CN116685583A - Pyrimidine compounds, compositions and pharmaceutical uses thereof - Google Patents

Abstract

The present disclosure relates to a class of pyrimidine compounds, stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof. The disclosure also relates to a method for preparing the pyrimidine compounds, a pharmaceutical composition containing the pyrimidine compounds and medical application of the pyrimidine compounds.

Description

Pyrimidine compounds, compositions and pharmaceutical uses thereof

Cross reference

The present application claims U.S. provisional patent application No. 63/108,185 filed on 10/30/2020; U.S. provisional patent application Ser. No. 63/236,194, filed 8/23 at 2021; and U.S. provisional patent application No. 63/271,991, filed on 10/26 of 2021, each of which is incorporated herein by reference in its entirety.

Background

Lung cancer accounts for the largest number of cancer deaths, and approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). Development of targeted therapies for lung cancer has focused mainly on tumors that display specific oncogenic drivers, namely mutations in the Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK). Three generation Tyrosine Kinase Inhibitors (TKIs) have been developed for cancers with most frequently observed EGFR mutations, however, other oncogenic drivers in the EGFR family of receptor tyrosine kinases are less of a research and development concern, and several oncogenic drivers, including insertion in the exon 20 gene of EGFR, currently do not have approved therapeutic agents to treat their cancers.

Given that many patients with mutations in EGFR are unable to obtain clinical benefit from currently available therapies against these targets, there remains a significant unmet need for developing novel therapies for treating cancers associated with EGFR mutations.

Disclosure of Invention

In one aspect, provided herein is a compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

x is-NH-or-O-;

R ¹ is- (C (R) ⁴ ) ₂ ) _n R ⁵ Wherein R is ⁵ Unsubstituted or substituted by 1R ⁵ ' substitution;

n is 0, 1, 2 or 3;

each R ⁴ Independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl;

R ⁵ is C _4-10 Cycloalkyl, aryl or heteroaryl;

each R ⁵ ' is independently deuterium, aryl, heteroaryl, alkyl, C ₃ -C ₆ Cycloalkyl, 3-8 membered heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH ₂ 、-NHR ⁶ 、-N(CH ₃ )R ₆ 、-N(R ⁶ ) ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHR ⁶ 、-C(＝O)N(R ⁶ ) ₂ 、-NR ⁶ C(＝O)R ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ NH ₂ 、-S(＝O) ₂ NHR ⁶ 、-S(＝O) ₂ N(R ⁶ ) ₂ 、-S(＝O) ₂ Heteroaryl, alkoxy or haloalkoxy;

each R ⁶ Independently alkyl, aminoalkyl, cycloalkyl, aryl or heteroaryl;

R ² is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with at least one R ⁷ And 0, 1 or 2R ⁸ Substitution;

each R ⁷ Independently is

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

R ⁹ 、R ⁹ ' and R ⁹ "independently hydrogen, deuterium, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl) heterocycloalkyl;

R ¹⁰ hydrogen, alkyl, haloalkyl or cycloalkyl;

each R ⁸ Independently is aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹¹ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy;

each R ¹¹ Independently alkyl, cycloalkyl, aryl or heteroaryl;

R ³ is 0, 1, 2 or 3R ¹² Substituted heteroaryl;

each R ¹² Independently is aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N (R) ¹³ ) ₂ 、-S(＝O) ₂ NH ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or cycloalkyl, wherein each of said aryl, heteroaryl, heterocycloalkyl or cycloalkyl is independently unsubstituted or substituted with 0, 1 or 2R ¹⁴ Substitution;

each R ¹³ Independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;

each R ¹⁴ Independently deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹⁵ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy; and is also provided with

Each R ¹⁵ Independently is alkyl, cycloalkyl, aryl or heteroaryl.

In some embodiments, X is-NH-.

In some embodiments, n is 0.

In some embodiments, R ⁵ Is phenyl, naphthyl, anthryl, phenanthryl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl or C-linked indolyl; wherein R is ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Unsubstituted. In some embodiments, R ⁵ Is 1R ⁵ 'substitution'.

In some embodiments, each R ⁵ ' is independently alkyl, haloalkyl, 3-8 membered heterocycloalkyl, halo, cyano, hydroxy, -N (R) ⁶ ) ₂ 、-N(CH ₃ )R ₆ 、-C(＝O)NHR ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ NH ₂ An alkoxy group or a haloalkoxy group. In some embodiments, each R ⁵ ' is independently methyl, ethyl, t-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N (R) ⁶ ) ₂ 、-C(＝O)NHR ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ NH ₂ Methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy. In some embodiments, each R ⁵ ' is independently methyl, morpholinyl, fluoro, chloro, cyano, -C (=o) NHMe, -NHC (=o) Me, -S (=o) ₂ NH ₂ Methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.

In some embodiments, each R ⁶ Independently an alkyl or aryl group. In some embodiments, each R ⁶ Independently methyl, ethyl, isopropyl, tert-butyl, phenyl or naphthyl. In some embodiments, each R ⁶ Independently isMethyl or phenyl.

In some embodiments, R ² Is monocyclic. In some embodiments, R ² Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is phenyl, cyclohexyl or pyrrolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is 1R ⁷ Substituted and not by R ⁸ And (3) substitution. In some embodiments, R ² Is 1R ⁷ And 1R ⁸ And (3) substitution. In some embodiments, R ² Is 1R ⁷ And 2R ⁸ And (3) substitution.

In some embodiments, R ² Is 1R ⁷ And (3) substitution.

In some embodiments, R ⁷ Is thatIn some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->

In some embodiments, Y is-C (=o) -. In some embodiments, Y is-S (=o) ₂ -。

In some embodiments, R ⁹ 、R ⁹ And R is ⁹ "independently is hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl) heterocycloalkyl. In some embodiments, R ⁹ 、R ⁹ And R is ⁹ "independently is hydrogen, fluorine, chlorine, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. In some embodiments, R ⁹ And R is ⁹ ' is independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl or (alkyl) heterocycloalkyl. In some embodiments, R ⁹ And R is ⁹ ' is independently hydrogen, fluorine, chlorine, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl.

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

In some embodiments, R ² Is not R ⁸ And (3) substitution. In some embodiments, R ² Is covered by 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is 1R ⁸ And (3) substitution. In some embodiments, R ² Is covered by 2R ⁸ And (3) substitution. In some embodiments, each R ⁸ Independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chloro, heteroalkyl, cyano, hydroxy, amino, -N (R) ¹¹ ) ₂ Methoxy, ethoxy or trifluoromethoxy. In some embodiments, each R ⁸ Independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, -N (R) ¹¹ ) ₂ Hydroxyethyl, methoxyethyl or cyano.

In some embodiments, each R ¹¹ Independently an alkyl or aryl group. In some embodiments, each R ¹¹ Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl or phenanthrenyl. In some embodiments, each R ¹¹ Independently methyl, ethyl, isopropyl, tert-butyl, phenyl or naphthyl. In some embodiments, each R ¹¹ Independently methyl or phenyl.

In some embodiments, R ³ Is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or naphthyridinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is imidazolyl, pyrazolyl, triazolyl, indolyl, indazolyl, thiazolyl, isothiazolyl or pyridyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution.

In some embodiments, R ³ The method comprises the following steps:

wherein R is ³ Is 0 to 3R ¹² And (3) substitution.

In some embodiments, R ³ The method comprises the following steps:

in some embodiments, R ³ The method comprises the following steps:

in some embodiments, R ³ Unsubstituted. In some embodiments, R ³ Is at least 1R ¹² And (3) substitution. In some embodiments, R ³ Is at least 2R ¹² And (3) substitution.

In some embodiments, each R ¹² Independently is aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, heterocycloalkyl, -N (R) ¹³ ) ₂ 、-S(＝O) ₂ NH ₂ 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, fluoro, chloro, cyano, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -N (R) ¹³ ) ₂ Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, each R ¹² Independently is methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl or cyclopropyl. In some embodiments, each R ¹² Independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl or chlorine. In some embodiments, each R ¹² Independently methyl or chloro.

In some embodiments, each R ¹³ Independently alkyl or cycloalkyl. In some embodiments, each R ¹³ Independently methyl, ethyl, n-propyl, isopropyl, n-butyl,Isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, each R ¹³ Independently methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl or cyclohexyl. In some embodiments, each R ¹³ Independently methyl, cyclopropyl or cyclohexyl.

In some embodiments, R ¹² Is unsubstituted. In some embodiments, R ¹² Aryl, heteroaryl, heterocycloalkyl or cycloalkyl of (2) are substituted by 1 or 2R ¹⁴ And (3) substitution.

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

In some embodiments, each R ¹⁵ Independently alkyl or cycloalkyl. In some embodiments, each R ¹⁵ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, each R ¹³ Independently methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl or cyclohexyl. In some embodiments, each R ¹³ Independently methyl, cyclopropyl or cyclohexyl.

In some embodiments:

x is-NH-or-O-;

n is 0;

R ⁵ is 0 or 1R ⁵ ' substituted phenyl;

R ² is at least one R ⁷ And 0, 1 or 2R ⁸ A substituted phenyl group; and is also provided with

R ³ Is 0, 1, 2 or 3R ¹² Substituted pyrazolyl.

In some embodiments, X is-NH-.

In some embodiments, R ⁵ ' is fluoromethyl, difluoromethyl or trifluoromethyl.

In some embodiments:

R ⁷ is thatAnd is also provided with

R ⁸ Is halo.

In some embodiments:

R ⁸ is fluorine;

y is-C (=O) -;

R ⁹ and R is ⁹ ' is hydrogen; and is also provided with

R ¹⁰ Is hydrogen.

In some embodiments, R ¹² Is alkyl.

In some embodiments, R ¹² Is methyl.

In some embodiments, the compound has formula I-A, formula I-B, formula I-C, formula I-D, formula I-E, formula I-F, or formula I-G:

Or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula I-a:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula I-a: />Or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula I-B:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compounds of formula I-B, wherein R ¹ Is R ⁵ . In some embodiments of the compounds of formula I-B, R ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments of the compounds of formula I-B, R ⁵ Unsubstituted. In some embodiments of the compounds of formula I-B, R ⁵ Is 1R ⁵ 'substitution'.

In some embodiments, the compound has the formula I-C:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compounds of formula I-B, wherein R ¹ Is R ⁵ . In some embodiments of the compounds of formula I-C, R ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments of the compounds of formula I-C, R ⁵ Unsubstituted. In some embodiments of the compounds of formula I-C, R ⁵ Is 1R ⁵ 'substitution'.

In some embodiments, the compound has the formula I-D: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula I-D: />Or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula I-E:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula I-E: />Or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has the formula I-F:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula I-F:or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has the formula I-G:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compounds of formulas I-G, wherein R ¹ Is R ⁵ . In some embodiments of the compounds of formulas I-G, R ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments of the compounds of formulas I-G, R ⁵ Unsubstituted. In some embodiments of the compounds of formulas I-G, R ⁵ Is 1R ⁵ ' getAnd (3) replacing.

In some embodiments, the compound is:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds described herein are selective inhibitors of EGFR but not HER 2.

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

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

In another aspect, provided herein is a method of inhibiting an Epidermal Growth Factor Receptor (EGFR) family kinase mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the EGFR family kinase mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR family kinase mutant is selected from del19/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, 773insNPH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dusv EGFR, 773insAH EGFR, M766_a767insAI, and any combination thereof.

In another aspect, provided herein is a method of inhibiting an Epidermal Growth Factor Receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the 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 EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof.

In another aspect, provided herein is a method of inhibiting a drug resistant Epidermal Growth Factor Receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the drug resistant EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR.

In another aspect, provided herein is a method of inhibiting Epidermal Growth Factor Receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound exhibits higher inhibition of EGFR mutants relative to wild-type EGFR.

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, L858 reffr, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR.

In another aspect, provided herein is a method of treating a disease or disorder associated with an Epidermal Growth Factor Receptor (EGFR) family kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. 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/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, 772insNP, 773insNPH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof.

In some embodiments, the disease or disorder of the subject comprises EGFR mutations. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR.

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

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

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 of the subject comprises EGFR mutations. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR.

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

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

In some embodiments, the inflammatory disease of the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR.

In another aspect, the present disclosure provides a compound, wherein the compound is:

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or a pharmaceutically acceptable salt or stereoisomer thereof.

The present disclosure discloses a process for preparing a compound of formula I or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, and to pharmaceutical compositions containing the same.

The compounds of the present disclosure may be useful in the treatment, prevention or suppression of diseases and conditions mediated by the Epidermal Growth Factor Receptor (EGFR).

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

Incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Detailed Description

Definition of the definition

Unless specifically stated otherwise, in the structural formulae given herein and throughout the present disclosure, the following terms have the indicated meanings.

As used herein, the term "optionally substituted" means that the group in question is 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 the same. 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 with one or more additional groups selected individually and independently from the following: halogen, -CN, -NH ₂ -NH (alkyl), -N (alkyl) ₂ 、-OH、-CO ₂ H、-CO ₂ Alkyl, -C (=o) NH ₂ -C (=o) NH (alkyl), -C (=o) N (alkyl) ₂ 、-S(＝O) ₂ NH ₂ 、-S(＝O) ₂ NH (alkyl), -S (=O) ₂ N (alkyl) ₂ Alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide,alkyl sulfones and aryl sulfones. In some other embodiments, the optional substituents are independently selected from: halogen, -CN, -NH ₂ 、-NH(CH ₃ )、-N(CH ₃ ) ₂ 、-OH、-CO ₂ H、-CO ₂ (C ₁ -C ₄ Alkyl), -C (=O) NH ₂ 、-C(＝O)NH(C ₁ -C ₄ Alkyl), -C (=O) N (C) ₁ -C ₄ Alkyl group ₂ 、-S(＝O) ₂ NH ₂ 、-S(＝O) ₂ NH(C ₁ -C ₄ Alkyl), -S (=o) ₂ N(C ₁ -C ₄ Alkyl group ₂ 、C ₁ -C ₄ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Fluoroalkyl, C ₁ -C ₄ Heteroalkyl, C ₁ -C ₄ Alkoxy, C1-C4 fluoroalkoxy, -SC ₁ -C ₄ Alkyl, -S (=o) C ₁ -C ₄ Alkyl and-S (=o) ₂ C ₁ -C ₄ An alkyl group. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH ₂ 、-OH、-NH(CH ₃ )、-N(CH ₃ ) ₂ 、-CH ₃ 、-CH ₂ CH ₃ 、-CHF ₂ 、-CF ₃ 、-OCH ₃ 、-OCHF ₂ and-OCF ₃ . In some embodiments, the substituted group is substituted with one or both of the previous groups. In some embodiments, the optional substituent on the aliphatic carbon atom (acyclic or cyclic) comprises an oxo (= O).

As used herein, C ₁ -C _x Comprises C ₁ -C ₂ 、C ₁ -C ₃ …C ₁ -C _x . By way of example only, designated as "C ₁ -C ₆ The group of "indicates that there are one to six carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C ₁ -C ₄ Alkyl "indicates the presence of one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

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

Unless otherwise mentioned, the term "cycloalkyl" refers to a carbocyclyl group of 3 to 6 carbon atoms having a single ring or multiple condensed rings or spiro or bridged rings. This definition encompasses saturated or partially unsaturated rings. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.

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

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 encompasses 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 ethenyl anthracene, ethenyl naphthalene, ethenyl phenanthrene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, obsidiene (pleiadene), pyrene, and benzophenanthrene. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "aryl-" (e.g., in "aralkyl") is intended to include optionally substituted aryl.

The term "phenyl" refers to an aromatic carbocyclyl group having 6 carbon atoms, which has a single ring.

The term "phenylalkyl" refers to a single radical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms, which is substituted with an aromatic carbocyclyl having 6 carbon atoms, the aromatic carbocyclyl having a single ring.

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 in at least one ring. "X-linked heteroaryl" refers to heteroaryl linked to the remainder of the molecule via an X atom. For example, the number of the cells to be processed,is N-linked imidazolyl, and +.>Is C-linked imidazolyl. />

Unless otherwise mentioned, the term "heterocycloalkyl" refers to a saturated, partially unsaturated or unsaturated group having a single ring or multiple condensed or spiro or bridged rings, having 2 to 10 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, sulfur, phosphorus and/or oxygen in the ring.

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

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

The term "amino" refers to-NH ₂ A group.

The term "cyano" refers to a-CN group.

The term "hydroxyl" refers to an-OH group.

The term "heteroalkyl" refers to an alkyl group as described above wherein one or more carbon atoms of the alkyl group are replaced with O, N or S atoms. Unless specifically stated otherwise in the specification, heteroalkyl groups are optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to, OCH ₂ CH ₂ OMe、-OCH ₂ CH ₂ OCH ₂ CH ₂ NH ₂ and-OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ N(Me) ₂ 。

"heterocycloalkyl" means cycloalkyl including at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidone, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidin-2, 5-disulphideAcyl, pyrrolidine-2, 5-dione, pyrrolidone, imidazolidine-2-one, or thiazolidine-2-one. In one aspect, heterocycloalkyl is C ₂ -C ₁₀ A heterocycloalkyl group. In another aspect, heterocycloalkyl is C ₄ -C ₁₀ A heterocycloalkyl group. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8 membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6 membered ring. In some embodiments, the heterocycloalkyl group is monocyclic and is a 3 or 4 membered ring. In some embodiments, heterocycloalkyl groups contain from 0 to 2N atoms in the ring. In some embodiments, heterocycloalkyl contains from 0 to 2N atoms, from 0 to 2O atoms, and from 0 to 1S atoms in the ring.

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

The term "aminoalkyl" refers to an alkyl group substituted with an amino (NH 2) group. In some embodiments, the aminoalkyl group is unsubstituted or substituted with an alkyl group on the nitrogen atom.

The term "alkoxy" refers to the group R-O-, wherein R is 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, and the like.

The compounds described herein include isotopically-labeled compounds, which are identical to those recited in the formulae and structures presented herein, but for the fact that one or more atoms By atoms of different atomic mass or mass number from those commonly found in nature. In some embodiments, the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, e.g. ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³⁵ S、 ¹⁸ F、 ³⁶ Cl、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹³¹ I、 ³² P and ³³ p. In one aspect, isotopically-labeled compounds described herein (e.g., wherein are incorporated, for example ³ H and ¹⁴ compounds of the radioisotope of C) are suitable for use in drug and/or substrate tissue distribution assays. In one aspect, substitution with an isotope such as deuterium results in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, the compounds described herein exist in the form of isotopic variants. In some embodiments, isotopic variants of the compounds described herein have one or more deuterium substituted hydrogen atoms.

In some embodiments, the compounds described herein contain one or more chiral centers and/or double bonds, and thus exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), regioisomers, enantiomers, or diastereomers. Thus, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as enantiomeric and stereoisomeric mixtures. In some embodiments, the enantiomeric and stereoisomeric mixtures 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 also exist in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.

In some embodiments, the compounds disclosed herein are in the form of a free base, salt, hydrate, isomer, diastereomer, prodrug (e.g., ester), metabolite, ion pair complex, or chelate. In some embodiments, the compounds exist in unsolvated forms as well as solvated forms (including hydrated forms and as N-oxide forms). In some embodiments, the compound is a hydrated, solvated, or N-oxide. Also encompassed within the scope of the present disclosure are analogs, hydrolysates, metabolites, and precursors or prodrugs of the compounds. In general, all physical forms are equivalent for the uses covered herein and are intended to be within the scope of this disclosure, unless otherwise specified.

"pharmaceutically acceptable salts" include salts with pharmaceutically acceptable acids or bases. Pharmaceutically acceptable acids include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic 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, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, or p-toluenesulfonic acid.

"pharmaceutical composition" refers to one or more active ingredients and one or more inert ingredients comprising a carrier, as well as any product that results, directly or indirectly, from the combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

"Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered. In some embodiments, such pharmaceutical carriers are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, water is the carrier when the pharmaceutical composition is administered orally. In some embodiments, when the pharmaceutical composition is administered intravenously, saline and aqueous dextrose are exemplary carriers. In some embodiments, aqueous saline and aqueous dextrose and glycerol solutions are used as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. In some embodiments, the composition comprises a small amount of a wetting or emulsifying agent, or a pH buffering agent. In some embodiments, these pharmaceutical compositions are in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. In some embodiments, the compositions are formulated as suppositories with conventional binders and carriers such as triglycerides. In some embodiments, the oral formulation comprises a carrier such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable drug carriers are described in "Remington' sPharmaceutical Sciences" of e.w. martin. Such compositions will contain a therapeutically effective amount of the therapeutic agent, for example in purified form, in combination with a suitable amount of carrier, so as to provide a form for appropriate administration to a patient. The formulation should meet the requirements of the mode of administration.

"combined" or "in combination" or "combination" is understood to mean a functional co-administration, covering the following cases: wherein the compounds are administered separately in different formulations, different modes of administration (e.g., subcutaneous, intravenous, or oral), and different times of administration. In some embodiments, the individual compounds of such combinations are administered sequentially in separate pharmaceutical compositions. In some embodiments, the individual compounds of such combinations are administered simultaneously in a combined pharmaceutical composition.

Compounds of formula (I)

In one aspect, provided herein is a compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

x is-NH-or-O-;

R ¹ is- (C (R) ⁴ ) ₂ ) _n R ⁵ Wherein R is ⁵ Is 0 or 1R ⁵ ' substitution;

n is 0, 1, 2 or 3;

each R ⁴ Independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl;

R ⁵ is C _4-10 Cycloalkyl, C-linked heterocycloalkyl, aryl, or heteroaryl;

each R ⁵ ' is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH ₂ 、-NHR ⁶ 、-N(R ⁶ ) ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHR ⁶ 、-C(＝O)N(R ⁶ ) ₂ 、-NR ⁶ C(＝O)R ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ NH ₂ 、-S(＝O) ₂ NHR ⁶ 、-S(＝O) ₂ N(R ⁶ ) ₂ 、-S(＝O) ₂ Heteroaryl groupAn alkoxy or haloalkoxy group;

Each R ⁶ Independently alkyl, cycloalkyl, aryl or heteroaryl;

R ² is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with at least one R ⁷ And 0, 1 or 2R ⁸ Substitution;

each R ⁷ Independently is

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

R ⁹ And R is ⁹ ' is independently hydrogen, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl) heterocycloalkyl;

R ¹⁰ hydrogen, alkyl, haloalkyl or cycloalkyl;

each R ⁸ Independently is aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹¹ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy;

each R ¹¹ Independently alkyl, cycloalkyl, aryl or heteroaryl;

R ³ is 0, 1, 2 or 3R ¹² Substituted heteroaryl;

each R ¹² Independently is aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N (R) ¹³ ) ₂ 、-S(＝O) ₂ NH ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or cycloalkyl, wherein each of said aryl, heteroaryl, heterocycloalkyl or cycloalkyl is independently unsubstituted or substituted with 0, 1 or 2R ¹⁴ Substitution;

each R ¹³ Independently alkyl, cycloalkyl, aryl or heteroaryl;

each R ¹⁴ Independently is aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹⁵ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy; and is also provided with

Each R ¹⁵ Independently alkyl, cycloalkyl, aryl or heteroaryl;

with the proviso that when X is-O-, R ⁵ Is not a C-linked heterocycloalkyl.

In one aspect, provided herein is a compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

x is-NH-or-O-;

R ¹ is- (C (R) ⁴ ) ₂ ) _n R ⁵ Wherein R is ⁵ Unsubstituted or substituted by 1R ⁵ ' substitution;

n is 0, 1, 2 or 3;

each R ⁴ Independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl;

R ⁵ is C _4-10 Cycloalkyl, aryl or heteroaryl;

each R ⁵ ' is independently deuterium, aryl, heteroaryl, alkyl, C ₃ -C ₆ Cycloalkyl, 3-8 membered heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH ₂ 、-NHR ⁶ 、-N(CH ₃ )R ₆ 、-N(R ⁶ ) ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHR ⁶ 、-C(＝O)N(R ⁶ ) ₂ 、-NR ⁶ C(＝O)R ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ NH ₂ 、-S(＝O) ₂ NHR ⁶ 、-S(＝O) ₂ N(R ⁶ ) ₂ 、-S(＝O) ₂ Heteroaryl, alkoxy or haloalkoxy;

each R ⁶ Independently alkyl, aminoalkyl, cycloalkyl, aryl or heteroaryl;

R ² Is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with at least one R ⁷ And 0, 1 or 2R ⁸ Substitution;

each R ⁷ Independently is

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

R ⁹ 、R ⁹ ' and R ⁹ "independently hydrogen, deuterium, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl) heterocycloalkyl;

R ¹⁰ hydrogen, alkyl, haloalkyl or cycloalkyl;

each R ⁸ Independently is aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹¹ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy;

each R ¹¹ Independently alkyl, cycloalkyl, aryl or heteroaryl;

R ³ is 0, 1, 2 or 3R ¹² Substituted heteroaryl;

each R ¹² Independently is aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N (R) ¹³ ) ₂ 、-S(＝O) ₂ NH ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or cycloalkyl, wherein each of said aryl, heteroaryl, heterocycloalkyl or cycloalkyl is independently unsubstituted or substituted with 0, 1 or 2R ¹⁴ Substitution;

each R ¹³ Independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;

Each R ¹⁴ Independently deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹⁵ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy; and is also provided with

Each R ¹⁵ Independently is alkyl, cycloalkyl, aryl or heteroaryl.

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

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

In some embodiments, R ⁵ Is phenyl, naphthyl, anthryl, phenanthryl, droyl, pyrenyl, C-linked bipyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl or C-linked indolyl; wherein R is ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is phenyl, naphthyl, anthryl, phenanthryl, C-linked bipyridyl and C-linked bipyridylA pyridyl, C-linked pyrazolyl or C-linked imidazolyl group; wherein R is ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is phenyl; wherein the phenyl group is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is naphthyl; wherein said naphthyl is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is anthryl; wherein said anthracenyl is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is phenanthryl; wherein the phenanthryl is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is a dropsy; wherein said yield is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is pyrenyl; wherein the pyrenyl group is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is a C-linked bipyridyl group; wherein the C-linked bipyridyl is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is C-linked pyrimidinyl; wherein said C-linked pyrimidinyl is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is C-linked pyrazolyl; wherein the C-linked pyrazolyl is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is C-linked imidazolyl; wherein the C-linked imidazolyl is substituted with 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Is C-linked indolyl; wherein the C-linked indolyl group is substituted with 0 or 1R ⁵ 'substitution'.

In some embodiments, R ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments, R ⁵ Unsubstituted. In some embodiments, R ⁵ Is 1R ⁵ 'substitution'.

In some embodiments, each R ⁴ Independently is hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl. In some embodiments, each R ⁴ Independently is hydrogen, alkyl, halo, haloalkyl or alkoxy. In some embodiments, each R ⁴ Independently 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 hydrogen, methyl, fluoro, trifluoromethyl, methoxy or trifluoromethoxy. In some embodiments, each R ⁴ Is hydrogen. In some embodiments, each R ⁴ Independently an alkyl group. In some embodiments, each R ⁴ Independently halo. In some embodiments, each R ⁴ Independently a haloalkyl group. In some embodiments, each R ⁴ Is hydroxyl. In some embodiments, each R ⁴ Independently an alkoxy group. In some embodiments, each R ⁴ Independently a heteroalkyl group. In some embodiments, each R ⁴ Is methyl. In some embodiments, each R ⁴ Is ethyl. In some embodiments, each R ⁴ Is n-propyl. In some embodiments, each R ⁴ Is isopropyl. In some embodiments, each R ⁴ Is n-butyl. In some embodiments, each R ⁴ Is isobutyl. In some embodiments, each R ⁴ Is sec-butyl. In some embodiments, each R ⁴ Is tert-butyl. In some embodiments, each R ⁴ Is fluorine. In some embodiments, each R ⁴ Is chlorine. In some embodiments, each R ⁴ Is trifluoromethyl. In some embodiments, each R ⁴ Is trifluoroethyl. In some embodiments, each R ⁴ Is pentafluoroethyl. In some embodiments, each R ⁴ Is methoxy. In some embodiments, each R ⁴ Is ethoxy. In some embodiments, each R ⁴ Is trifluoromethoxy.

In some embodiments, each R ⁵ ' is independently alkyl, haloalkyl, heterocycloalkyl, halo, cyano, hydroxy, -N (R) ⁶ ) ₂ 、-C(＝O)NHR ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ NH ₂ An alkoxy group or a haloalkoxy group. In some embodiments, each R ⁵ ' is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloHeteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ⁶ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy. In some embodiments, each R ⁵ Independently is aryl, heteroaryl, alkyl, heterocycloalkyl, halo, cyano, hydroxy, -N (R) ⁶ ) ₂ Or an alkoxy group. In some embodiments, each R ⁵ ' is independently aryl. In some embodiments, each R ⁵ ' is independently heteroaryl. In some embodiments, each R ⁵ ' is independently an alkyl group. In some embodiments, each R ⁵ ' is independently cycloalkyl. In some embodiments, each R ⁵ ' is independently heterocycloalkyl. In some embodiments, each R ⁵ ' is independently halo. In some embodiments, each R ⁵ ' is independently a heteroalkyl group. In some embodiments, each R ⁵ ' is independently haloalkyl. In some embodiments, each R ⁵ ' is cyano. In some embodiments, each R ⁵ ' is hydroxy. In some embodiments, each R ⁵ ' is an amino group. In some embodiments, each R ⁵ ' independently is-N (R) ⁶ ) ₂ . In some embodiments, each R ⁵ ' independently, -S (=o) ₂ An alkyl group. In some embodiments, each R ⁵ ' independently, -S (=o) ₂ Aryl groups. In some embodiments, each R ⁵ ' independently, -S (=o) ₂ Heteroaryl groups. In some embodiments, each R ⁵ ' is independently an alkoxy group. In some embodiments, each R ⁵ ' is independently phenyl, naphthyl, anthracenyl, phenanthrenyl, droyl, pyrenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, naphthyridinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butylGroup, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N (R) ⁶ ) ₂ Methoxy, ethoxy or trifluoromethoxy. In some embodiments, each R ⁵ ' is independently phenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, methyl, ethyl, t-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N (R) ⁶ ) ₂ Methoxy, ethoxy or trifluoromethoxy. In some embodiments, each R ⁵ ' is independently methyl, ethyl, t-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N (R) ⁶ ) ₂ 、-C(＝O)NHR ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ NH ₂ Methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy. In some embodiments, each R ⁵ ' is independently methyl, morpholinyl, fluoro, chloro, cyano, -C (=o) NHMe, -NHC (=o) Me, -S (=o) ₂ NH ₂ Methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy. In some embodiments, each R ⁵ ' is independently phenyl, imidazolyl, pyridyl, methyl, t-butyl, pyrrolidinyl, morpholinyl, fluoro, cyano, hydroxy, -N (R) ⁶ ) ₂ Or methoxy. In some embodiments, each R ⁵ ' is phenyl. In some embodiments, each R ⁵ ' is naphthyl. In some embodiments, each R ⁵ ' is anthryl. In some embodiments, each R ⁵ ' is phenanthryl. In some embodiments, each R ⁵ ' is a dropsy. In some embodiments, each R ⁵ ' is pyrenyl. In some embodiments, each R ⁵ ' is a pyrrolyl group. In some embodiments, each R ⁵ ' is imidazolyl. In some embodiments, each R ⁵ ' is pyrazolyl. In some embodiments of the present invention, in some embodiments,each R ⁵ ' is a triazolyl group. In some embodiments, each R ⁵ ' is tetrazolyl. In some embodiments, each R ⁵ ' is indolyl. In some embodiments, each R ⁵ ' is indazolyl. In some embodiments, each R ⁵ ' is benzimidazolyl. In some embodiments, each R ⁵ ' is azaindolyl. In some embodiments, each R ⁵ ' is thiazolyl. In some embodiments, each R ⁵ ' is isothiazolyl. In some embodiments, each R ⁵ ' is an oxazolyl group. In some embodiments, each R ⁵ ' is isoxazolyl. In some embodiments, each R ⁵ ' is pyridinyl. In some embodiments, each R ⁵ ' is pyrimidinyl. In some embodiments, each R ⁵ ' is a pyridazinyl group. In some embodiments, each R ⁵ ' is pyrazinyl. In some embodiments, each R ⁵ ' is triazinyl. In some embodiments, each R ⁵ ' is quinolinyl. In some embodiments, each R ⁵ ' is isoquinolinyl. In some embodiments, each R ⁵ ' is a quinoxalinyl group. In some embodiments, each R ⁵ ' is a quinazolinyl group. In some embodiments, each R ⁵ ' is cinnolinyl. In some embodiments, each R ⁵ ' is naphthyridinyl. In some embodiments, each R ⁵ ' is methyl. In some embodiments, each R ⁵ ' is ethyl. In some embodiments, each R ⁵ ' is n-propyl. In some embodiments, each R ⁵ ' is isopropyl. In some embodiments, each R ⁵ ' is n-butyl. In some embodiments, each R ⁵ ' is isobutyl. In some embodiments, each R ⁵ ' sec-butyl. In some embodiments, each R ⁵ ' is tert-butyl. In some embodiments, each R ⁵ ' is azetidinyl. In some embodiments, each R ⁵ ' is oxetanyl. In some embodiments, each R ⁵ ' is pyrrolidinyl. In some embodiments, each R ⁵ ' is an imidazolidinyl group. In some embodiments, each R ⁵ ' is tetrahydrofuranyl. In some embodiments, each R ⁵ ' is piperidinyl. In some embodiments, each R ⁵ ' is piperazinyl. In some embodiments, each R ⁵ ' is tetrahydropyranyl. In some embodiments, each R ⁵ ' is morpholinyl. In some embodiments, each R ⁵ ' is fluorine. In some embodiments, each R ⁵ ' is chlorine. In some embodiments, each R ⁵ ' is methoxy. In some embodiments, each R ⁵ ' is ethoxy. In some embodiments, each R ⁵ ' is trifluoromethoxy. In some embodiments, each R ⁵ ' is-C (=o) NHMe. In some embodiments, each R ⁵ ' is-NHC (=o) Me. In some embodiments, each R ⁵ ' is-S (=O) ₂ NH ₂ . In some embodiments, each R ⁵ ' is difluoromethoxy.

In some embodiments, each R ⁶ Independently is alkyl, cycloalkyl, aryl or heteroaryl. In some embodiments, each R ⁶ Independently an alkyl or aryl group. In some embodiments, each R ⁶ Independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthryl, phenanthryl, droyl or pyrenyl. In some embodiments, each R ⁶ Independently methyl, ethyl, isopropyl, tert-butyl, phenyl or naphthyl. In some embodiments, each R ⁶ Independently methyl or phenyl. In some embodiments, each R ⁶ Is methyl. In some embodiments, each R ⁶ Is ethyl. In some embodiments, each R ⁶ Is n-propyl. In some embodiments, each R ⁶ Is isopropyl. In some embodiments, each R ⁶ Is n-butyl. In some embodiments, each R ⁶ Is isobutyl. In some embodiments, each R ⁶ Is sec-butyl. In some embodiments, each R ⁶ Is tert-butyl. In some embodiments, eachR is a number of ⁶ Is phenyl. In some embodiments, each R ⁶ Is naphthyl. In some embodiments, each R ⁶ Is anthryl. In some embodiments, each R ⁶ Is phenanthryl. In some embodiments, each R ⁶ Is a dropsy. In some embodiments, each R ⁶ Is pyrenyl.

In some embodiments, R ² Is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is aryl, wherein R ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is heteroaryl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cycloalkyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a heterocycloalkyl group; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is monocyclic. In some embodiments, R ² Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is phenyl, cyclohexyl or pyrrolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is phenyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cyclopropyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cyclobutyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cyclopentyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cyclohexyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a pyrrole group; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is imidazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is pyrazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is triazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is tetrazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is thiazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is isothiazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is oxazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is isoxazolyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a pyridyl group; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is pyrimidinyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a pyridazinyl group; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is pyrazinyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is triazinyl; wherein R is ² Is at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R2 is substituted with at least one R ⁷ Substituted and not by R ⁸ And (3) substitution. In some embodiments, R2 is substituted with at least one R ⁷ Substituted and substituted by 1R ⁸ And (3) substitution. In some embodiments, R2 is substituted with at least one R ⁷ Substituted and substituted with 2R ⁸ And (3) substitution.

In some embodiments, R ² Is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is aryl, wherein R ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is heteroaryl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cycloalkyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a heterocycloalkyl group; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is monocyclic. In some embodiments, R ² Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is phenyl, cyclohexyl or pyrrolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is phenyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cyclopropyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some casesIn embodiments, R ² Is cyclobutyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cyclopentyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is cyclohexyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a pyrrole group; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is imidazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is pyrazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is triazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is tetrazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is thiazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is isothiazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is oxazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is isoxazolyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a pyridyl group; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is pyrimidinyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is a pyridazinyl group; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is pyrazinyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is triazinyl; wherein R is ² Is 1R ⁷ And 0, 1 or 2R ⁸ And (3) substitution. In some embodiments, R2 is substituted with 1R ⁷ Substituted and not by R ⁸ And (3) substitution. In some embodiments, R2 is substituted with 1R ⁷ Substituted and substituted by 1R ⁸ And (3) substitution. In some embodiments, R2 is substituted with 1R ⁷ Substituted and substituted with 2R ⁸ And (3) substitution.

In some embodiments, R ⁷ Is thatIn some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->

In some embodiments, Y is-C (=o) -. In some embodiments, Y is-S (=o) -. In some embodiments, Y is-S (=o) ₂ -。

In some embodiments, R ⁷ Is thatIn some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is thatIn some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is thatIn some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is thatIn some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is thatIn some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is->In some embodiments, R ⁷ Is that

In some embodiments, R ⁹ And R is ⁹ ' is independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl or (alkyl) heterocycloalkyl. In some embodiments, R ⁹ Is hydrogenHalo, alkyl, cycloalkyl or heteroalkyl. In some embodiments, R ⁹ Is hydrogen, halo or heteroalkyl. In some embodiments, R ⁹ And R is ⁹ ' is independently hydrogen, fluorine, chlorine, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. In some embodiments, R ⁹ Hydrogen, fluorine, chlorine, hydroxyethyl or methoxyethyl. In some embodiments, R ⁹ Is hydrogen. In some embodiments, R ⁹ Is fluorine. In some embodiments, R ⁹ Is chlorine. In some embodiments, R ⁹ Is hydroxyethyl. In some embodiments, R ⁹ Is methoxyethyl. In some embodiments, R ⁹ Is methyl. In some embodiments, R ⁹ Is methoxymethyl. In some embodiments, R ⁹ Is dimethylaminomethyl. In some embodiments, R ⁹ Is 1-piperidinylmethyl. In some embodiments, R ⁹ Is 1-morpholinomethyl. In some embodiments, R ⁹ Is a fluoromethyl group. In some embodiments, R ⁹ ' is hydrogen. In some embodiments, R ⁹ ' is fluorine. In some embodiments, R ⁹ ' is chlorine. In some embodiments, R ⁹ ' is hydroxyethyl. In some embodiments, R ⁹ ' is methoxyethyl. In some embodiments, R ⁹ ' is methyl. In some embodiments, R ⁹ ' is methoxymethyl. In some embodiments, R ⁹ ' is dimethylaminomethyl. In some embodiments, R ⁹ ' is 1-piperidinylmethyl. In some embodiments, R ⁹ ' is 1-morpholinomethyl. In some embodiments, R ⁹ ' is fluoromethyl.

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

In some embodiments, R ² Is not R ⁸ And (3) substitution. In some embodiments, R ² Is covered by 1 or 2R ⁸ And (3) substitution. In some embodiments, R ² Is 1R ⁸ And (3) substitution. In some embodiments, R ² Is covered by 2R ⁸ And (3) substitution.

In some embodiments, each R ⁸ Independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chloro, heteroalkyl, cyano, hydroxy, amino, -N (R) ¹¹ ) ₂ Methoxy, ethoxy or trifluoromethoxy. In some embodiments, each R ⁸ Independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, -N (R) ¹¹ ) ₂ Hydroxyethyl, methoxyethyl or cyano. In some embodiments, each R ⁸ Is methyl. In some embodiments, each R ⁸ Is ethyl. In some embodiments, each R ⁸ Is n-propyl. In some embodiments, each R ⁸ Is isopropyl. In some embodiments, each R ⁸ Is n-butyl. In some embodiments, each R ⁸ Is isobutyl. In some embodiments, each R ⁸ Is sec-butyl. In some embodiments, each R ⁸ Is tert-butyl. In some embodiments, each R ⁸ Is fluorine. In some embodiments, each R ⁸ Is chlorine. In some embodiments, each R ⁸ Independently is-N (R) ¹¹ ) ₂ . In some embodiments, each R ⁸ Is hydroxyethyl. In some embodiments, each R ⁸ Is methoxyethyl. In some embodiments, each R ⁸ Is cyano.

In some embodiments, each R ¹¹ Independently is alkyl, cycloalkyl, aryl or heteroaryl. In some embodiments, each R ¹¹ Independently an alkyl or aryl group. In some embodiments, each R ¹¹ Independently an alkyl group. In some embodiments, each R ¹¹ Independently cycloalkyl. In some embodiments, each R ¹¹ Independently an aryl group. In some embodiments, each R ¹¹ Independently heteroaryl. In some embodiments, each R ¹¹ Independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthryl, phenanthryl, droyl or pyrenyl. In some embodiments, each R ¹¹ Independently methyl, ethyl, isopropyl, tert-butyl, phenyl or naphthyl. In some embodiments, each R ¹¹ Independently methyl or phenyl. In some embodiments, each R ¹¹ Is methyl. In some embodiments, each R ¹¹ Is ethyl. In some embodiments, each R ¹¹ Is n-propyl. In some embodiments, each R ¹¹ Is isopropyl. In some embodiments, each R ¹¹ Is n-butyl. In some embodiments, each R ¹¹ Is isobutyl. In some embodiments, each R ¹¹ Is sec-butyl. In some embodiments, each R ¹¹ Is tert-butyl. In some embodiments, each R ¹¹ Is phenyl. In some embodiments, each R ¹¹ Is naphthyl. In some embodiments, each R ¹¹ Is anthryl. In some embodiments, each R ¹¹ Is phenanthryl. In some embodiments, each R ¹¹ Is a dropsy. In some embodiments, each R ¹¹ Is pyrenyl.

In some embodiments, R ³ Is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isothiazolyl, and pyrazinylQuinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is imidazolyl, pyrazolyl, triazolyl, indolyl, indazolyl, thiazolyl, isothiazolyl or pyridyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is a pyrrole group; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is imidazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is pyrazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is triazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is tetrazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is indolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is indazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is benzimidazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is azaindolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is thiazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is isothiazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is oxazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is isoxazolyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is a pyridyl group; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is pyrimidinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is a pyridazinyl group; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is pyrazinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is triazinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is quinolinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is isoquinolinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is a quinoxalinyl group; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is a quinazolinyl group; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is cinnolinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution. In some embodiments, R ³ Is naphthyridinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution.

In some embodiments, R ³ Unsubstituted. In some embodiments, R ³ Is at least 1R ¹² And (3) substitution. In some embodiments, R ³ Is at least 2R ¹² And (3) substitution. In some embodiments, R ³ Is 1R ¹² And (3) substitution. In some embodiments, R ³ Is covered by 2R ¹² And (3) substitution. In some embodiments, R ³ Is covered by 3R ¹² And (3) substitution.

In some embodiments, R ³ Is that/>Wherein R is ³ Is 0 to 3R ¹² And (3) substitution. In some embodiments, R ³ Is->

Wherein R is ³ Is covered by 1 or 2R ¹² And (3) substitution.

In some embodiments, R ³ The method comprises the following steps:

/>

in some embodiments, R ³ The method comprises the following steps:

/>

in some embodiments, R ³ The method comprises the following steps:

in some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments，R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments，R ³ Is thatIn some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->In some embodiments, R ³ Is->

In some embodiments, each R ¹² Independently is aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N (R) ¹³ ) ₂ 、-S(＝O) ₂ NH ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or cycloalkyl. In some embodiments, each R ¹² Independently is alkyl, heteroalkyl, haloalkyl, halo, cyano, heterocycloalkyl, -N (R) ¹³ ) ₂ Or cycloalkyl. In some embodiments, each R ¹² Independently an aryl group. In some embodiments, each R ¹² Independently heteroaryl. In some embodiments, each R ¹² Independently an alkyl group. In some embodiments, each R ¹² Independently a heteroalkyl group. In some embodiments, each R ¹² Independently a haloalkyl group. In some embodiments, each R ¹² Independently halo. In some embodiments, each R ¹² Is cyano. In some embodiments, each R ¹² Independently an alkoxy group. In some embodiments, each R ¹² Independently a heterocycloalkyl group. At the position ofIn some embodiments, each R ¹² Independently is-N (R) ¹³ ) ₂ . In some embodiments, each R ¹² Independently is-S (=o) ₂ NH ₂ . In some embodiments, each R ¹² Independently is-S (=o) ₂ An alkyl group. In some embodiments, each R ¹² Independently is-S (=o) ₂ Aryl groups. In some embodiments, each R ¹² Independently is-S (=o) ₂ Heteroaryl groups. 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, fluoro, chloro, cyano, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -N (R) ¹³ ) ₂ Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, each R ¹² Independently is methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl or cyclopropyl. In some embodiments, each R ¹² Independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl or chlorine. In some embodiments, each R ¹² Independently methyl or chloro. In some embodiments, each R ¹² Is methyl. In some embodiments, each R ¹² Is ethyl. In some embodiments, each R ¹² Is n-propyl. In some embodiments, each R ¹² Is isopropyl. In some embodiments, each R ¹² Is n-butyl. In some embodiments, each R ¹² Is isobutyl. In some embodiments, each R ¹² Is sec-butyl. In some embodiments, each R ¹² Is tert-butyl. In some embodiments, each R ¹² Is hydroxyethyl. In some embodiments, each R ¹² Is methoxyethyl. In some embodiments, each R ¹² Is three in threeFluoromethyl. In some embodiments, each R ¹² Is trifluoroethyl. In some embodiments, each R ¹² Is pentafluoroethyl. In some embodiments, each R ¹² Is fluorine. In some embodiments, each R ¹² Is chlorine. In some embodiments, each R ¹² Is azetidinyl. In some embodiments, each R ¹² Is oxetanyl. In some embodiments, each R ¹² Is pyrrolidinyl. In some embodiments, each R ¹² Is an imidazolidinyl group. In some embodiments, each R ¹² Is tetrahydrofuranyl. In some embodiments, each R ¹² Is piperidinyl. In some embodiments, each R ¹² Is piperazinyl. In some embodiments, each R ¹² Is tetrahydropyranyl. In some embodiments, each R ¹² Is morpholinyl. In some embodiments, each R ¹² Is cyclopropyl. In some embodiments, each R ¹² Is cyclobutyl. In some embodiments, each R ¹² Is cyclopentyl. In some embodiments, each R ¹² Is cyclohexyl.

In some embodiments, each R ¹³ Independently is alkyl, cycloalkyl, aryl or heteroaryl. In some embodiments, each R ¹³ Independently alkyl or cycloalkyl. In some embodiments, each R ¹³ Independently an alkyl group. In some embodiments, each R ¹³ Independently cycloalkyl. In some embodiments, each R ¹³ Independently an aryl group. In some embodiments, each R ¹³ Independently heteroaryl. In some embodiments, each R ¹³ Independently 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 methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl or cyclohexyl. In some embodiments, each R ¹³ Independently methyl, cyclopropyl or cyclohexyl. In some embodiments, eachR ¹³ Is methyl. In some embodiments, each R ¹³ Is ethyl. In some embodiments, each R ¹³ Is n-propyl. In some embodiments, each R ¹³ Is isopropyl. In some embodiments, each R ¹³ Is n-butyl. In some embodiments, each R ¹³ Is isobutyl. In some embodiments, each R ¹³ Is sec-butyl. In some embodiments, each R ¹³ Is tert-butyl. In some embodiments, each R ¹³ Is cyclopropyl. In some embodiments, each R ¹³ Is cyclobutyl. In some embodiments, each R ¹³ Is cyclopentyl. In some embodiments, each R ¹³ Is cyclohexyl.

In some embodiments, R ¹² Is unsubstituted. In some embodiments, R ¹² Aryl, heteroaryl, heterocycloalkyl or cycloalkyl of (2) are substituted by 1 or 2R ¹⁴ And (3) substitution. In some embodiments, R ¹² Aryl, heteroaryl, heterocycloalkyl or cycloalkyl of (1) are substituted by 1R ¹⁴ And (3) substitution. In some embodiments, R ¹² Aryl, heteroaryl, heterocycloalkyl or cycloalkyl of (2) are substituted by 2R ¹⁴ And (3) substitution.

In some embodiments, each R ¹⁴ Independently is aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹⁵ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy. In some embodiments, each R ¹⁴ Independently alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, -N (R) ¹⁵ ) ₂ Or an alkoxy group. In some embodiments, each R ¹⁴ Independently an aryl group. In some embodiments, each R ¹⁴ Independently heteroaryl. In some embodiments, each R ¹⁴ Independently an alkyl group. In some embodiments, each R ¹⁴ Independently cycloalkyl. In some embodiments, each R ¹⁴ Independently and separatelyIs a heterocycloalkyl group. In some embodiments, each R ¹⁴ Independently halo. In some embodiments, each R ¹⁴ Independently a heteroalkyl group. In some embodiments, each R ¹⁴ Independently a haloalkyl group. In some embodiments, each R ¹⁴ Is cyano. In some embodiments, each R ¹⁴ Is hydroxyl. In some embodiments, each R ¹⁴ Is amino. In some embodiments, each R ¹⁴ Independently is-N (R) ¹⁵ ) ₂ . In some embodiments, each R ¹⁴ Independently is-S (=o) ₂ An alkyl group. In some embodiments, each R ¹⁴ Independently is-S (=o) ₂ Aryl groups. In some embodiments, each R ¹⁴ Independently is-S (=o) ₂ Heteroaryl groups. In some embodiments, each R ¹⁴ Independently an alkoxy group. In some embodiments, each R ¹⁴ Independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, -N (R) ¹⁵ ) ₂ Methoxy, ethoxy or trifluoromethoxy. In some embodiments, each R ¹⁴ Independently methyl, ethyl, isopropyl, tert-butyl, pyrrolidinyl, piperidinyl, morpholinyl, fluoro, chloro, -N (R) ¹⁵ ) ₂ Or methoxy. In some embodiments, each R ¹⁴ Is methyl. In some embodiments, each R ¹⁴ Is ethyl. In some embodiments, each R ¹⁴ Is n-propyl. In some embodiments, each R ¹⁴ Is isopropyl. In some embodiments, each R ¹⁴ Is n-butyl. In some embodiments, each R ¹⁴ Is isobutyl. In some embodiments, each R ¹⁴ Is sec-butyl. In some embodiments, each R ¹⁴ Is tert-butyl. In some embodiments, each R ¹⁴ Is cyclopropyl. In some embodimentsEach R is ¹⁴ Is cyclobutyl. In some embodiments, each R ¹⁴ Is cyclopentyl. In some embodiments, each R ¹⁴ Is cyclohexyl. In some embodiments, each R ¹⁴ Is azetidinyl. In some embodiments, each R ¹⁴ Is oxetanyl. In some embodiments, each R ¹⁴ Is pyrrolidinyl. In some embodiments, each R ¹⁴ Is an imidazolidinyl group. In some embodiments, each R ¹⁴ Is tetrahydrofuranyl. In some embodiments, each R ¹⁴ Is piperidinyl. In some embodiments, each R ¹⁴ Is piperazinyl. In some embodiments, each R ¹⁴ Is tetrahydropyranyl. In some embodiments, each R ¹⁴ Is morpholinyl. In some embodiments, each R ¹⁴ Is fluorine. In some embodiments, each R ¹⁴ Is chlorine. In some embodiments, each R ¹⁴ Is methoxy. In some embodiments, each R ¹⁴ Is ethoxy. In some embodiments, each R ¹⁴ Is trifluoromethoxy.

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

In some embodiments:

x is-NH-or-O-;

n is 0;

R ⁵ is 0 or 1R ⁵ ' substituted phenyl;

R ² is at least one R ⁷ And 0, 1 or 2R ⁸ A substituted phenyl group; and is also provided with

R ³ Is 0, 1, 2 or 3R ¹² Substituted pyrazolyl.

In some embodiments, R ² Is 1R ⁷ And 0, 1 or 2R ⁸ A substituted phenyl group.

In some embodiments, X is-NH-.

In some embodiments, R ⁵ ' is fluoromethyl, difluoromethyl or trifluoromethyl.

In some embodiments:

R ⁷ is thatAnd is also provided with

R ⁸ Is halo.

In some embodiments:

R ⁸ is fluorine;

y is-C (=O) -;

R ⁹ and R is ⁹ ' is hydrogen; and is also provided with

R ¹⁰ Is hydrogen.

In some embodiments, R ¹² Is alkyl.

In some embodiments, R ¹² Is methyl.

In some embodiments, the compound has formula I-A, formula I-B, formula I-C, formula I-D, formula I-E, formula I-F, or formula I-G:

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Or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula I-a:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula I-a: />Or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula I-B:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compounds of formula I-B, wherein R ¹ Is R ⁵ . In some embodiments of the compounds of formula I-B, R ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments of the compounds of formula I-B, R ⁵ Unsubstituted. In some embodiments of the compounds of formula I-B, R ⁵ Is 1R ⁵ 'substitution'.

In some embodiments, the compound has the formula I-C:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compounds of formula I-B, wherein R ¹ Is R ⁵ . In some embodiments of the compounds of formula I-C, R ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments of the compounds of formula I-C, R ⁵ Unsubstituted. In the compounds of the formula I-CIn some embodiments, R ⁵ Is 1R ⁵ 'substitution'.

In some embodiments, the compound has the formula I-D: Or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula I-D:or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula I-E:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has formula I-E: />Or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has the formula I-F:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound has the formula I-F:or a pharmaceutically acceptable salt or stereoisomer thereof. />

In some embodiments, the compound has the formula I-G:or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compounds of formulas I-G, wherein R ¹ Is R ⁵ . In some embodiments of the compounds of formulas I-G, R ⁵ Is 0 or 1R ⁵ 'substitution'. In some embodiments of the compounds of formulas I-G, R ⁵ Unsubstituted. In some embodiments of the compounds of formulas I-G, R ⁵ Is 1R ⁵ 'substitution'.

In some embodiments, the compound of formula I is:

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or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

Particular embodiments of the present disclosure are compounds of formula I or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, selected from the group consisting of:

n- (3- ((5-chloro-2- ((1- (4-hydroxycyclohexyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 1),

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

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

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

(E) -N- (3- ((5-chloro-2- ((1- (4-hydroxycyclohexyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 5),

(E) -N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4-methoxybut-2-enamide (compound 6),

(E) -N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4-fluorobut-2-enamide (compound 7),

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

(E) -N- (4-chloro-3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (compound 9),

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

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

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

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

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

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

(E) -N- (3- ((5-chloro-2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 16),

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

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

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

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

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

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

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

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

1- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) -2-fluoroprop-2-en-1-one (compound 25),

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

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

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

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

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

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

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

(E) -N- (3- ((5- (benzylamino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (compound 33),

4- ((3-acrylamidophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) -N- (1-phenethyl) pyrimidine-5-carboxamide (compound 34),

(E) -4- ((3- (4- (dimethylamino) but-2-enamido) phenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) -N- (1-phenethyl) pyrimidine-5-carboxamide (compound 35),

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

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

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

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

N- (3- ((2- ((5-chlorothien-3-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide trifluoroacetate (compound 41),

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

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

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

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

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

N- (3- ((5- (1- (N-benzyl acetamido) ethyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 47),

N- (3- ((5- ((N-benzyl acetamido) methyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 48),

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

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

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

(E) -4- ((3- (4-dimethylamino) but-2-enamido) phenyl) amino (-2- ((2-methoxy-4- (piperidin-1-yl) phenyl) amino) -N-methyl-N-phenylpyrimidine-5-carboxamide (compound 52),

(E) -N- (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (compound 53),

(E) -N- (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (compound 54),

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

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 56),

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 57),

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

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

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

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

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

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

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

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

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (6-methylpyridin-3-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 66),

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (5-methylpyridin-3-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 67),

N- (4-fluoro-3- ((5- (2-methoxypyridin-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 68),

N- (4-fluoro-3- ((5- (5-fluoropyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 69),

N- (3- ((5- (6- (difluoromethoxy) pyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 70),

N- (3- ((5- (2- (difluoromethoxy) pyridin-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 71),

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

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

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

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

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),

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),

N- (4-fluoro-3- ((2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 78),

N- (4-fluoro-3- ((5- (2-methoxypyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 79),

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (2-methylpyridin-4-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 80),

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

N- (4-fluoro-3- ((5- (2-fluoropyridin-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 82),

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (2- (trifluoromethyl) pyridin-4-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 83),

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

N- (4-fluoro-3- ((2- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 85),

N- (4-fluoro-3- ((5- (6-methoxypyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 86),

N- (4-fluoro-3- ((2- ((3-fluoro-1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 87),

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

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

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

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

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

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

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

N- (3- ((5- (5- (difluoromethoxy) pyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 95),

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

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

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (1H-pyrazol-4-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 98),

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

N- (4-fluoro-3- ((5- (6-fluoropyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 100),

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

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

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

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

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

N- (3- ((5- (6- (difluoromethyl) pyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 106),

N- (3- ((5- (6- (dimethylamino) pyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 107),

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

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

N- (3- ((5- (5- (difluoromethyl) pyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 110),

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

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

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),

N- (4-fluoro-3- ((5- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 114),

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

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

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

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

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),

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

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

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

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

N- (3- ((5- (3, 6-dihydro-2H-pyran-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 124),

N- (3- ((5- (3- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 125),

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

N- (3- ((5- ([ 1,1' -biphenyl ] -4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 127),

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

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

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (2, 2-trifluoroethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide trifluoroacetate (compound 130),

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

N- (4-fluoro-3- ((5- (imidazo [1,2-a ] pyridin-7-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 132),

N- (4-fluoro-3- ((5- (imidazo [1,2-a ] pyridin-6-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide trifluoroacetate (compound 133),

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

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

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (naphthalen-1-yl) pyrimidin-4-yl) amino) phenyl) acrylamide trifluoroacetate (compound 136),

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

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

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

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

N- (4-fluoro-3- ((5- (5-methoxypyridin-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 141),

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

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

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),

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

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

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),

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (naphthalen-2-yl) pyrimidin-4-yl) amino) phenyl) acrylamide trifluoroacetate (compound 149),

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

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

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

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

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

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

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

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

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

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

(E) -N- (3- (5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 160),

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

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

4-acrylamido-2- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-phenylbenzamide (compound 163),

4-acrylamido-2- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-phenylbenzamide (compound 164),

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

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

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

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

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

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

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

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

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

(E) -N- (2- (((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) methyl) -3-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 174),

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

(E) -4- (dimethylamino) -N- (2- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) - [1,1' -biphenyl ] -4-yl) but-2-enamide (compound 176),

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

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

(E) -N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4- (phenylethynyl) phenyl) -4- (dimethylamino) but-2-enamide (compound 179),

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

N- (3- ((2- (Cyclobutylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 181),

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

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

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

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

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

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

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

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

N- (3- ((5- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) phenyl) acrylamide (compound 190),

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

N- (3- ((5- (3, 6-dihydro-2H-pyran-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) phenyl) acrylamide (compound 192),

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

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

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

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

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

N- (5-fluoro-4- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) pyridin-2-yl) acrylamide (compound 198),

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 199),

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

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

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

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

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

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

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

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

N- (3- ((5- (4-bromophenyl) -2- ((3-chloro-1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 208),

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

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

N- (4-fluoro-3- ((2- ((3-methylisothiazol-5-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 211),

N- (4-fluoro-3- ((2- ((5-methylisothiazol-3-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 212),

N- (4-fluoro-3- ((2- ((4-methylthiazol-2-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 213),

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

N- (4-fluoro-3- ((2- (thiazol-2-ylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 215),

N- (3- ((2- ((1- (3- (dimethylamino) propyl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 216),

N- (4-fluoro-3- ((2- ((5-methylthiophene-3-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 217),

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

N- (4-fluoro-3- ((2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 219),

N- (4-fluoro-3- ((2- ((1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 220),

N- (3- ((2- ((3-chloro-1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 221),

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

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

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

N- (4-fluoro-3- ((2- (isoxazol-4-ylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 225),

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

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

N- (4-fluoro-3- (methyl (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 228),

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

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

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

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

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

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

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

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

N- (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (3, 6-dihydro-2H-pyran-4-yl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 237),

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

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

N- (4-fluoro-3- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 240), N- (3- ((2- ((3-chloro-1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 241),

N- (4-fluoro-3- ((2- ((1- (methyl-d)) ₃ ) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl acrylamide (compound 242),

N- (4-fluoro-3- ((2- ((1- (methyl-)) ¹³ C-d ₃ ) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl acrylamide (compound 243),

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

N- (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -5-fluorophenyl) acrylamide (compound 245),

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

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide-3, 3-d ₂ (Compound 247),

N- (4-fluoro-3- ((2- ((1- (methyl-d)) ₃ ) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl acrylamide-3, 3-d ₂ (Compound 248),

N- (3- ((2- ((3-chloro-1-methyl-1)H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl acrylamide-3, 3-d ₂ (Compound 249),

N- (3- ((5- (4-bromophenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide-3, 3-d ₂ (Compound 250),

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

2-chloro-N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acetamide (compound 252),

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

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

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (tetrahydro-2H-pyran-4-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 255),

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

N ⁴ - (5-amino-2-fluorophenyl) -N ² - (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (compound 257),

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

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

N- (4-fluoro-3- ((5- (1-methyl-1H-indol-4-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 260),

N- (3- ((5- (2, 5-dihydrofuran-3-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 261),

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

N- (3- ((5- ([ 1,1' -biphenyl ] -2-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 263),

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

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

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

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

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

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

N- (4-fluoro-3- ((5- (1-methyl-1H-indazol-5-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 270),

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

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

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

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

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

N- (4-fluoro-3- ((5- (4- ((3-fluorobenzyl) oxy) phenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 276),

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

N- (3- ((5- ([ 1,2,4] triazolo [1,5-a ] pyridin-7-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 278),

N- (3- ((5- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 279),

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

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

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

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

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

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

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

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

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

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

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

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

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

N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (2, 2-trifluoroethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 293),

N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (1- (trifluoromethyl) cyclopropyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 294),

N- (3-fluoro-5- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (2, 2-trifluoroethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 295),

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

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

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

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

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

(E) -4- (dimethylamino) -N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (2, 2-trifluoroethyl) phenyl) pyrimidin-4-yl) amino) phenyl) but-2-enamide (compound 301),

N- (3-bromo-5- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (2, 2-trifluoroethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 302),

(E) -4-fluoro-N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (2, 2-trifluoroethyl) phenyl) pyrimidin-4-yl) amino) phenyl) but-2-enamide (compound 303),

(E) -N- (3- ((5- (4-bromophenyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 304), and

n- (4-fluoro-3- ((5- (3-fluoro-5-methoxyphenyl) -2- (methyl (1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 305).

One embodiment of the present disclosure relates to a compound of formula I, or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, for use in the treatment of diseases associated with Epidermal Growth Factor Receptor (EGFR) family kinases.

Another embodiment of the present disclosure relates to compounds of formula I or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, for use in the treatment of cancer.

Another embodiment of the present disclosure relates to compounds of formula I or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof for use in the treatment of diseases or conditions associated with non-small cell or small cell lung cancer or prostate cancer or head and neck cancer or breast cancer or colorectal cancer.

The present 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.

The present disclosure further relates to methods of preparing compounds of formula I or stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof.

In another aspect, the present disclosure provides a compound selected from the group consisting of:

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or a pharmaceutically acceptable salt or stereoisomer thereof.

Use of the same

Some embodiments provided herein describe a class of compounds useful as inhibitors of Epidermal Growth Factor Receptor (EGFR) family kinases. Some embodiments provided herein describe a class of compounds suitable for use as EGFR inhibitors. Some embodiments provided herein describe a class of compounds useful as EGFR del19/T790M inhibitors. Some embodiments provided herein describe a class of compounds useful as EGFR L858R/T790M inhibitors. In some embodiments, the compounds described herein have improved potency and/or beneficial activity profile and/or beneficial selectivity profile and/or increased potency and/or improved safety profile (e.g., reduced side effects) and/or improved pharmacokinetic profile. In some embodiments, the compounds described herein are selective inhibitors of EGFR del19/T790M but not WT EGFR. In some embodiments, the compounds described herein are selective inhibitors of EGFR L858R/T790M but not WT EGFR.

In some embodiments, the compounds described herein are selective inhibitors of EGFR but not HER 2.

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

In some embodiments, the compounds described herein are useful for treating, preventing, or ameliorating a disease or disorder that exhibits resistance associated with EGFR del19/T790M activation. In some embodiments, the compounds described herein are useful for treating, preventing, or ameliorating a disease or disorder that exhibits resistance associated with EGFR L858R/T790M activation.

In some embodiments, EGFR family kinase mutants are detected using commercially available test kits. In some embodiments, EGFR family kinase mutants are detected using a reverse transcription polymerase chain reaction (RT-PCR) based method. In some embodiments, EGFR family kinase mutants are detected using a sequencing-based method. In some embodiments, EGFR family kinase mutants are detected using a mass spectrometry based genotyping method. In some embodiments, EGFR family kinase mutants are detected using immunohistochemical-based methods. In some embodiments, EGFR family kinase mutants are detected using a molecular diagnostic set. 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, the EGFR family kinase mutant is detected from a tumor cell.

In one aspect, provided herein is a method of inhibiting an Epidermal Growth Factor Receptor (EGFR) family kinase mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In another aspect, provided herein is a method of inhibiting a human epidermal growth factor receptor 2 (HER 2) mutant in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. 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 the group consisting of 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.

In another aspect, provided herein is a method of inhibiting an Epidermal Growth Factor Receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In another aspect, provided herein is a method of inhibiting a drug resistant Epidermal Growth Factor Receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the drug resistant EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR.

In another aspect, provided herein is a method of inhibiting human epidermal growth factor receptor 2 (HER 2) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound exhibits higher inhibition of 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 the group consisting of 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.

In another aspect, provided herein is a method of inhibiting Epidermal Growth Factor Receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound exhibits higher inhibition of EGFR mutants relative to wild-type EGFR.

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, L858 reffr, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR. In some embodiments, the EGFR mutant is del19/T790M EGFR. In some embodiments, the EGFR mutant is L858R/T790M EGFR.

In another aspect, provided herein is a method of treating a disease or disorder associated with the Epidermal Growth Factor Receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the disease or disorder of the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from the group consisting of 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 is mutated to a775_g776insyvma. In some embodiments, the HER2 mutation is a775_g776inssvma. In some embodiments, the HER2 is mutated to a775_g776insvvma. In some embodiments, the HER2 is mutated to G776del insVC. In some embodiments, the HER2 is mutated to G776del insLC. In some embodiments, the HER2 is mutated to G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 is mutated to S310F. In some embodiments, the HER2 is mutated to S310Y. In some embodiments, the HER2 is mutated to p95. In some embodiments, the HER2 is mutated to V842I. In some embodiments, the HER2 is mutated to p780_y781insGSP.

In some embodiments, the disease or disorder of the subject comprises EGFR mutations. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR. In some embodiments, the EGFR mutation is del19/T790M EGFR. In some embodiments, the EGFR mutation is L858R/T790M EGFR.

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

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 a 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.

In some embodiments, the cancer of the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from the group consisting of 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 is mutated to a775_g776insyvma. In some embodiments, the HER2 mutation is a775_g776inssvma. In some embodiments, the HER2 is mutated to a775_g776insvvma. In some embodiments, the HER2 is mutated to G776del insVC. In some embodiments, the HER2 is mutated to G776del insLC. In some embodiments, the HER2 is mutated to G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 is mutated to S310F. In some embodiments, the HER2 is mutated to S310Y. In some embodiments, the HER2 is mutated to p95. In some embodiments, the HER2 is mutated to V842I. In some embodiments, the HER2 is mutated to p780_y781insGSP.

In some embodiments, the cancer of the subject comprises EGFR mutations. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR. In some embodiments, the EGFR mutation is del19/T790M EGFR. In some embodiments, the EGFR mutation is L858R/T790M EGFR.

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

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.

In some embodiments, the inflammatory disease of the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from the group consisting of 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 is mutated to a775_g776insyvma. In some embodiments, the HER2 mutation is a775_g776inssvma. In some embodiments, the HER2 is mutated to a775_g776insvvma. In some embodiments, the HER2 is mutated to G776del insVC. In some embodiments, the HER2 is mutated to G776del insLC. In some embodiments, the HER2 is mutated to G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 is mutated to S310F. In some embodiments, the HER2 is mutated to S310Y. In some embodiments, the HER2 is mutated to p95. In some embodiments, the HER2 is mutated to V842I. In some embodiments, the HER2 is mutated to p780_y781insGSP.

In some embodiments, the inflammatory disease of the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_n771insSVD EGFR), 770insNPG EGFR (or D770_n771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupasv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR. In some embodiments, the EGFR mutation is del19/T790M EGFR. In some embodiments, the EGFR mutation is L858R/T790M EGFR.

Administration and pharmaceutical compositions

In certain embodiments, the EGFR inhibiting compound as described herein is administered in pure chemical form. In other embodiments, the EGFR inhibitory compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of the route of administration selected and standard pharmaceutical practice, as described, for example, in Remington The Science and Practice of Pharmacy (Gennaro, 21 st edition, mack pub.co., easton, PA (2005)).

Provided herein is a pharmaceutical composition comprising at least one EGFR inhibiting compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject or patient) of the composition.

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.

In certain embodiments, the EGFR inhibiting compounds disclosed herein are substantially pure in that they contain less than about 5% or less than about 1% or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis byproducts produced in one or more steps of the synthesis process.

Suitable oral dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose or another suitable material which readily dissolves in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (see, e.g., remington: the Science and Practice of Pharmacy (Gennaro, 21 st edition, mack pub. Co., easton, PA (2005)).

The dosage of a composition comprising at least one EGFR inhibiting compound as described herein varies depending on the patient's condition (i.e., stage of the disease), general health, age, and other factors.

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, for example: patient condition, type and severity of patient disease, specific form of active ingredient and method of administration. Generally, the appropriate dosages and treatment regimens provide the compositions in amounts sufficient to provide a therapeutic and/or prophylactic benefit (e.g., improved clinical outcome) or reduce the severity of the symptoms. Experimental models and/or clinical trials are often used to determine the optimal dose. The optimal dose depends on the body mass, weight or blood volume of the patient.

The oral dosage is typically in the range of about 1.0mg to about 1000mg, once to four or more times a day.

Examples

Example 1: synthesis procedure

Yields reported herein refer to purified products (unless specified) and are not optimized. In Merck silica gel 60F ₂₅₄ Analytical TLC was performed on an aluminum backing plate. The compounds are visualized by UV light and/or staining with iodine, potassium permanganate or ninhydrin solution. Flash column chromatography is performed using silica gel (100-200M) or flash chromatography. Recording on a Bruker Avance-400 MHz spectrometer with BBO (broadband observational) and BBFO (broadband fluorine observational) probes ¹ H-NMR spectrum. Chemical shifts (δ) are expressed in parts per million (ppm) low fields with reference to Tetramethylsilane (TMS) as an internal standard. Split versions (splitting pattern) are expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and bs (broad singlet). The coupling constant (J) is given in hertz (Hz). LC-MS analysis was performed using electrospray ionization (ESI) techniques on either an acquisition BEH C-18 column (2.10X100 mm,1.70 μm) or an acquisition HSS-T3 column (2.10X100 mm,1.80 μm).

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

TLC thin layer chromatography

DCM dichloromethane

THF tetrahydrofuran

MeOH methanol

EtOH ethanol

IPA isopropyl alcohol

EtOAc ethyl acetate

Et ₂ O-diethyl ether

DMA N, N-dimethylacetamide

DMF N, N-dimethylformamide

TEA/Et ₃ N-triethylamine

DMSO dimethylformamide

DIPEA diisopropylethylamine (Hu Ningshi base (Hunig's base))

MeI methyl iodide

NBS N-bromosuccinimide

TBAB tetrabutylammonium bromide

TBAI tetrabutylammonium iodide

DIBAL-H diisobutylaluminum hydride

TFA trifluoroacetic acid

AcOH acetic acid

Boc t-Butoxycarbonyl group

Cat catalysis

mL of

mmol millimoles

h hours

min

g

mg

Mu l microliters

eq equivalent weight

RT or RT room temperature, ambient temperature, about 27 °c

MS mass spectrum

Boc t-Butoxycarbonyl group

m-CPBA m-chloroperoxybenzoic acid

T3P propane phosphonic acid anhydride

BH ₃ -DMS borane dimethyl sulfide complex

LiBH ₄ Lithium aluminum hydride

NaBH ₄ Sodium borohydride

H ₂ Hydrogen gas

Pd/C palladium/charcoal

1,2-DCE 1, 2-dichloroethane

General procedure a:

sodium hydride (60% dispersion in mineral oil, 3.0 eq) was added in portions to an ice-cold solution of arylamine (1.0 eq) in tetrahydrofuran. The resulting reaction mixture was stirred at room temperature for 30 minutes and then 2,4, 5-trichloropyrimidine or 2, 4-dichloro-5-bromopyrimidine (1.0 eq) was added. The resulting reaction mixture was heated at 60 ℃ for 16 hours. After completion (TLC monitoring), quench with ice and extract with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was wet-milled with diethyl ether, filtered and dried in vacuo to give the desired product.

General procedure B:

cesium carbonate (3.0 eq) and aryl amine (1.2 eq) were added to a solution of aryl halide (1.0 eq) in 1, 4-dioxane or toluene. The resulting reaction mixture was degassed under nitrogen for 15 minutes, followed by the addition of 2-dicyclohexylphosphino-2 ',4',6' -triisopropylbiphenyl (XPhos, 0.1 eq) and tris (dibenzylideneacetone) dipalladium (0) (0.1 eq) under nitrogen atmosphere. The resulting reaction mixture was again degassed for 15 minutes and then heated at 100 ℃ for 16 hours. After the reaction was completed (TLC monitoring), 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 material was purified by flash chromatography using 4-8% methanol in dichloromethane as eluent and the desired fractions were concentrated under reduced pressure to give the desired product.

General procedure C:

to an ice-cold solution of primary or secondary arylamine (1.0 eq) triethylamine (3.0 eq) and acetyl chloride (1.2 eq) were added dropwise. The resulting reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (TLC monitoring), 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 material was purified by combiflash, eluting with 4-5% methanol in dichloromethane, and concentrating the desired fractions under reduced pressure to give the desired product.

General procedure D:

to a solution of aldehyde (1.0 eq) in methanol was added 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 completed (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.

General procedure E:

to a solution of the product (1.0 eq) obtained from general procedure D in methanol (2.5 volumes) was added acetic acid (1.0 volumes), and then sodium borohydride (1.0 eq) was added. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (TLC monitoring), the reaction mixture was quenched with ice-cold water and the resulting solid was filtered and washed with water. The solid was dried under vacuum to give the desired product.

General procedure F:

diisopropylethylamine (4.0 eq) was added to an ice-cold solution of the product (1.0 eq) 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 completed (TLC monitoring), saturated sodium bicarbonate solution was added and extracted with dichloromethane (3 times). The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was wet-milled with diethyl ether to give the desired product.

General procedure G:

to an ice-cold solution of the product (1.0 eq) obtained from general procedure F in dichloromethane was added m-chloroperbenzoic acid (2.0 eq). The resulting reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed (TLC monitoring), 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. Wet milling the crude product with diethyl ether to give the desired product.

General procedure H:

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

General procedure I:

an ice-cold solution of the product obtained from general procedure H (1.0 eq) in dichloromethane with 20% trifluoroacetic acid was stirred at room temperature for 3-16 hours. After the reaction was completed (TLC monitoring), the solvent was evaporated. The reaction mass was diluted with saturated sodium bicarbonate solution and extracted with 5% methanol in dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over sodium sulfate and evaporated under reduced pressure. Wet milling the crude product with diethyl ether or purifying with combiflash, eluting with 5% -10% methanol in dichloromethane to give the desired product.

General procedure J:

to an ice-cold solution of the product (1.0 eq) obtained from general procedure I in dichloromethane was added triethylamine (3-5 eq) and the corresponding acid (1.1 eq) followed by propylphosphonic anhydride (T ₃ P,50% in ethyl acetate, 2.5 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed (TLC monitoring), the reaction mass was diluted with saturated sodium bicarbonate solution and extracted with 5% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by combflash or preparative TLC or preparative HPLC to give the final compound.

General procedure K:

a solution of the product (1.0 eq) obtained from general procedure I in dichloromethane: tetrahydrofuran (1:1) was cooled to-40℃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 completed (monitored by TLC), water was added 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 material was purified by preparative HPLC purification to give the final compound.

General procedure K ₁ ：

To a solution of the product (1.0 eq) obtained from general procedure I in tetrahydrofuran and water (3:1) at-0 ℃ was added triethylamine (5 eq) and acryloyl chloride (1.0 eq). The reaction mixture was stirred at the same temperature for 2 hours. After the reaction was completed (monitored by TLC), water was added and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC purification to give the final compound.

General procedure K ₂ ：

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

General procedure L:

zinc powder 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 completed (TLC monitoring), the reaction mixture was passed through a celite bed, washing with 5% methanol in dichloromethane. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the amino derivative.

General procedure L ₁ ：

To a solution of the nitro derivative (1.0 eq) in methanol or ethanol (10 vol) was added 10% palladium on carbon (20% w/w). The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. After the reaction was completed (TLC monitoring), the reaction mixture was filtered through celite bed and washed with methanol. The combined filtrates were concentrated under reduced pressure to give an amino derivative.

General procedure M ₁ : (bell wood coupling):

to a solution of the halo derivative (1.0 eq) in acetonitrile under argon purge was added the corresponding boric acid/ester derivative (1.0 eq) followed by the addition of an aqueous potassium carbonate solution (2.0 eq). The resulting reaction mixture was degassed for 15 minutes, then [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride dichloromethane complex (0.1 eq) was added, and the reaction mixture was heated at 80 ℃ for 16 hours. After the reaction was completed (TLC monitoring), 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, eluting with 40-60% ethyl acetate in hexane, and concentrating the desired fractions under reduced pressure to give the desired product.

General procedure M ₂ ：

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

General procedure M ₃ ：

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

General procedure N:

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

General procedure O:

to a solution of primary or secondary alcohol (1.0 eq) in dichloromethane under nitrogen atmosphere was added activated manganese dioxide (10 eq) at room temperature. The resulting reaction mixture was stirred at the same temperature for 16 hours. After the reaction was complete (TLC monitoring), the reaction mixture was filtered through celite 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.

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

Step 1: synthesis of 5- (hydroxymethyl) pyrimidine-2, 4 (1H, 3H) -dione (2):

pyrimidine 2,4- (1H, 3H) -dione (1) (10 g,89.21 mmol) and paraformaldehyde (9.63 g,107.05 mmol) were heated in an ice-cold solution of aqueous potassium hydroxide (132 mL,0.5M,66.74 mmol) at 55deg.C for 14 hours. After completion of the starting material (TLC), the reaction mixture was cooled to 0 ℃ and pH was adjusted to 6 with 12N hydrochloric acid, and 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 directly used in the next step. ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

Step 2: synthesis of 2, 4-dichloro-5- (chloromethyl) pyrimidine (3):

to an ice-cold solution of 5- (hydroxymethyl) pyrimidine-2, 4- (1H, 3H) -dione (2) (10 g,70.36 mmol) in toluene (25 mL) was added phosphorus oxychloride (14 mL,140.72 mmol) followed by N, N-diisopropylethylamine (37 mL,211 mmol). The reaction mixture was heated at 120 ℃ for 16 hours. After complete disappearance of starting material on TLC, the reaction mixture was quenched slowly 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,CDCl ₃ ):δ8.66(s,1H),4.64(s,2H)。MS:[M+H] ⁺ 197.0。

Step 3: synthesis of 2, 4-dichloro-5- (iodomethyl) pyrimidine (4):

to a solution of 2, 4-dichloro-5- (chloromethyl) pyrimidine (3) (8.0 g,40.51 mmol) in acetone (40 mL) was added sodium iodide (9.71 g,64.82 mmol). The reaction mixture was stirred at room temperature for 30min and heated to reflux for 2 hours. After the reaction was completed (TLC monitoring), 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,CDCl ₃ ):δ8.60(s,1H),4.39(s,2H)。

Step 4: synthesis of N- ((2, 4-dichloropyrimidin-5-yl) methyl) aniline (6):

to an ice-cold solution of 2, 4-dichloro-5- (iodomethyl) pyrimidine (4) (5.0 g,17.30 mmol) in acetone (50 mL) was added potassium carbonate (5.26 g,38.06 mmol) and aniline (5) (1.93 g,20.76 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed (monitored by TLC), the resulting white precipitate was filtered through a sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography (100-200 mesh) using 15% ethyl acetate-hexane as an eluent to give 6 (2.5 g, yield: 57%) as a brown solid. ¹ H-NMR(400MHz,CDCl ₃ ):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。

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

to an ice-cold solution of N- ((2, 4-dichloropyrimidin-5-yl) methyl) aniline (6) (500 mg,1.96 mmol) in isopropanol (5 mL) was added N, N-diisopropylethylamine (1.47 mL,8.42 mmol) and tert-butyl (3-aminophenyl) carbamate (7) (169 mg,1.96 mmol). The resulting reaction mixture was heated in a sealed tube at 100 ℃ for 16 hours. After the reaction was completed (TLC monitoring), the solvent was then evaporated under reduced pressure and the resulting crude material was purified by silica gel column chromatography (100-200 mesh) using 30% ethyl acetate in hexane as an eluent to give 8 (500 mg, yield: 60%) as a brown solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.41(s,1H),8.96(s,1H),8.10(s,1H),7.73(s,1H),7.25(m,2H),7.12(m,3H),6.61(m,3H),6.14(t,J＝7.2Hz,1H),4.26(m,2H),1.53(s,9H)。LCMS:[M+H] ⁺ 426.14。

Scheme 2: synthesis of 2- (4-amino-1H-pyrazol-1-yl) ethan-1-ol (11):

step 1: synthesis of 2- (4-nitro-1H-pyrazol-1-yl) ethan-1-ol (10)

To a stirred solution of 4-nitro-1-pyrazole (9) (2.00 g,17.7 mmol) in acetonitrile (20.0 mL) was added 2-bromoethyl-1-ol (1.38 mL,19.5 mmol), potassium carbonate (2.93 g,21.2 mmol), and the reaction mixture was heated at 80℃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 45% ethyl acetate in hexane to give the title compound (10) (2.5 g, 90%) as a white solid. LCMS [ M+H ] ] ⁺ 158.0。

Step 2: synthesis of 2- (4-amino-1H-pyrazol-1-yl) ethan-1-ol (11)

To 2- (4-nitro-1H-pyrazol-1-yl) ethan-1-ol (10)(2.50 g,15.9 mmol) in ethanol (20 mL) nitrogen for 5min, palladium on carbon (0.25 g,10% w/w) was added and the reaction mixture was hydrogenated for 15 h. The reaction mixture was filtered through celite and the filtrate was evaporated to give the title compound (11) (2.0 g, crude material) as a brown liquid. ¹ H NMR(400MHz,DMSO-d ₆ ):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)。

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):

step 1: synthesis of 2, 5-dichloro-N- (2-fluoro-5-nitrophenyl) pyrimidin-4-amine (14):

the title compound is prepared in a manner substantially similar to the procedure 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) pyrimidin-4-amine (14) (10.0 g, 34% yield) as a pale yellow solid. ¹ H-NMR(400MHz,CDCl ₃ ):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)。

Step 2: synthesis of 4- (4- ((5-chloro-4- ((2-fluoro-5-nitrophenyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) cyclohex-1-ol (16):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (16) (0.75 g, yield: 84.7%) as a pale yellow solid, MS: [ m+h ] ⁺ 448.21。

Step 3: synthesis of 4- (4- ((4- ((5-amino-2-fluorophenyl) amino) -5-chloropyrimidin-2-yl) amino) -1H-pyrazol-1-yl) cyclohex-1-ol (17):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (17) as a brown solid (0.55 g, yield: 78.57%). MS [ M+H ]] ⁺ 418.18。

Step 4: synthesis of N- (3- ((5-chloro-2- ((1- (4-hydroxycyclohexyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (Compound 1):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give compound 1 (45 mg, yield: 13.27%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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),7.08-7.13(m,2H),6.38-6.45(m,1H),6.24(d,J＝17.2Hz,1H),5.75(d,J＝10.4Hz,1H),4.62(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。

Table 1: the following compounds were prepared using the procedure described above:

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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):

step 1: 5-chloro-N4- (2-fluoro-5-nitrophenyl) -N2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (20)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (20) as a pale yellow solid (0.2 g, yield: 23％)，LCMS:[M+H] ⁺ 447.2。

Step 2: n4- (5-amino-2-fluorophenyl) -5-chloro-N2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (21)

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

Step 3: n- (3- ((5-chloro-2- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 14)

The title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give compound 14 (17 mg, yield: 14%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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＝15.2Hz,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。

Table 2: the following compounds were prepared using the procedure described above:

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):

step 1: synthesis of tert-butyl (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((phenylamino) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (23):

The title compound is prepared in a manner substantially similar to the procedure described in general procedure B. The crude material was purified by combiflash chromatography using 5% methanol in methylene chloride as an eluent, and the desired fraction was concentrated under reduced pressure to give tert-butyl (23) (500 mg; yield: 87%) of (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((phenylamino) methyl) pyrimidin-4-yl) amino) phenyl) carbamate as a light brown solid. MS [ M+H ]] ⁺ 487.25。

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

the title compound is prepared in a manner substantially similar to the procedure described in general procedure I. Wet milling of the crude material with diethyl ether afforded N4- (3-aminophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- ((phenylamino) methyl) pyrimidine-2, 4-diamine (24) as a brown solid. (0.50 g, yield: 84%) as TFA salt, MS: [ M+H] ⁺ 387.25。

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)

The title compound is prepared in a manner substantially similar to the procedure described in general procedure J. The crude material obtained was purified by combiflash eluting with 8% methanol in dichloromethane. The title compound was further purified by preparative HPLC to give (E) -N- (3- ((5-chloro-2- ((1- (4-hydroxycyclohexyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 17) as a white solid (66 mg; yield: 20.52%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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％)。

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):

step 1: synthesis of tert-butyl (3- ((2-chloro-5- ((N-phenylacetamido) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (26

The title compound is prepared in a manner substantially similar to the procedure described in general procedure C. The crude material was purified over silica gel (100-200 mesh) eluting with 3-5% methanol in dichloromethane and the desired fractions were concentrated to dryness to give tert-butyl (3- ((2-chloro-5- ((N-phenylacetamido) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (26) as a light brown solid. (300 mg, yield: 54.84%). MS [ M+H ]] ⁺ 468.06。

Step 2: synthesis of tert-butyl (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((N-phenylacetamido) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (27):

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

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

the title compound is prepared in a manner substantially similar to the procedure described in general procedure I. Wet milling of the crude material with diethyl ether gave N- ((4- ((3-aminophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) methyl) -N-phenylacetamide (28) as a brown solid. (130 mg, yield: 55.3%) as TFA salt, MS: [ M+H] ⁺ 429.25。

Step 4: synthesis of N- (3- ((5-chloro-2- ((1- (4-hydroxycyclohexyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (Compound 18):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give N- (3- ((5-chloro-2- ((1- (4-hydroxycyclohexyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 18) as a white solid (22 mg; yield: 15.0%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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

Scheme 7: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((N- (1-phenethyl) acetamido) methyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 19):

Step 1: synthesis of tert-butyl (E) - (3- ((2- (methylthio) -5- (((1-phenethyl) imino) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (31):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure D to give tert-butyl (E) - (3- ((2- (methylthio) -5- (((1-phenethyl) imino) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (31) as a light brown solid. (1.20 g, yield: 93.70%). MS [ M+H ]] ⁺ 464.31。

Step 2: synthesis of tert-butyl (3- ((2- (methylsulfanyl) -5- (((1-phenethyl) amino) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (32):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure E to give (3- ((2- (methylthio) -5- (((1-phenethyl) amino) methyl) pyrimidin-4-yl) amino) phenyl) as a pale yellow solid) Tert-butyl carbamate (32) (1.0 g, yield: 83%). MS [ M+H ]] ⁺ 466.25。

Step 3: synthesis of tert-butyl (3- ((2- (methylthio) -5- ((N- (1-phenethyl) acetamido) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (33):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure C. The crude material obtained was purified over silica gel (100-200 mesh) eluting with 4-5% methanol in dichloromethane and the desired fraction 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。

Step 4: synthesis of tert-butyl (3- ((2- (methylsulfonyl) -5- ((N- (1-phenethyl) acetamido) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (34):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure G to give tert-butyl (3- ((2- (methylsulfonyl) -5- ((N- (1-phenethyl) acetamido) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (34) as an off-white solid (400 mg; yield: 75%). MS [ M+H ]] ⁺ 540.15。

Step 5: synthesis of tert-butyl (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((N- (1-phenethyl) acetamido) methyl) pyrimidin-4-yl) amino) phenyl) carbamate (35):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give 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%) LCMS: [ M+H ]] ⁺ 557.31。

Step 6: synthesis of N- ((4- ((3-aminophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) methyl) -N- (1-phenethyl) acetamide (36):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure I to give N- ((4- ((3-aminophenyl) amino) -2- ((1-methyl) as a brown solid 1H-pyrazol-4-yl) amino) pyrimidin-5-yl methyl) -N- (1-phenethyl) acetamide (36). (150 mg; yield: 91.64%) as TFA salt, MS: [ M+H ]] ⁺ 457.25。

Step 7: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((N- (1-phenethyl) acetamido) methyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 19):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((N- (1-phenethyl) acetamido) methyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 19) as a white solid (30 mg; yield: 15.0%). ¹ H NMR(400MHz,DMSO d ₆ ):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),5-76-5.73(m,1H),5.25-5.23(m,1H),4.53-4.41(m,1H),4.25-4.15(m,1H),3.64(bs,3H),2.15(s,3H),1.61(d,J＝6.8Hz,3H)。LCMS:[M+H] ⁺ 511.37。

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):

step 1: synthesis of 2-fluoro-5-nitro-N-phenylaniline (38):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure B. The crude material was purified by combiflash chromatography using hexane containing 10-20% ethyl acetate as an eluent, and the desired fraction 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: [ M-H ] ^- 230.96。

Step 2: synthesis of 2, 5-dichloro-N- (2-fluoro-5-nitrophenyl) -N-phenylpyrimidin-4-amine (39):

to 2, 5-dichloro-N- (2-fluoro-5-nitrophenyl) pyrimidin-4-amine (38) (2.00 g,8.61 mmol) in N, N-dimethylformamide (20 mL)To the solution of (2.40 g,17.22 mmol) was added potassium carbonate and 2,4, 5-trichloropyrimidine (13) (1.60 g,8.61 mmol). The resulting reaction mixture was heated at 100 ℃ for 16 hours. After the reaction was completed (TLC monitoring), 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 material was purified by flash chromatography using 5-10% ethyl acetate in hexane as eluent, and the desired fraction was concentrated under reduced pressure to give 2, 5-dichloro-N- (2-fluoro-5-nitrophenyl) -N-phenylpyrimidin-4-amine (39) as a light brown solid (1.40 g; yield: 42.9%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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)。

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

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give 5-chloro-N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -N4-phenylpyrimidine-2, 4-diamine (40) as a light brown solid (550 mg; yield: 94.8%), MS: [ m+h ] ⁺ 440.17。

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

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give N4- (5-amino-2-fluorophenyl) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) -N4-phenylpyrimidine-2, 4-diamine (41) as a brown solid. (450 mg; yield: 88%). MS [ M+H ]] ⁺ 410.01。

Step 5: synthesis of N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) (phenyl) amino) -4-fluorophenyl) acrylamide (Compound 20):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidine-4 as a white solid-yl) (phenyl) amino) -4-fluorophenyl acrylamide (compound 20) (95 mg, yield: 33.56%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of 5-chloro-N4- (2-fluoro-5-nitrophenyl) -N2- (5- (methoxymethyl) -1-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamine (43)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give 5-chloro-N4- (2-fluoro-5-nitrophenyl) -N2- (5- (methoxymethyl) -1-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamine (43) as a light brown solid (500 mg; yield: 62.11%). LCMS [ M+H ]] ⁺ 407.97。

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

to a solution of 5-chloro-N4- (2-fluoro-5-nitrophenyl) -N2- (5- (methoxymethyl) -1-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamine (43) (250 mg,0.61 mmol) in methanol (15 mL) was added raney nickel (100 mg). The resulting reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed (TLC monitoring), the reaction mixture was filtered through celite bed and washed with 10% methanol in dichloromethane (3×5 mL). The combined organics 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。

Step 3: synthesis of N- (3- ((5-chloro-2- ((5- (methoxymethyl) -1-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (Compound 21):

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K, N4- (5-amino-2-fluorophenyl) -5-chloro-N2- (5- (methoxymethyl) -1-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamine (44) and acryloyl chloride (18) 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) as a white solid (45 mg, yield: 19.77%). ¹ H NMR(400MHz,DMSO-d ₆ ):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。

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

step 1: synthesis of N1- (2, 5-dichloropyrimidin-4-yl) -6-fluorobenzene-1, 3-diamine (46)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give N1- (2, 5-dichloropyrimidin-4-yl) -6-fluorobenzene-1, 3-diamine (46) (2.0 g; yield: 62.11%) as an off-white solid LCMS: [ m+h] ⁺ 272.88。

Step 2: synthesis of N- (3- ((2, 5-dichloropyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (47):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material obtained was purified by silica gel (100-200 mesh), eluting with 3-5% methanol in methylene chloride, and the desired fraction was concentrated under reduced pressure to give N- (3- ((2, 5-dichloropyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (47) as an off-white solid (800 mg, yield: 94.2%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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)。

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

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified over silica gel (100-200 mesh), eluted with 4-6% methanol in dichloromethane and the desired fractions were concentrated under reduced pressure. The resulting solid was again purified by preparative HPLC to give N- (3- ((5-chloro-2- ((6-methoxypyridin-3-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 22) as an off-white solid (30 mg, yield: 19.77%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of N- (3- ((2, 5-dichloropyrimidin-4-yl) amino) -4-fluorophenyl) -2-fluoroacrylamide (50):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure J. The crude material obtained was purified by combiflash, eluting with 10% methanol in dichloromethane, and the desired fraction was concentrated under reduced pressure to give N- (3- ((2, 5-dichloropyrimidin-4-yl) amino) -4-fluorophenyl) -2-fluoroacrylamide (50) as an off-white solid (350 mg; yield: 34%). MS [ M+H ] ] ⁺ 345.18

Step 2: synthesis of N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -2-fluoroacrylamide (compound 23):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. Crude material prepared byPLC purification to give N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -2-fluoroacrylamide (compound 23) as an off-white solid (55 mg, yield: 31.42%). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.46(s,1H),9.25(s,1H),8.95(s,1H),8.05(s,1H),7.85-7.74(m,2H),7.37(s,1H),7.11(m,1H),6.98(m,1H),5.78-5.65(m,1H),5.47-5.42(m,1H),3.52(s,3H)。LCMS:[M+H] ⁺ 405.82。

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):

step 1: synthesis of tert-butyl (3-aminocyclohexyl) carbamate (52):

to an ice-cold solution of cyclohexane-1, 3-diamine (51) (15.0 g,131.57 mmol) in chloroform (300 mL) was added dropwise di-tert-butyl dicarbonate (14.93 mL,65.78 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (TLC monitoring), water was added and 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 was purified by silica gel (100-200 mesh), eluted with 3-5% methanol in methylene chloride, and the desired fraction was concentrated under reduced pressure to give tert-butyl (3-aminocyclohexyl) carbamate (52) as a white solid (21.0 g; yield: 75%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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)。

Step 2: synthesis of tert-butyl (3- ((2, 5-dichloropyrimidin-4-yl) amino) cyclohexyl) carbamate (53):

to an ice-cold solution of tert-butyl (3-aminocyclohexyl) carbamate (52) (2.33 g,10.9 mmol) in ethanol (20 mL) was added N, N-diisopropylethylamine (9.5 mL,54.51 mmol) and 2,4, 5-trichloropyrimidine (13) (2.0 g,10.9 mmol). The resulting reaction mixture was heated at 90 ℃ for 16 hours. After completion of the reaction (TLC monitoring), useThe reaction mixture was extracted with ethyl acetate (3X 100 mL). The combined organics were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography using 30-50% ethyl acetate in hexane as eluent, and the desired fraction 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。

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

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by silica gel (100-200 mesh), eluting with 2-4% methanol in dichloromethane, and the desired fraction was concentrated under reduced pressure to give tert-butyl (54) (600 mg, yield: 85.83%) of (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) cyclohexyl) carbamate as a light brown solid, MS: [ M+H ] ⁺ 422.38。

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

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

Step 5: synthesis of N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) (phenyl) amino) -4-fluorophenyl) acrylamide (Compound 24):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure J. The crude material was purified by preparative HPLC to give N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) (phenyl) amino) -4-fluorophenyl) acrylamide (compound 24) as a white solid (35 mg; yield: 10%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

Table 3: the following compounds were prepared using the procedure described above:

scheme 13: synthesis of (E) -N- (3- ((5-chloro-2- ((3-methylisothiazol-5-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 27):

step 1: synthesis of 5-chloro-N4- (2-fluoro-5-nitrophenyl) -N2- (3-methylisothiazol-5-yl) pyrimidine-2, 4-diamine (57):

The title compound is prepared in a manner substantially similar to the procedure described in general procedure B. The crude material was purified by silica gel (100-200 mesh), eluting with 3-5% methanol in methylene chloride, and the desired fractions were concentrated to dryness to give 5-chloro-N4- (2-fluoro-5-nitrophenyl) -N2- (3-methylisothiazol-5-yl) pyrimidine-2, 4-diamine (57) (500 mg; yield: 79.74%) as a pale brown solid, MS: [ M+H] ⁺ 381.13。

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

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give N4- (5-amino-2-fluorophenyl) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (58) as a brown solid. (300 mg; yield: 65%), MS: [ M+H ]] ⁺ 350.94。

Step 3: synthesis of (E) -N- (3- ((5-chloro-2- ((3-methylisothiazol-5-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 27):

in a manner substantially similar to that described in general procedure JThe title compound was prepared. The crude product was purified by combiflash, eluting with 8% methanol in dichloromethane, concentrating the desired fractions under reduced pressure and purifying again using preparative HPLC to give (E) -N- (3- ((5-chloro-2- ((3-methylisothiazol-5-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -4- (dimethylamino) but-2-enamide (compound 27) as a white solid (20 mg, yield: 5.06%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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),6.69-6.76(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。

Scheme 14: synthesis of N- (4- ((3-acrylamidophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) benzamide (Compound 28):

step 1: synthesis of tert-butyl (3- ((2-chloro-5-nitropyrimidin-4-yl) amino) phenyl) carbamate (60):

to an ice-cold solution of tert-butyl (3-aminophenyl) carbamate (7) (5.0 g,26.04 mmol) in tetrahydrofuran (45 mL) was added N, N-diisopropylethylamine (9.3 mL,52.082 mmol) and 2, 4-dichloro-5-nitropyrimidine (59) (5.0 g,26.04 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (TLC monitoring), ice-cold water was added, the resulting solid precipitate was filtered and dried under vacuum to give the desired product (60) as a pale yellow solid (8.1 g, yield: 85.23%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

Step 2: synthesis of tert-butyl (3- ((5-amino-2-chloropyrimidin-4-yl) amino) phenyl) carbamate (61):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (61) as a brown solid (6.4 g, yield: 85%). LCMS: [ M ]H] ⁺ 336.11。

Step 3: synthesis of tert-butyl (3- ((5-benzoylamino-2-chloropyrimidin-4-yl) amino) phenyl) carbamate (63):

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

Step 4: synthesis of tert-butyl (3- ((5-benzoylamino-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) carbamate (64):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by combiflash chromatography eluting with 4% methanol in methylene chloride to give the desired product (64) as a brown solid (720 mg; yield: 57%). LCMS [ M+H ]] ⁺ 501.23。

Step 5: synthesis of N- (4- ((3-aminophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) benzamide (65).

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired product (65) as a brown solid (510 mg, yield: 91.01%). MS [ M+H ]] ⁺ 401.21。

Step 6: synthesis of N- (4- ((3-acrylamidophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) benzamide (Compound 28).

The title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by prep HPLC to give the desired product compound 28 as an off-white color(65 mg, yield: 19.12%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

Scheme 15: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (phenylsulfamido) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 29):

Step 1: synthesis of tert-butyl (3- ((2-chloro-5- (phenylsulfamido) pyrimidin-4-yl) amino) phenyl) carbamate (67):

to an ice-cold solution of tert-butyl (3- ((5-amino-2-chloropyrimidin-4-yl) amino) phenyl) carbamate (61) (1.0 g,2.98 mmol) in dichloromethane (15 mL) was added pyridine (0.69 mL,11.98 mmol) and benzenesulfonyl chloride (66) (525 mg,2.98 mmol) under a nitrogen atmosphere at the same temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction mixture (TLC monitoring), the reaction was 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) as a semisolid (700 mg, yield: 50%). LCMS [ M+H ]] ⁺ 476.11。

Step 2: synthesis of N- (4- ((3-aminophenyl) amino) -2-chloropyrimidin-5-yl) benzenesulfonamide (68):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired product (68) as a brown solid (480 mg, yield: 96%). LCMS [ M+H ]] ⁺ 376.11。

Step 3: synthesis of N- (3- ((2-chloro-5- (phenylsulfamido) pyrimidin-4-yl) amino) phenyl) acrylamide (69).

The title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by combiflash with 4% methanol Eluting with methylene chloride, provided the desired product (69) as a brown solid (340 mg, yield: 67%). MS [ M+H ]] ⁺ 430.07

Step 4: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (phenylsulfamido) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 29):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by preparative HPLC to give the desired product compound 29 as an off-white solid (10 mg, yield: 9%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

Table 4: the following compounds were prepared using the procedure described above:

scheme 16: synthesis of N- (3- ((5- (benzylamino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 32):

step 1: synthesis of tert-butyl (3- ((5- (benzylamino) -2-chloropyrimidin-4-yl) amino) phenyl) carbamate (71):

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

Step 2: synthesis of N- (3-aminophenyl) -N5-benzyl-2-chloropyrimidine-4, 5-diamine (72):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired product (72) as an off-white solid (820 mg, yield: 97%). MS [ M+H ]] ⁺ 326.17。

Step 3: synthesis of N- (3- ((5- (benzylamino) -2-chloropyrimidin-4-yl) amino) phenyl) acrylamide (73).

The title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude product was purified by combiflash eluting with 2% methanol in dichloromethane to give the desired product (73) as an off-white solid (260 mg; yield: 55.7%). MS [ M+H ]] ⁺ 380.13

Step 4: synthesis of N- (3- ((5- (benzylamino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 32)

The title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by preparative HPLC to give the desired product compound 32 (40 mg; yield: 14%) as a white solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

Step 1: synthesis of (E) -N- (3- ((5- (benzylamino) -2-chloropyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (74)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure J to give the desired product (74) as an off-white solid (210 mg; yield: 40%). MS [ M+H ]] ⁺ 437.17。

Step 2: (E) -N- (3- ((5- (benzylamino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (compound 33)

The title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by preparative HPLC to give the desired product compound 33 (35 mg; yield: 16%) as an off-white solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

Scheme 18: synthesis of 4- ((3-acrylamidophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) -N- (1-phenethyl) pyrimidine-5-carboxamide (Compound 34):

step 1: synthesis of ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2-chloropyrimidine-5-carboxylate (76):

to a solution of ethyl 2, 4-dichloropyrimidine-5-carboxylate (75) (3.0 g,13.56 mmol) in tetrahydrofuran (30 mL) was added N, N-diisopropylethylamine (4.82 mL,27.02 mmol) at room temperature ) And (3-aminophenyl) carbamic acid tert-butyl ester (7) (2.82 g,13.56 mmol). The resulting reaction mixture was heated at 100 ℃ for 4 hours. After the reaction was complete (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, 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。

Step 2: synthesis of 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2-chloropyrimidine-5-carboxylic acid (77):

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

Step 3: synthesis of tert-butyl (3- ((2-chloro-5- ((1-phenethyl) carbamoyl) pyrimidin-4-yl) amino) phenyl) carbamate (78):

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure J to give the desired product (78) as an off-white solid (800 mg; yield: 66.62%). MS [ M+H ]] ⁺ 468.17。

Step 4: synthesis of tert-butyl (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((1-phenethyl) carbamoyl) pyrimidin-4-yl) amino) phenyl) carbamate (79):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by combiflash, eluting with 2% methanol in methylene chloride, to give the desired product (79) as a semi-solid (600 mg; yield: 61.32%). LCMS [ M+H ]] ⁺ 529.16。

Step 5: synthesis of 4- ((3-aminophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) -N- (1-phenethyl) pyrimidine-5-carboxamide (80):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired product (80) as an off-white solid (430 mg, yield: 88.21%). LCMS [ M+H ]] ⁺ 429.21。

Step 6: synthesis of 4- ((3-acrylamidophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) -N- (1-phenethyl) pyrimidine-5-carboxamide (Compound 34):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give the desired product compound 34 (40 mg; yield: 14.21%) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):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,3H),7.21-7.24(m,2H),6.39-6.46(m,1H),6.22-6.26(m,1H),5.74(dd,J＝10.4&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。

Scheme 19: synthesis of (E) -4- ((3- (4- (dimethylamino) but-2-enamido) phenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) -N- (1-phenethyl) pyrimidine-5-carboxamide (Compound 35):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure J. The crude material was purified by preparative HPLC to give the desired product compound 35 (48 mg; yield: 15.23%) as an off-white solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of tert-butyl (4-fluoro-3-nitrophenyl) carbamate (82):

to a solution of 4-fluoro-3-nitroaniline (81) (10 g,64.102 mmol) in t-butanol (50 mL) was added boc anhydride (13.99 g,64.102 mmol) at room temperature. The resulting reaction was heated at 80 ℃ for 16 hours. After the reaction was completed (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with hexane and dried under vacuum to give the desired product (82) as a pale yellow solid (14 g; yield: 85.32%). ¹ H NMR(400MHz,DMSO-d ₆ ):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)。

Step 2: synthesis of tert-butyl (3-amino-4-fluorophenyl) carbamate (83):

to a solution of tert-butyl (4-fluoro-3-nitrophenyl) carbamate (82) (14 g,54.68 mmol) in ethanol (50 mL) was added 10% palladium on carbon (1.4 g,10% w/w). The resulting reaction was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete (TLC monitoring), 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) as an off-white solid (11 g; yield: 89.21%). ¹ HNMR(400MHz,DMSO-d ₆ ):δ9.01(bs,1H),6.60-7.20(m,3H),5.21(s,2H),1.49(s,9H)。LCMS:[M+1H] ⁺ 227.24。

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

the title compound is prepared in a manner substantially similar to the procedure described in general procedure a. The crude material was purified by combiflash, eluting with 70% ethyl acetate in hexane, to give the desired product (85) (600 mg; yield: 21.42%). MS [ M+H ]] ⁺ 407.08。

Step 4: synthesis of tert-butyl (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) carbamate (86):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by combiflash, eluting with 1% methanol in methylene chloride, to give (86) (300 mg; yield: 43.47%). MS [ M+H ]] ⁺ 468.17

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

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired product (87) (150 mg; yield: 63.24%). MS [ M+H ]] ⁺ 368.15

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

The title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give compound 36 as an off-white solid (20 mg; yield: 12.62%). ¹ H NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of 5-bromo-2-chloro-N- (2-fluoro-5-nitrophenyl) pyrimidin-4-amine (89):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure a. The crude material was purified by combiflash, eluting with 40% ethyl acetate in hexane, to give (89) as a pale yellow solid (1.3 g, yield: 44.24%). MS [ M ]+H] ⁺ 346.97。

Step 2: synthesis of 2-chloro-N- (2-fluoro-5-nitrophenyl) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-amine (91):

in a manner substantially similar to general procedure M ₃ The title compound was prepared by the procedure described in (i). The crude material was purified by combiflash, eluting with 35% ethyl acetate in hexane, to give the desired product (91) as a pale yellow solid (700 mg; yield: 50.12%). MS [ M+H ]] ⁺ 413.10

Step 3: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (92):

The title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The crude material was purified by combiflash eluting with 1% methanol in methylene chloride to give the desired product (92) as a pale yellow solid (500 mg; yield: 70.24%). MS [ M+H ]] ⁺ 474.09

Step 4: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (93):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give (93) as a semi-solid (350 mg; yield: 74.78%). MS [ M+H ]] ⁺ 444.11

Step 5: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 37):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give compound 37 as an off-white solid (30 mg, yield: 13.33%). ¹ H NMR(400MHz,DMSO-d ₆ ):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。

Table 5: the following compounds were prepared using the procedure described above:

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scheme 22: synthesis of N- (3- ((5- (1- (N-benzyl acetamido) ethyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 47):

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

A solution of tert-butyl (3- ((5-formyl-2- (methylsulfanyl) pyrimidin-4-yl) amino) phenyl) carbamate (29) (8.0 g,22.22 mmol) in tetrahydrofuran (150 mL) was cooled at-78deg.C followed by the addition of methylmagnesium bromide (3.0M in diethyl ether, 22.22mL,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 material was purified on silica gel (100-200 mesh), eluting with 40-50% ethyl acetate in hexane, and the desired fractions were concentrated to dryness to give tert-butyl (3- ((5- (1-hydroxyethyl) -2- (methylsulfanyl) pyrimidin-4-yl) amino) phenyl) carbamate (94) (4.0 g; yield: 48%) as an off-white solid. MS [ M+H ]] ⁺ 377.43。

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

based onThe title compound was prepared in this manner analogous to the procedure described in general procedure O, affording tert-butyl (3- ((5-acetyl-2- (methylthio) pyrimidin-4-yl) amino) phenyl) carbamate (95) (1.5 g; yield: 60%) as a light brown solid. MS [ M+H ] ] ⁺ 375.42。

Step 3: preparation of tert-butyl (E) - (3- ((5- (1- (benzylimino) ethyl) -2- (methylthio) pyrimidin-4-yl) amino) phenyl) carbamate (97):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure D to give the desired product (97) as an off-white solid (1.0 g; yield: 58%). MS [ M+H ]] ⁺ 464.25。

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

the title compound is prepared in a manner substantially similar to the procedure described in general procedure E. The crude material obtained was purified over silica gel (100-200 mesh), eluted with 4-5% methanol in methylene chloride, and the desired fraction was concentrated under reduced pressure to give tert-butyl (3- ((5- (1- (benzylamino) ethyl) -2- (methylsulfanyl) pyrimidin-4-yl) amino) phenyl) carbamate (98) (400 mg; yield: 40%) as a pale yellow solid. MS [ M+H ]] ⁺ 466.30。

Step 5: synthesis of tert-butyl (3- ((5- (1- (N-benzylacetamido) ethyl) -2- (methylthio) pyrimidin-4-yl) amino) phenyl) carbamate (99):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure C. The crude material was purified on silica gel (100-200 mesh) eluting with 3% methanol in dichloromethane and the desired fraction was concentrated under reduced pressure to give tert-butyl (3- ((5- (1- (N-benzyl acetamido) ethyl) -2- (methylsulfanyl) pyrimidin-4-yl) amino) phenyl) carbamate (99) as a light brown solid. (220 mg; yield: 50.45%). MS: [ M+H ] ⁺ 508.27。

Step 6: synthesis of tert-butyl (3- ((5- (1- (N-benzylacetamido) ethyl) -2- (methylsulfonyl) pyrimidin-4-yl) amino) phenyl) carbamate (100):

in a manner substantially similar to the procedure described in general procedure GThe title compound was prepared as an off-white solid to give the desired product (100) (130 mg; yield: 61%). MS [ M+H ]] ⁺ 540.06。

Step 7: synthesis of tert-butyl (3- ((5- (1- (N-benzyl acetamido) ethyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) carbamate (101):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give tert-butyl (3- ((5- (1- (N-benzyl acetamido) 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。

Step 8: synthesis of N- (1- (4- ((3-aminophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethyl) -N-benzylacetamide (102):

the title compound was prepared in a manner substantially similar to the procedure described in general procedure I to give N- (1- (4- ((3-aminophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) ethyl) -N-benzylacetamide (102) as a TFA salt as a light brown solid. (100 mg; yield: 98%). MS [ M-H ] ] ^- 455.33。

Step 9: synthesis of N- (3- ((5- (1- (N-benzyl acetamido) ethyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 47)

The title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC to give compound 47 as an off-white solid (6.0 mg, 6.7%). ¹ H NMR(400MHz,DMSO-d ₆ ):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。

Scheme 23: synthesis of N- (3- ((5- ((N-benzyl acetamido) methyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 48):

step 1: synthesis of tert-butyl (3- ((5- ((N-benzyl acetamido) methyl) -2- (methylthio) pyrimidin-4-yl) amino) phenyl) carbamate (104):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure C to give tert-butyl (104) (700 mg, quantitative yield) carbamate (3- ((5- ((N-benzyl acetamido) methyl) -2- (methylsulfanyl) pyrimidin-4-yl) amino) phenyl) as a brown solid. MS [ M+H ]] ⁺ 494.37。

Step 2: synthesis of tert-butyl (3- ((5- ((N-benzyl acetamido) methyl) -2- (methylsulfinyl) pyrimidin-4-yl) amino) phenyl) carbamate (105):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure G to give the desired product (105) as an off-white solid (650 mg; yield: 90%). MS [ M+H ] ] ⁺ 510.34。

Step 3: synthesis of tert-butyl (3- ((5- ((benzyl acetamido) methyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) carbamate (106)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (106) as an off-white solid (650 mg, yield: 92%). MS [ M+H ]] ⁺ 543.18。

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

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired product (107) as an off-white solid (450 mg; yield: 94.9%). MS [ M+H ]] ⁺ 443.19

Step 5: preparation of N- (3- ((5- ((N-benzyl acetamido) methyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 48):

to be substantially similar to general procedureThe title compound was prepared by the procedure described in sequence K. The final compound was purified by preparative HPLC to give N- (3- ((5- ((N-benzyl acetamido) methyl) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 48) as an off-white solid (30 mg; yield: 15%). ¹ H-NMR(400MHz,DMSO d ₆ ):δ10.15(bs,1H),9.50(bs,1H),9.01(bs,1H),7.87(s,1H),7.65(s,1H),7.62(s,1H),7.53(d,J＝7.2Hz,1H),7.40-7.36(m,4H),7.31-7.27(m,3H),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。

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):

step 1: synthesis of ethyl 2-chloro-4- ((2-fluoro-5-nitrophenyl) amino) pyrimidine-5-carboxylate (108):

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

Step 2: synthesis of 2-chloro-4- ((2-fluoro-5-nitrophenyl) amino) pyrimidine-5-carboxylic acid (109):

to 2-chloro-4- [ (2-fluoro-5-nitrophenyl) amino)]To an ice-cold solution of pyrimidine-5-carboxylic acid ethyl ester (108) (800 mg,2.35 mmol) in tetrahydrofuran (10 mL) and water (2.00 mL) was added lithium hydroxide monohydrate (246 mg,5.87 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (TLC monitoring), the reaction mass was concentrated under reduced pressure. The crude material was diluted with ice-cold water and the pH was adjusted to about 4 using 1N hydrochloric acid. Filtering the precipitate and drying under vacuum to obtain To 2-chloro-4- ((2-fluoro-5-nitrophenyl) amino) pyrimidine-5-carboxylic acid (109) as an off-white solid (720 mg; yield: 98%). LCMS [ M-H ]] ^- 311.26。

Step 3: synthesis of 2-chloro-4- ((2-fluoro-5-nitrophenyl) amino) -N-methyl-N-phenylpyrimidine-5-carboxamide (111):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure J to give 2-chloro-4- ((2-fluoro-5-nitrophenyl) amino) -N-methyl-N-phenylpyrimidine-5-carboxamide (111) as an off-white solid (150 mg; yield: 20%). LCMS [ M+H ]] ⁺ 401.98。

Step 4: synthesis of 4- ((2-fluoro-5-nitrophenyl) amino) -N-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) -N-phenylpyrimidine-5-carboxamide (112):

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

Step 5: synthesis of 4- ((5-amino-2-fluorophenyl) amino) -N-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) -N-phenylpyrimidine-5-carboxamide (113):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give 4- ((5-amino-2-fluorophenyl) amino) -N-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) -N-phenylpyrimidine-5-carboxamide (113) as a pale green solid (220 mg; yield: 48.62%). MS [ M+H ] ] ⁺ 433.20。

Step 6: synthesis of 4- ((5-acrylamido-2-fluorophenyl) amino) -N-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) -N-phenylpyrimidine-5-carboxamide (Compound 49):

the title compound is prepared in a manner substantially similar to the procedure 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) as an off-white solid (10 mg, yield: 8%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of tert-butyl (3- ((2-chloro-5-nitropyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (115):

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

Step 2: synthesis of tert-butyl (3- ((5-amino-2-chloropyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (116):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give 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。

step 3: synthesis of tert-butyl (3- ((5-benzoylamino-2-chloropyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (117):

under nitrogen atmosphereTo an ice-cold solution of tert-butyl (3- ((5-amino-2-chloropyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (116) (1.0 g, 2.830 mmol) in tetrahydrofuran (10 mL) was added pyridine (810 mg,11.32 mmol) followed by benzoyl chloride (62) (400 mg, 2.830 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (TLC monitoring), 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, eluting with 8% ethyl acetate in hexane, to give tert-butyl (3- ((5-benzamide-2-chloropyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (117) (800 mg, yield: 61.53%), MS: [ M+H ] ] ⁺ 458.23。

Step 4: synthesis of (3- ((5-benzoylamino-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) carbamic acid tert-butyl ester (118):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The residue was purified by combiflash, eluting with 2% methanol in methylene chloride, to give tert-butyl (3- ((5-benzamide-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。

Step 5: synthesis of N- (4- ((5-amino-2-fluorophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) benzamide (119).

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure I to give N- (4- ((5-amino-2-fluorophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) benzamide (119) (280 mg, yield: 77.10%), MS: [ m+h] ⁺ 419.24

Step 6: synthesis of N- (4- ((5-acrylamido-2-fluorophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) benzamide (Compound 50).

The title compound is prepared in a manner substantially similar to the procedure described in general procedure K. The crude material was purified by preparative HPLC purification to give N- (4- ((5-acrylamide) Phenyl-2-fluorophenyl) amino) -2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-5-yl) benzamide compound 50 (17 mg, yield: 10.03%). ¹ H-NMR (400MHz,DMSO-d ₆ ):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。

Scheme 26: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (phenylsulfanomido) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 51):

step 1: synthesis of tert-butyl (3- ((2-chloro-5- (phenylsulfamido) pyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (120):

to an ice-cold solution of tert-butyl (3- ((5-amino-2-chloropyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (116) (1.0 g,2.83 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere was added pyridine (0.95 mL,11.32 mmol), benzenesulfonyl chloride (66) (0.36 mL,2.83 mmol) and a catalytic amount of N, N-dimethylaminopyridine. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3X 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 eluting with 40% ethyl acetate in hexane to give tert-butyl (3- ((2-chloro-5- (phenylsulfonamide) pyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (120) (600 mg, 42.85% yield). MS [ M+H ] ] ⁺ 494.10。

Step 2: synthesis of N- (4- ((5-amino-2-fluorophenyl) amino) -2-chloropyrimidin-5-yl) benzenesulfonamide (121):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired product (121) (410 mg; yield: 54.14%). MS [ M+H ]] ⁺ 394.21

Step 3: synthesis of N- (3- ((2-chloro-5- (phenylsulfamido) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (122):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (122) (330 mg; yield: 29.48%). MS [ M+H ]] ⁺ 448.11

Step 4: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (phenylsulfanomido) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 51):

the title compound is prepared in a manner substantially similar to the procedure 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- (phenylsulfanomido) pyrimidin-4-yl) amino) phenyl) acrylamide compound 51 (43 mg; yield: 19.14%). ¹ H-NMR(400MHz,DMSO-d ₆ ):δ10.17(bs,1H),9.02(bs,1H),8.24(bs,1H),7.74-7.79(m,3H),7.53-7.60(m,5H),7.38(s,1H),7.19-7.24(m,3H),6.38-6.45(m,1H)6.23-6.27(m,1H),5.77(d,J＝10.0Hz,1H),3.56(s,3H),LCMS:[M+H] ⁺ 509.35。

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):

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

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure J to give tert-butyl (3- ((5- (methyl (phenyl) carbamoyl) -2- (methylsulfanyl) pyrimidin-4-yl) amino) phenyl) carbamate (124) (1.8 g, yield: 75.21%), MS: [ M+H ]] ⁺ 466.21。

Step 2: synthesis of 4- ((3-aminophenyl) amino) -N-methyl-2- (methylsulfanyl) -N-phenylpyrimidine-5-carboxamide (125).

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure I to give 4- ((3-aminophenyl) amino) -N-methyl-2- (methylsulfanyl) -N-phenylpyrimidine-5-carboxamide (125) (1.1 g, yield: 78.15%), MS: [ m+h] ⁺ 366.18

Step 3: synthesis of (E) -4- ((3- (4- (dimethylamino) but-2-enamido) phenyl) amino) -N-methyl-2- (methylsulfanyl) -N-phenylpyrimidine-5-carboxamide (126):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure J. The crude material was purified by combiflash, eluting with 2.5% methanol in dichloromethane, to give (E) -4- ((3- (4- (dimethylamino) but-2-enamido) phenyl) amino) -N-methyl-2- (methylsulfanyl) -N-phenylpyrimidine-5-carboxamide (126) (600 mg; yield: 46.15%), MS: [ M+H ] ⁺ 477.23

Step 4: synthesis of (E) -4- ((3- (4- (dimethylamino) but-2-enamido) phenyl) amino) -N-methyl-2- (methylsulfonyl) -N-phenylpyrimidine-5-carboxamide (127):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure G to give (E) -4- ((3- (4- (dimethylamino) but-2-enamido) phenyl) amino) -N-methyl-2- (methylsulfonyl) -N-phenylpyrimidine-5-carboxamide (127) (510 mg, yield: 79.68%), MS: [ m+h] ⁺ 509.19。

Step 5: synthesis of (E) -4- ((3- (4- (dimethylamino) but-2-enamido) phenyl) amino) -2- ((2-methoxy-4- (piperidin-1-yl) phenyl) amino) -N-methyl-N-phenylpyrimidine-5-carboxamide (compound 52):

the title compound is prepared in a manner substantially similar to the procedure described in general procedure H. The final compound was purified by preparative HPLC to give compound 52 (44 mg, yield: 7.06%) as an off-white solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):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),3.37(s,3H),3.03-3.06(m,6H),2.17(s,6H),1.61(s,4H),1.51-1.52(m,2H)。LCMS:[M+H] ⁺ 635.18。

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):

step 1: synthesis of tert-butyl (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) phenyl) carbamate (129):

to a solution of tert-butyl (3-aminophenyl) carbamate (7) (5 g,22.13 mmol) in N, N-dimethylformamide (50 mL) was added potassium carbonate (6.10 g,44.26 mmol) and 5-bromo-2, 4-dichloropyrimidine (88) (4.97 g,22.13 mmol) at room temperature. The resulting reaction mixture was heated at 110 ℃ for 16 hours. After the reaction was completed (TLC monitoring), the reaction mixture was cooled to room temperature and ice-cold water (100 mL) was added. The resulting solid precipitate was filtered and dried under vacuum to give tert-butyl (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) phenyl) carbamate (129) (3.5 g; yield: 39.98%), LCMS: [ M+H) ] ⁺ 399.48。

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

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (130) (1.4 g; yield: 35.12%). LCMS [ M+H ]] ⁺ 465.38。

Step 3: synthesis of tert-butyl (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) carbamate (132):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (132) (600 mg; yield: 37.54%). LCMS [ M+H ]] ⁺ 559.17。

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):

in a manner substantially similar to that described in general procedure IThe title compound was prepared by (i) to give the desired product (133) (320 mg, yield: 65.04%). MS [ M+H ]] ⁺ 460.48。

Step 5: synthesis of (E) -N- (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (compound 53):

the title compound is prepared in a manner substantially similar to the procedure 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. ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of tert-butyl (3- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) carbamate (134):

to a solution of tert-butyl (3-aminophenyl) carbamate (84) (5.0 g,24.038 mmol) in N, N-dimethylformamide (50 mL) was added potassium carbonate (6.63 g,48.16 mmol) and 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (7) (5.16 g,24.038 mmol) at room temperature. The resulting reaction mixture was heated at 100 ℃ for 16 hours. After the reaction was completed (TLC monitoring), 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。

Step 2: synthesis of tert-butyl (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) carbamate (135):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (135) (400 mg; yield: 32.25%), MS: [ M+H ] ] ⁺ 484.24。

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

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (136) (310 mg; yield: 97.12%), LCMS: [ M+H ]] ⁺ 384.11。

Step 4: synthesis of (E) -N- (3- ((2- ((3-chloro-1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide (compound 54):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure J and after purification by preparative HPLC, desired product compound 54 (40 mg, yield: 15.56%) is obtained as an off-white solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (137):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (137) (yield: 70%) as a pale yellow solid, LCMS: [ M+H ] ⁺ 407.90。

Step 2: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [6- (morpholin-4-yl) pyridin-3-yl ] pyrimidine-2, 4-diamine (139)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure M3 to give the desired product (139) as a red solid. LCMS [ M+H ]] ⁺ 492.50

Step 3: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [6- (morpholin-4-yl) pyridin-3-yl ] pyrimidine-2, 4-diamine (140)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (140) as a pale yellow solid. LCMS [ M+H ]] ⁺ 462.0

Step 4: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [6- (morpholin-4-yl) pyridin-3-yl ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 55)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product as an off-white solid. ¹ H NMR (400 MHz, DMSO-d 6): delta 10.19 (s, 1H), 9.08 (bs, 1H), 8.19 (s, 1H), 7.84 (s, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.63 (d, J=6.8 Hz, 1H), 7.55 (bs, 1H), 7.25 (bs, 2H), 7.13-7.11 (m, 2H), 6.92 (d, J=8.8 Hz, 1H), 6.42-6.36 (m, 1H), 6.24-6.20 (m, 1H), 5.74 (d, J=11.6 Hz, 1H), 3.70 (s, 3H), 3.53-3.48 (m, 4H), 3.30 (4H), combined with water peaks. LCMS [ M+H ] ] ⁺ 516.0。

Table 6: the following compounds were prepared using the procedure described above:

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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):

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)

In a manner substantially similar to general procedure M ₃ The title compound was prepared by the procedure described in (i) to give the desired product (141) as an off-white solid (0.4 g,97% yield). LCMS [ M+H ]] ⁺ 474.1。

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [3- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (142)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure L1 to give the desired product (142) as a brown liquid (0.2 g,crude material). LCMS [ M+H ]] ⁺ 444.2。

Step 3: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [3- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 89)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give an off-white solid (0.13 g, crude). 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。

Table 7: the following compounds were prepared using the procedure described above:

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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):

step 1: synthesis of 5- {4- [ (2-fluoro-5-nitrophenyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-5-yl } -1H-indole-1-carboxylic acid tert-butyl ester (144)

To a stirred solution of 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (137) (0.35 g,0.85 mmol) in 1, 4-dioxane (4.50 mL), water (0.5 mL) was added cesium carbonate (0.83 g,2.57 mmol) and { { {1- [ (tert-butoxy) carbonyl]-1H-indol-5-yl } boronic acid (143) (0.279 g,1.2eq.,1.03 mmol). The reaction mixture was then purged with nitrogen for 5 minutes and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride(II) (0.7 g,0.085 mmol) and heating the reaction mixture at 100deg.C for 16 hours. The progress of the reaction was monitored by TLC/LCMS. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with water (25 ml×2), 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 40-60% ethyl acetate in hexane to give the title compound (144) as a pale yellow solid. LCMS [ M+H ] ] ⁺ 545.2。

Step 2: synthesis of 5- {4- [ (5-amino-2-fluorophenyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-5-yl } -1H-indole-1-carboxylic acid tert-butyl ester (145)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (145) as a brown solid (0.2 g, crude material). LCMS [ M+H ]] ⁺ 515.2。

Step 3: synthesis of tert-butyl 5- (4- { [ 2-fluoro-5- (prop-2-enamido) phenyl ] amino } -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-5-yl) -1H-indole-1-carboxylate (146)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (146) as a white solid (0.19 g). LCMS [ M+H ]] ⁺ 569.3。

Step 4: synthesis of N- (4-fluoro-3- { [5- (1H-indol-5-yl) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl ] amino } phenyl) prop-2-enamide (compound 97)

To 5- (4- { [ 2-fluoro-5- (prop-2-enamido) phenyl group]Amino } -2- [ (1-methyl-1H-pyrazol-4-yl) amino)]To a stirred solution of pyrimidine-5-yl) -1H-indole-1-carboxylic acid tert-butyl ester (0.15 g,0.264 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.00 mL) and stirred at room temperature for 2 hours. The progress of the reaction was monitored by LCMS/TLC. The reaction mixture was then concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound (0.05 g,0.107 mmol) as a pale 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。

Table 8: the following compounds were prepared using the procedure described above:

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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):

step 1: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (pyridin-4-yl) pyrimidine-2, 4-diamine (148)

To a stirred solution of 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (137) (300 mg,0.73 mmol) in 1, 4-dioxane (4.00 mL), water (1.0 mL) was added cesium carbonate (599 mg,1.84 mmol) and (pyridin-4-yl) boronic acid (147) (111 mg, 0.906 mmol). Next, the reaction mixture was purged with nitrogen for 5 minutes, and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium (II) chloride (60.0 mg,0.073 mmol) and the reaction mixture was heated at 100℃for 16 hours. The progress of the reaction was monitored by TLC. The reaction water was diluted with water (20 mL) and extracted with ethyl acetate (3X 50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and evaporated. The crude compound was purified by combiflash column chromatography using 20% ethyl acetate in hexane as an eluent to give the title compound (155) (300 mg, 100%). LCMS [ M+H ] ] ⁺ 407.0

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)

To be substantially similar to general procedure L ₁ The title compound was prepared by the procedure described in (i) to give the desired product (149) (0.22 g, crude material) as a brown solid. LCMS [ M+H ]] ⁺ 377。

Step 3: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (pyridin-4-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 137)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K to give an off-white solid (0.028 g, 12.24%). ¹ H 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,3H),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

Table 9: the following compounds were prepared using the procedure described above:

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scheme 34: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) oxy) phenyl) acrylamide (Compound 151):

step 1: synthesis of 5-bromo-2-chloro-4- (3-nitrophenoxy) pyrimidine (151)

To a stirred solution of 5-bromo-2, 4-dichloropyrimidine (88) (20.0 g,87.76 mmol) and 3-nitrophenol (150) (12.20 g,87.76 mmol) in N, N-dimethylformamide (100.0 mL) was added potassium carbonate (14.53 g,105.31 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed (TLC monitoring), 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 (2X 100 mL). The solid was dried under vacuum to give the desired product (151) as an off-white solid (25 g, yield: 86%). ¹ H NMR(400MHz,DMSO-d ₆ ):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.

Step 2: synthesis of 5-bromo-N- (1-methyl-1H-pyrazol-4-yl) -4- (3-nitrophenoxy) pyrimidin-2-amine (152)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound as a yellow solid (5.0 g, yield: 30%). LCMS [ M+H ]] ⁺ 391.27。

Step 3: synthesis of N- (1-methyl-1H-pyrazol-4-yl) -4- (3-nitrophenoxy) -5- (4- (trifluoromethyl) phenyl) pyrimidin-2-amine (153):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure M3 to give the desired compound as an off-white solid (0.2 g, yield: 38%). LCMS [ M+H ]] ⁺ 457.13

Step 4: synthesis of 4- (3-aminophenoxy) -N- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidin-2-amine (154):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound as an off-white solid (0.12 g, yield: 65%). LCMS [ M+H ]] ⁺ 427.07

Step 5: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) oxy) phenyl) acrylamide (Compound 151):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure K and after purification by preparative HPLC the desired compound is obtained as an off-white solid (0.010 g, yield: 15%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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

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):

step 1: synthesis of tert-butyl (6-bromo-3-chloropyrazin-2-yl) carbamate (156):

to a solution of 6-bromo-3-chloropyrazin-2-amine (155) (500 mg,2.40 mmol) in dichloromethane (10.0 mL) was added triethylamine (170 mg,1.68 mmol), N-dimethylpyridin-4-amine (29.3 mg,0.240 mmol) and di-tert-butyl dicarbonate (1.05 g,4.80 mmol) at room temperature. 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 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 10-40% ethyl acetate in heptane to give tert-butyl (6-bromo-3-chloropyrazin-2-yl) carbamate (156) as a white solid (600 mg, yield: 81%). LCMS [ M-tBu+H ]] ⁺ 251.97.

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

to a solution of tert-butyl (6-bromo-3-chloropyrazin-2-yl) carbamate (156) (400 mg,1.30 mmol) in 1, 4-dioxane (10.0 mL) was added cesium carbonate (845 mg,2.59 mmol), followed by purging the reaction mixture with nitrogen for 15 min, 1-methyl-1H-pyrazol-4-amine (22) (126 mg,1.30 mmol), tris (dibenzylideneacetone) dipalladium (0) (119 mg,0.130 mmol) and xanthos (150 mg,0.26 mmol) were added at room temperature. The resulting reaction mixture was heated at 120 ℃ for 16 hours. After the reaction was completed (monitored by TLC), the reaction solution was cooled to room temperature, filtered through a celite pad 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。

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

to be substantially similar toThe title compound was prepared in analogy to the procedure described in general procedure H to give 5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrazine-2, 6-diamine (158) as a green solid (150 mg, yield: 27.1%). LC-MS: [ M+H ]] ⁺ 225.12。

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

To a stirred solution of 5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrazine-2, 6-diamine (158) (50.0 mg,0.223 mmol) and 2-bromo-1-fluoro-4-nitrobenzene (159) (49.0 mg,0.223 mmol) in 1, 4-dioxane (2.0 mL) was added cesium carbonate (145 mg,0.45 mmol) at room temperature. The reaction mass was purged with nitrogen for 15 minutes, followed by tris (dibenzylideneacetone) dipalladium (0) (20.4 mg,0.022 mmol) and [5- (diphenylphosphanyl) -9, 9-dimethyl-9H-dibenzopyran-4-yl]Diphenyl phosphate (25.8 mg,0.044 mmol) was added to the reaction mixture. The resulting reaction mixture was heated at 120 ℃ for 16 hours. After the reaction was completed (monitored by TLC), 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) pyrazine-2, 6-diamine (160) as a semi-solid (30.0 mg, yield: 13%). MS [ M+H ] ] ⁺ 364.23。

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

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give N2- (5-amino-2-fluorophenyl) -3-chloro-N6- (1-methyl-1H-pyrazol-4-yl) pyrazine-2, 6-diamine (161) (60.0 mg, yield: 63%). MS [ M+H ]] ⁺ 334.09。

Step 6: synthesis of N- (3- ((3-chloro-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) amino) -4-fluorophenyl) acrylamide (Compound 153):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure J, N2- (5-amino-2-fluorophenyl) -3-chloro-N6- (1-methyl-1H-pyrazol-4-yl) pyrazine-2, 6-diamine (161) and acryloyl chloride (18)The compound, after purification by preparative HPLC, gave N- (3- ((3-chloro-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) amino) -4-fluorophenyl) acrylamide compound 153 (8.0 mg, yield: 4.92%) as a white solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):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＝9.6Hz,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。

Scheme 36: synthesis of N- (3- ((3-chloro-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) acrylamide (Compound 218):

step 1: synthesis of tert-butyl (3- ((6-bromo-3-chloropyrazin-2-yl) oxy) phenyl) carbamate (164):

To a stirred solution of tert-butyl (3-hydroxyphenyl) carbamate (163) (1.84 g,8.81 mmol) in acetonitrile (10.0 mL) was added triethylamine (3.01 mL,22.0 mmol) and 3, 5-dibromo-2-chloropyrazine (162) (2.0 g,7.34 mmol) at room temperature. The reaction mixture was stirred at 85 ℃ for 16 hours. After the starting material was consumed (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 flash column chromatography on silica gel (5-25% ethyl acetate in heptane) to give tert-butyl (164) (1.90 g, yield: 64.57%) carbamate as a yellow solid (3- ((6-bromo-3-chloropyrazin-2-yl) oxy) phenyl). LCMS [ M-H ]] ^- 397.97。

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

to a stirred solution of 1-methyl-1H-pyrazol-4-amine (22) (650 mg,6.74 mmol) in toluene (10.0 mL) was added cesium carbonate (2.20 g,6.74 mmol) and tert-butyl (3- ((6-bromo-3-chloropyrazin-2-yl) oxy) phenyl) carbamateEster (164) (900 mg,2.25 mmol). The resulting reaction mixture was purged with nitrogen for 20 minutes, followed by addition of 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (367 mg,0.449 mmol) and stirring of the resulting reaction mixture at 110 ℃ for 20 hours. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a celite pad 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 (165) (1.30 g, yield: 28.75%) of (3- ((3-chloro-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) carbamate as a brown solid, which was used as such in the next step. MS [ M+H ] ] ⁺ 417.28。

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

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I, (3- ((3-chloro-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) carbamic acid tert-butyl ester (165) to give 6- (3-aminophenoxy) -5-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrazin-2-amine (166) as a green solid (720 mg; yield: 72.89%). MS [ M+H ]] ⁺ 317.15。

Step 4: synthesis of N- (3- ((3-chloro-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) acrylamide (Compound 154):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure J, 6- (3-aminophenoxy) -5-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrazin-2-amine (166) and acryloyl chloride (18), affording 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%) as a brown solid after purification by preparative HPLC. ¹ H-NMR (400MHz,DMSO-d ₆ ):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。

Scheme 37: synthesis of N- (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) -4-fluorophenyl) acrylamide (Compound 155):

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

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

Step 2: synthesis of tert-butyl (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) -4-fluorophenyl) carbamate (169):

to a stirred solution of tert-butyl (3- ((3, 6-dichloro-1, 2, 4-triazin-5-yl) amino) -4-fluorophenyl) carbamate (168) (1.10 g,2.94 mmol) in isopropanol (3.0 mL) was added 1-methyl-1H-pyrazol-4-amine (22) (714 mg,7.35 mmol) and camphorsulfonic acid (178 mg,2.06 mmol). The reaction mixture was heated at 100 ℃ for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (169) (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) -4-fluorophenyl) carbamate (2.20 g, yield: 44.13%) as a viscous liquid. MS [. Sup.M+H ] +435.53.

Step 3: preparation of N5- (5-amino-2-fluorophenyl) -6-chloro-N3- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazine-3, 5-diamine (170)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure I, (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) -4-fluorophenyl) carbamic acid tert-butyl ester (169) to give N5- (5-amino-2-fluorophenyl) -6-chloro-N3- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazine-3, 5-diamine (170) (700 mg; yield: 20.58%) as a viscous liquid. MS [ M+H ]] ⁺ 335.12。

Step 4: synthesis of N- (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) -4-fluorophenyl) acrylamide (Compound 155)

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

Scheme 38: synthesis of N- (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) phenyl) acrylamide (Compound 156):

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

to a solution of 3,5, 6-trichloro-1, 2, 4-triazine (167) (3.0 g,16.3 mmol) in dichloromethane (30.0 mL) was added triethylamine (3.29 g,32.5 mmol) and (3-aminophenyl) at room temperature) Tert-butyl carbamate (7) (2.37 g,11.4 mmol). The reaction mixture was stirred at the same temperature for 3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3X 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 (10-20% ethyl acetate in heptane) 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。

Step 2: synthesis of tert-butyl (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) phenyl) carbamate (172):

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

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

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I, (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) phenyl) carbamic acid tert-butyl ester (172) to give N5- (3-aminophenyl) -6-chloro-N3- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazine-3, 5-diamine (173) as a pale red solid (350 mg; yield: 76%). MS [ M+H ]] ⁺ 317.17。

Step 4: synthesis of N- (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) phenyl) acrylamide (Compound 156):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure K, N5- (3-aminophenyl) -6-chloro-N3- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazine-3, 5-diamine (173) and acryloyl chloride (18), affording N- (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) amino) phenyl) acrylamide compound 156 (15.0 mg, yield: 4.21%) as a white solid after purification by preparative HPLC. ¹ H-NMR(400MHz,DMSO-d ₆ ):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

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):

Step 1: synthesis of tert-butyl (3- ((3, 6-dichloro-1, 2, 4-triazin-5-yl) oxy) phenyl) carbamate (174):

to a stirred solution of 3,5, 6-trichloro-1, 2, 4-triazine (177) (2.0 g,10.8 mmol) in dichloromethane (30 mL) was added triethylamine (1.44 g,14.2 mmol) and tert-butyl (3-hydroxyphenyl) carbamate (163) (1.75 g,8.34 mmol) at 0 ℃ and then allowed to warm to room temperature and stirred at the same temperature for 16 hours. After the reaction was completed (monitored by TLC), water (50 mL) was added and 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 5-10% ethyl acetate in heptane to give tert-butyl (3- ((3, 6-dichloro-1, 2, 4-triazin-5-yl) oxy) phenyl) carbamate (174) as a white solid (1.90 g; yield: 63.76%). LCMS [ M-H ]] ^- 355.11。

Step 2: synthesis of tert-butyl (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) oxy) phenyl) carbamate (175):

to a stirred solution of tert-butyl (3- ((3, 6-dichloro-1, 2, 4-triazin-5-yl) oxy) phenyl) carbamate (174) (500 mg,1.40 mmol) and 1-methyl-1H-pyrazol-4-amine (22) (136 mg,1.40 mmol) in toluene (3.0 mL) was added cesium carbonate (1.37 g,4.20 mmol) at room temperature. The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by addition of [1,1' -bis (diphenylphosphino) ferrocene ]Palladium (II) dichloride (complex with dichloromethane) (229 mg,0.28 mmol). The resulting reaction mixture was heated at 110 ℃ for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude material 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 tert-butyl (175) (200 mg; yield: 34.19%) of (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) oxy) phenyl) carbamate as a yellow gel. MS [ M+H ]] ⁺ 418.32。

Step 3: synthesis of 5- (3-aminophenoxy) -6-chloro-N- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazin-3-amine (176):

the title compound was prepared in a manner substantially analogous to the procedure described in general procedure I, (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) oxy) phenyl) carbamic acid tert-butyl ester (175) to give 5- (3-aminophenoxy) -6-chloro-N- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazin-3-amine (176) (280 mg; yield: 28%) as a brown solid. MS [ M+H ]] ⁺ 318.08。

Step 4: synthesis of N- (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) amino) -1,2, 4-triazin-5-yl) oxy) phenyl) acrylamide (Compound 157):

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K, 5- (3-aminophenoxy) -6-chloro-N- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazin-3-amine (176) and acryloyl chloride (18), and after purification by preparative HPLC, N- (3- ((6-chloro-3- ((1-methyl-1H-pyrazol-4-yl) ammonia is obtained as a white solidPhenyl) -1,2, 4-triazin-5-yl) oxy) phenyl) acrylamide compound 157 (20 mg, yield: 6.1%). ¹ H-NMR(400MHz,DMSO-d ₆ ):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

Scheme 40: synthesis of N- (3- ((3-methyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) acrylamide (Compound 158):

step 1: synthesis of tert-butyl (3- ((6-chloro-3-methylpyrazin-2-yl) oxy) phenyl) carbamate (178)

To a solution of 3, 5-dichloro-2-methylpyrazine (177) (1.00 g,6.13 mmol) in dimethyl sulfoxide (10.0 mL) was added cesium fluoride (2.80 g,18.4 mmol) and tert-butyl (3-hydroxyphenyl) carbamate (163) (1.28 g,6.13 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After 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 (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with 15-25% ethyl acetate in heptane to give tert-butyl (3- ((6-chloro-3-methylpyrazin-2-yl) oxy) phenyl) carbamate (178) as a white solid (1.90 g; yield: 82.08%). LCMS [ M+H ] ] ⁺ 336.25

Step 2: synthesis of tert-butyl (3- ((3-methyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) carbamate (179)

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

Step 3: synthesis of 6- (3-aminophenoxy) -5-methyl-N- (1-methyl-1H-pyrazol-4-yl) pyrazin-2-amine (180)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure I, (3- ((3-methyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) carbamic acid tert-butyl ester (179) to give 6- (3-aminophenoxy) -5-methyl-N- (1-methyl-1H-pyrazol-4-yl) pyrazin-2-amine (180) as a brown liquid (1.40 g, yield: 28.95%). MS [ M+H ]] ⁺ 297.36。

Step 4: synthesis of N- (3- ((3-methyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrazin-2-yl) oxy) phenyl) acrylamide (Compound 158)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K, 6- (3-aminophenoxy) -5-methyl-N- (1-methyl-1H-pyrazol-4-yl) pyrazin-2-amine (180) and acryloyl chloride (18), affording 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%) as a light brown solid after purification by preparative HPLC. ¹ H-NMR(400MHz,DMSO-d ₆ ):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。

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):

step 1: synthesis of 2, 5-dichloro-4- (2-fluoro-5-nitrophenyl) pyrimidine (182)

To a stirred solution of 2,4, 5-trichloropyrimidine (13) (0.3 g,1.64 mmol) in 1, 4-dioxane (5.00 mL), water (0.5 mL) was added 2- (2-fluoro-5-nitrophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolane (181) (0.52 g,1.96 mmol), sodium carbonate (0.34 g,3.27 mmol) and purged with nitrogen for 5 minutes. Then [1,1' -bis (diphenylphosphino) ferrocene was added ]Palladium (II) dichloride (complex with dichloromethane) (0.067 g,0.081 mmol) and stirred at 90℃for 2 hours. The progress of the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate (50 ml×2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by using a combiflash purifier and eluted with 1-5% ethyl acetate in hexane to give the title compound (182) as an off-white solid (0.5 g, 90%). LCMS [ M+H ]] ⁺ 288.0

Step 2: synthesis of 5-chloro-4- (2-fluoro-5-nitrophenyl) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (183)

To a stirred solution of 2, 5-dichloro-4- (2-fluoro-5-nitrophenyl) pyrimidine (182) (0.35 g,1.22 mmol) in propan-2-ol (10.0 mL) was added 1-methyl-1H-pyrazol-4-amine (22) (0.118 g,1.22 mmol), N-diisopropylethylamine (0.43 mL,2.43 mmol) and stirred in a sealed tube at 100 ℃ for 16 hours. The progress of the reaction was monitored by LCMS. After the reaction was completed, 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 5-7% methanol in methylene chloride to give the title compound (183) (0.36 g, 84%). LCMS [ M+H ] ] ⁺ 349.1

Step 3: synthesis of 4- (5-amino-2-fluorophenyl) -5-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (184):

to 5-chloro-4- (2-fluoro-5-nitrophenyl) -N- (1-methyl-1H-pyrazole at 0deg.CTo a stirred solution of-4-yl) pyrimidin-2-amine (183) (0.36 g,1.03 mmol) in tetrahydrofuran (10.0 mL), methanol (10.0 mL), water (10.0 mL) was added zinc (0.34 g,5.16 mmol) and ammonium chloride (0.27 g,5.16 mmol). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (100 mL. Times.2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by combiflash purifier and eluted with 4-6% methanol in dichloromethane to give the title compound (184) (0.2 g, 60.7%) as a pale reddish brown gummy 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。

Step 4: synthesis of N- (3- { 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } -4-fluorophenyl) prop-2-enamide (compound 159)

To a stirred solution of 4- (5-amino-2-fluorophenyl) -5-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (184) (0.1 g,0.314 mmol) in dichloromethane (10.0 mL) was added a solution of triethylamine (0.088 mL,0.63 mmol) and propane-2-acryloyl chloride (0.031 g,0.35 mmol) in dichloromethane (2 mL) at-30 ℃. The progress of the reaction was then monitored by TLC. After the reaction was completed, the reaction mixture was quenched with saturated sodium bicarbonate solution (5 mL) at-30 ℃ and extracted with ethyl acetate (50 ml×2). The combined organic layers were concentrated under reduced pressure. The crude product was purified by combiflash chromatography eluting with 2-4% methanol in dichloromethane to give the crude product. The crude material was purified by preparative HPLC to give the title compound as a yellow solid (0.038 g, 33.1%). ¹ H 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),7.35-7.31(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。

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):

the title compound was prepared as a yellow solid in a manner substantially analogous to the procedure described in general procedure J (0.016 g; yield: 12%). 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。

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):

step 1: synthesis of tert-butyl (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (185)

To a microwave vial was added 5-bromo-2, 4-dichloropyrimidine (88) (1.00 g,4.39 mmol), tert-butyl N- (3-amino-4-fluorophenyl) carbamate (83) (0.993 g,4.39 mmol), N-dimethylformamide (10.0 mL), and dipotassium carbonate (1.21 g,8.78 mmol). The reaction mixture was heated in a microwave at 100 ℃ for 1 hour. The reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was diluted with cold water (25 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), water (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude residue was purified by a combiflash purifier using 50% ethyl acetate in hexane to give the title compound (185) (1.1 g, crude material) as a pale yellow solid. LCMS [ M+H ] ] ⁺ 417.0

Step 2: synthesis of tert-butyl N- [3- ({ 5-bromo-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) -4-fluorophenyl ] carbamate (186)

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

Step 3: synthesis of tert-butyl N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (2-phenylethynyl) pyrimidin-4-yl } amino) phenyl ] carbamate (188)

N- [3- ({ 5-bromo-2- [ (1-methyl-1H-pyrazol-4-yl) amino) was added to the sealed tube]Pyrimidin-4-yl } amino) -4-fluorophenyl]Tert-butyl carbamate (186) (0.6 g,1.25 mmol), N-dimethylformamide (10.0 mL), and triethylamine (0.35 mL,2.51 mmol). The reaction mixture was degassed with nitrogen for 10 min and copper iodide (0.048 g,0.25 mmol), bis (triphenylphosphine) palladium (II) dichloride (0.088 g,0.125 mmol) and ethynylbenzene (197) (0.19 g,1.88 mmol) were added. The reaction mixture was heated at 85℃for 9 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2X 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 with 60% ethyl acetate in hexane as an eluent to give the title compound (188) (0.4 g, crude product) as a yellow solid. LCMS [ M+H ] ] ⁺ 500.3

Step 4: synthesis of 2, 2-trifluoro-N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (2-phenylethynyl) pyrimidin-4-yl } amino) phenyl ] acetamide (189)

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

Step 5: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (2-phenylethynyl) pyrimidin-4-yl } amino) phenyl ] prop-2-enamide. TFA salt (Compound 161)

To 2, 2-trifluoro-N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino)]-5- (2-phenylethynyl) pyrimidin-4-yl } amino) phenyl]To a stirred solution of acetamide (189) (0.1 g,0.2 mmol) in dichloromethane (5 mL) was added triethylamine (0.08 mL,0.60 mmol) and cooled to-40℃and stirred for 10 min. After 10 minutes, prop-2-enoyl chloride (18) (0.02 g,0.2 mmol) was added and stirred at-40 ℃ for 20 minutes. The reaction mixture was quenched with water (5 mL) and extracted into dichloromethane (2X 5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by combiflash purifier with 5% methanol in dichloromethane as eluent. It was further purified by preparative HPLC to give the title compound (compound 161) as a white solid (0.02 g, 22%). ¹ H NMR(400MHz,DMSO d6)δ10.3(s,1H),9.72(s,1H),9.15(s,1H),8.24(s,1H),7.87(bs,2H),7.63-7.62(m,3H),7.41-7.39(m,4H),7.17-7.11(m,2H),6.44-6.38(m,1H),6.27-6.23(m,1H),5.76(d,J＝10.0Hz,1H),3.56(s,3H)。LCMS:[M+H] ⁺ 454.5

Scheme 43: synthesis of (2E) -4- (dimethylamino) -N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (2-phenylethynyl) pyrimidin-4-yl } amino) phenyl ] but-2-enamide (compound 162):

the title compound (compound 162) was prepared as a white solid (0.035 g, 28%) in a manner substantially analogous to the procedure described in general procedure J. ¹ H NMR(400MHz,DMSO d6)δ10.20(s,1H),9.47(s,1H),8.83(s,1H),8.20(s,1H),7.82(d,J＝5.6Hz,1H),7.65-7.60(m,3H),7.40-7.35(m,4H),7.14-7.10(m,2H),6.76-6.69(m,1H),6.26-6.22(m,1H),3.52(s,3H),3.04(d,J＝5.2Hz,2H),2.15(s,6H)。LCMS:[M+H] ⁺ 511.5。

Scheme 48: synthesis of 2- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) -N-phenyl-4- (prop-2-enamido) benzamide (Compound 163):

step 1: synthesis of 2-amino-4-nitro-N-phenylbenzamide (191)

To a stirred solution of 2-amino-4-nitrobenzoic acid (190) (2.00 g,11.0 mmol) in dichloromethane (30.0 mL) was added 1H-1,2, 3-benzotriazol-1-ol hydrate (1.68 g,11.0 mmol), (3- { [ (ethylimino) methylene]Amino } propyl) dimethylamine (1.70 g,11.0 mmol) was added followed by N, N-diisopropylethylamine (2.13 g,16.5 mmol) and aniline (1.12 g,12.1 mmol) and stirred at 25℃for 6 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3×25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography and eluted with 12-20% ethyl acetate in hexane to give (191) (1.70 g, 60%). LCMS [ M+H ] ] ⁺ 258.1。

Step 2: synthesis of 2- [ (2, 5-dichloropyrimidin-4-yl) amino ] -4-nitro-N-phenylbenzamide (192)

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

Step 3: synthesis of 2- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) -4-nitro-N-phenylbenzamide (193)

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

Step 4: synthesis of 4-amino-2- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) -N-phenylbenzamide (194)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound 194 as a brown solid (0.15 g, yield: 53%). LCMS [ M+H ]] ⁺ 435.1。

Step 5: synthesis of 2- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) -N-phenyl-4- (prop-2-enamido) benzamide (compound 163)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.95(bs,1H),10.43(s,1H),9.19(s,1H),8.78(s,1H),8.01(s,1H),7.84-7.81(m,2H),7.42-7.38(m,3H),7.11-6.96(m,3H),6.42(m,2H),6.31-6.26(m,1H),5.81-5.78(m,1H),5.73(s,1H),3.49(s,3H)。LCMS:[M+H] ⁺ 489.1。

Scheme 44: synthesis of N4- (5-amino-2-chlorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-bisaminoprop-2-enoyl chloride (Compound 165):

step 1: synthesis of 2-chloro-N- (2-chloro-5-nitrophenyl) pyrimidin-4-amine (197):

to 2-chloro-5-nitroaniline (196) (1.16 g,1eq,6.71 mmol) in N, N-dimethylTo a stirred solution of formamide (10.0 mL) was added sodium hydride (805 mg,3eq,20.1 mmol) and stirred for 10 min, followed by 2, 4-dichloropyrimidine (195) (1.00 g,6.71 mmol) and stirring the reaction mixture for 1 h. After the reaction was complete (TLC monitoring), the crude material was diluted with ice water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude compound, which was purified by combiflash column chromatography and eluted with 20% ethyl acetate in hexane to give the title compound (197) (0.50 g, 26%). LCMS [ M+H ] ] ⁺ 285.0。

Step 2: synthesis of N4- (2-chloro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (198)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (198) (300 mg, 49%) as a white solid. LCMS [ M+H ]] ⁺ 346.0。

Step 3: synthesis of N4- (5-amino-2-chlorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (199)

To a stirred suspension of N4- (2-chloro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (198) (0.50 g,1.45 mmol) in anhydrous methanol (20.0 mL) was added at room temperatureNickel (0.255 g,4.34 mmol) and the reaction mixture was stirred under a hydrogen atmosphere for 2 hours. After completion (TLC monitoring), the reaction mixture was filtered through celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound (199) as a colorless gum solid. LCMS [ M+H] ⁺ 316.1。

Step 4: synthesis of N4- (5-amino-2-chlorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine prop-2-enoyl chloride (Compound 165)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound (25 mg, 21%) as a white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.35(s,1H),9.18(bs,2H),7.95(d,J＝5.6Hz,2H),7.63(d,J＝8.4Hz,1H),7.50(d,J＝8.4Hz,2H),7.27(bs,1H),6.44-6.37(m,1H),6.24(d,J＝16.8Hz,1H),6.15(d,J＝6.0Hz,1H),5.76(d,J＝10.0Hz,1H),3.58(s,3H)。LCMS:[M+H] ⁺ 370.0。

Scheme 45: synthesis of N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) -4-fluorophenyl) acrylamide (Compound 166):

Step 1: synthesis of 5-amino-2-fluorophenol (201)

To be substantially similar to general procedure L ₁ The title compound was prepared by the procedure described in (i) to give the desired compound (201) as an off-white solid (0.4 g, 49%). ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.20(s,1H),6.72-6.67(m,1H),6.14(dd,J＝8.0Hz&2.0Hz,1H),5.91-5.89(m,1H),4.72(s,2H)。

Step 2: synthesis of tert-butyl (4-fluoro-3-hydroxyphenyl) carbamate (202)

To a stirred solution of 5-amino-2-fluorophenol (201) (0.2 g,1.57 mmol) in tetrahydrofuran (5.00 mL) was added di-tert-butyl dicarbonate (0.552 mL,2.36 mmol) at 0deg.C and the reaction mixture was heated at 70deg.C for 15 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (20 mL), dehydrated over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using a combiflash purifier and eluted with 25% ethyl acetate in hexane to give the title compound (202) (0.28 g, 78%) as a brown liquid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.67(s,1H),9.18(s,1H),7.19(d,J＝6.8Hz,1H),6.97-6.92(m,1H),6.77-6.75(m,1H),1.44(s,9H)。

Step 3: synthesis of tert-butyl (3- ((2, 5-dichloropyrimidin-4-yl) oxy) -4-fluorophenyl) carbamate (203)

To 2,4, 5-trichloropyrimidine (13) (0.10 g,0.545 mmol) and tert-butyl N- (4-fluoro-3-hydroxyphenyl) carbamate (202) (0.124 g,0.545 mmol) in N, N-dimethylformamide (3.00 mL) ) Potassium carbonate (0.124 g,0.54 mmol) was added to the stirred solution of (B) and the reaction mixture was heated at 60℃for 2 hours. The reaction mixture was then cooled to room temperature, diluted with water (25 mL), and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with water (25 ml×2), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using a combiflash purifier and eluted with 25% ethyl acetate in hexane to give the title compound (203) as a white solid (0.15 g, 73%). LCMS [ M+H ]] ⁺ 374.0

Step 4: synthesis of tert-butyl (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) -4-fluorophenyl) carbamate (204)

To N- {3- [ (2, 5-dichloropyrimidin-4-yl) oxy]To a stirred solution of tert-butyl 4-fluorophenyl } carbamate (203) (0.140 g,0.374 mmol) in propan-2-ol (3.00 mL) was added 1-methyl-1H-pyrazol-4-amine (22) (0.043 g,0.449 mmol) and N, N-diisopropylethylamine (0.14 mL,0.748 mmol) and the reaction mixture was heated at 100 ℃ for 5 hours. The reaction mixture was cooled to room temperature and evaporated. The residue was diluted with water and extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The crude compound was purified by column chromatography using a combiflash purifier and eluted with 40% ethyl acetate in hexane to give the title compound (204) as an off-white solid (0.15 g, 92%). LCMS [ M+H ] ] ⁺ 435.2。

Step 5: synthesis of 4- (5-amino-2-fluorophenoxy) -5-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (205)

To N- [3- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino) at 0 ℃C]Pyrimidin-4-yl } oxy) -4-fluorophenyl]To a stirred solution of tert-butyl carbamate (204) (0.1 g,0.230 mmol) in dichloromethane (3.00 mL) was added trifluoroacetic acid (0.5 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness. The residue was washed with diethyl ether (20 mL), pentane (20 mL) and dried to give the title compound (205) (0.1 g, crude material) as an off-white solid. LCMS [ M+H ]] ⁺ 335.1。

Step 6: synthesis of N- (3- ((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) -4-fluorophenyl) acrylamide (Compound 166)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound as a white solid (0.045 g, 51%). ¹ H NMR(400MHz,CD ₃ OD):δ8.28(s,1H),7.47-7.65(m,2H),7.33-7.20(m,2H),6.93(bs,1H),6.45-6.34(m,2H),5.79(d,J＝8.8Hz,1H),3.62(s,3H)。LCMS:[M+H] ⁺ 389.0

Scheme 46: synthesis of N- (3- ((5-chloro-2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) -4-fluorophenyl) acrylamide (Compound 167):

step 1: synthesis of 2, 5-dichloro-4- (2-fluoro-5-nitrophenoxy) pyrimidine (207)

To a stirred solution of 2,4, 5-trichloropyrimidine (13) (1.10 g,6.00 mmol) and 2-fluoro-5-nitrophenol (206) (0.942 g,6.00 mmol) in N, N-dimethylformamide (10.0 mL) was added potassium carbonate (1.24 g,9.0 mmol) and the reaction mixture was heated at 60℃for 3 hours. The reaction mixture was then cooled to room temperature, diluted with water (25 mL), and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with water (25 ml×2), 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 6% ethyl acetate in hexane to give the title compound (207) (1.4 g, 76.78%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.94(s,1H),8.55-8.53(m,1H),8.34-8.31(m,1H),7.80(t,J＝9.2Hz,1H)。

Step 2: synthesis of 3- ((2, 5-dichloropyrimidin-4-yl) oxy) -4-fluoroaniline (208)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (208) as a yellow solid (0.64 g, 78%). LCMS [ M+H ]] ⁺ 274。

Step 3: synthesis of N- (3- ((2, 5-dichloropyrimidin-4-yl) oxy) -4-fluorophenyl) acrylamide (209)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound (209) as an off-white solid (0.6 g, 77%). LCMS [ M+H ]] ⁺ 328.0

Step 4: synthesis of N- (3- ((5-chloro-2- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) -4-fluorophenyl) acrylamide (Compound 167)

To N- {3- [ (2, 5-dichloropyrimidin-4-yl) oxy]To a stirred solution of 4-fluorophenyl } prop-2-enamide (209) (0.15 g,0.457 mmol) and 2- (4-amino-1H-pyrazol-1-yl) ethan-1-ol (11) (0.087 g,0.686 mmol) in prop-2-ol (3.00 mL) was added N, N-diisopropylethylamine (0.169 mL,0.914 mmol) and the reaction mixture was heated in a sealed tube at 100℃for 15 hours. The reaction mixture was cooled and evaporated. The residue was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were washed with 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 4.5% methanol in dichloromethane to give the title compound (compound 167) as an off-white solid (0.1 g, 52%). ¹ H NMR (400MHz,DMSO-d ₆ ):δ10.36(bs,1H),9.84(bs,1H),8.42(s,1H),7.85(bs,1H),7.57(bs,1H),7.44(bs,1H),7.06(s,1H),6.90(bs,1H),6.42-6.36(m,1H),6.27-6.23(m,1H),5.77(d,J＝10.0Hz,1H),4.70(bs,1H),3.80(bs,2H),3.53(bs,2H)。LCMS:[M+H] ⁺ 419.0

Table 10: the following compounds were prepared using the procedure described above:

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scheme 47: synthesis of N- [3- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } oxy) -4-methoxyphenyl ] prop-2-enamide (compound 172):

step 1: synthesis of 2, 5-dichloro-4- (2-methoxy-5-nitrophenoxy) pyrimidine (211)

To a stirred solution of 2,4, 5-trichloropyrimidine (13) (3.0 g,16.4 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (6.78 g,49.1 mmol), 2-methoxy-5-nitrophenol (210) (2.77 g,16.4 mmol) and stirred at 60℃for 3 hours. The reaction mixture was poured into ice water (100 mL) and extracted with 5% methanol in dichloromethane (50 ml×3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography using 25% ethyl acetate in hexane as eluent to give the title compound (211) as an off-white solid. (4.8 g, yield: 92.84%); LCMS [ M+H ]] ⁺ 316.0

Step 2: synthesis of 5-chloro-4- (2-methoxy-5-nitrophenoxy) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (212)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (212) (0.15 g, crude material) as an off-white solid. LCMS [ M+H ] ] ⁺ 377.1

Step 3: synthesis of 4- (5-amino-2-methoxyphenoxy) -5-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (213)

To a stirred solution of 5-chloro-4- (2-methoxy-5-nitrophenoxy) -N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (212) (0.30 g,0.796 mmol) in methanol (30 mL) was added raney nickel (0.140 g) and stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through celite bed and evaporated to give the title compound (213) (0.167 g, yield: 60%) as a brown solid. LCMS [ M+H ]] ⁺ 347.0

Step 4: synthesis of N- [3- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } oxy) -4-methoxyphenyl ] prop-2-enamide (compound 172)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound (compound 172) as a white solid (0.03 g, 23%). ¹ H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.74(s,1H),8.35(s,1H),7.63(s,2H),7.23(s,1H),7.03(s,1H),6.72(s,1H),6.33-6.40(m,1H),6.19-6.23(m,1H),5.72(d,J＝10.0Hz,1H),3.66(s,3H),3.49(s,3H)。LCMS:[M+H] ⁺ 401.1。

Scheme 48: synthesis of N- (2- (((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) methyl) -3-fluorophenyl) acrylamide (compound 173):

step 1: synthesis of 2, 5-dichloropyrimidin-4-amine (214)

To a stirred solution of 2,4, 5-trichloropyrimidine (13) (2.00 g,10.9 mmol) in methanol (2 mL) was added a methanol solution of ammonia (20 mL) and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in water, and the precipitated solid was filtered, washed with water and dried to give the title compound (214) (1.6 g, 89%) as a white solid. ¹ H-NMR(400MHz,DMSO-d ₆ ):δ8.16(s,2H),7.52(bs,1H)。

Step 2: synthesis of 2, 5-dichloro-N- (2-fluoro-6-nitrobenzyl) pyrimidin-4-amine (216)

To a stirred solution of 2, 5-dichloropyrimidin-4-amine (214) (0.50 g,3.05 mmol) in N, N-dimethylformamide (10.0 mL) was added sodium hydride (0.18 g,4.57 mmol) at 0deg.C and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0 ℃ and a solution of 2- (bromomethyl) -1-fluoro-3-nitrobenzene (215) (0.71 g,3.05 mmol) in N, N-dimethylformamide (10 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3X 50 mL). The combined organic extracts were washed with water (2×50 mL), brine (25 mL), dried over anhydrous sulfate and evaporated. The crude product was purified by column chromatography using a combiflash purifierThe title compound (216) (0.8 g, 82%) was obtained as an off-white solid, eluting with 25% ethyl acetate in hexane. LCMS [ M+H ]] ⁺ 317.0

Step 3: synthesis of 5-chloro-N4- (2-fluoro-6-nitrobenzyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (217)

The title compound was prepared in a manner substantially analogous to general procedure H to give the title compound (217) as a reddish brown solid (0.85 g; yield: 89%). LCMS [ M+H ] ] ⁺ 378.1

Step 4: synthesis of N4- (2-amino-6-fluorobenzyl) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (218)

The title compound was prepared in a manner substantially analogous to general procedure L to give the title compound (218) as an off-white solid (0.55 g; yield: 80%). LCMS [ M+H ]] ⁺ 348.1。

Step 5: synthesis of N- (2- (((5-chloro-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) methyl) -3-fluorophenyl) acrylamide (compound 173)

The title compound was prepared in a manner substantially analogous to general procedure K1 to give the title compound (compound 173) as a white solid (80 mg; yield: 46%). ¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.84(bs,1H),8.94(bs,1H),7.87(s,1H),7.76(s,1H),7.42(s,1H),7.34(bs,2H),7.07-7.01(m,2H),6.47-6.41(m,1H),6.25-6.21(m,1H),5.74(bs,1H),4.64(s,2H),3.75(s,3H)。LCMS:[M+H] ⁺ 402.0

Scheme 49: synthesis of N- [2- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) - [1,1' -biphenyl ] -4-yl ] prop-2-enamide (compound 175):

step 1: synthesis of N- (2-bromo-5-nitrophenyl) -2-chloropyrimidin-4-amine (220)

To a stirred solution of 2-bromo-5-nitroaniline (219) (1.00 g,4.61 mmol) in N, N-dimethylformamide (3 mL) at 0deg.C was added sodium hydride (0.83 g,20.7mmol,60%) and the reaction mixture was stirred at room temperature for 1 hour. 2, 4-dichloropyrimidine (195) (0.82 g,5.53 mmol) was then added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (200 ml×3). The combined organic layers were washed with water (250 ml×2), brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using a combiflash purifier and eluted with 60% ethyl acetate in hexane to give the title compound (220) as a brown solid (450 mg, 30%). ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.09(s,1H),8.53(s,1H),8.24(d,J＝8.0Hz,1H),8.02-7.91(m,2H),6.87(d,J＝8.0Hz,1H)。

Step 2: synthesis of N4- (2-bromo-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (221)

The title compound was prepared in a manner substantially analogous to general procedure H to give the title compound (221) as a yellow solid (0.25 g; yield: 70%). LCMS [ M+H ]] ⁺ 390.1

Step 3: synthesis of N2- (1-methyl-1H-pyrazol-4-yl) -N4- { 4-nitro- [1,1' -biphenyl ] -2-yl } pyrimidine-2, 4-diamine (222)

To a stirred solution of N4- (2-bromo-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (221) (400 mg,1.03 mmol) in 1, 4-dioxane (4.00 mL), water (1.00 mL) was added phenylboronic acid (137 mg,1.13 mmol), potassium carbonate (283 mg,2.05 mmol). The reaction mixture was then purged with nitrogen for 10 minutes, bis (triphenylphosphine) palladium (II) dichloride (72.0 mg,0.103 mmol) was added and the reaction mixture was heated at 100 ℃ for 12 hours. The reaction mixture was cooled, diluted with water (25 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with water (25 ml×2), 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 70% ethyl acetate in hexane to give white solid (222) (350 mg, 88%). LCMS [ M+H ] ] ⁺ 388.0

Step 4: synthesis of N4- { 4-amino- [1,1' -biphenyl ] -2-yl } -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (223)

To be substantially similar toThe title compound was prepared in the manner of general procedure L to give the title compound (223) as a white solid (0.32 g; yield: 99%). LCMS [ M+H ]] ⁺ 358.38

Step 5: synthesis of N- [2- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) - [1,1' -biphenyl ] -4-yl ] prop-2-enamide (compound 175)

The title compound was prepared in a manner substantially analogous to general procedure K to give the title compound (compound 175) as a yellow solid (0.07 g; yield: 40%). ¹ H NMR (400 MHz, DMSO-d 6): delta 10.51 (bs, 1H), 10.45 (s, 2H), 7.93 (s, 2H), 7.81 (bs, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.36-7.29 (m, 6H), 7.18-6.96 (m, 1H), 6.48-6.41 (m, 1H), 6.29-6.19 (m, 2H), 5.79 (d, J=10.0 Hz, 1H), 3.53 (s, 3H), combined with DMSO water peaks. LCMS [ M+H ]] ⁺ 412.5

Table 11: the following compounds were prepared using the procedure described above:

scheme 55: synthesis of N- [3- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) -4- (2-phenylethynyl) phenyl ] prop-2-enamide (compound 178):

step 1: synthesis of 5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) -N4- [ 5-nitro-2- (2-phenylethynyl) phenyl ] pyrimidine-2, 4-diamine (225)

To a stirred solution of N4- (2-bromo-5-nitrophenyl) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (224) (600 mg,1.41 mmol), triethylamine (394 μl,2eq.,2.83 mmol) in N, N-dimethylformamide (3.0 mL) was added copper iodide (53.8 mg,0.283 mmol), and the reaction mixture was purged with nitrogen for 10 minutes. Bis (triphenylphosphine) palladium (II) dichloride (99.2 mg,0.141 mmol), acetylene benzene (187) (0.233 ml,2.12 mmol) were then added and the reaction mixture was heated in a sealed tube at 85 ℃ for 9 hours.The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2X 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 combiflash purifier and eluted with 10% methanol in dichloromethane to give the title compound (225) (0.330 g, 53%) as a white solid. LCMS [ M+H ]] ⁺ 444.1

Step 2: n4- [ 5-amino-2- (2-phenylethynyl) phenyl ] -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (226)

The title compound was prepared in a manner substantially analogous to general procedure L to give the title compound (226) as a white solid (0.25 g; yield: 68%). LCMS [ M+H ] ] ⁺ 416.9

Step 3: synthesis of N- [3- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) -4- (2-phenylethynyl) phenyl ] prop-2-enamide (compound 178):

the title compound was prepared in a manner substantially analogous to general procedure K to give the title compound (compound 178) as a white solid (0.045 g; yield: 33%). Delta 10.45 (s, 1H), 9.30 (s, 1H) 9.01 (bs, 2H), 8.12 (s, 1H) 7.97 (s, 1H), 7.76-7.74 (d, j=8.0 hz, 1H), 7.62 (s, 1H), 7.36-7.18 (m, 7H), 6.50-6.44 (m, 1H), 6.29-6.25 (m, 1H), 5.79 (d, j=10.0 hz, 1H), 3.54 (s, 3H), combined with DMSO water peaks. LCMS [ M+H ]] ⁺ 470.0。

Scheme 50: synthesis of N- (3- ((2- (cyclopropylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 249)

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Step 1: synthesis of N2-cyclopropyl-N4- (2-fluoro-5-nitrophenyl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (228)

To 2-chloro-N- (2-fluoro-5-nitrophenyl) -5- [4- (trifluoromethyl) phenyl ]]Solutions of pyrimidin-4-amine (91) (0.6 g,1.45 mmol) and cyclopropylamine (227) (0.125 g,2.18 mmol) in propan-2-ol (7.00 mL)N, N-diisopropylethylamine (0.76 mL,4.36 mmol) was added. The reaction mixture was heated at 100 ℃ for 36 hours. The progress of the reaction mixture was monitored by TLC and LCMS. After the reaction was completed, 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 (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a combiflash purifier and eluted with 40% ethyl acetate in hexane to give N2-cyclopropyl-N4- (2-fluoro-5-nitrophenyl) -5- [4- (trifluoromethyl) phenyl) ]Pyrimidine-2, 4-diamine (228) (0.5 g). LCMS [ M+H] ⁺ 434.03

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -N2-cyclopropyl-5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (229)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (229) as a brown solid. LCMS [ M+H] ⁺ 404.04

Step 3: synthesis of N- (3- { [2- (cyclopropylamino) -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl ] amino } -4-fluorophenyl) prop-2-enamide (compound 180)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 180) as an off-white solid. 1H NMR (400 MHz, DMSO-d 6): delta 10.23 (s, 1H), 9.37 (bs, 1H), 7.98 (s, 1H), 7.88-7.93 (m, 2H), 7.69-7.80 (m, 3H), 7.43-7.28 (m, 3H), 6.36-6.43 (m, 1H), 6.21-6.26 (m, 1H), 5.78 (d, J=10.0 Hz, 1H), 2.53 (m, 1H), 1.22 (m, 1H), 0.58-0.85 (m, 4H). LCMS [ M+H] ⁺ 458.15

Scheme 51: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyridin-4-yl) oxy) phenyl) acrylamide (Compound 182)

Step 1: synthesis of 5-bromo-2-chloro-4- (3-nitrophenoxy) pyridine (230)

Stirring dissolution of 3-nitrophenol (160) (1.53 g,11 mmol) in dimethyl sulfoxide (15 mL) Potassium tert-butoxide (16.5 mL,16.5 mmol) was added to the solution and stirred at room temperature for 20 min. Dimethyl sulfoxide (5 mL) containing 5-bromo-2, 4-dichloropyridine (88) (2.5 g,11 mmol) was added to the above reaction mixture and the reaction mixture was heated at 60℃for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was diluted with cold water (25 mL), the precipitated solid was filtered, washed with cold water (150 mL) and dried to give the desired product (230) as a yellow solid. (2.5 g, 68.85%). LCMS [ M+H] ⁺ 328.0。

Step 2: synthesis of 5-bromo-2-chloro-4- (3-nitrophenoxy) pyridine (231)

To a stirred solution of 5-bromo-2-chloro-4- (3-nitrophenoxy) pyridine (230) (2.00 g,6.07 mmol) in 1,4 dioxane (50 mL) and water (10 mL) was added [4- (trifluoromethyl) phenyl ]]Boric acid (90) (1.38 g,7.28 mmol), sodium bicarbonate (1.02 g,12.1 mmol) and nitrogen purge the reaction mixture for 10 min. Addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (complex with dichloromethane) (4960.607 mg, 607 mmol) and the reaction mixture was heated in a sealed tube at 90℃for 1.5 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (150 ml×2). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using a combiflash purifier to give the desired product (231) as a white solid (1.3 g, 58.4%). LCMS [ M+H ] ⁺ 395.1

Step 3: n- (1-methyl-1H-pyrazol-4-yl) -4- (3-nitrophenoxy) -5- (4- (trifluoromethyl) phenyl) pyridin-2-amine (232)

To 2-chloro-4- (3-nitrophenoxy) -5- [4- (trifluoromethyl) phenyl ]]To a stirred solution of pyridine (251) (1.3 g,3.29 mmol) in 1, 4-dioxane (30 mL) was added 1-methyl-1H-pyrazol-4-amine (22) (0.48 g,4.94 mmol), cesium carbonate (2.15 g,6.59 mmol), and the reaction mixture was purged with nitrogen for 15 minutes. Next, xantphos (0.19 g,0.032 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.30 g,0.032 mmol) were added, followed by heating the reaction mixture in a sealed tube at 100℃for 16 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was cooled, filtered through celite andthe filtrate was concentrated. The crude product was purified by using a combiflash purifier with 0 to 60% ethyl acetate in heptane as eluent to give the desired product (232) as a yellow solid (0.7 g, 41.54%). LCMS [ M+H] ⁺ 456.1

Step 4:4- (3-Aminophenoxy) -N- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyridin-2-amine (233)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (233) as a brown solid. LCMS [ M+H ] ⁺ 426.4

Step 5: n- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyridin-4-yl } oxy) phenyl ] prop-2-enamide; trifluoroacetic acid (Compound 182)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure K1 to give the desired product (compound 182) as a white solid (0.07 g, 13.56%). ¹ HNMR@90℃(400MHz,DMSO-d6)δ10.35(s,1H),9.15(bs,1H),8.11(s,1H),7.88 -7.60(m,7H),7.48-7.38(m,3H),6.97-6.95(m,1H),6.44-6.37(m,1H),6.27-6.22(m,1H),6.11(s,1H),5.77(dd,J＝8.0Hz,1.6Hz,1H),3.78(s,3H)。LCMS[M+H] ⁺ 480.3

Scheme 52: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (5-methylpyridin-3-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide (Compound 183)

Step 1: synthesis of tert-butyl N- {3- [ (5-bromo-2-chloropyrimidin-4-yl) oxy ] phenyl } carbamate (234)

To a stirred solution of 5-bromo-2, 4-dichloropyrimidine (88) (10.0 g,43.9 mmol) and tert-butyl N- (3-hydroxyphenyl) carbamate (163) (9.18 g,43.9 mmol) in N, N-dimethylformamide was added potassium carbonate (100.0 mL) (12.1 g,87.8 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed (TLC monitoring), the reaction mixture was cooled to room temperature and diluted with ice-cold water (250 mL). The precipitated solid was filtered off and cooled with iceWashed with water (2X 100 mL). The solid was dried under vacuum to give the desired product (234) as an off-white solid (55 g, yield: 80%). LCMS [ M+H ] ⁺ 399.9

Step 2: synthesis of tert-butyl N- [3- ({ 5-bromo-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } oxy) phenyl ] carbamate (235)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound as a yellow solid (3.5 g, yield: 57%). LCMS [ M+H] ⁺ 461.07。

Step 3: synthesis of tert-butyl (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (5-methylpyridin-3-yl) pyrimidin-4-yl) oxy) phenyl) carbamate (237):

to a solution of tert-butyl (3- ((5-bromo-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) phenyl) carbamate (235) (1.00 g,2.17 mmol) in N, N-dimethylformamide (10.0 mL) was added an aqueous solution (2.00 mL) of (5-methylpyridin-3-yl) boronic acid (236) (0.356 g,2.60 mmol) and cesium carbonate (2.12 g,6.50 mmol). The reaction mass was degassed under nitrogen for 10 min, followed by the addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (complex with dichloromethane) (0.177 g,0.217 mmol) and the reaction mixture was heated at 100℃for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with cold water (100 mL) and extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by a combiflash purifier and eluted with 65% ethyl acetate in hexane to give tert-butyl (237) (0.480 g, yield: 48%) of (3- ((5-bromo-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) oxy) phenyl) carbamate (LCMS [ M+H) ] ⁺ 474.44。

Step 4:4- (3-aminophenoxy) -N- (1-methyl-1H-pyrazol-4-yl) -5- (5-methylpyridin-3-yl) pyrimidin-2-amine (238):

to N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino)]-5- (5-methylpyridin-3-yl) pyrimidin-4-yl } oxy) phenyl]To an ice-cold solution of tert-butyl carbamate (237) (0.480 g,1.01 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (5)0 mL) and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 4- (3-aminophenoxy) -N- (1-methyl-1H-pyrazol-4-yl) -5- (5-methylpyridin-3-yl) pyrimidin-2-amine (238) (0.350 g, yield: 92.51%), LCMS [ M+H)] ⁺ 374.08

Step 5: synthesis of N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (5-methylpyridin-3-yl) pyrimidin-4-yl } oxy) phenyl ] prop-2-enamide (compound 183):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure K and after purification by preparative HPLC the desired compound (compound 183) is obtained as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.37(bs,1H),9.78(bs,1H),8.69(bs,1H),8.48(s,1H),8.38(s,1H),7.91(s,1H),7.70(bs,1H),7.62(bs,1H),7.51(bs,1H),7.11(bs,1H),7.05-7.03(m,1H),6.86(bs,1H),6.46-6.39(m,1H),6.27-6.23(m,1H),5.75(d,J＝10.0Hz,1H),3.50(s,3H),2.36(s,3H)。LCMS[M+H] ⁺ 428.02

Table 12: the following compounds were prepared using the procedure described above:

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scheme 53: synthesis of N- (3- ((2- ((2-methoxyphenyl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) oxy) phenyl) acrylamide (compound 193)

Step 1: synthesis of tert-butyl N- [3- ({ 5-bromo-2- [ (2-methoxyphenyl) amino ] pyrimidin-4-yl } oxy) phenyl ] carbamate (240):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (260) as an off-white solid. LCMS [ M+H] ⁺ 487.1

Step 2: synthesis of tert-butyl N- [3- ({ 2- [ (2-methoxyphenyl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } oxy) phenyl ] carbamate (241):

in a manner substantially similar to general procedure M ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (241) LCMS [ M+H ] as an off-white solid] ⁺ 553.2

Step 3: synthesis of 4- (3-aminophenoxy) -N- (2-methoxyphenyl) -5- [4- (trifluoromethyl) phenyl ] pyrimidin-2-amine (242):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired compound (242) as an off-white solid. LCMS [ M+H] ⁺ 452.4

Step 4 Synthesis of N- [3- ({ 2- [ (2-methoxyphenyl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } oxy) phenyl ] prop-2-enamide (compound 193):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound (compound 193) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.30(s,1H),8.55(s,1H),8.18(s,1H),7.72-7.79(m,4H),7.01-7.69(m,4H),6.89-7.01(m,3H),6.56-6.59(m,2H),6.37-6.44(m,1H),6.22-6.37(m,1H),5.73-5.76(m,1H),3.78(s,3H)。LCMS[M+H] ⁺ 507.2

Scheme 54: synthesis of N- (5- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) pyridin-3-yl) acrylamide (compound 195)

Step 1: synthesis of 5-bromo-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (244)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (244) as an off-white solid. LCMS [ M+H] ⁺ 269.1。

Step 2: synthesis of N2- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (245)

To a stirred solution of 5-bromo-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (244) (5 g 18.6 mmol) in 1, 2-dimethoxyethane (20.0 mL), water (5.00 mL), ethanol (5.00 mL) was added [4- (trifluoromethyl) phenyl ]]Boric acid (90) (4.23 g,22.3 mmol), sodium bicarbonate (3.12 g,37.2 mmol), and purged with nitrogen for 5 minutes. Bis (triphenylphosphine) palladium (II) dichloride (0.65 g,0.93 mmol) was then added and the reaction mixture heated at 80 ℃ for 16 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled and concentrated under reduced pressure. The crude product was purified by using a combiflash purifier and eluted with 70-80% ethyl acetate in hexane to give the desired product (245). LCMS [ M+H ] ⁺ 335.1。

Step 3: synthesis of tert-butyl (5- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) pyridin-3-yl) carbamate (247)

To N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]Pyrimidine-2, 4-diamine (245) (0.6 g,1.79 mmol), tert-butyl N- (5-bromopyridin-3-yl) carbamate (246) (0.54 g,1.97 mmol) and cesium carbonate (1.17 g,3.59 mmol) in 1, 4-dioxane (7.0 mL) were purged with nitrogen for 10 min. 4, 5-bis (diphenylphosphino) -9, 9-dimethylbenzopyran (0.026 g,0.045 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.082 g,0.089 mmol) were then added and the reaction mixture was heated at 110℃for 12 hours. The reaction mixture was cooled, quenched with saturated sodium bicarbonate solution (40.0 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate-containing hexane as eluent to give N- [5- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) as a yellow solid]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) pyrazinesPyridin-3-yl]Tert-butyl carbamate (247) (0.71 g, yield: 75%). LCMS [ M+H ] ⁺ 527。

Step 4: synthesis of N4- (5-aminopyridin-3-yl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (248)

To N- [5- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) at 0 ℃C]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) pyridin-3-yl]To a stirred solution of tert-butyl carbamate (247) (0.4 g,0.76 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (2.0 mL) and the resulting reaction mixture was stirred at room temperature for 1.5 hours. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated in vacuo to give N4- (5-aminopyridin-3-yl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl as a yellow gum]Pyrimidine-2, 4-diamine (248) (0.34 g, crude). LCMS [ M+H] ⁺ 427.2。

Step 5: synthesis of N- (5- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) pyridin-3-yl) acrylamide (compound 195)

In a manner substantially similar to general procedure K ₁ The title compound was prepared by the procedure described in (d) to give the desired product (compound 270) as a white solid. 1H NMR (400 MHz, DMSO-d 6): delta 10.56 (s, 1H), 9.98 (bs, 1H), 9.54 (bs, 1H), 8.64 (s, 2H), 8.43 (s, 1H), 8.03 (bs, 1H), 7.74-7.86 (m, 4H), 7.31-7.40 (m, 3H), 6.40-6.47 (m, 1H), 6.28 (d, J=8.0 Hz, 1H), 5.82 (d, J=10.4 Hz, 1H), 3.74 (s, 3H); LCMS [ M+H ] ⁺ 481.3。

Table 13: the following compounds were prepared using the procedure described above:

scheme 55: synthesis of N- [ 5-fluoro-4- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) pyridin-2-yl ] prop-2-enamide; trifluoroacetic acid (Compound 198)

Step 1: synthesis of N4- (2-chloro-5-fluoropyridin-4-yl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (250)

To N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (265) (1.00 g,2.99 mmol) in 1, 4-dioxane (25 mL) was added 2-chloro-5-fluoro-4-iodopyridine (269) (0.77 g,2.99 mmol) and cesium carbonate (1.95 g,5.98 mmol) and the reaction mixture was degassed with nitrogen for 10 minutes. 4, 5-bis (diphenylphosphino) -9, 9-dimethylbenzopyran (0.17 g,0.299 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.274 g,0.299 mmol) were then added at 90℃in a sealed tube, and the reaction mixture was heated at 90℃for 16 hours in a sealed tube. The reaction was monitored by TLC and LCMS. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude product was purified using a combiflash purifier with 2% methanol in dichloromethane as solvent to give the desired product (250) as an off-white solid (1.00 g, 67.03%). LCMS [ M+H ] ⁺ 464.1。

Step 2: synthesis of tert-butyl N- [ 5-fluoro-4- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) pyridin-2-yl ] carbamate (252)

To N4- (2-chloro-5-fluoropyridin-4-yl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (270) (1.00 g,2.16 mmol) in 1, 4-dioxane (20 ml) was added tert-butyl carbamate (271) (0.379 g,3.23 mmol), cesium carbonate (1.40 g,4.31 mmol) and degassed with nitrogen for 10 minutes. 4, 5-bis (diphenylphosphino) -9, 9-dimethyldibenzopyran (0.125 g,0.216 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.197g, 0.216 mmol) were then added in a sealed tube and the reaction mixture was heated to 90℃in a sealed tube for 16 hours. The reaction was monitored by LCMS. The reaction mixture was filtered through celite bed and the filtrate was concentrated. The crude product was purified using a combiflash purifier with 40% ethyl acetate in heptane as solvent to give the desired product (252) (0.55 g, crude material) as a solid. LCMS [ M+H] ⁺ 545.2。

Step 3: n- [ 5-fluoro-4- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) pyridin-2-yl ] carbamic acid tert-butyl ester (253)

To N- [ 5-fluoro-4- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) at 0 ℃C]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) pyridin-2-yl]To a stirred solution of tert-butyl carbamate (272) (0.55 g,1.01 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and pentane to give the desired product (253) as a brown solid (0.3 g, crude material). LCMS [ M+H] ⁺ 445.2。

Step 4: synthesis of N- [ 5-fluoro-4- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) pyridin-2-yl ] prop-2-enamide; trifluoroacetic acid (Compound 198)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 198) as a white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.77(s,1H),9.56(s,1H),9.17(s,1H),8.35-8.28(m,2H),8.14(s,1H),7.83-7.74(m,2H),7.72-7.57(m,2H),7.30-6.98(m,3H),6.62-6.55(m,1H),6.29-6.25(m,1H),5.78-5.77(m,1H),3.65(s,3H)；LCMS[M+H] ⁺ 499.2。

Scheme 56: synthesis of 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) prop-2-enamide (compound 274).

Step 1: synthesis of 4-bromo-N- [2- (dimethylamino) ethyl ] -N-methyl-2-nitroaniline (256)

To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (274) (1.50 g,6.82 mmol) in acetonitrile (15.00 mL) was added potassium carbonate (1.88 g,13.6 mmol) and [2- (dimethylamino) ethyl ] (methyl) amine (275) (0.69 g,6.82 mmol). The reaction mass was stirred in a sealed tube at 90℃for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (256) (1.8 g, 87.37%) as a yellow liquid.

Step 2: synthesis of N4- (4- { [2- (dimethylamino) ethyl ] (methyl) amino } -3-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (257)

To N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (265) (0.6 g,1.79 mmol) in toluene (15 mL) was added 4-bromo-N- [2- (dimethylamino) ethyl]-N-methyl-2-nitroaniline (276) (0.65 g,2.15 mmol) and cesium carbonate (1.17 g,3.59 mmol). The reaction mixture was degassed with nitrogen for 10 min, then 4, 5-bis (diphenylphosphino) -9, 9-dimethylbenzopyran (0.104 g,0.18 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.164 g,0.18 mmol) were added and the reaction mixture was heated at 100 ℃ for 16 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was filtered through celite bed and the filtrate was concentrated. The crude product was purified by using a combiflash purifier with 3% methanol in dichloromethane as eluent to give the desired product (257) (0.65 g, 65.19%) as an orange solid. LCMS [ M+H ] ⁺ 556.4。

Step 3: synthesis of N1- [2- (dimethylamino) ethyl ] -N1-methyl-N4- {2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } benzene-1, 2, 4-triamine (258)

To be substantially similar to general procedure L ₁ The title compound was prepared by the procedure described in (i) to give the desired product (258) as a brown solid (0.41 g, crude material). LCMS [ M+H] ⁺ 526.3。

Step 4: synthesis of 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) prop-2-enamide (compound 199)

The title compound is synthesized in a manner substantially similar to the procedure described in general procedure KThe desired product (compound 199) was obtained as a white solid (0.034 g, 12.33%). 1HNMR (400 MHz, DMSO-d 6) delta 10.21 (s, 1H), 9.19 (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 7.95 (s, 1H), 7.75-7.73 (m, 2H), 7.67-7.65 (m, 2H), 7.35-7.21 (m, 4H), 6.39-6.32 (m, 1H), 6.21-6.16 (m, 1H), 5.75 (d, J=8.4 Hz, 1H), 3.61 (s, 3H), 2.80-2.77 (m, 2H), 2.65 (s, 3H), 2.34-2.26 (m, 2H), 2.17 (s, 6H). LCMS [ M-H ]] ^- 578.2。

Scheme 57: synthesis of N- (4- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) pyridin-2-yl) acrylamide (Compound 200)

Step 1: synthesis of tert-butyl N- (4-bromopyridin-2-yl) carbamate (260):

to a stirred solution of 4-bromopyridin-2-amine (279) (2.00 g,11.6 mmol) in N, N-dimethylformamide (20.0 mL) were added triethylamine (2.42 mL,17.3 mmol), N-dimethylpyridin-4-amine (0.14 g,1.16 mmol) and di-tert-butyl dicarbonate (3.21 mL,14.0 mmol), and the reaction was stirred at 90℃for 4 hours. After completion of the starting material (as monitored by TLC), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography and eluted with 30% ethyl acetate in hexane to give tert-butyl N- (4-bromopyridin-2-yl) carbamate (280) (2.50 g,9.15 mmol). LCMS [ M+H] ⁺ 216.8 (carbamic acid substance)

Step 2: synthesis of N4- (2-aminopyridin-4-yl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (261):

to N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (245) (0.5 g,1.50 mmol) in 1, 4-dioxane (5.0 mL) was added tert-butyl N- (4-bromopyridin-2-yl) carbamate (260) (0.61 g,2.24 mmol), cesium carbonate (1.22 g,3.74 mmol) and the reaction mixture was purged under nitrogen for 10 minutes. Then add rac-BINAP (0.18 6g,0.299 mmol) and palladium acetate (0.033 g,0.150 mmol) and heating the reaction mixture at 110℃for 16 hours. The progress of the reaction was monitored by TLC and LCMS. To the reaction mixture was added water and extracted with ethyl acetate (3X 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by using a combflash purifier with 10% methanol in dichloromethane as eluent to give N4- (2-aminopyridin-4-yl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl)]Pyrimidine-2, 4-diamine (261) (0.2 g,0.469 mmol). LCMS [ M+H] ⁺ 427.1

Step 3: synthesis of N- (4- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) pyridin-2-yl) acrylamide (Compound 200)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 200) as a white solid. ¹ H NMR(400MHz,DMSO-d6):δ11.11(bs,2H),9.60(bs,2H),8.22-8.16(m,2H),7.97(s,1H),7.80(d,J＝8.4Hz,2H),7.69(d,J＝8.0Hz,2H),7.40(bs,2H),7.20-6.90(m,1H),6.57-6.53(m,1H),6.50-6.34(m,1H),5.86(d,J＝9.6Hz,1H),3.88(s,3H)。LCMS[M+H] ⁺ 481.2

Table 14: the following compounds were prepared using the procedure described above:

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scheme 58: synthesis of N- (3- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -7- (trifluoromethyl) -9H-pyrimido [4,5-b ] indol-9-yl) phenyl) acrylamide (Compound 209)

Step 1: synthesis of 5- [ 2-bromo-4- (trifluoromethyl) phenyl ] -N2- (1-methyl-1H-pyrazol-4-yl) -N4- (3-nitrophenyl) pyrimidine-2, 4-diamine (263):

In a manner substantially similar to general procedure M ₃ The title compound was prepared by the procedure described in (d) to give the desired product (263) as a yellow solid. LCMS [ M+H] ⁺ 534.2

Step 2: 1-methyl-N- [9- (3-nitrophenyl) -7- (trifluoromethyl) -9H-pyrimido [4,5-b ] indol-2-yl ] -1H-pyrazol-4-amine (264):

to 5- [ 2-bromo-4- (trifluoromethyl) phenyl ]]To a stirred solution of N2- (1-methyl-1H-pyrazol-4-yl) -N4- (3-nitrophenyl) pyrimidine-2, 4-diamine (301) (0.4 g,0.74 mmol) in 1, 4-dioxane (20 mL) was added cesium carbonate (0.73 g, 2.25) and purged with argon for 10 minutes. Tri (dibenzylideneacetone) dipalladium (0) (0.06 g,0.07 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylbenzopyran (0.04 g,0.07 mmol) were then added and the reaction mixture was heated at 110℃for 16 hours. The reaction mixture was poured into water (70 mL) and extracted with ethyl acetate (2X 40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography using 70% ethyl acetate in hexane as eluent to give 1-methyl-N- [9- (3-nitrophenyl) -7- (trifluoromethyl) -9H-pyrimido [4,5-b ] as a yellow solid ]Indol-2-yl]-1H-pyrazol-4-amine (264) (0.1 g, 29%). LCMS [ M+H] ⁺ 454.1

Step 3: synthesis of 1-methyl-N- [9- (3-nitrophenyl) -7- (trifluoromethyl) -9H-pyrimido [4,5-b ] indol-2-yl ] -1H-pyrazol-4-amine (265):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (265) as a white solid. LCMS [ M+H] ⁺ 423.9

Step 4: synthesis of 1-methyl-N- [9- (3-nitrophenyl) -7- (trifluoromethyl) -9H-pyrimido [4,5-b ] indol-2-yl ] -1H-pyrazol-4-amine (Compound 209):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 209) as a yellow solid. ¹ H NMR(400MHz,DMSO-d6):δ10.51(s,1H),9.92(s,1H),9.32(s,1H),8.34(d,J＝8.0Hz,1H),8.22(bs,1H),7.88-7.83(m,2H),7.69-7.54(m,4H),7.45(s,2H),6.52-6.46(m,1H),6.32-6.27(m,1H),5.82-5.79(m,1H),3.69(s,3H)；LCMS[M+H] ⁺ 478.2

Scheme 59: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyridin-4-yl) amino) phenyl) acrylamide (Compound 308)

Step 1: synthesis of 2-chloro-5- [4- (trifluoromethyl) phenyl ] pyridin-4-amine (267):

in a manner substantially similar to general procedure M ₃ The title compound was prepared by the procedure described in (i) to give the desired product (267) as a white solid. LCMS [ M+H] ⁺ 272.8

Step 2: synthesis of tert-butyl N- [ (tert-butoxy) carbonyl ] -N- { 2-chloro-5- [4- (trifluoromethyl) phenyl ] pyridin-4-yl } carbamate (268):

To 2-chloro-5- [4- (trifluoromethyl) phenyl ] at room temperature]To a solution of pyridin-4-amine (267) (2.00 g,7.34 mmol) in tetrahydrofuran (30.0 mL) was added di-tert-butyl dicarbonate (0.978 g,4.48 mmol), N-dimethylpyridin-4-amine (0.896 g,7.34 mmol), triethylamine (2.84 mL,20.3 mmol) and the reaction mixture was heated at 65℃for 8 hours. The progress of the reaction was monitored by LCMS and TLC. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and extracted with ethyl acetate (2×35 mL). The combined organic layers were washed with saturated ammonium chloride solution (2×15 mL), brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography using a combiflash purifier and eluted with 7% ethyl acetate in hexane to give N- [ (tert-butoxy) carbonyl]-N- { 2-chloro-5- [4- (trifluoromethyl) phenyl ]]Pyridin-4-yl } carbamic acid tert-butyl ester (268) (1.40 g, 72%). LCMS [ M+H] ⁺ 473.1。

Step 3: synthesis of tert-butyl N- [ (tert-butoxy) carbonyl ] -N- {2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyridin-4-yl } carbamate (269)

To N- [ (tert-butoxy) carbonyl group]-N- { 2-chloro-5- [4- (trifluoromethyl) phenyl ]]A solution of pyridin-4-yl } carbamic acid tert-butyl ester (268) (1.50 g,3.17 mmol), 1-methyl-1H-pyrazol-4-amine (22) (0.308 g,3.17 mmol), cesium carbonate (3.10 g,9.52 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethyldibenzopyran (0.091 g, 0.1592 mmol) in 1, 4-dioxane (25.0 mL) was purged with argon for 15 minutes. Palladium (II) acetate (0.071 g,0.317 mmol) was then added and the reaction mixture heated at 106℃for 12 hours. The reaction was monitored by LCMS. The reaction mixture was cooled and filtered through celite. The filtrate was diluted with water (30 mL) and extracted with dichloromethane (3X 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- [ (tert-butoxy) carbonyl ]-N- {2- [ (1-methyl-1H-pyrazol-4-yl) amino group]-5- [4- (trifluoromethyl) phenyl ]]Pyridin-4-yl } carbamate (269) (1.25 g,2.34 mmol). LCMS [ M-H ]] ^- 534.2

Step 4: synthesis of N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyridine-2, 4-diamine (270):

at 0℃to N- [ (tert-butoxy) carbonyl group]-N- {2- [ (1-methyl-1H-pyrazol-4-yl) amino group]-5- [4- (trifluoromethyl) phenyl ]]To a stirred solution of tert-butyl pyridin-4-yl } carbamate (269) (1.25 g,2.34 mmol) in dichloromethane (20.0 mL) was added dioxane (5.00 mL,144mmol,4 n) containing hydrochloric acid and the reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and dried to give N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]Pyridine-2, 4-diamine (270) (0.8 g,1.66 mmol). LCMS [ M+H] ⁺ 334.1

Step 5: synthesis of tert-butyl N- [ (tert-butoxy) carbonyl ] -N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyridin-4-yl } amino) phenyl ] carbamate (272):

to N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyridine-2, 4-diamine (270) (0.5 g,1.50 mmol) in 1, 4-dioxane (10.0 mL) was added N- (3-bromo-4-fluorophenyl) -N- [ (tert-butoxy) carbonyl ]Tert-butyl carbamate (271) (0.58)5g,1.50 mmol), cesium carbonate (0.977 g,3.00 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethyldibenzopyran (0.021 g,0.037 mmol) and purging the reaction mixture with argon for 10 min. Tris (dibenzylideneacetone) dipalladium (0) (0.068 g,0.075 mmol) was then added and the reaction mixture was heated at 110 ℃ for 12 hours. The reaction was monitored by TLC. The reaction mixture was cooled, filtered through a celite bed, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with dichloromethane (3X 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by using a combiflash purifier and eluted with 10% methanol in dichloromethane to give N- [ (tert-butoxy) carbonyl group]-N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino)]-5- [4- (trifluoromethyl) phenyl ]]Pyridin-4-yl } amino) phenyl]Tert-butyl carbamate (272) (0.350 g,0.545 mmol). LCMS [ M+H] ⁺ 443.3

Step 6: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyridine-2, 4-diamine (273)

At 0℃to N- [ (tert-butoxy) carbonyl group ]-N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino)]-5- [4- (trifluoromethyl) phenyl ]]Pyridin-4-yl } amino) phenyl]To a stirred solution of tert-butyl carbamate (310) (0.3 g,0.467 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (3.00 mL,39.2 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by LCMS. After completion of the starting material reaction, concentrated under reduced pressure and washed to give N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]Pyridine-2, 4-diamine (273) (0.15 g,0.237 mmol). LCMS [ M+H] ⁺ 443.2

Step 7: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyridin-4-yl } amino) phenyl ] prop-2-enamide (Compound 210)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 210) as a white solid. ¹ H NMR(400MHz,DMSO-d6):δ12.4(bs,1H),10.29(bs,1H),9.34(bs,1H),8.65(bs,1H),7.86-7.84(m,4H),7.68-7.66(m,2H),7.55(s,1H),7.44(bs,2H),7.36-7.31(m,1H),6.42-6.36(m,1H),6.26-6.22(m,1H),5.89(s,1H),5.77(d,J＝10.8Hz,1H),3.80(s,3H)；LCMS[M+H] ⁺ 497.3

Scheme 60: synthesis of N- (4-fluoro-3- ((2- ((3-methylisothiazol-5-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 211)

Step 1: synthesis of N1- { 2-chloro-5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } -6-fluorobenzene-1, 3-diamine (274)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (274) as a white solid. LCMS [ M+H] ⁺ 383.0

Step 2: synthesis of tert-butyl N- [3- ({ 2-chloro-5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) -4-fluorophenyl ] carbamate (275)

To N1- { 2-chloro-5- [4- (trifluoromethyl) phenyl ]]To a stirred solution of pyrimidin-4-yl } -6-fluorobenzene-1, 3-diamine (274) (1.50 g,3.92 mmol) in tetrahydrofuran (20.0 mL) was added di-tert-butyl dicarbonate (2.25 mL,9.80 mmol), sodium bicarbonate (1.65 g,19.6 mmol) in water (10.0 mL) and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3X 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give N- [3- ({ 2-chloro-5- [4- (trifluoromethyl) phenyl) h-enyl]Pyrimidin-4-yl } amino) -4-fluorophenyl]Tert-butyl carbamate (275) (1.50 g,2.70 mmol). LCMS [ M-H ]] ^- 482.8

Step 3: synthesis of tert-butyl N- [ 4-fluoro-3- ({ 2- [ (3-methyl-1, 2-thiazol-5-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] carbamate (276):

to N- [3- ({ 2-chloro-5- [4- (trifluoromethyl) phenyl)]Pyrimidin-4-yl } amino) -4-fluorophenyl ]To a stirred solution of tert-butyl carbamate (275) (0.5 g,1.04 mmol) in 1, 4-dioxane (12.0 mL) was added 3-methyl-1, 2-thiazol-5-amineHydrochloride (0.118 g,1.04 mmol), cesium carbonate (0.675 g,2.07 mmol) and purging the reaction mixture with argon for 10 minutes. Tris (dibenzylideneacetone) dipalladium (0) (0.094 g,0.104 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylbenzopyran (0.059 g,0.104 mmol) was then added and the reaction mixture was heated at 105 ℃ for 8 hours. The reaction mixture was filtered through celite bed, and the filtrate was diluted with water (25 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N- [ 4-fluoro-3- ({ 2- [ (3-methyl-1, 2-thiazol-5-yl) amino group)]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]Tert-butyl carbamate (276) (0.7 g,0.937 mmol). LCMS [ M+H] ⁺ 560.9

Step 4: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (3-methyl-1, 2-thiazol-5-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (277):

to N- [ 4-fluoro-3- ({ 2- [ (3-methyl-1, 2-thiazol-5-yl) amino) at 0 ℃C]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]To a stirred solution of tert-butyl carbamate (276) (0.68 g,1.21 mmol) in dichloromethane (10.0 mL) was added dioxane (6.00 mL,173mmol,4 n) containing hydrochloric acid and the reaction mixture was stirred at room temperature for 5 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The crude product was washed with pentane and dried to give N4- (5-amino-2-fluorophenyl) -N2- (3-methyl-1, 2-thiazol-5-yl) -5- [4- (trifluoromethyl) phenyl ]Pyrimidine-2, 4-diamine (278) (0.5 g,0.76 mmol). LCMS [ M+H] ⁺ 461.1

Step 5: synthesis of N- [ 4-fluoro-3- ({ 2- [ (3-methyl-1, 2-thiazol-5-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 211)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 211) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ11.04(s,1H),10.20(s,1H),8.76(s,1H),8.12(s,1H),7.84(d,J＝7.2Hz,3H),7.75(d,J＝8.4Hz,3H),7.52(d,J＝8.4Hz,1H),7.27-7.20(m,1H),6.55(bs,1H),6.45-6.38(m,1H),6.24(dd,J＝14.0Hz,1H),2.20(s,3H)。LCMS[M+H] ⁺ 515.1。

Table 15: the following compounds were prepared using the procedure described above:

scheme 61: synthesis of 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):

step 1: synthesis of tert-butyl N- (3- { [2- ({ 1- [3- (dimethylamino) propyl ] -1H-pyrazol-4-yl } amino) -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl ] amino } -4-fluorophenyl) carbamate (279):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired product (279) as a brown solid. LCMS [ M+H] ⁺ 615.4

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -N2- {1- [3- (dimethylamino) propyl ] -1H-pyrazol-4-yl } -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (280):

to N- (3- { [2- ({ 1- [3- (dimethylamino) propyl) ]-1H-pyrazol-4-yl } amino) -5- [4- (trifluoromethyl) phenyl]Pyrimidin-4-yl]To a stirred solution of tert-butyl amino } -4-fluorophenyl) carbamate (279) (0.5 g,0.8 mmol) in dichloromethane (15.0 mL) was added dioxane (2.00 mL,4 n) containing hydrochloric acid and stirred at room temperature for 1 hour. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The crude product was washed with diethyl ether and dried to give N4- (5-amino-2-fluorophenyl) -N2- {1- [3- (dimethylamino) propyl as a brown solid]-1H-pyrazol-4-yl } -5- [4- (trifluoromethyl) phenyl)]Pyrimidine-2, 4-diamine (280) (0.4 g, 95%). LCMS [ M+H] ⁺ 515.5

Step 3: synthesis of N- (3- { [2- ({ 1- [3- (dimethylamino) propyl ] -1H-pyrazol-4-yl } amino) -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl ] amino } -4-fluorophenyl) prop-2-enamide (compound 216):

in a manner substantially similar to general procedure K ₁ The title compound was prepared by the procedure described in (i) to give the desired product (compound 216) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.33(s,1H),9.46(s,1H),8.03(s,1H),7.93-7.91(m,1H),7.85-7.83(m,1H),7.74-7.32(m,2H),7.66(bs,2H),7.48(s,1H),7.36-7.10(m,4H),6.43-6.37(m,1H),6.26-6.31(m,1H),5.76(d,J＝12.0Hz,1H),3.87(s,2H),3.01(s,2H),2.73-2.65(m,6H),1.95(s,2H)；LCMS[M+H] ⁺ 567.2

Table 16: the following compounds were prepared using the procedure described above:

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scheme 62: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (N-morpholinyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 222)

Step 1: synthesis of 5- (N-morpholinyl) pyrimidine-2, 4 (1H, 3H) -dione (282):

the sealed tube was charged with 5-bromopyrimidine-2, 4 (1H, 3H) -dione (281) (25.0 g,131 mmol) and morpholine (50 mL) under nitrogen, and the resulting reaction mixture was heated at 130℃for 30 minutes. The reaction was monitored by TLC, after completion of the reaction, the reaction mixture was quenched with ice-cold water, the resulting solid was filtered, washed with water and dried to give 5- (N-morpholinyl) pyrimidine-2, 4 (1H, 3H) -dione 3 (282) (25.0 g, yield: 96.86%) as an off-white solid, LCMS [ M+H] ⁺ 197.97

Step 2: synthesis of 4- (2, 4-dichloropyrimidin-5-yl) morpholine (283):

to 5- (N-morpholin) under nitrogen atmosphereLinyl) pyrimidine-2, 4 (1H, 3H) -dione (282) (25.0 g,131 mmol) in POCl ₃ (175 mL) in a stirred solution. Anhydrous dimethylformamide (5.0 mL) was added dropwise to the reaction mixture. The resulting reaction mixture was heated to reflux at 110 ℃ for 36 hours. The resulting reaction mixture was monitored by TLC and after completion of the reaction POCl was evaporated under reduced pressure ₃ Ice-cold water was then added and neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulfate, filtered and concentrated to give 4- (2, 4-dichloropyrimidin-5-yl) morpholine (283) as a brown viscous solid (10.0 g, yield: 33.68%). ¹ H NMR(400MHz,DMSO-d6):δ8.52(s,1H),3.71-3.74(m,4H),3.10-3.20(m,4H)。

Step 3: synthesis of 2-chloro-N- (2-fluoro-5-nitrophenyl) -5- (N-morpholinyl) pyrimidin-4-amine (284):

to an ice-cold solution of 2-fluoro-5-nitroaniline (12) (1.60 g,10.3 mmol) in N, N-dimethylformamide (9.00 mL) and methane sulfinyl methane (1.00 mL) was added sodium hydride (0.92 g,38.4 mmol), followed by the addition of 4- (2, 4-dichloropyrimidin-5-yl) morpholine (283) (3.00 g,12.8 mmol) in portions and stirring at 0deg.C for 15min. After completion of the reaction (TLC monitoring), the reaction mass was diluted with water (100 mL) and extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography using 10% ethyl acetate in hexane as eluent, and the desired fraction was concentrated to dryness to give 2-chloro-N- (2-fluoro-5-nitrophenyl) -5- (N-morpholinyl) pyrimidin-4-amine (284) (0.6 g, yield: 10.34%). LCMS [ M+H] ⁺ 353.98

Step 4: synthesis of N1- (2-chloro-5- (N-morpholinyl) pyrimidin-4-yl) -6-fluorobenzene-1, 3-diamine (285):

to a solution of 2-chloro-N- (2-fluoro-5-nitrophenyl) -5- (morpholin-4-yl) pyrimidin-4-amine (284) (0.60 g,1.70 mmol) in ethanol (5.00 mL) and water (5.00 mL) was added iron (0.947 g,17.0 mmol) and ammonium chloride (0.90 g,17.0 mmol). The reaction mixture was heated to 50 ℃ and maintained for 7 hours. After the reaction was completed (TLC monitoring), the reaction mixture was cooled to room temperature. The mixture was filtered through a celite bed, washing with ethyl acetate (3×150 mL). Will be The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography using 5% methanol in dichloromethane as eluent and the desired fractions were concentrated to dryness to give N1- [ 2-chloro-5- (morpholin-4-yl) pyrimidin-4-yl as an off-white solid]-6-fluorobenzene-1, 3-diamine (285) (0.5 g, yield: 62.3%). LCMS [ M+H] ⁺ 324.04

Step 5: synthesis of N- (3- ((2-chloro-5- (N-morpholinyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (286):

to N1- [ 2-chloro-5- (morpholin-4-yl) pyrimidin-4-yl at-78 ℃C]To a solution of 6-fluorobenzene-1, 3-diamine (285) (0.50 g,1.54 mmol), triethylamine (1.12 mL,7.72 mmol) in dichloromethane (7.00 mL) and tetrahydrofuran (7.00 mL) was added prop-2-enoyl chloride (18) (0.168 g,1.85 mmol) and stirred at the same temperature for 30 minutes. After completion, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (25 ml×3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give N- (3- ((2-chloro-5- (N-morpholinyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (286) as an off-white solid. LCMS [ M-H ]] ^- 376.00

Step 6: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (N-morpholinyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 222):

To a stirred solution of N- (3- ((2-chloro-5- (N-morpholinyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (286) (0.3 g,0.79 mmol), 1-methyl-1H-pyrazol-4-amine (22) (0.092 g,0.95 mmol) in butan-2-ol (5.00 mL) was added potassium carbonate (0.546 g,3.95 mmol). The reaction mixture was purged with nitrogen for 20 minutes and dicyclohexyl [2',4',6 '-tris (prop-2-yl) - [1,1' -biphenyl ] was added]-2-yl]Phosphane (0.046 g,0.079 mmol) and tris (1, 5-diphenylpentan-1, 4-dien-3-one) (0.072 g,0.079 mmol) were stirred at 100℃for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give N- (4-fluoro) as an off-white solid-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (N-morpholinyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 320) (52 mg, yield: 11.84%). ¹ H NMR (400 MHz, DMSO-d 6): delta 10.11 (s, 1H), 9.60-9.80 (m, 2H), 8.20 (d, J=5.2 Hz, 1H), 7.78 (bs, 1H), 7.32-7.50 (m, 4H), 6.62-6.69 (m, 2H), 6.24-6.28 (m, 1H), 5.80 (d, J=10.0 Hz, 1H), 3.79-3.83 (m, 4H), 3.67 (bs, 3H) and 2.86-2.88 (m, 4H). LCMS [ M+H ] ⁺ 439.03

Scheme 63: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide (Compound 223)

Step 1: synthesis of 5- (4-methylpiperazin-1-yl) pyrimidine-2, 4 (1H, 3H) -dione (282):

1-methylpiperazine (11.7 mL,105 mmol) was heated to 100deg.C and 5-bromo-1, 2,3, 4-tetrahydropyrimidine-2, 4-dione (281) (5.00 g,26.2 mmol) was added and the reaction mixture was heated at 130deg.C for 15 min. The reaction mixture was then cooled to room temperature, methanol (100 mL) was added and stirred at room temperature for 15h. The solid was filtered, washed with methanol (50 mL), diethyl ether (50 mL) and dried to give the desired product (326) (5.0 g, crude material) as an off-white solid. LCMS [ M+H] ⁺ 211.1

Step 2: synthesis of 2, 4-dichloro-5- (4-methylpiperazin-1-yl) pyrimidine (283)

A stirred solution of 5- (4-methylpiperazin-1-yl) -1,2,3, 4-tetrahydropyrimidine-2, 4-dione (282) (3.00 g,14.3 mmol) in phosphoryl trichloride (20.0 mL) was heated at 100deg.C for 15h. The reaction mixture was then cooled and evaporated. The residue was diluted with cold water (20 mL) and basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated to give the desired product (283) (1 g, crude material) as an off-white solid. LCMS [ M+H ] ⁺ 246.8

Step 3: synthesis of tert-butyl (3- ((2-chloro-5- (4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) carbamate (284)

To a stirred solution of 2, 4-dichloro-5- (4-methylpiperazin-1-yl) pyrimidine (283) (0.91 g,3.68 mmol) and tert-butyl N- (3-hydroxyphenyl) carbamate (163) (0.85 g,4.05 mmol) in N, N-dimethylformamide (10.0 mL) was added potassium carbonate (1.53 g,11.0 mmol), and the reaction mixture was stirred at room temperature for 15h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sulfate and evaporated. The crude product was purified by column chromatography using a combiflash purifier and eluted with 10% methanol in dichloromethane to give the desired product (284) as an off-white solid (1 g, 64%). LCMS [ M+H] ⁺ 420.3

Step 4: synthesis of tert-butyl (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) carbamate (285)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give tert-butyl (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) carbamate (285) (0.42 g, yield: 74%). LCMS [ M+H ] ⁺ 481.3

Step 5: synthesis of 4- (3-aminophenoxy) -N- (1-methyl-1H-pyrazol-4-yl) -5- (4-methylpiperazin-1-yl) pyrimidin-2-amine (286)

To N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino)]-5- (4-methylpiperazin-1-yl) pyrimidin-4-yl } oxy) phenyl]To a stirred solution of tert-butyl carbamate (285) (0.425 g,0.884 mmol) in dichloromethane (5.00 mL) was added dioxane (2.00 mL,4 n) containing hydrochloric acid and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was evaporated to dryness. The residue was washed with diethyl ether and dried to give the desired product (330) as an off-white solid (0.45 g, crude material). LCMS [ M+H] ⁺ 380.9

Step 6: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide (Compound 223)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the title compound as whiteN- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4-methylpiperazin-1-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide (compound 223) as a color solid (110 mg, yield: 21%). ¹ H NMR(400MHz,DMSO-d6):δ10.32(s,1H),9.14(bs,1H),8.04(s,1H),7.63-7.45(m,2H),7.49-7.45(m,1H),7.13(bs,1H),6.98-6.96(m,2H),6.46-6.39(m,1H),6.28 -6.23(m,1H),5.79-5.76(m,1H),3.55(bs,3H),3.07(bs,4H),2.55(bs,4H),2.27(bs,3H)；LCMS:[M+H] ⁺ 435.3

Scheme 64: synthesis of N- (3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -6- (methylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 224)

Step 1: synthesis of 5-bromo-2, 6-dichloro-N- (3-nitrophenyl) pyrimidin-4-amine (288):

to a stirred solution of 5-bromo-2, 4, 6-trichloropyrimidine (287) (3.00 g,11.4 mmol) in propan-2-ol (30.0 mL) was added N, N-diisopropylethylamine (4.82 mL,34.3 mmol), 3-nitroaniline (1.26 g,9.15 mmol) at room temperature and the reaction mixture was continued at 100deg.C for 15 hours. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, the precipitated solid was filtered and dried to give 5-bromo-2, 6-dichloro-N- (3-nitrophenyl) pyrimidin-4-amine (288) (2.50 g, 60%). LCMS [ M+H] ⁺ 362.9

Step 2: synthesis of 5-bromo-2-chloro-N4-methyl-N6- (3-nitrophenyl) pyrimidine-4, 6-diamine (289):

to a suspension of 5-bromo-2, 6-dichloro-N- (3-nitrophenyl) pyrimidin-4-amine (288) (2.50 g,6.87 mmol) in methanol (50.00 mL) was added dropwise methylamine (17.2 mL,34.3 mmol) at 0 ℃ and the reaction mixture stirred at room temperature for 3 hours. After the reaction was complete (TLC monitoring), the reaction mixture was concentrated under reduced pressure to give 5-bromo-2-chloro-N4-methyl-N6- (3-nitrophenyl) pyrimidine-4, 6-diamine (289) (1.3 g, 53%) as a yellow solid. LCMS [ M+H] ⁺ 358.0

Step 3: synthesis of 2-chloro-N4-methyl-N6- (3-nitrophenyl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-4, 6-diamine (290):

In a manner substantially similar to general procedure M ₂ The title compound was prepared by the procedure described in (3-nitrophenyl) -5- [4- (trifluoromethyl) phenyl ] 2-chloro-N4-methyl-N6- (trifluoromethyl) phenyl)]Pyrimidine-4, 6-diamine (290) (0.35 g, yield: 30%). LCMS [ M+H] ⁺ 423.8

Step 4: synthesis of N4-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -N6- (3-nitrophenyl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4, 6-triamine (292)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give N4-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -N6- (3-nitrophenyl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4, 6-triamine (292). LCMS [ M+H] ⁺ 485.5

Step 5: synthesis of N4- (3-aminophenyl) -N6-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4, 6-triamine (293):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give N4- (3-aminophenyl) -N6-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]Pyrimidine-2, 4, 6-triamine (293). LCMS [ M+H] ⁺ 455.4

Step 6: synthesis of (N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -6- (methylamino) -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 224):

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) as an off-white solid]-6- (methylamino) -5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]Prop-2-enamide (compound 224). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.12(s,1H),9.10(s,2H),(d,J＝8.0Hz,2H),7.62-7.25(m,8H),7.01-6.93(m,2H),6.43-6.37(m,1H),6.23-6.19(m,1H),5.72(d,J＝10.4Hz,1H),3.73(s,3H),2.79(s,3H)；LCMS[M+H] ⁺ 509.3

Scheme 65: synthesis of N- (4-fluoro-3- ((2- (isoxazol-4-ylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 225)

Step 1: synthesis of 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1, 2-oxazol-4-yl) pyrimidine-2, 4-diamine (295)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (295). LCMS [ M+H] ⁺ 394.1

Step 2: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (1, 2-oxazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (296)

To 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1, 2-oxazol-4-yl) pyrimidine-2, 4-diamine (295) (1.50 g,3.80 mmol), [4- (trifluoromethyl) phenyl ]]A stirred solution of boric acid (90) (1.08 g,5.69 mmol), tripotassium phosphate (1.61 g,7.59 mmol) in 1, 4-dioxane (2.00 mL) and water (3 mL) was purged with nitrogen for 15 minutes. XPhos Pd G2 (0.3G, 0.38 mmol) was then added and the reaction mixture was heated at 100deg.C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography using a combiflash purifier and eluted with 30% ethyl acetate in hexane to give N4- (2-fluoro-5-nitrophenyl) -N2- (1, 2-oxazol-4-yl) -5- [4- (trifluoromethyl) phenyl ]Pyrimidine-2, 4-diamine (296) (0.9 g,1.96 mmol). LCMS [ M+H] ⁺ 461

Step 3: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1, 2-oxazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (297)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (297). LCMS [ M+H] ⁺ 431.0

Step 4: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1, 2-oxazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 225)

In a manner substantially similar to general procedure K ₁ The said inThe title compound was prepared by the procedure of providing the desired compound (compound 225) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d6):δ10.2(s,1H),9.61(s,1H),8.86(s,1H),8.41(s,1H),8.15(s,2H),7.08-7.72(m,6H),7.47-7.7.50(m,1H),7.23-7.7.28(m,1H),6.35-6.42(m,1H),6.20(d,J＝4.0Hz,1H),5.73(d,J＝4.0Hz,1H)；LCMS[M+H] ⁺ 485.1

Scheme 66: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (1-methyl-2, 5-dihydro-1H-pyrrol-3-yl) pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 324) and N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (1-methylpyrrolidin-3-yl) pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 325)

Step 1: synthesis of 3- {4- [ (2-fluoro-5-nitrophenyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-5-yl } -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (299)

In a manner substantially similar to general procedure M ₁ The title compound was prepared by the procedure described in (i) to give the desired product (299) as a brown solid. LCMS [ M+H] ⁺ 497.2

Step 2: synthesis of tert-butyl 3- {4- [ (5-amino-2-fluorophenyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-5-yl } -2, 5-dihydro-1H-pyrrole-1-carboxylate (300) and tert-butyl 3- {4- [ (5-amino-2-fluorophenyl) amino ] -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-5-yl } pyrrolidine-1-carboxylate (301)

The title compound was prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (300 and 301) as a brown solid. The mixture of products was used directly in the next step. LCMS [ M+H] ⁺ 467.4

Step 3: n4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (1-methyl-2, 5-dihydro-1H-pyrrol-3-yl) pyrimidine-2, 4-diamine (302) and N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (1-methylpyrrolidin-3-yl) pyrimidine-2, 4-diamine (303)

To 3- {4- [ (5-amino-2-fluorophenyl) amino group at 0 ℃C]-2- [ (1-methyl-1H-pyrazol-4-yl) amino group]To a stirred solution of pyrimidine-5-yl } pyrrolidine-1-carboxylic acid tert-butyl esters (343 and 344) (0.3 g,0.321 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (1.93 mL,1.93 mmol) and the reaction mixture was heated at 80℃for 16 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to room temperature, quenched with ammonium chloride solution (25 mL) and extracted with dichloromethane (50 ml×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (0.28 g, crude material) as a mixture of the two compounds (302 and 303). The crude product was carried forward to the next step. LCMS [ M+H ] ⁺ 383.2&381.2

Step 4: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (1-methyl-2, 5-dihydro-1H-pyrrol-3-yl) pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 226) and N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (1-methylpyrrolidin-3-yl) pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 227)

In a manner substantially similar to general procedure K ₁ The title compound was prepared by the procedure described in (i) to give the desired products (compound 226 and compound 227).

Analytical data for compound 226: ¹ H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.12(s,1H),8.10(s,1H),7.90(s,1H),7.81(d,J＝4.0Hz,1H),7.62(s,1H),7.33-7.28(m,1H),7.15-6.9(m,2H),6.46-6.39(m,1H),6.28-6.23(m,1H),6.08(s,1H),5.78-5.75(m,1H),3.75(s,2H),3.58-3.54(m,5H),2.45(s,3H)。LCMS[M+H] ⁺ 435.3

analytical data for compound 227: ¹ H NMR(400MHz,DMSO-d6):δ11.01(s,1H),10.14(s,1H),8.74(s,1H),8.10(s,1H),7.80(s,1H),7.60-7.49(m,2H),7.28-7.23(m,2H),6.46-6.39(m,1H),6.27-6.22(m,1H),5.77-5.74(m,1H),3.58(s,3H),3.40-3.36(m,2H),3.14(t,J＝8Hz,1H),2.92-2.89(m,1H),2.37(s,3H),2.34(s,1H),2.33-2.07(m,1H),1.84-1.80(m,1H)。LCMS[M+H] ⁺ 437.3

scheme 67: synthesis of 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)

Step 1: synthesis of N4- (2-fluoro-5-nitrophenyl) -N4-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (304):

to N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (92) (2.80 g,5.91 mmol) in N, N-dimethylformamide (25.0 mL) was added dipotassium carbonate (1.225 g,8.86 mmol), followed by dropwise addition of methyl iodide (0.36 mL,5.91 mmol) at 0deg.C, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (TLC monitoring), the reaction mass was diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography eluting with 40% ethyl acetate in hexane to give N4- (2-fluoro-5-nitrophenyl) -N4-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl as a pale yellow solid ]Pyrimidine-2, 4-diamine (347) (0.9 g, yield: 31.25%). LCMS [ M+H] ⁺ 487.99

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -N4-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -5- (4- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (305):

to N4- (2-fluoro-5-nitrophenyl) -N4-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (347) (0.9 g,1.85 mmol) in water (8.00 mL) and ethanol (8.00 mL) was added iron (1.03 g,18.5 mmol) and ammonium chloride (0.988 g,18.5 mmol). The resulting reaction mixture was heated at 75 ℃ for 8 hours. After the reaction was complete (TLC monitoring), the reaction mass was cooled and passed through a celite bed, washing with ethyl acetate. The combined filtrates were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography with 5% methanol in dichloromethaneEluting to obtain N4- (5-amino-2-fluorophenyl) -N4-methyl-N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] as a light brown solid]Pyrimidine-2, 4-diamine (348) (0.8 g, yield: 85.24%) LCMS [ M+H] ⁺ 458.05

Step 3: synthesis of 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):

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound (compound 228) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.01(s,1H),9.41(s,1H),9.33(s,1H),7.99(s,1H),7.62-7.63(m,1H),7.40-7.48(m,4H),7.26(m,1H),7.16(m,1H),6.87(m,1H),6.30-6.37(m,1H),6.16-6.24(m,1H),5.74(d,J＝9.6Hz,1H),3.85(s,3H),3.30(s,3H),LCMS:[M+H] ⁺ 511.98

Scheme 68: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (thiazol-5-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 230)

Step 1: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (thiazol-5-yl) pyrimidine-2, 4-diamine (307):

to a solution of 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (137) (0.4 g,0.98 mmol) in toluene (8 mL) was added 5- (tributylstannyl) thiazole (349) (0.440 g,1.18 mmol), and the reaction mixture was purged with argon for 15 minutes, tetrakis (triphenylphosphine) palladium (0) (0.057 g,0.049 mmol) was added and the reaction mixture was heated at 100 ℃ for 16 hours. After the reaction mixture was complete (TLC monitoring), the reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification of the crude product by flash chromatography eluting with 50% ethyl acetate in hexane gave N4- (2-fluoro-5-nitrophenyl) ) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (thiazol-5-yl) pyrimidine-2, 4-diamine (350) (0.25 g, yield: 47%), LCMS [ M+H] ⁺ 412.97。

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (thiazol-5-yl) pyrimidine-2, 4-diamine (308):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (308) as a brown solid. LCMS [ M+H] ⁺ 382.99

Step 3: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (thiazol-5-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 230):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 230) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.33(s,1H),9.96(s,1H),9.24(s,2H),8.06-8.08(m,3H),7.84(s,1H),7.59(s,1H),7.35-7.38(m,1H),7.20(s,1H),7.11(s,1H),6.38-6.44(m,1H),6.22-6.27(m,1H),5.75(d,J＝10.4Hz,1H),3.56(s,3H)；LCMS[M+H] ⁺ 437.15

Scheme 69: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -6- (trifluoromethyl) quinazolin-4-yl) amino) phenyl) acrylamide (Compound 231):

step 1: synthesis of 6- (trifluoromethyl) quinazoline-2, 4 (1H, 3H) -dione (310):

to a solution of 2-amino-5- (trifluoromethyl) benzonitrile (309) (10.0 g,53.7 mmol) in dimethylformamide (100 mL) was added DBU (24.5 g,161 mmol) under CO 2. The reaction mixture was heated at 100 ℃ for 16 hours. After the reaction was complete (TLC monitoring), the reaction mixture was diluted with water (200 mL), the precipitated solid was filtered and washed with cold water (200 mL) and dried under vacuum to give 6- (trifluoromethyl) -1,2,3, 4-tetrahydroquinazoline-2, 4-dione (310) (12.0 g, yield: 97.08%). LCMS [ M-H ] ] ^- 228.91

Step 2: synthesis of 2, 4-dichloro-6- (trifluoromethyl) quinazoline (311):

to an ice-cold solution of 6- (trifluoromethyl) -1,2,3, 4-tetrahydroquinazoline-2, 4-dione (310) (5.00 g,21.7 mmol) in phosphorus oxychloride (41.6 g,272 mmol) was added phosphorus pentachloride (22.6 g,109 mmol). The resulting reaction mixture was heated at 100 ℃ for 16 hours. After the reaction was completed (TLC monitoring), the reaction mixture was concentrated under reduced pressure. The residue was diluted with cold water (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by using a combiflash purifier and eluted with 1% ethyl acetate in hexane to give 2, 4-dichloro-6- (trifluoromethyl) quinazoline (311) (2.2 g, yield: 37.92%). ¹ H-NMR(400MHz,CDCl ₃ ):δ8.29(s,1H),8.137-8.09(m,1H),7.78-7.37(m,1H)。

Step 3: synthesis of 2-chloro-N- (2-fluoro-5-nitrophenyl) -6- (trifluoromethyl) quinazolin-4-amine (312):

to a solution of 2, 4-dichloro-6- (trifluoromethyl) quinazoline (311) (1.50 g,5.62 mmol) in propan-2-ol (15.0 mL) was added 2-fluoro-5-nitroaniline (12) (0.877 g,5.62 mmol) at room temperature and the reaction mixture was heated at 100deg.C for 16 hours. After the reaction was completed (TLC monitoring), the reaction mixture was concentrated under reduced pressure. The crude product was purified by a combiflash purifier and eluted with 40% ethyl acetate in hexane to give 2-chloro-N- (2-fluoro-5-nitrophenyl) -6- (trifluoromethyl) quinazolin-4-amine (312) (1.2 g, yield: 55%) as the desired product, LCMS [ M+H ] ] ⁺ 386.88。

Step 4: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -6- (trifluoromethyl) quinazoline-2, 4-diamine (313):

to a stirred solution of 1-methyl-1H-pyrazol-4-amine (22) (0.362 g,3.73 mmol), 4-chloro-N- (2-fluoro-5-nitrophenyl) -6- (trifluoromethyl) quinazolin-2-amine (312) (1.2 g,3.1 mmol) in propan-2-ol (40.0 mL) was added trifluoroacetic acid (1.3 mL,15.5 mmol), and the reaction mixture was heated at 100 ℃ for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and dichloromethane(100 mL. Times.2) extraction. The combined organic layers were washed with saturated NaHCO ₃ The solution (100 mL), brine (100 mL) was washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by a combiflash purifier and eluted with 40% ethyl acetate in hexane to give N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -6- (trifluoromethyl) quinazoline-2, 4-diamine (313) (1.0 g, yield: 76%). LCMS [ M+H] ⁺ 447.96

Step 5: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -6- (trifluoromethyl) quinazoline-2, 4-diamine (314):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (314) as a brown solid. LCMS [ M+H ] ⁺ 418.01

Step 6: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -6- (trifluoromethyl) quinazolin-4-yl) amino) phenyl) acrylamide (Compound 231):

the title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired product (compound 231) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.27(bs,1H),9.87(bs,1H),9.47(bs,1H),8.72(s,1H),7.86(bs,2H),7.31-7.69(m,4H),7.07-7.13(m,1H),6.40-6.46(m,1H),6.24-6.29(m,1H),5.76(d,J＝10.0Hz,1H),3.53(s,3H)；LCMS[M+H] ⁺ 471.94

Scheme 70: synthesis of N- (4-fluoro-3- ((2- (pyridin-3-ylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 232)

Step 1: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (pyridin-3-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (315)

To 2-chloro-N- (2-fluoro-5-nitrophenyl) -5- [4- (trifluoromethyl) phenyl ]]To a stirred solution of pyrimidin-4-amine (91) (0.50 g,1.21 mmol) in butan-2-ol (5.00 mL) was added pyridin-3-amine (0.137 g,1.45 mmol), potassium carbonate (0.837 g,6.06 mmol) and the reaction mixture was purged with nitrogen for 10 minutes. Tri (dibenzylideneacetone) dipalladium (0) (0.11 g,0.121 mmol) was then added and stirred at 100℃for 16 hours. After the reaction was complete (TLC monitoring), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using 5% methanol in dichloromethane as eluent to give N4- (2-fluoro-5-nitrophenyl) -N2- (pyridin-3-yl) -5- [4- (trifluoromethyl) phenyl ] as an off-white solid ]Pyrimidine-2, 4-diamine (315) (0.2 g, 28%). LCMS [ M+H] ⁺ 470.97

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (pyridin-3-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (316)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired product (316) as a brown solid. LCMS [ M+H] ⁺ 440.96

Step 3: synthesis of N- (4-fluoro-3- ((2- (pyridin-3-ylamino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 232)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K and after purification by preparative HPLC the desired compound (compound 232) is obtained as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.21(s,1H),10.07(s,1H),8.89(s,1H),8.84(s,1H),8.36-8.42(m,1H),8.28(d,J＝5.20Hz,1H),8.14(s,1H),7.84-7.86(m,2H),7.74-7.80(m,3H),7.48-7.53(m,3H),7.27-7.31(m,1H),6.36-6.43(m,1H),6.20-6.25(m,1H),5.76(d,J＝10.0Hz,1H)。LCMS[M+H] ⁺ 494.97

Scheme 71: synthesis of N- [3- ({ 2- [ (3-chloro-1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } oxy) phenyl ] prop-2-enamide (compound 233):

step 1: synthesis of tert-butyl (3- ((2-chloro-5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) oxy) phenyl) carbamate (317)

In a manner substantially similar to general procedure M ₂ The title compound was prepared by the procedure described in (b) to give the desired compound (317) as a yellow solid. LCMS [ M+H] ⁺ 466.1

Step 2: synthesis of tert-butyl N- [3- ({ 2- [ (3-chloro-1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } oxy) phenyl ] carbamate (319)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (319) as a red solid. LCMS [ M+H] ⁺ 561.2

Step 3: synthesis of 4- (3-aminophenoxy) -N- (3-chloro-1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidin-2-amine (320)

The title compound is prepared in a manner substantially similar to the procedure described in general procedure I to give the desired compound (320) as a yellow gum material. LCMS [ M+H] ⁺ 461.1

Step 4: synthesis of N- [3- ({ 2- [ (3-chloro-1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } oxy) phenyl ] prop-2-enamide (compound 233)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure K to give the desired compound (compound 233) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.37(bs,1H),8.52(bs,1H),7.96-7.79(m,5H),7.65(s,1H),7.55-7.45(m,2H),7.02(d,J＝8.0Hz,2H),6.44-6.37(m,1H),6.24(dd,J＝17.2Hz,1.6Hz,1H),5.76(dd,J＝10.0Hz,2.0Hz,1H),3.51(bs,3H)。LCMS[M+H] ⁺ 515.1。

Table 17: the following compounds were prepared using the procedure described above:

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scheme 72: synthesis of 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)

Step 1: synthesis of tert-butyl (3- ((5-bromo-2- (methylthio) pyrimidin-4-yl) amino) -4-fluorophenyl) carbamate (322)

To a stirred solution of tert-butyl N- (3-amino-4-fluorophenyl) carbamate (83) (9.45 g,41.8 mmol) in tetrahydrofuran (300 mL) was added sodium hydride (8.35 g,209 mmol) in portions and stirred for 30 min at 0deg.C. 5-bromo-4-chloro-2- (methylsulfonyl) pyrimidine (321) (10.0 g,41.8 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was then quenched with ice-cold water (300 mL) and extracted with ethyl acetate (100 mL. Times.2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was washed with 10% diethyl ether in pentane (150 ml) and dried to give the desired product (322) as a pale brown solid (12.0 g, 67%). LCMS [ M+H] ⁺ 429.1

Step 2: synthesis of tert-butyl (4-fluoro-3- ((2- (methylthio) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) carbamate (323)

In a manner substantially similar to general procedure M ₂ The title compound was prepared by the procedure described in (ii) to give the desired compound (323) as an off-white solid. LCMS [ M+H] ⁺ 495.1

Step 3: synthesis of tert-butyl (4-fluoro-3- ((2- (methylsulfonyl) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) carbamate (324)

N- (4-fluoro-3- { [2- (methylsulfonyl) -5- [4- (trifluoromethyl) phenyl ] at 0℃C ]Pyrimidin-4-yl]To a stirred solution of tert-butyl amino } phenyl) carbamate (323) (1.20 g,2.43 mmol) in dichloromethane (100 mL) was added 3-chlorobenzene-1-peroxyformic acid (1.67) in portionsg,9.71 mmol) and the reaction mixture was stirred at 0℃for 30min. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered and the filtrate quenched with sodium bicarbonate solution (100 mL) and extracted with dichloromethane (20 ml×3). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was washed with diethyl ether (50 mL) and dried to give the title compound (324) (0.6 g, crude material) as a brown solid. LCMS [ M+H] ⁺ 527.0

Step 4: synthesis of tert-butyl (4-fluoro-3- ((2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) carbamate (326)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (326) as an off-white solid. LCMS [ M+H] ⁺ 602.2

Step 5: synthesis of 1- (4- ((4- ((5-amino-2-fluorophenyl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (327)

To N- { 4-fluoro-3- [ (2- { [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) ]Amino } -5- [4- (trifluoromethyl) phenyl)]Pyrimidin-4-yl) amino groups]To a stirred solution of tert-butyl phenyl } carbamate (326) (0.15 g, 0.247 mmol) in dichloromethane (5.00 mL) was added 1, 4-dioxane (1.0 mL, 4M) containing hydrochloric acid and the reaction stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC and LC-MS. Evaporating the reaction mixture to obtain 1- [4- ({ 4- [ (5-amino-2-fluorophenyl) amino group)]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-2-yl } amino) -1H-pyrazol-1-yl]-2-methylpropan-2-ol (327) (0.15 g, crude). LCMS [ M+H] ⁺ 502.2

Step 6: synthesis of 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)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 240) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.22(bs,1H),8.74(bs,1H),8.00(s,1H),7.81-7.71(m,5H),7.55(bs,1H),7.26(s,3H),6.44-6.38(m,1H),6.26-6.22(m,1H),5.76-5.73(m,1H),4.49(s,1H),3.71(s,2H),0.96(s,6H)。LCMS[M+H] ⁺ 556.2

Scheme 73: synthesis of N- { 4-fluoro-3- [ (2- { [1- ] ² H ₃ ) methyl-1H-pyrazol-4-yl]Amino } -5- [4- (trifluoromethyl) phenyl)]Pyrimidin-4-yl) amino groups]Phenyl } prop-2-enamide (Compound 242)

Step 1: synthesizing 1- ( ² H ₃ ) methyl-4-nitro-1H-pyrazole (329)

To a stirred solution of 4-nitro-1H-pyrazole (9) (0.2 g,1.77 mmol) in tetrahydrofuran (5 mL) at 0deg.C was added sodium hydride (0.1 g,2.65 mmol) in portions and stirred for 30 min. Then add ² ₃ Iodine (H) methane (0.122 mL, 1.95mmol)and the reaction mass was stirred at room temperature for 3.5 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the desired product (329) (0.23 g, 99%) as a yellow solid. LCMS [ M+H] ⁺ 131.0

Step 2: synthesizing 1- ( ² H ₃ ) methyl-1H-pyrazol-4-amine (330)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (330) as a brown solid. The crude product was used directly in the next step.

Step 3: n- { 4-fluoro-3- [ (2- { [1- ] ² H ₃ ) methyl-1H-pyrazol-4-yl]Amino } -5- [4- (trifluoromethyl) phenyl)]Pyrimidin-4-yl) amino groups]Phenyl } carbamic acid tert-butyl ester (331)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (331) as an off-white solid. LCMS [ M+H] ⁺ 547.2。

Step 4: n4- (5-amino-2-fluorophenyl) -N2- [1- ], and process for preparing the same ² H ₃ ) methyl-1H-pyrazol-4-yl]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidine-2, 4-diamine (332)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure I to give the desired compound (332) as a brown solid. LCMS [ M+H ] ⁺ 447.3

Step 5: n- { 4-fluoro-3- [ (2- { [1- ] ² H ₃ ) methyl-1H-pyrazol-4-yl]Amino } -5- [4- (trifluoromethyl) phenyl)]Pyrimidin-4-yl) amino groups]Phenyl } prop-2-enamide (Compound 242)

In a manner substantially similar to general procedure K ₁ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 242) as a white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.22(bs,1H),8.51(bs,1H),7.99(s,1H),7.82-7.72(m,5H),7.58(bs,1H),7.18-7.10(m,3H),6.45-6.38(m,1H),6.27-6.22(m,1H),5.77-5.74(m,1H)。LCMS[M+H] ⁺ 501.2

Scheme 74: synthesis of N- (3- { [5- (2-cyclopropylethynyl) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl ] amino } -4-fluorophenyl) prop-2-enamide (compound 244)

Step 1: preparation of 5- (2-cyclopropylethynyl) -N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (334)

To a stirred solution of 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (137) (0.3 g,0.735 mmol), triethylamine (0.2 mL,1.47 mmol) in N, N-dimethylformamide (10.0 mL) was purged with nitrogen for 10 minutes, bis (triphenylphosphine) palladium (II) dichloride (51.6 mg,0.073 mmol) and ethynyl cyclopropane (333) (0.102 g,1.54 mmol) were added. The reaction mixture was heated in a sealed tube at 100 ℃ for 16 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography The chromatography was purified using a combiflash purifier and eluted with 65% ethyl acetate in hexane to give 5- (2-cyclopropylethynyl) -N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (334) (0.25 g,636 μmol) as a brown gummy solid. LCMS [ M+H] ⁺ 394.4

Step 2: preparation of N4- (5-amino-2-fluorophenyl) -5- (2-cyclopropylethynyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (335)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (335) as a red solid. LCMS [ M+H] ⁺ 364.4

Step 3: preparation of N- (3- { [5- (2-cyclopropylethynyl) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl ] amino } -4-fluorophenyl) prop-2-enamide (compound 244)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 244) as a red solid. ¹ H NMR(400MHz,DMSO-d6):δ10.48(s,1H),9.59(bs,1H),8.62(bs,1H),8.08-8.06(m,1H),7.83-7.80(m,3H),7.57-7.39(m,1H),7.30-6.90(m,1H),6.46-6.42(m,1H),6.31-6.27(m,2H),5.82-5.80(m,1H),3.70(s,3H),1.67-1.63(m,1H),0.88-0.83(m,2H),0.79-0.70(m,2H)。LCMS[M+H] ⁺ 418.2

Scheme 75: synthesis of N- [3- ({ 2- [ (3-chloro-1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) -4-fluorophenyl ] prop-2-enamide (compound 245)

Step 1: synthesis of 5-bromo-N2- (3-chloro-1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (337)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (337) as an off-white solid. LCMS [ M+H] ⁺ 302.6

Step 2: synthesis of 5-bromo-N2- (3-chloro-1-methyl-1H-pyrazol-4-yl) -N4- (3-fluoro-5-nitrophenyl) pyrimidine-2, 4-diamine (338)

To a stirred solution of 5-bromo-N2- (3-chloro-1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (337) (0.6 g,1.98 mmol) in N, N-dimethylformamide (5.00 mL) was added 1, 3-difluoro-5-nitrobenzene (0.377 g,2.37 mmol), potassium carbonate (1.37 g,9.88 mmol), and stirred at 100 ℃ for 16 hours. The progress of the reaction was monitored by LCMS. After 16h, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3X 20 mL). The combined organic layers were washed with brine (60 mL), dehydrated over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column purification using a combiflash purifier and eluted with 50% ethyl acetate in hexane to give 5-bromo-N2- (3-chloro-1-methyl-1H-pyrazol-4-yl) -N4- (3-fluoro-5-nitrophenyl) pyrimidine-2, 4-diamine (338) (0.2 g,0.452 mmol) as a pale yellow solid. LCMS [ M+H] ⁺ 466.4

Step 3: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (3-chloro-1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (339)

In a manner substantially similar to general procedure M ₂ The title compound was prepared by the procedure described in (ii) to give the desired compound (339) as an off-white solid. LCMS [ M+H] ⁺ 508.4

Step 4: preparation of N4- (5-amino-2-fluorophenyl) -N2- (3-chloro-1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (340)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (340) as a pale yellow solid. LCMS [ M+H] ⁺ 478.4

Step 5: preparation of N- [3- ({ 2- [ (3-chloro-1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) -4-fluorophenyl ] prop-2-enamide (compound 245)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 245) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d6):δ10.26(s,1H),9.10(bs,2H),8.01(bs,1H),7.85-7.83(m,3H),7.73-7.70(m,2H),7.50(bs,1H),7.34-7.32(m,3H),6.45-6.38(m,1H),6.29-6.24(m,1H),5.80-5.77(m,1H),3.74(s,3H)。LCMS[M+H] ⁺ 532.2

Scheme 76: synthesis of N- (3- ((2- ((1- (2-cyanoprop-2-yl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 347)

Step 1: synthesis of 2-methyl-2- (4-nitro-1H-pyrazol-1-yl) propanamide (342)

To a stirred solution of 4-nitro-1H-pyrazole (9) (2.00 g,17.7 mmol) and 2-bromo-2-methylpropanamide (341) (3.23 g,19.5 mmol) in N, N-dimethylformamide (15.0 mL) was added potassium carbonate (2.69 g,19.5 mmol) and the reaction mixture was heated at 60℃for 20 hours. The reaction mixture was cooled, diluted with 1N sodium hydroxide solution (50 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was washed with diethyl ether (50 mL) and dried to give the title compound (342) (2.4 g, 68%) as a white solid. LCMS [ M+H ] ⁺ 199.1

Step 2: synthesis of 2-methyl-2- (4-nitro-1H-pyrazol-1-yl) propionitrile (343)

A stirred solution of 2-methyl-2- (4-nitro-1H-pyrazol-1-yl) propionamide (342) (0.5 g,2.52 mmol) in phosphorus oxychloride (7.00 mL) was heated at 90℃for 2 hours. The reaction mixture was cooled and evaporated. The residue was diluted with cold water (10 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using a combiflash purifier and eluted with 30% ethyl acetate in hexane to give the title compound (343) (0.42 g, 85%) as a colorless liquid. ¹ H NMR(400MHz,CDCl ₃ ):δ8.45(s,1H),8.19(s,1H),2.06(s,6H)。

Step 3: synthesis of 2- (4-amino-1H-pyrazol-1-yl) -2-methylpropanenitrile (344)

In a manner substantially similar to the procedure described in general procedure LThe title compound was prepared to give the desired compound (344) as a brown solid. LCMS [ M+H] ⁺ 151.1

Step 4: synthesis of 2- (4- ((5-bromo-4- ((2-fluoro-5-nitrophenyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropanenitrile (346)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (346) as an off-white solid. LCMS [ M+H ] ⁺ 461.0

Step 5: synthesis of 2- (4- ((4- ((2-fluoro-5-nitrophenyl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropanenitrile (347)

In a manner substantially similar to general procedure M ₁ The title compound was prepared by the procedure described in (a) to give the desired compound (347) as an off-white solid. LCMS [ M+H] ⁺ 527.1

Step 6: synthesis of 2- (4- ((4- ((5-amino-2-fluorophenyl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropanenitrile (348)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (348) as a brown solid. LCMS [ M+H] ⁺ 497.2

Step 7: synthesis of N- (3- ((2- ((1- (2-cyanoprop-2-yl) -1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 246)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 246) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.75(bs,1H),8.97(bs,1H),8.00(s,1H),7.83-7.70(m,5H),7.49(bs,4H),7.28-7.23(m,1H),6.41-6.34(m,1H),6.24-6.19(m,1H),5.74-5.71(m,1H),1.72(s,6H)；LCMS[M+H] ⁺ 551.2

Scheme 77: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] (3, 3-2H 2) prop-2-enamide (compound 247)

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Step 1: synthesis of diethyl ({ [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] carbamoyl } methyl) phosphonate (350)

To N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a solution of pyrimidine-2, 4-diamine (93) (0.5 g,1.13 mmol) in tetrahydrofuran (5.00 mL) was added N, N-diisopropylethylamine (0.189 g,1.47 mmol), 2- (diethoxyphosphoryl) acetic acid (349) (0.243 g,1.24 mmol), followed by HATU (0.557 g,1.47 mmol) and stirring at room temperature for 4 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2X 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give ({ [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino)]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]Carbamoyl } methyl) phosphonic acid diethyl ester (350) (0.52 g, 74%). LCMS [ M+H] ⁺ 621.5

Step 2: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] (3, 3-2H 2) prop-2-enamide (compound 247):

To ({ [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino)]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]To a solution of diethyl carbamoyl } methyl) phosphonate (350) (0.5 g,0.804 mmol) in tetrahydrofuran (4.00 mL), water (0.8 mL) was added lithium hydroxide (0.023 g,0.965 mmol), followed by potassium hydroxide (0.099 g,1.77 mmol) and paraformaldehyde-d 2 (0.0077 g,0.241 mmol) and stirred at room temperature for 4 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2X 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to give N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) as a white solid]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl](3, 3-2H 2) propan-2-Enamide (compound 247) (30.0 mg, 7%). ¹ H NMR(400MHz,DMSO-d6):δ10.29(s,1H),9.97(bs,1H),9.30(bs,1H),8.00(s,1H),7.86-7.84(m,3H),7.73-7.73(m,2H),7.56(s,1H),7.35(s,1H),7.20-7.10(m,3H),6.38(s,1H),3.55(s,3H)；LCMS[M+H] ⁺ 500.5

Table 18: the following compounds were prepared using the procedure described above:

scheme 78: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) but-2, 3-dienamide (compound 251)

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Step 1: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) phenyl) but-2, 3-dienamide (compound 251)

To N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl at room temperature]To a stirred solution of pyrimidine-2, 4-diamine (93) (0.2 g, 0.457 mmol) and but-2-ynoic acid (0.045 g,0.541 mmol) in dichloromethane (4.00 mL) was added triethylamine (0.157 mL,1.13 mmol) followed by 2-chloro-1-methylpyridin-1-ium iodide (351) (0.138 g,0.541 mmol). The reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LCMS and TLC. The reaction mixture was quenched with water (30.0 mL) and extracted with dichloromethane (3X 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to give N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) as an off-white solid]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]But-2, 3-dienamide (compound 251) (20.0 mg, 9%). ¹ H NMR(400MHz,DMSO-d6):δ10.07(s,1H),9.24(bs,1H),8.52(bs,1H),7.96(s,1H),7.65-7.79(m,5H),7.50(bs,1H),7.26(bs,1H),7.13(bs,1H),7.05(bs,1H),5.92(t,J＝6.8Hz,1H),5.40(d,J＝6.0Hz,2H),3.53(s,3H)。LCMS[M+H] ⁺ 510.2

Scheme 79: synthesis of 2-chloro-N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] acetamide 2, 2-trifluoroacetate (compound 252)

Step 1: synthesis of 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)

To N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (93) (0.2 g,0.451 mmol) in tetrahydrofuran (4.00 mL) and water (0.4 mL) was added triethylamine (0.189 mL,1.35 mmol), 2-chloroacetyl chloride (352) (0.043 mL,0.541 mmol) and stirred at 0deg.C for 10min. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3X 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by preparative HPLC to give 2-chloro-N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) as an off-white solid]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]Acetamide (Compound 252) (0.2 g,0.385 mmol). ¹ H NMR(400MHz,DMSO-d6):δ10.43(s,1H),9.89(bs,1H),9.24(bs,1H),7.99(s,1H),7.84(d,J＝8.4Hz,2H),7.73(d,J＝8.0Hz,3H),7.49(bs,2H),7.35(bs,1H),7.70(s,1H),6.94(s,1H),4.23(s,2H),3.57(s,3H)。LCMS[M+H] ⁺ 520.1

Scheme 80: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] ethylene-1-sulfonamide (compound 253)

Step 1: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] ethylene-1-sulfonamide (compound 253):

to N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) at room temperature ]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]To a stirred solution of ethylene-1-sulfonamide (93) (0.5 g,1.06 mmol) in dichloromethane (10.0 mL) was added triethylamine (0.321 g,3.17 mmol), followed by 2-chloroethane-1-sulfonyl chloride (353) (0.207 g,1.27 mmol) and stirred for 6 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (25 mL) and extracted with dichloromethane (50 ml×2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by preparative HPLC to give N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) as a white solid]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) phenyl]Ethylene-1-sulfonamide (compound 253) (0.20 g, 35%). ¹ H NMR(400MHz,DMSO-d6):δ10.10(bs,2H),9.33(bs,1H),8.01(bs,1H),7.85(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),7.34(s,1H),7.14-7.08(m,3H),7.04-7.02(m,2H),6.70-6.70(m,1H),6.06-6.01(m,1H),5.99-5.93(m,1H),3.59(s,3H)。LCMS[M+H] ⁺ 534.3

Scheme 81: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-ynyl amide (compound 357)

Step 1: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-ynyl amide (compound 254)

To N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl at 0 ℃C ]Pyrimidine-2, 4-diamine (93) (0.25 g,to a stirred solution of 0.564 mmol) in dichloromethane (20.0 mL) was added prop-2-ynoic acid (354) (0.045 mL,0.73 mmol), followed by N, N' -dicyclohexylmethane diimine (0.151 g,0.733 mmol), N-dimethylpyridin-4-amine (0.006g, 0.056 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (compound 254) as an off-white solid (0.035 g, 12%). ¹ H NMR(400MHz,DMSO-d6):δ10.90(s,1H),9.25(bs,1H),8.55(bs,1H),8.00(s,1H),7.81(d,J＝8.4Hz,2H),7.73-7.67(m,3H),7.51(bs,1H),7.31(bs,1H),7.15(bs,1H),7.06(bs,1H),4.43(s,1H),3.57(s,3H)。LCMS[M+H] ⁺ 496.4

Scheme 82: synthesis of 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)

Step 1: synthesis of 5- (3, 6-dihydro-2H-pyran-4-yl) -N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (356)

In a manner substantially similar to general procedure M ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (356) as a brown solid. LCMS [ M+H] ⁺ 412.0

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4-diamine (357)

To a stirred solution of 5- (3, 6-dihydro-2H-pyran-4-yl) -N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (356) (0.4 g,0.972 mmol) in methanol (20.0 mL) and tetrahydrofuran (20.0 mL) was added palladium on carbon (0.8 g,7.52mmol,10% w/w), and the reaction mixture was hydrogenated at 80 ℃ in a par shaker with 80 torr hydrogen pressure for 14 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give a pale yellow liquid Is a desired product of (357). (0.4 g, crude material). LCMS [ M+H] ⁺ 384.2

Step 3: synthesis of 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)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 255) as a white solid. ¹ H NMR (400 MHz, DMSO-d 6): delta 10.24 (s, 1H), 8.78 (bs, 1H), 8.44 (bs, 1H), 8.17 (s, 1H), 7.84 (s, 1H), 7.75-7.74 (m, 1H), 7.57 (bs, 1H), 7.33-7.16 (m, 2H), 7.11 (bs, 2H), 6.42-6.36 (m, 1H), 6.25-6.21 (m, 1H), 5.75-5.72 (m, 1H), 3.95-3.91 (m, 2H), 3.50-3.44 (m, 2H), 3.33 (bs, 3H, combined with DMSO peaks), 2.95-2.90 (m, 1H), 1.77-1.66 (m, 2H), 1.64-1.60 (m, 2H); LCMS [ M+H] ⁺ 438.2

Scheme 83: synthesis of N- (3- ((5-bromo-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 359)

Step 1: synthesis of N4- (5-amino-2-fluorophenyl) -5-bromo-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (408)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (358) as a brown solid. LCMS [ M+H] ⁺ 378.1

Step 2: synthesis of N- (3- ((5-bromo-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -4-fluorophenyl) acrylamide (compound 256)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 256) as a white solid. ¹ H NMR (400 MHz, DMSO-d 6): delta 10.29 (s, 1H), 9.42 (bs, 1H), 8.95 (bs, 1H), 8.16 (s, 1H), 7.81-7.79 (m, 1H), 7.67 (bs, 1H), 7.36 (bs, 2H), 7.22-7.01 (m, 2H), 6.46-6.39 (m, 1H), 6.29-6.24 (m, 1H), 5.79-5.76 (m, 1H), 3.45 (bs, 3H), combined with DMSO peaks; LCMS [ M+H] ⁺ 432.1

Table 19: the following compounds were prepared using the procedure described above:

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scheme 84: synthesis of N- (3- { [5- (2, 5-dihydrofuran-3-yl) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl ] amino } -4-fluorophenyl) prop-2-enamide (compound 261)

Step 1: synthesis of 5- (2, 5-dihydrofuran-3-yl) -N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (360)

To a stirred solution of 5-bromo-N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (137) (0.25 g,0.61 mmol) in 1, 4-dioxane (2.4 mL) was added 2- (2, 5-dihydrofuran-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (359) (0.12 g,0.61 mmol), potassium carbonate (0.25 g,1.84 mmol) and [ 2-dicyclohexylphosphino-2 ] ¹ ,4 ¹ ,6 ¹ Triisopropylbiphenyl](0.058 g,0.122 mmol). The reaction mixture was then purged with nitrogen for 5 minutes, tris (dibenzylideneacetone) dipalladium (0) (0.056 g,0.061 mmol) was added and the reaction mixture was heated at 100 ℃ for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using a combiflash purifier and eluted with 10% methanol in dichloromethane to give the title compound (360) (0.2 g, 82%) as an off-white solid. LCMS [ M+H ] ⁺ 398.2。

Step 2: synthesis of N4- (5-amino-2-fluorophenyl) -5- (2, 5-dihydrofuran-3-yl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (361)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (361) as a pale yellow solid. LCMS [ M+H] ⁺ 368.2。

Step 3: synthesis of N- (3- { [5- (2, 5-dihydrofuran-3-yl) -2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl ] amino } -4-fluorophenyl) prop-2-enamide (compound 261)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 261) as an off-white solid.

¹ H NMR(400MHz,DMSO-d6):δ10.34(s,1H),10.19(bs,1H),9.33(s,1H),7.94-7.90(m,2H),7.63(s,1H),7.39(s,1H),7.20-7.08(m,3H),6.47-6.38(m,2H),6.29-6.24(m,1H),5.79-5.76(m,1H),4.86(d,J＝4.0Hz,2H),4.79(d,J＝4.0Hz,2H),3.58(bs,3H)；LCMS[M+H] ⁺ 422.1。

Table 20: the following compounds were prepared using the procedure described above:

scheme 85: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (oxacyclopent-3-yl) pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 266):

step 1: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (oxacyclopent-3-yl) pyrimidine-2, 4-diamine (363)

To stirring 5- (2, 5-dihydrofuran-3-yl) -N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (362) (0.15 g,0.377 mmol) in methanol (10 mL), tetrahydrofuran (10 mL) Palladium on carbon (0.1 g,10% w/w) was added to the solution. The reaction mixture was hydrogenated at 80℃under 100 Torr hydrogen pressure for 14 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the mixture was filtered through celite and washed with methanol (50 mL). The filtrate was concentrated in vacuo to give the desired product N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (oxacyclopent-3-yl) pyrimidine-2, 4-diamine (363) (0.14 g, 100%) as a pale yellow liquid. LCMS [ M+H] ⁺ 370.2。

Step 2: synthesis of N- [ 4-fluoro-3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- (oxacyclopent-3-yl) pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 266)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 266) as an off-white solid.

¹ H NMR(400MHz,DMSO-d6):δ10.25(s,1H),8.87(bs,1H),8.46(s,1H),7.91(s,1H),7.80(dd,J＝6.8Hz,J＝2.4Hz,1H),7.63-7.61(m,1H),7.33-7.28(m,1H),7.14(s,2H),6.45-6.39(m,1H),6.28-6.23(m,1H),5.78-5.75(m,1H),4.03-4.00(m,1H),3.97-3.91(m,1H),3.82-3.77(m,1H),3.68-3.64(m,1H),3.54-3.44(m,4H),2.36-2.28(m,1H),1.99-1.91(m,1H)。LCMS[M+H] ⁺ 424.2。

Table 21: the following compounds were prepared using the procedure described above:

scheme 86: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (piperidin-1-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 383)

Step 1: synthesis of 5- (piperidin-1-yl) pyrimidine-2, 4 (1H, 3H) -dione (415)

A mixture of 5-bromo-1, 2,3, 4-tetrahydropyrimidine-2, 4-dione (281) (3.00 g,15.7 mmol) in piperidine (6.22 mL,62.8 mmol) was heated at 110deg.C for 15 min. The reaction mixture was then cooled to room temperature, methanol (25 mL) was added and stirred at room temperature for 30 minutes. The solid was filtered off, washed with methanol (50 mL) and dried to give the desired product (364) (2.9 g, crude material) as a white solid. LCMS [ M+H ] ⁺ 196.2。

Step 2: synthesis of 2, 4-dichloro-5- (piperidin-1-yl) pyrimidine (365)

To a stirred solution of 5- (piperidin-1-yl) -1,2,3, 4-tetrahydropyrimidine-2, 4-dione (364) (0.5 g,2.56 mmol) in phosphoryl trichloride (5 mL) was added triethylamine (0.714 mL,5.12 mmol) and the reaction mixture was heated at 110℃for 15 hours. The reaction mixture was then cooled and evaporated. The residue was diluted with cold water (20 mL) and extracted with ethyl acetate (30 mL. Times.3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography using a combiflash purifier and eluted with 25% ethyl acetate in hexane to give the desired product (365) (0.53 g, 89%) as a colorless liquid. LCMS [ M+H] ⁺ 231.9。

Step 3: synthesis of 2-chloro-N- (2-fluoro-5-nitrophenyl) -5- (piperidin-1-yl) pyrimidin-4-amine (366)

To a stirred solution of 2-fluoro-5-nitroaniline (12) (0.336 g,2.15 mmol) in N, N-dimethylformamide (10 mL) was added sodium hydride (0.172 g,4.31mmol,60% in mineral oil) at 0deg.C and the reaction mixture was stirred at the same temperature for 30min. A solution of 2, 4-dichloro-5- (piperidin-1-yl) pyrimidine (365) (0.5 g,2.15 mmol) in N, N-dimethylformamide (1 mL) was then added and the reaction mixture stirred at room temperature for 15 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sulfate and evaporated. The crude product was purified by using a combiflash purifier and eluted with 20% ethyl acetate in hexane to give the desired product as a yellow solid Product (366) (0.1 g, 13%). LCMS [ M+H] ⁺ 352.1。

Step 4: synthesis of N4- (2-fluoro-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (piperidin-1-yl) pyrimidine-2, 4-diamine (367)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (367) as a brown solid. LCMS [ M+H] ⁺ 413.2。

Step 5: synthesis of N4- (5-amino-2-fluorophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- (piperidin-1-yl) pyrimidine-2, 4-diamine (368)

To be substantially similar to general procedure L ₁ The title compound was prepared by the procedure described in (ii) to give the desired compound (368) as a brown solid. LCMS [ M+H] ⁺ 383.2。

Step 6: synthesis of N- (4-fluoro-3- ((2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- (piperidin-1-yl) pyrimidin-4-yl) amino) phenyl) acrylamide (compound 269)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (i) to give the desired compound (compound 269) as an off-white solid.

¹ H NMR(400MHz,DMSO-d6):δ10.33(s,1H),9.85(bs,1H),9.49(s,1H),8.01(d,J＝5.2Hz,1H),7.73(bs,1H),7.61-7.59(m,1H),7.42-7.37(m,2H),7.28-7.21(m,2H),6.46-6.40(m,1H),6.29-6.24(m,1H),5.79(dd,J＝10.0Hz,J＝2.0Hz,1H),3.64(s,3H),2.84(bs,4H),1.74(bs,4H),1.54(bs,2H)。LCMS[M+H] ⁺ 437.3。

Table 22: the following compounds were prepared using the procedure described above:

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scheme 87: synthesis of N- (3- ((5-chloro-4- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound 275)

Step 1: synthesis of 5-bromo-2-chloro-N- (2-fluoro-3-nitrophenyl) pyrimidin-4-amine (369)

To a solution of 2,4, 5-trichloropyrimidine (13) (0.50 g,2.73 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (0.94 g,6.81 mmol) and 1-methyl-1H-pyrazol-4-amine (22) (0.265 g,2.73 mmol). The reaction mixture was then heated at 100 ℃ for 3 hours. After the reaction was complete (TLC and LCMS monitoring), the reaction mixture was cooled to room temperature. The reaction mixture was added to ice cold water (50 mL) and stirred for 10 minutes. The precipitated solid was filtered, dried and used in other steps without any purification. LCMS [ M+H] ⁺ 244.0。

Step 2: synthesis of 5-chloro-N4- (1-methyl-1H-pyrazol-4-yl) -N2- (3-nitrophenyl) pyrimidine-2, 4-diamine (370)

To a solution of 2, 5-dichloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-amine (420) (0.25 g,1.02 mmol) in isopropanol (10 mL) was added 3-nitroaniline (0.141 g,1.02 mmol) and trifluoroacetic acid (0.078 mL). The reaction mixture was then heated at 100 ℃ for 12 hours. After 12 hours, (TLC monitoring) the reaction mixture was cooled to room temperature and the precipitated solid was filtered and washed with ice-cold isopropanol (5 mL). The solid was dried and used in other steps without any purification. LCMS [ M+H] ⁺ 346.1。

Step 3: synthesis of N2- (3-aminophenyl) -5-chloro-N4- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (371)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (371) as a brown solid. LCMS [ M+H] ⁺ 316.1。

Step 4: synthesis of N- (3- ((5-chloro-4- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound 275)

In a manner substantially similar to general procedure K ₂ The title was prepared by the procedure described inThe compound gave the desired compound (compound 275) as an off-white solid.

¹ H NMR(400MHz,DMSO-d6):δ10.11(s,1H),9.46(bs,1H),9.29(bs,1H),8.11(s,1H),8.06(s,1H),7.92(s,1H),7.70(s,1H),7.36-7.32(m,2H),7.26-6.90(m,2H),6.49-6.42(m,1H),6.26-6.21(m,1H),5.75-5.72(m,1H),3.75(s,3H)。LCMS[M+H] ⁺ 370.1。

Table 23: the following compounds were prepared using the procedure described above:

table 39: the following compounds were prepared using the procedure described above:

scheme 88: synthesis of N- [3- ({ 5-fluoro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 280)

Step 1: synthesis of 2-chloro-5-fluoro-N- (3-nitrophenyl) pyrimidin-4-amine (373)

To a stirred solution of 2, 4-dichloro-5-fluoropyrimidine (372) (1 g,5.99 mmol), 3-nitroaniline (0.91 g,6.59 mmol) in isopropanol (10 mL) was added N, N-diisopropylethylamine (2.33 g,18 mmol) and the reaction mixture was stirred at 100deg.C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was then cooled to room temperature, the precipitated solid was filtered, washed with hexane and dried to give 2-chloro-5-fluoro-N- (3-nitrophenyl) pyrimidin-4-amine (373) (1.25 g, 78%) as a pale yellow solid. LCMS [ M+H ] ⁺ 269.1。

Step 2: synthesis of 2-chloro-5-fluoro-N- (3-nitrophenyl) pyrimidin-4-amine (374)

In a manner substantially similar to that of general procedure HThe title compound was prepared by the procedure described above to give the desired compound (374) as a pale yellow solid. LCMS [ M+H] ⁺ 330.2。

Step 3: synthesis of N4- (3-aminophenyl) -5-fluoro-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (375)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (375) as a pale yellow solid. LCMS [ M+H] ⁺ 300.2。

Step 4: synthesis of N- [3- ({ 5-fluoro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 280)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (ii) to give the desired compound (compound 280) as an off-white solid.

¹ H NMR(400MHz,DMSO-d6):δ10.27(m,2H),8.20(bs,1H),7.94(s,1H),7.73-7.34(m,6H),6.64-6.49(s,1H),6.42-6.23(m,1H),6.07-6.03(m,1H),5.77-5.74(m,1H),2.83(s,3H)；LCMS[M+H] ⁺ 354.2。

Scheme 89: synthesis of N- [ 3-bromo-5- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 283)

Step 1: synthesis of N- (3-bromo-5-nitrophenyl) -2, 5-dichloropyrimidin-4-amine (376)

To a stirred solution of 2,4, 5-trichloropyrimidine (13) (0.5 g,2.73 mmol), 3-bromo-5-nitroaniline (0.651 g,3.0 mmol) in dimethylformamide (5.0 mL) was added potassium carbonate (0.94 g,6.81 mmol) at room temperature and the reaction mixture was heated at 110 ℃ for 12 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and eluted with 75% heptane in ethyl acetate to give the product as a solid N- (3-bromo-5-nitrophenyl) -2, 5-dichloropyrimidin-4-amine (0.6 g, 62%) -1,3, 2-dioxaborolan-2-yl) aniline (376) as a yellow solid (0.8 g, 33%). LCMS [ M+H] ⁺ 364.9。

Step 2: synthesis of N4- (3-bromo-5-nitrophenyl) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (377)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure H to give the desired compound (377) as a pale yellow solid. LCMS [ M+H] ⁺ 424。

Step 3: synthesis of N4- (3-amino-5-bromophenyl) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (378)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (378) as a pale yellow solid. LCMS [ M+H] ⁺ 394.2。

Step 4: synthesis of N- [ 3-bromo-5- ({ 5-chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide (compound 283)

In a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (d) to give the desired compound (compound 283) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6):δ10.33(s,1H),9.35(bs,1H),9.12(bs,1H),8.17-8.07(m,1H),7.86-7.78(m,2H),7.49-7.31(m,4H),6.44-6.39(m,1H),6.35-6.26(m,1H),5.81-5.78(m,1H),3.65(s,3H)；LCMS[M+H] ⁺ 448.1。

Table 24: the following compounds were prepared using the procedure described above:

scheme 90: synthesis of N- [ 3-bromo-5- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide TFA salt (compound 290)

Step 1: synthesis of tert-butyl N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) -5-nitrophenyl ] carbamate (380)

To N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (245) (1 g,2.99 mmol) in 1, 4-dioxane (20 mL) was added tert-butyl N- (3-bromo-5-nitrophenyl) carbamate (379) (1.42 g,4.49 mmol), cesium carbonate (2.92 g,8.97 mmol). The reaction mixture was purged with argon for 10 minutes, followed by addition of tris (1, 5-diphenylpenta-1, 4-dien-3-one) dipalladium (0.137 g,0.150 mmol), [5- (diphenylphosphanyl) -9, 9-dimethyl-9H-dibenzopyran-4-yl)]Diphenyl phosphate (0.086 g,0.150 mmol) and the reaction mixture was heated at 105 ℃ for 12 hours. The reaction mixture was then cooled and filtered through celite. The filtrate was diluted with water (10 mL) and extracted with dichloromethane (10 mL. Times.2). The combined organic layers were washed with saturated ammonium chloride solution (10 mL), dried over anhydrous sodium sulfate and evaporated to give N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) as a brown solid]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) -5-nitrophenyl]Tert-butyl carbamate (380) (1 g, 46%). LCMS [ M+H ] ⁺ 571.1。

Step 2: synthesis of N4- (3-amino-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (381)

To N- [3- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino) at room temperature]-5- [4- (trifluoromethyl) phenyl ]]Pyrimidin-4-yl } amino) -5-nitrophenyl]To a stirred solution of tert-butyl carbamate (380) (0.480 g,1.72 mmol) in dichloromethane (10 mL) was slowly added dropwise HCl-containing dioxane (10 mL) and stirred for 6 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was then concentrated under reduced pressure. The crude product was washed with diethyl ether to give N4- (3-amino-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl)]Pyrimidine-2, 4-diamine (381) (0.8 g, 69%). LCMS [ M+H] ⁺ 471.0

Step 3: synthesis of N4- (3-bromo-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (382)

To N4- (3-amino-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl]To a stirred solution of pyrimidine-2, 4-diamine (381) (0.8 g,1.7 mmol) in dichloromethane (10 mL), water (10 mL) was added bromotrichloromethane (4.19 mL,42.5 mmol), sodium nitrite (0.587 g,8.5 mmol) and acetic acid (2.92 mL,51 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (20 ml×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was washed with diethyl ether to give N4- (3-bromo-5-nitrophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl) ]Pyrimidine-2, 4-diamine (382) (0.8 g, 62%). LCMS [ M+H] ⁺ 536.0。

Step 4: synthesis of N4- (3-amino-5-bromophenyl) -N2- (1-methyl-1H-pyrazol-4-yl) -5- [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4-diamine (383)

The title compound is prepared in a manner substantially analogous to the procedure described in general procedure L to give the desired compound (383) as a brown solid. LCMS [ M+H] ⁺ 506.0。

Step 5: synthesis of N- [ 3-bromo-5- ({ 2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl } amino) phenyl ] prop-2-enamide TFA salt (compound 290):

in a manner substantially similar to general procedure K ₂ The title compound was prepared by the procedure described in (ii) to give the desired compound as an off-white solid (compound 2290). ¹ H NMR(400MHz,DMSO-d6):δ10.30(s,1H),9.70(bs,1H),9.13(bs,1H),8.22(bs,1H),8.02(s,1H),7.84-7.72(m,6H),7.47-7.38(m,3H),6.45-6.38(m,1H),6.29-6.24(m,1H),5.81-5.78(m,1H),3.68(bs,3H)。LCMS[M+H] ⁺ 560.1。

Table 25: the following compounds were prepared using the procedure described above:

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example 2: cell proliferation (Alamar blue) assay

Details of the cell lines:

1. EGFR (D770_N771 insSVD) expressing Ba/F3 stable cell line

2. EGFR expressing Ba/F3 stable cell line (A767_dupASV)

A431 cells

4. EGFR (H773 insNPH) expressing Ba/F3 stable cell line

5. HER2 (A775_G776 insYVMA) expressing Ba/F3 stable cell line

Measurement procedure:

1. 5000 cells of A431 and 15,000 cells of Ba/F3 (DMEM with 10% FBS for A431 and RPMI with 10% FBS for Ba/F3 cells) were seeded at 100. Mu.L/well in complete medium in 96-well tissue culture plates. Leaving cell-free external wells for background measurement. At 37 degrees Celsius at 5% CO ₂ Incubate in a humidified incubator for 16-18 hours.

2. 0.025ml of 5X concentration compound dilutions or DMSO controls were added. The final compound concentration ranged from 10-0.0005 μm prepared in 3-fold serial dilutions. At 37 degrees Celsius at 5% CO ₂ Incubate in a humidified incubator for 72 hours.

3. 0.0125ml Alamar Blue was pipetted into a multichannel pipette ^TM Reagents were added to each well and gently tapped on each side of the plate for mixing. At 37 degrees Celsius at 5% CO ₂ Incubate in a humidified incubator for 3 hours.

4. Plates were read on a fluorescence reader (Tecan Spark control, device: spark, accession number # 1801006040) at 540nm excitation, 590nm emission wavelength.

5. Data analysis was performed using XLfit 5.5.0.5.

Table 26 shows the activity of the compounds of the present disclosure in EGFR and HER2 cell proliferation assays.

Table 26: cell proliferation data.

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ND: not measured.

Claims (96)

1. A compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

x is-NH-or-O-;

R ¹ is- (C (R) ⁴ ) ₂ ) _n R ⁵ Wherein R is ⁵ Unsubstituted or substituted by 1R ⁵ ' substitution;

n is 0, 1, 2 or 3;

each R ⁴ Independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl;

R ⁵ is C _4-10 Cycloalkyl, aryl or heteroaryl;

Each R ⁵ ' is independently deuterium, aryl, heteroaryl, alkyl, C ₃ -C ₆ Cycloalkyl, 3-8 membered heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -NH ₂ 、-NHR ⁶ 、-N(CH ₃ )R ₆ 、-N(R ⁶ ) ₂ 、-C(＝O)NH ₂ 、-C(＝O)NHR ⁶ 、-C(＝O)N(R ⁶ ) ₂ 、-NR ⁶ C(＝O)R ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ NH ₂ 、-S(＝O) ₂ NHR ⁶ 、-S(＝O) ₂ N(R ⁶ ) ₂ 、-S(＝O) ₂ Heteroaryl, alkoxy or haloalkoxy;

each R ⁶ Independently alkyl, aminoalkyl, cycloalkyl, aryl or heteroaryl;

R ² is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with at least one R ⁷ And 0, 1 or 2R ⁸ Substitution;

each R ⁷ Independently is

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

R ⁹ 、R ⁹ ' and R ⁹ "independently hydrogen, deuterium, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl) heterocycloalkyl;

R ¹⁰ hydrogen, alkyl, haloalkyl or cycloalkyl;

each R ⁸ Independently is aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹¹ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy;

each R ¹¹ Independently alkyl, cycloalkyl, aryl or heteroaryl;

R ³ is 0, 1, 2 or 3R ¹² Substituted heteroaryl;

each R ¹² Independently is aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, -N (R) ¹³ ) ₂ 、-S(＝O) ₂ NH ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or cycloalkyl, wherein each of said aryl, heteroaryl, heterocycloalkyl or cycloalkyl is independently unsubstituted or substituted with 0, 1 or 2R ¹⁴ Substitution;

each R ¹³ Independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;

each R ¹⁴ Independently deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, -N (R) ¹⁵ ) ₂ 、-S(＝O) ₂ Alkyl, -S (=o) ₂ Aryl, -S (=o) ₂ Heteroaryl or alkoxy; and is also provided with

Each R ¹⁵ Independently is alkyl, cycloalkyl, aryl or heteroaryl.

2. The compound of claim 1, wherein X is-NH-.

3. The compound of any one of claims 1 to 2, wherein n is 0.

4. A compound according to any one of claims 1 to 3 wherein R ⁵ Is phenyl, naphthyl, anthryl, phenanthryl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl or C-linked indolyl; wherein R is ⁵ Unsubstituted or substituted by 1R ⁵ 'substitution'.

5. The method of any one of claims 1 to 4Wherein R is a compound of formula (I) ⁵ Unsubstituted.

6. The compound of any one of claims 1 to 4, wherein R ⁵ Is 1R ⁵ 'substitution'.

7. The compound of claim 6, wherein each R ⁵ ' is independently alkyl, haloalkyl, heterocycloalkyl, halo, cyano, hydroxy, -N (R) ⁶ ) ₂ 、-C(＝O)NHR ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ NH ₂ An alkoxy group or a haloalkoxy group.

8. The compound of claim 7, wherein each R ⁵ ' is independently methyl, ethyl, t-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, -N (R) ⁶ ) ₂ 、-N(CH ₃ )R ₆ 、-C(＝O)NHR ⁶ 、-NHC(＝O)R ⁶ 、-S(＝O) ₂ NH ₂ Methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy.

9. The compound of claim 8, wherein each R ⁵ ' is independently methyl, morpholinyl, fluoro, chloro, cyano, -C (=o) NHMe, -NHC (=o) Me, -S (=o) ₂ NH ₂ Methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.

10. The compound of any one of claims 1 to 4 or 6 to 9, wherein each R ⁶ Independently an alkyl or aryl group.

11. The compound of claim 10, wherein each R ⁶ Independently methyl, ethyl, isopropyl, tert-butyl, phenyl or naphthyl.

12. The compound of claim 11, wherein each R ⁶ Independently methyl or phenyl.

13. The compound of any one of claims 1 to 12, wherein R ² Is monocyclic.

14. The compound of any one of claims 1 to 13, wherein R ² Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl; wherein the phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl is substituted with at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution.

15. The compound of any one of claims 1 to 14, wherein R ² Is phenyl, cyclohexyl or pyrrolyl; wherein the phenyl, cyclohexyl or pyrrolyl group is substituted with at least one R ⁷ And 0, 1 or 2R ⁸ And (3) substitution.

16. The compound of any one of claims 1 to 15, wherein R ⁷ Is that

17. The compound of any one of claims 1 to 15, wherein R ⁷ Is that

18. The compound of any one of claims 1 to 15 Wherein R is ⁷ Is that

19. The compound of any one of claims 1 to 15, wherein R ⁷ Is that

20. The compound of any one of claims 1 to 19, wherein Y is-C (=o) -.

21. The compound of any one of claims 1 to 19, wherein Y is-S (=o) ₂ -。

22. The compound of any one of claims 1 to 21, wherein R ⁹ 、R ⁹ ' and R ⁹ "independently is hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl) heterocycloalkyl.

23. The compound of any one of claims 1 to 22, wherein R ⁹ 、R ⁹ ' and R ⁹ "independently is hydrogen, fluorine, chlorine, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl.

24. The compound of any one of claims 1 to 15, 17 or 19 to 23, wherein R ¹⁰ Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl or cyclopropyl.

25. The compound of claim 24, wherein R ¹⁰ Is hydrogen or methyl.

26. The method of any one of claims 1 to 25Said compound wherein R ² Is covered by 1 or 2R ⁸ And (3) substitution.

27. The compound of any one of claims 1 to 26, wherein each R ⁸ Independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chloro, heteroalkyl, cyano, hydroxy, amino, -N (R) ¹¹ ) ₂ Methoxy, ethoxy or trifluoromethoxy.

28. The compound of any one of claims 1 to 27, wherein each R ⁸ Independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, -N (R) ¹¹ ) ₂ Hydroxyethyl, methoxyethyl or cyano.

29. The compound of any one of claims 1 to 28, wherein each R ¹¹ Independently an alkyl or aryl group.

30. The compound of any one of claims 1 to 29, wherein each R ¹¹ Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl or phenanthrenyl.

31. The compound of any one of claims 1 to 30, wherein each R ¹¹ Independently methyl, ethyl, isopropyl, tert-butyl, phenyl or naphthyl.

32. The compound of any one of claims 1 to 31, wherein each R ¹¹ Independently methyl or phenyl.

33. The compound of any one of claims 1 to 25, wherein R ² Unsubstituted.

34. The compound of any one of claims 1 to 33, wherein R ³ Is phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution.

35. The compound of any one of claims 1 to 34, wherein R ³ Is phenyl, imidazolyl, pyrazolyl, triazolyl, indolyl, indazolyl, thiazolyl, isothiazolyl or pyridyl; wherein R is ³ Is substituted with 0, 1, 2 or 3R ¹² And (3) substitution.

36. The compound of any one of claims 1 to 35, wherein R ³ The method comprises the following steps:

wherein R is ³ Is 0 to 3R ¹² And (3) substitution.

37. The compound of any one of claims 1 to 33, wherein R ³ The method comprises the following steps:

38. the compound of any one of claims 37, wherein R ³ The method comprises the following steps:

39. the compound of any one of claims 1 to 36, wherein R ³ Unsubstituted.

40. The compound of any one of claims 1 to 36, wherein R ³ Is at least 1R ¹² And (3) substitution.

41. The compound of claim 40, wherein R is ³ Is at least 2R ¹² And (3) substitution.

42. The compound of any one of claims 1 to 36, claim 40 or claim 41, wherein each R ¹² Independently is aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, heterocycloalkyl, -N (R) ¹³ ) ₂ 、-S(＝O) ₂ NH ₂ Or cycloalkyl.

43. The compound of claim 42, wherein each R ¹² Independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluoro, chloro, cyano, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, -N (R) ¹³ ) ₂ Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

44. As claimed in43, wherein each R ¹² Independently is methyl, isopropyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl or cyclopropyl.

45. The compound of claim 44, wherein each R ¹² Independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl or chlorine.

46. The compound of claim 45, wherein each R ¹² Independently methyl or chloro.

47. The compound of any one of claims 1 to 36 or 40 to 43, wherein each R ¹³ Independently alkyl or cycloalkyl.

48. The compound of claim 47, wherein each R ¹³ Independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

49. The compound of claim 48, wherein each R ¹³ Independently methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl or cyclohexyl.

50. The compound of claim 49, wherein each R ¹³ Independently methyl, cyclopropyl or cyclohexyl.

51. The compound of any one of claims 1 to 42, wherein R ¹² Is unsubstituted.

52. The compound of any one of claims 1 to 42, wherein R ¹² Is substituted with 1 or 2R' s ¹⁴ And (3) substitution.

53. The compound of any one of claims 1 to 42 or claim 52, wherein each R ¹⁴ Independently alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, -N (R) ¹⁵ ) ₂ Or an alkoxy group.

54. The compound of claim 53, wherein each R ¹⁴ Independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, -N (R) ¹⁵ ) ₂ Methoxy, ethoxy or trifluoromethoxy.

55. The compound of claim 54, wherein each R ¹⁴ Independently methyl, ethyl, isopropyl, tert-butyl, pyrrolidinyl, piperidinyl, morpholinyl, fluoro, chloro, -N (R) ¹⁵ ) ₂ Or methoxy.

56. The compound of any one of claims 1 to 42 or 52 to 55, wherein each R ¹⁵ Independently alkyl or cycloalkyl.

57. The compound of claim 56, wherein each R ¹⁵ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

58. The compound of any one of claims 1 to 42 or 52 to 57, wherein each R ¹³ Independently methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl or cyclohexyl.

59. The according to claim 58The compound, wherein each R ¹³ Independently methyl, cyclopropyl or cyclohexyl.

60. The compound of any one of claims 1 to 59, wherein:

x is-NH-or-O-;

n is 0;

R ⁵ is 0 or 1R ⁵ ' substituted phenyl;

R ² is at least one R ⁷ And 0, 1 or 2R ⁸ A substituted phenyl group; and is also provided with

R ³ Is 0, 1, 2 or 3R ¹² Substituted pyrazolyl.

61. The compound of claim 60, wherein X is-NH-.

62. The compound of claim 60 or 61, wherein R ⁵ ' is fluoromethyl, difluoromethyl or trifluoromethyl.

63. The compound of any one of claims 60 to 62, wherein:

R ⁷ is thatAnd is also provided with

R ⁸ Is halo.

64. The compound of any one of claims 60 to 63, wherein:

R ⁸ is fluorine;

y is-C (=O) -;

R ⁹ 、R ⁹ ' and R ⁹ "is hydrogen; and is also provided with

R ¹⁰ Is hydrogen.

65. The compound of any one of claims 60 to 64, wherein R ¹² Is alkyl.

66. The compound of any one of claims 60 to 65, wherein R ¹² Is methyl.

67. The compound of any one of claims 60 to 66, wherein the compound has formula I-a, formula I-B, formula I-C, formula I-D, formula I-E, formula I-F, or formula I-G:

Or a pharmaceutically acceptable salt or stereoisomer thereof.

68. The compound of claim 1, wherein the compound is:

/>

/>

/>

/>

/>

/>

/>

/>

/>

/>

/>

or alternatively, a method of manufacturing the samePharmaceutically acceptable salts.

69. A compound, wherein the compound is selected from the group consisting of:

/>

/>

/>

/>

/>

/>

/>

/>

or a pharmaceutically acceptable salt or stereoisomer thereof.

70. A pharmaceutical composition comprising a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

71. A method of inhibiting an Epidermal Growth Factor Receptor (EGFR) family kinase mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof.

72. The method of claim 71, wherein 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.

73. The method of any one of claims 71 or 72, wherein the EGFR family kinase mutant is selected from del19/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupa EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof.

74. A method of inhibiting an Epidermal Growth Factor Receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-69, or a pharmaceutically acceptable salt or stereoisomer thereof.

75. The method of claim 74, wherein 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.

76. The method of any one of claims 74 or 75, wherein the EGFR mutant is selected from del19/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupamv EGFR, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof.

77. A method of inhibiting a drug resistant Epidermal Growth Factor Receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-69, or a pharmaceutically acceptable salt or stereoisomer thereof.

78. The method of claim 77, wherein the drug resistant EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR.

79. A method of inhibiting Epidermal Growth Factor Receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound exhibits higher inhibition of EGFR mutants relative to wild-type EGFR.

80. The method of claim 79, wherein 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.

81. The method of claim 80, wherein the EGFR mutant is selected from del19/T790M EGFR, L858R EGFR, L861QEGFR, 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, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupAEGFR, 773insAH EGFR, M766_A767insAI EGFR and any combination thereof.

82. A method of treating a disease or disorder associated with an Epidermal Growth Factor Receptor (EGFR) family kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof.

83. The method of claim 82, wherein the disease or disorder of the subject comprises an EGFR mutation.

84. The method of claim 83, wherein the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.

85. The method of claim 84, wherein the EGFR mutation is selected from the group consisting of del19/T790M EGFR, L858R EGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupaegfr, 773insAH EGFR, M766 a767insAI EGFR, and any combination thereof.

86. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof.

87. The method of claim 86, wherein the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, or non-small cell lung cancer.

88. The method of claim 87, wherein the cancer is non-small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, colorectal cancer, or glioblastoma.

89. The method of any one of claims 86-88, wherein the cancer of the subject comprises EGFR mutations.

90. The method of claim 89, wherein the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.

91. The method of claim 90, wherein the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupaegfr, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof.

92. A method of treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof.

93. The method of claim 92, wherein the inflammatory disease is psoriasis, eczema, or atherosclerosis.

94. The method of claim 92, wherein the inflammatory disease of the subject comprises an EGFR mutation.

95. The method of claim 94, wherein the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.

96. The method of claim 95, wherein the EGFR mutation is selected from del19/T790M EGFR, L858R EGFR, L861QEGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupaegfr, 773insAH EGFR, M766_a767insAI EGFR, and any combination thereof.