl)-3-chloro-N6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2,6-diamine (161) and acryloyl chloride (18) in a manner substantially similar to that described in General Procedure J. After preparative HPLC purification, N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazine-2-yl)amino)-4-fluorophenyl)acrylamide compound 153 (8.0 mg, yield: 4.92%) was obtained as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.27(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=15.6Hz,1H),5.74(d,J=11.2Hz,1H),3.54(s,3H). LCMS:[M+H] + 388.21.

[1135] Scheme 36: Synthesis of N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 218):

[1136]

[1137] Step 1: Synthesis of tert-butyl (3-((6-bromo-3-chloropyrazine-2-yl)oxy)phenyl)carbamate (164):

[1138] Triethylamine (3.01 mL, 22.0 mmol) and 3,5-dibromo-2-chloropyrazine (162) (2.0 g, 7.34 mmol) were added to a stirred solution of tert-butyl (3-hydroxyphenyl)carbamate (163) (1.84 g, 8.81 mmol) in acetonitrile (10.0 mL) at room temperature. The reaction mixture was stirred at 85 °C for 16 h. After the starting material was exhausted (as monitored by TLC), 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 rapid column chromatography (heptane containing 5-25% ethyl acetate) to give tert-butyl (3-((6-bromo-3-chloropyrazine-2-yl)oxy)phenyl)carbamate (164) (1.90 g, yield: 64.57%) as a yellow solid. LCMS:[MH]- 397.97.

[1139] Step 2: Synthesis of tert-butyl (3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (165):

[1140] Cesium carbonate (2.20 g, 6.74 mmol) and (3-(((6-bromo-3-chloropyrazine-2-yl)oxy)phenyl)carbamate tert-butyl ester (164) (900 mg, 2.25 mmol) were added to a stirred solution of 1-methyl-1H-pyrazole-4-amine (22) (654 mg, 6.74 mmol) in toluene (10.0 mL). The resulting reaction mixture was purged with nitrogen for 20 min, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (367 mg, 0.449 mmol), and the reaction mixture was stirred at 110 °C for 20 h. After the reaction was complete (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth mat and concentrated under reduced pressure. The crude residue was dissolved 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%), a brown solid, which was used as is in the next step. MS: [M+H] + 417.28.

[1141] Step 3: Preparation of 6-(3-aminophenoxy)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (166):

[1142] The title compound was prepared by tert-butyl (3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (165) in a manner substantially similar to that described in General Procedure I, yielding 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.

[1143] Step 4: Synthesis of N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 154):

[1144] The title compound was prepared by 6-(3-aminophenoxy)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (166) and acryloyl chloride (18) in a manner substantially similar to that described in General Procedure J. After preparative HPLC purification, N-(3-((3-chloro-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide compound 154 (64.0 mg, yield: 7.81%) was given as a brown solid. 1 H-NMR (400MHz, DMSO-d6): δ10.38(s,1H),9.71(s,1H),7.67-7.61(m,3H),7.50(t,J=8.0Hz,1H),7.14(s,1H ),7.09-6.98(m,2H),6.39-6.45(m,1H),6.23(d,J=16.0Hz,1H),5.76(d,J=10.0Hz,1H),3.53(s,3H). LCMS:[M+H] + 371.18.

[1145] Scheme 37: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)-4-fluorophenyl)acrylamide (compound 155):

[1146]

[1147] Step 1: Synthesis of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (168):

[1148] At 0 °C, triethylamine (1.54 g, 15.2 mmol) and tert-butyl (3-amino-4-fluorophenyl)carbamate (83) (2.06 g, 9.11 mmol) were added to a stirred solution of 3,5,6-trichloro-1,2,4-triazine (167) (1.40 g, 7.59 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (according to TLC monitoring), 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-triazine-5-yl)amino)-4-fluorophenyl)carbamate (168) (1.70 g, yield: 13.2%) as a yellow solid, which was used as is in the next step. MS:[M+H] + 374.04.

[1149] Step 2: Synthesis of tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)-4-fluorophenyl)carbamate (169):

[1150] To a stirred solution of (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate tert-butyl ester (168) (1.10 g, 2.94 mmol) in isopropanol (3.0 mL), 1-methyl-1H-pyrazole-4-amine (22) (714 mg, 7.35 mmol) and camphor sulfonic acid (478 mg, 2.06 mmol) were added. The reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete (according to TLC monitoring), 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 (169g) (2.20g, yield: 44.13%), a viscous liquid. MS: [M+H]+435.53.

[1151] Step 3: Preparation of N5-(5-amino-2-fluorophenyl)-6-chloro-N3-(1-methyl-1H-pyrazole-4-yl)-1,2,4-triazine-3,5-diamine (170)

[1152] The title compound was prepared by tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)amino)-4-fluorophenyl)carbamate (169) in a manner substantially similar to that described in General Procedure I, yielding N5-(5-amino-2-fluorophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazin-3,5-diamine (170) (700 mg; yield: 20.58%) as a viscous liquid. MS: [M+H] + 335.12.

[1153] Step 4: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)-4-fluorophenyl)acrylamide (compound 155)

[1154] The title compound was prepared by 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) in a manner substantially similar to that described in General Procedure K. After preparative HPLC purification, N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)-4-fluorophenyl)acrylamide compound 155 (3.5 mg, yield: 5.29%) was given as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.34(s,1H),9.81-9.58(bs,2H),7.83(s,1H),7.66(s,1H),7.38(s,1 H), 7.20 (bs, 2H), 6.38-6.45 (m, 1H), 6.25 (d, J = 16.8Hz, 1H), 5.77 (d, J = 11.6Hz, 1H), 3.60 (s, 3H). LCMS:[M+H] + 389.21.

[1155] Scheme 38: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)phenyl)acrylamide (compound 156):

[1156]

[1157] Step 1: Synthesis of tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)carbamate (171):

[1158] Triethylamine (3.29 g, 32.5 mmol) and tert-butyl (3-aminophenyl)carbamate (7) (2.37 g, 11.4 mmol) were added to a solution of 3,5,6-trichloro-1,2,4-triazine (167) (3.0 g, 16.3 mmol) in dichloromethane (30.0 mL) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. After the reaction was complete (according to TLC monitoring), the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (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 product was purified by combiflash column chromatography (heptane containing 10-20% ethyl acetate) to give tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)carbamate (171) (2.0 g, yield: 34.51%), as a yellow solid. LCMS: [M+H] +356.09.

[1159] Step 2: Synthesis of tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)phenyl)carbamate (172):

[1160] To a stirred solution of (3-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)carbamate tert-butyl (171) (1.50 g, 4.21 mmol) in propan-2-ol (5.0 mL), 1-methyl-1H-pyrazole-4-amine (22) (1.02 g, 10.5 mmol) and camphorsulfonic acid (685 mg, 2.95 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete (according to TLC monitoring), 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 heptane containing 10-20% ethyl acetate 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) (700 mg, 1.68 mmol), a yellow solid. [M+H] + 417.49.

[1161] Step 3: Synthesis of N5-(3-aminophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (173):

[1162] The title compound was prepared by tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazole-4-yl)amino)-1,2,4-triazin-5-yl)amino)phenyl)carbamate (172) in a manner substantially similar to that described in General Procedure I, yielding N5-(3-aminophenyl)-6-chloro-N3-(1-methyl-1H-pyrazole-4-yl)-1,2,4-triazin-3,5-diamine (173) as a pale red solid (350 mg; yield: 76%). MS: [M+H] + 317.17.

[1163] Step 4: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)phenyl)acrylamide (compound 156):

[1164] The title compound was prepared by N5-(3-aminophenyl)-6-chloro-N3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3,5-diamine (173) and acryloyl chloride (18) in a manner substantially similar to that described in General Procedure K. After preparative HPLC purification, N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)amino)phenyl)acrylamide compound 156 (15.0 mg, yield: 4.21%) was given as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.26(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=16.8Hz,2.0Hz 1H), 5.75 (d, J = 10.4Hz, 1H), 3.63 (bs, 3H). LCMS:[M+H] + 371.15

[1165] 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):

[1166]

[1167] Step 1: Synthesis of tert-butyl (3-((3,6-dichloro-1,2,4-triazine-5-yl)oxy)phenyl)carbamate (174):

[1168] Triethylamine (1.44 g, 14.2 mmol) and tert-butyl (3-hydroxyphenyl)carbamate (163) (1.75 g, 8.34 mmol) were added to a stirred solution of 3,5,6-trichloro-1,2,4-triazine (177) (2.0 g, 10.8 mmol) in dichloromethane (30 mL) at 0 °C. The mixture was then heated to room temperature and stirred at the same temperature for 16 h. After the reaction was complete (according to TLC monitoring), water (50 mL) was added and the mixture was extracted with dichloromethane (5 × 50 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 heptane containing 5-10% ethyl acetate to give tert-butyl (3-((3,6-dichloro-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (174) (1.90 g; yield: 63.76%) as a white solid. LCMS: [MH] - 355.11.

[1169] Step 2: Synthesis of tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)oxy)phenyl)carbamate (175):

[1170] Cesium carbonate (1.37 g, 4.20 mmol) was added to a stirred solution of (3-((3,6-dichloro-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (174) (500 mg, 1.40 mmol) and 1-methyl-1H-pyrazole-4-amine (22) (136 mg, 1.40 mmol) in toluene (3.0 mL) at room temperature. The resulting reaction mixture was purged with nitrogen for 15 min, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (a complex with dichloromethane) (229 mg, 0.28 mmol). The resulting reaction mixture was heated at 110 °C for 16 h. After the reaction was complete (according to TLC monitoring), the reaction mixture was concentrated under reduced pressure. The crude product was dissolved 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 a yellow gel-like tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (175) (200 mg; yield: 34.19%). MS: [M+H + 418.32.

[1171] Step 3: Synthesis of 5-(3-aminophenoxy)-6-chloro-N-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3-amine (176):

[1172] The title compound was prepared by tert-butyl (3-((6-chloro-3-((1-methyl-1H-pyrazole-4-yl)amino)-1,2,4-triazin-5-yl)oxy)phenyl)carbamate (175) in a manner substantially similar to that described in General Procedure I, yielding 5-(3-aminophenoxy)-6-chloro-N-(1-methyl-1H-pyrazole-4-yl)-1,2,4-triazin-3-amine (176) as a brown solid (280 mg; yield: 28%). MS: [M+H] + 318.08.

[1173] Step 4: Synthesis of N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)oxy)phenyl)acrylamide (compound 157):

[1174] The title compound was prepared by 5-(3-aminophenoxy)-6-chloro-N-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazine-3-amine (176) and acryloyl chloride (18) in a manner substantially similar to that described in General Procedure K. After preparative HPLC purification, N-(3-((6-chloro-3-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-5-yl)oxy)phenyl)acrylamide compound 157 (20 mg, yield: 6.1%) was given as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.37-10.35(m,2H),7.70(s,1H),7.57(d,J=8.4Hz,1H),7.49-7.45(m,2H),7.41( s,1H),7.00(d,J=8.0Hz,1H),6.39-6.46(m,1H),6.24(d,J=16.8Hz,1H),5.77(d,J=10.0Hz,1H),3.64(s,3H). LCMS:[M+H] + 372.15

[1175] Scheme 40: Synthesis of N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 158):

[1176]

[1177] Step 1: Synthesis of tert-butyl (3-((6-chloro-3-methylpyrazin-2-yl)oxy)phenyl)carbamate (178)

[1178] At room temperature, cesium fluoride (2.80 g, 18.4 mmol) and tert-butyl (3-hydroxyphenyl)carbamate (163) (1.28 g, 6.13 mmol) were added to a solution of 3,5-dichloro-2-methylpyrazine (177) (1.00 g, 6.13 mmol) in dimethyl sulfoxide (10.0 mL). The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete (according to TLC monitoring), 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 column chromatography, eluting with heptane containing 15-25% ethyl acetate, to give tert-butyl (3-((6-chloro-3-methylpyrazin-2-yl)oxy)phenyl)carbamate (178) (1.90 g; yield: 82.08%) as a white solid. LCMS:[M+H] + 336.25

[1179] Step 2: Synthesis of tert-butyl (3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (179)

[1180] Cesium carbonate (4.37 g, 13.4 mmol) and (3-((6-chloro-3-methylpyrazin-2-yl)oxy)phenyl)carbamate tert-butyl ester (178) (1.50 g, 4.47 mmol) were added to a stirred solution of 1-methyl-1H-pyrazole-4-amine (22) (1.30 g, 3 eq, 13.4 mmol) in toluene (15.0 mL) at room temperature. The reaction mixture was degassed with nitrogen for 15 min, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (a complex with dichloromethane) (1.09 g, 1.34 mmol) at room temperature. The resulting reaction mixture was stirred at 110 °C for 16 h. After the reaction was complete (according to TLC monitoring), the reaction mixture was cooled at 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 obtain tert-butyl (3-((3-methyl-6-(((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (179 g) (1.00 g), a viscous liquid. MS: [M+H]+397.32.

[1181] Step 3: Synthesis of 6-(3-aminophenoxy)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (180)

[1182] The title compound was prepared by tert-butyl (3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)carbamate (179) in a manner substantially similar to that described in General Procedure I, yielding 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.

[1183] Step 4: Synthesis of N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide (compound 158)

[1184] The title compound was prepared by 6-(3-aminophenoxy)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (180) and acryloyl chloride (18) in a manner substantially similar to that described in General Procedure K. After preparative HPLC purification, N-(3-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazin-2-yl)oxy)phenyl)acrylamide compound 158 (76.0 mg, yield: 5.09%) was obtained as a light brown solid. 1 H-NMR (400MHz, DMSO-d6): δ10.33(s,1H),9.25(s,1H),7.70(s,1H),7.62(s,1H),7.58(d,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),7.12( s,1H),7.02(s,1H),6.92(d,J=6.4Hz,1H),6.38-6.45(m,1H),6.23(d,J=16.8Hz,1H),5.76(d,J=11.6,1H),3.52(s,3H),2.40(s,3H). LCMS:[M+H] + 351.18.

[1185] 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):

[1186]

[1187] Step 1: Synthesis of 2,5-dichloro-4-(2-fluoro-5-nitrophenyl)pyrimidine (182)

[1188] 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-dioxoboronylcyclopentane (181) (0.52 g, 1.96 mmol) and sodium carbonate (0.34 g, 3.27 mmol) were added and the mixture was purged with nitrogen for 5 min. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (a complex with dichloromethane) (0.067 g, 0.081 mmol) was added, and the mixture was stirred at 90 °C for 2 h. The reaction progress was monitored by LCMS. After the reaction was complete, 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 using a combiflash purifier and eluted with hexane containing 1-5% ethyl acetate to give the title compound (182) (0.5 g, 90%) as a grayish-white solid. LCMS: [M+H] + 288.0

[1189] Step 2: Synthesis of 5-chloro-4-(2-fluoro-5-nitrophenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (183)

[1190] 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-pyrazole-4-amine (22) (0.118 g, 1.22 mmol) and N,N-diisopropylethylamine (0.43 mL, 2.43 mmol) were added and the mixture was stirred in a sealed tube at 100 °C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by combiflash column chromatography, eluting with dichloromethane containing 5–7% methanol, to give the title compound (183) (0.36 g, 84%). LCMS: [M+H] + 349.1

[1191] Step 3: Synthesis of 4-(5-amino-2-fluorophenyl)-5-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2-amine (184):

[1192] Zinc (0.34 g, 5.16 mmol) and ammonium chloride (0.27 g, 5.16 mmol) were added 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) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth 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 a combiflash purifier and eluted with dichloromethane containing 4–6% methanol to give the title compound (184) (0.2 g, 60.7%) as a pale reddish-brown colloidal solid. 1 H NMR (400MHz, DMSO-d6) δ9.66(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.

[1193] 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)

[1194] A solution of triethylamine (0.088 mL, 0.63 mmol) and prop-2-acryloyl chloride (0.031 g, 0.314 mmol) in dichloromethane (10.0 mL) was added 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 (2 mL) at -30 °C. The reaction was then monitored by TLC. After the reaction was complete, 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 dichloromethane containing 2–4% methanol to give the crude product. The crude material was purified by preparative HPLC to obtain the title compound (0.038 g, 33.1%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.55(s,1H),7.94(s,2H),7.82(s,1H),7.73(s,1H),7.45(s,1H),7.3 5-7.31(m,1H),6.43-6.36(m,1H),6.27-6.23(d,J=16.0Hz,1H),5.77-5.75(d,J=11.6Hz,1H),3.76(s,3H). LCMS:[M+H] + 372.9.

[1195] 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):

[1196]

[1197] The title compound (0.016 g; yield: 12%) was prepared as a yellow solid in a manner substantially similar to that described in General Procedure J. 1 H NMR (400MHz, DMSO-d6) δ10.57(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=15.2Hz,1H),3.93(s,2H),3.76(s,3H),2.78(s,6H). LCMS:[M+H] + 430.2.

[1198] 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):

[1199]

[1200] Step 1: Synthesis of tert-butyl (3-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-fluorophenyl)carbamate (185)

[1201] 5-Bromo-2,4-dichloropyrimidine (88) (1.00 g, 4.39 mmol), N-(3-amino-4-fluorophenyl)carbamate tert-butyl ester (83) (0.993 g, 4.39 mmol), N,N-dimethylformamide (10.0 mL), and dipotassium carbonate (1.21 g, 8.78 mmol) were added to a microwave-safe vial. The reaction mixture was heated in a microwave-safe environment at 100 °C for 1 hour. The reaction was monitored by TLC and LCMS. After the reaction was complete, 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) and water (20 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude residue was purified by a combiflash purifier using hexane containing 50% ethyl acetate to give the title compound (185) (1.1 g, crude substance) as a pale yellow solid. LCMS: [M+H] + 417.0

[1202] Step 2: Synthesis of N-[3-({5-bromo-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-4-fluorophenyl]tert-butyl carbamate (186)

[1203] Trifluoroacetic acid (0.1 mL) was added to a stirred solution of N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-4-fluorophenyl}carbamate tert-butyl ester (185) (1.00 g, 2.39 mmol) and 1-methyl-1H-pyrazole-4-amine (22) (0.233 g, 2.39 mmol) in propan-2-ol (10.0 mL). The reaction mixture was heated in a microwave at 90 °C for 30 min. The reaction mixture was evaporated under reduced pressure. The crude product was purified by a combiflash purifier using hexane containing 50% ethyl acetate as eluent to give the title compound (186) (0.75 g, 65%) as a brown solid. LCMS: [M+H] + 478.1

[1204] Step 3: Synthesis of N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(2-phenylethynyl)pyrimidin-4-yl}amino)phenyl]tert-butyl carbamate (188)

[1205] N-[3-({5-bromo-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)-4-fluorophenyl]carbamate tert-butyl ester (186) (0.6 g, 1.25 mmol), N,N-dimethylformamide (10.0 mL), and triethylamine (0.35 mL, 2.51 mmol) were added to a sealed tube. The reaction mixture was degassed with nitrogen for 10 min and then copper iodide (0.048 g, 0.25 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.088 g, 0.125 mmol), and acetylenebenzene (197) (0.19 g, 1.88 mmol) were added. The reaction mixture was heated at 85 °C for 9 h. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 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 gel column containing hexane with 60% ethyl acetate as the eluent to give the title compound (188) (0.4 g, crude product) as a yellow solid. LCMS: [M+H] + 500.3

[1206] Step 4: Synthesis of 2,2,2-trifluoro-N-[4-fluoro-3-({...

Claims

1. A compound of formula I: Formula I Or its pharmaceutically acceptable salt, wherein: R 1 -(C(R) 4 )2) n R 5 ; X is -NH; n is 0; R 5 For 0 or 1 R 5' Substituted phenyl; R 2 For being an R 7 And 0, 1 or 2 R 8 Substituted phenyl; and R 3 For 0, 1, 2 or 3 R 12 Substituted pyrazol group, Each R 5' It is independently methyl, ethyl, tert-butyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, fluorine, chlorine, hydroxyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, or trifluoromethyl; R 7 for ; R 8 It is fluorine; Y is -C(=O)-; R 9 R 9' and R 9'' It is hydrogen; R 10 It is hydrogen; and Each R 12 It can be methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholino, or cyclopropyl.

2. The compound of claim 1, wherein each R 5' It can be methyl, morpholino, fluorine, chlorine, methoxy, fluoromethyl, difluoromethyl, or trifluoromethyl independently.

3. The compound of claim 1, wherein R 2 By 1 or 2 R 8 replace.

4. The compound of claim 1, wherein R 2 By 0 R 8 replace.

5. The compound of claim 1, wherein R 3 It has not been replaced.

6. The compound of claim 1, wherein R 3 At least 1 R 12 replace.

7. The compound of claim 6, wherein R 3 At least 2 Rs 12 replace.

8. The compound of claim 7, wherein each R 12 It can be methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chlorine independently.

9. The compound of claim 8, wherein each R 12 It can be methyl or chlorine on its own.

10. The compound of claim 1, wherein R 5' It is fluoromethyl, difluoromethyl or trifluoromethyl.

11. The compound of claim 1, wherein R 12 It is a methyl group.

12. The compound of claim 1, wherein the compound has the formula IA: Formula IA; Or its pharmaceutically acceptable salt.

13. The compound of claim 1, wherein the compound has the formula IB: Formula IB; Or its pharmaceutically acceptable salt.

14. The compound of claim 1, wherein the compound has the formula C1: IC; Or its pharmaceutically acceptable salt.

15. The compound of claim 1, wherein the compound has formula ID: Formula ID; Or its pharmaceutically acceptable salt.

16. The compound of claim 1, wherein the compound has the formula IE: Formula IE; Or its pharmaceutically acceptable salt.

17. The compound of claim 1, wherein the compound has the formula IF: Formula IF; Or its pharmaceutically acceptable salt.

18. The compound of claim 1, wherein the compound has the formula IG: IG style; Or its pharmaceutically acceptable salt.

19. A compound selected from: Or its pharmaceutically acceptable salt.

20. The compound of claim 19, wherein the compound is: Or its pharmaceutically acceptable salt.

21. A pharmaceutical composition comprising the compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. Use of any compound of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a subject of need.

23. The use as described in claim 22, wherein the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, or lung cancer.

24. The use as described in claim 23, wherein the lung cancer is non-small cell lung cancer.

25. The use as claimed in claim 22, wherein the cancer of the subject comprises an EGFR mutation selected from: substitution in exon 18, deletion in exon 19, substitution in exon 20, insertion in exon 20, mutation in the extracellular domain, and substitution in exon 21.

26. The use as claimed in claim 25, wherein the EGFR mutation is selected from 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, 773insNPHEGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAHEGFR, M766_A767insAI EGFR and any combination thereof.

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