CN111718332B

CN111718332B - 2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof

Info

Publication number: CN111718332B
Application number: CN202010194749.XA
Authority: CN
Inventors: 张强; 王中祥; 冯守业; 李兰涛; 张宏波; 杨海龙; 徐占强; 周利凯
Original assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Current assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Priority date: 2019-03-19
Filing date: 2020-03-19
Publication date: 2021-08-17
Anticipated expiration: 2040-03-19
Also published as: WO2020187292A1; CN111718332A

Abstract

The invention relates to a novel compound serving as a JAK kinase inhibitor, a composition and application thereof. Specifically, the invention provides a compound (shown as a formula (1)) with strong JAK kinase inhibition activity, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a metabolite, an isotopic derivative and a solvate thereofAnd pharmaceutical compositions comprising said compounds. The invention also discloses the use of a compound or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of an autoimmune disease or cancer.

Description

2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof

Technical Field

The invention belongs to the field of chemical medicine, and particularly relates to a compound with JAK kinase inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in preparation of medicines.

Background

JAK kinases (Janus kinases) and their downstream effector, signal transduction and transcriptional activator proteins form an important cytokine signaling pathway, the JAK-STAT pathway. Researches show that the JAK-STAT pathway can be activated by various cytokines, growth factors and receptors and participate in the processes of cell proliferation, differentiation, apoptosis, angiogenesis, immunoregulation and the like. The JAK kinase is a key kinase in the JAK-STAT signal pathway, which was found more than two decades later, the first JAK kinase inhibitor (tofacitinib) was approved for rheumatoid arthritis treatment in 2012 [ Norman p, Selective JAK inhibitors in details for rhematoid arthritis, Expert Opin Investig Drugs,2014,23: 1067-.

In mammals, the four members of the JAK kinase family: JAK1, JAK2, JAK3 and TYK2 are composed of more than 1100 amino acids, the relative molecular mass can reach 120000-140000, the homology can reach 40% -70%, and the JAK kinase family members can be sequentially divided into 7 homologous structural domains (JH) from the C end to the N end: JH1 is a kinase region, highly conserved in the JAK family; JH2 is a kinase-like region or "pseudo" kinase region, the pseudo kinase domain is a unique property of JAK protein which is different from other tyrosine proteins, the kinase region has no catalytic activity but has a regulating effect on the activity of JH1, and mutations in the domain can often lead to the enhancement or the reduction of the JAK kinase activity and further lead to the occurrence of certain diseases; JH3-JH4 is the SH 2domain (Src homology 2domain) which contains about 100 amino acid residues that specifically recognize and bind phosphorylated tyrosine residues on ligands; JH5-JH7 are FERM domains that are conserved, primarily regulating JAK binding to receptors. JAK3, a member of the JAK kinase family, structurally contains the kinase domain described above, and changes in kinase activity are caused by mutations in specific amino acids in different domains.

The JAK-STAT signal pathway is an important intracellular signal transduction pathway in the processes of growth, activation, differentiation, apoptosis and function development of various cells. STATs are cytoplasmic proteins that bind to DNA in the regulatory region of target genes and are downstream substrates of JAK. The STAT family includes 7 members including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, and the like. The interaction between JAKs and STATs plays an important role in Cytokine receptor signaling pathways [ O' Sullivan LA et al, Cytokine receptor signaling through the JAK-Stat-Socs pathway in disease, Mol Immunol,2007,44:2497-2506 ]. Cytokine receptors on cell surfaces, when bound to their respective cytokine ligands, cause dimerization of the receptor molecules, allowing JAK kinases coupled to the receptors to approach each other and become activated by interactive tyrosine phosphorylation. The JAK-STAT signaling pathway is a signaling pathway stimulated by multiple cytokine receptors, JAK kinases mediate signaling of most intracellular cytokines, such as Interleukins (ILs), Interferons (IFNs), Erythropoietins (EPO), Granulocyte and Macrophage Colony Stimulating Factor (GMCSF), somatotropin (GH), Prolactin (PRL), Thrombopoietin (TPO), platelet derived factor (PDGF), and Epidermal Growth Factor (EGF), and the like, and different receptors activate different subtypes of JAK kinases to exhibit differential biological functions [ Pesu m.et al, Therapeutic targeting of Janus kinases, Immunol Rev,2008,223: 132-.

JAK1 and JAK2 are expressed in each tissue cell of the human body, and JAK3 is mainly expressed in each hematopoietic tissue cell, and is mainly present in bone marrow cells, thymocytes, NK cells, activated B lymphocytes, and T lymphocytes. The deletion of JAK1 and JAK2 can cause lethal injury to human body, and the deletion of JAK3 can avoid toxic adverse reaction for damaging other tissue cells [ Yamaoka K., et al., JAK3 novel ligands-cell cytokine production and survival, Blood,2005,106:3227-3233 ]. Based on the functional characteristics and special tissue distribution of each subtype in the JAK kinase family, JAK3 has become a popular target for treating autoimmune diseases, and more clinical researches focus on blocking the JAK3 signal transduction path for treating rheumatoid arthritis. In 2012, the selective JAK3 inhibitor Tofacitinib passed clinical trials and was approved for the treatment of rheumatoid arthritis.

Tofacitinib (CP690550) is a pyrrolopyrimidine selective JAK3 kinase inhibitor developed by Pfizer, and has inhibitory activity (IC) on JAK3₅₀1nmol/L) is JAK2 (IC)₅₀20 times of 20nmol/L) and JAK1 (IC)₅₀112nmol/L) of the total. The study on the stereochemistry of Tofacitinib shows that the chiral structure of Tofacitinib determines that Tofacitinib can be specifically bound to JAK3 molecules, so that JAK3 phosphorylation is inhibited, STAT phosphorylation is further inhibited, and downstream inflammatory cytokine synthesis is inhibited. Tofacitinib shows good clinical treatment in clinical researchIn the clinical trial study of rheumatoid arthritis, the 5mg or 10mg Tofacitinib measuring group and the placebo group with the same amount show obvious statistical difference, but Tofacitinib is found to be related to the increased risk of serious infection in the clinical trial study, and the long-term safety of Tofacitinib is further researched.

The JAK-STAT signal pathway plays an important role in the cell differentiation and proliferation processes, and the change of the JAK activity also causes the change of the signal transmission of the pathway, thereby influencing the cell function. Based on the key role of JAK kinase in JAK-STAT signal transmission and the specific histiocyte distribution of JAK3 kinase, JAK3 becomes a good therapeutic target for diseases such as rheumatoid arthritis.

At present, JAK3 inhibitors are mainly used for treating patients with moderate and severe rheumatoid arthritis, and the drugs show good treatment effect and good safety in treatment, but the long-term safety of the drugs still needs to be further improved. During the clinical research process of Tofacitinib, certain adverse reactions including infection, tuberculosis, tumor and liver injury and the like can be caused after the medicament is used, so that the key problems to be solved urgently in the research field are to improve the drug effect of the JAK3 inhibitor and reduce toxic and side effects.

The JAK kinase has high ATP binding site homology of several subtypes and small structural difference, which is an important reason for low selectivity of JAK inhibitors. There is still room for improvement in therapeutic effect, selectivity and safety of a series of JAK kinase inhibitors disclosed so far, and there is still a need to develop JAK inhibitors with better drug efficacy and better safety, wherein the development of highly selective JAK inhibitors is a key point. The compound shows excellent biological activity and high selectivity, and can be used as a JAK kinase inhibitor in treatment of related diseases.

Disclosure of Invention

In view of the above problems, the present application provides a 2- (1-substituted pyrazol-4-) amino-4-substituted amino-5-pyrimidine carboxamide compound and its use for the preparation of a medicament for the treatment or prevention of a disease caused by a tyrosine kinase (e.g., JAK1, JAK2, JAK3, TYK2) or a variant thereof.

According to one aspect of the present invention, there is provided a compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, having the structural formula (I):

wherein n1 is an integer from 1 to 3, n2 is an integer from 1 to 2, preferably n1 is 3, n2 is 1 or n1 is 2, n2 is 2 or n1 is 2, n2 is 1;

R₁is selected from 1 to 3 of C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio radical, C₁-C₃Acyl, hydroxy, halogen, halogeno C₁- C₃Alkyl, cyano, -CONH₂Oxo (═ O) or-NR^aR^bC substituted or unsubstituted by the substituent in (1)₃-C₈A cycloalkyl group,

or from 1 to 3 selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio radical, C₁-C₃Acyl, hydroxy, halogen, halogeno C₁-C₃Alkyl, cyano, -CONH₂Oxo (═ O) or-NR^aR^bA 4-7 membered heterocycloalkyl group which is substituted or unsubstituted with the substituent(s) in (1),

or from 1 to 3 selected from C₁-C₆Alkoxy radical, C₁-C₆Alkylthio radical, C₁-C₃Acyl, hydroxy, halogen, halogeno C₁-C₃Alkyl, 4-7 membered heterocycloalkyl, cyano, -CONH₂、C₃-C₈Cycloalkyl, or-NR^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₁₀An alkyl group, a carboxyl group,

or from 1 to 3 selected from C₁-C₁₀Alkyl, halogen, halogeno C₁-C₁₀Alkyl, cyano, hydroxy-substituted C₁-C₁₀Alkyl radical, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、-CO-R₅’、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl radical C₁-C₆Alkyl, (C)₃-C₈Cycloalkyl) -O- (C₁-C₆Alkyl), 4-7 membered heterocycloalkyl optionally substituted or unsubstituted with one or more A, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, aryl or heteroaryl optionally substituted with one or more B, -NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

a is C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl, cyano-substituted C₁-C₆Alkyl radical, C₁-C₃Acyl, cyano-substituted C₁-C₃Acyl, - (CH)₂)t-NR^aR^b，

B is hydrogen, C₁-C₆An alkyl group, a carboxyl group,

R₅is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl, cyano-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, - (CH)₂)t-NR^aR^b4-7 membered heterocycloalkyl substituted C₁-C₆An alkyl group, a carboxyl group,

-(CH₂)t-NR^aR^bwherein t is an integer of 0 to 6,

R₅' is hydrogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl, cyano-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-7 membered heterocycloalkyl, -NR^aR^b4-7 membered heterocycloalkyl substituted C₁-C₆An alkyl group, a carboxyl group,

the aryl group is a monocyclic or bicyclic group having 6 to 12 carbon ring atoms and having at least one aromatic ring, the heteroaryl group is a monocyclic or bicyclic group having 1 to 3 heteroatoms selected from N, O, S as ring atoms and having 5 to 10 ring atoms, the 4-7-membered heterocycloalkyl group is a 4-7-membered heterocycloalkyl group having 1 to 2 atoms selected from N, O, S as ring atoms,

R^aand R^bEach independently is hydrogen, C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-7 membered heterocycloalkyl, C₁-C₆Alkoxy substituted C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl, cyano-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical C₁-C₆Alkyl, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₆Alkyl or mono-or di-C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₆An alkyl group;

R₂or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 8,

R₄is hydrogen, hydroxy, C₁-C₃Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₃Alkoxy radical, C₁-C₃Alkylthio, -NR^cR^dOr by 1 to 3 substituents selected from C₁-C₃Alkyl, aldehyde group, C₁-C₄Alkyl acyl, amino acyl, mono-or disubstituted C₁-C₃Aminoacyl, C_1-C₃Alkyl sulfone group, C_1-C₃Alkyl sulfoxide, hydroxy, halogen, oxo (═ O), hydroxy C₁-C₃Alkyl, amino, mono-or di-C_1-C₃Alkyl substituted amino, halo C₁-C₃A 4-7 membered heterocycloalkyl group which may be unsubstituted or substituted with a substituent in the alkyl group,

R^cand R^dIndependently of each other are hydrogen and C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, hydroxy substituted C₁-C₆Alkyl or C_1-C₃Alkoxy substituted C₁- C₆An alkyl group, a carboxyl group,

the 4-7 membered heterocycloalkyl group is a 4-7 membered heterocycloalkyl group containing 1-2 atoms selected from N, O, S as ring atoms.

In some embodiments of the present application, R₁Is C₃-C₈Cycloalkyl, 4-7 membered heterocycloalkyl,

or from 1 to 3 selected from C₁-C₃Alkoxy radical, C₁-C₃Alkylthio radical, C₁-C₃Acyl, hydroxy, halogen, halogeno C₁-C₃Alkyl, 4-7 membered heterocycloalkyl, cyano, -CONH₂、C₃-C₆Cycloalkyl, or-NR^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₆An alkyl group, a carboxyl group,

or from 1 to 3 selected from C₁-C₆Alkyl, halogen, halogeno C₁-C₆Alkyl, cyano, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、- CO-R₅’、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl, hydroxy substituted C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyl radical C₁-C₆Alkyl, (C)₃-C₆Cycloalkyl) -O- (C₁-C₆Alkyl), 4-7 membered heterocycloalkyl optionally substituted or unsubstituted with one or more A, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, aryl or heteroaryl optionally substituted with one or more B, -NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

a is C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl radical, C₁-C₃Acyl, cyano-substituted C₁-C₃Acyl, - (CH)₂)t-NR^aR^b，

B is hydrogen, C₁-C₃An alkyl group, a carboxyl group,

R₅is hydrogen, C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, - (CH)₂)t-NR^aR^b4-7 membered heterocycloalkyl substituted C₁-C₃An alkyl group, a carboxyl group,

-(CH₂)t-NR^aR^bwherein t is an integer of 0 to 3,

R₅' is hydrogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl, 4-7 membered heterocycloalkyl, -NR^aR^b4-7 membered heterocycloalkyl substituted C₁-C₃An alkyl group, a carboxyl group,

R^aand R^bEach independently is hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-7 membered heterocycloalkyl, C₁-C₃Alkoxy substituted C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl radical C₁-C₃Alkyl, 4-7 membered heterocycloalkyl substituted C₁-C₃Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₃Alkyl or mono-or di-C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₃An alkyl group, a carboxyl group,

the aryl is phenyl, naphthyl,

The heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 1, 5-naphthyridinyl, 1, 6-naphthyridonyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo [3,4-d ] group]Pyrimidinyl, pyrido [3,2-d ]]Pyrimidinyl, pyrido [3,4-d ]]Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinoxalinyl,

In some preferred embodiments of the present application, R₁Is C₃-C₇Cycloalkyl, 4-6 membered heterocycloalkyl,

or from 1 to 3 substituents selected from methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, formyl, acetyl, hydroxy, fluoro, chloro, trifluoromethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyano, -CONH₂Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or-NR^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₆An alkyl group, a carboxyl group,

or from 1 to 3 substituents selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluoro, chloro, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂-R₅、-SO- R₅、-CO-R₅’、-O-R₅Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxylphylPhenylpropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazin-1-yl, 4-hydroxyethylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4- (2-cyanoacetyl) piperazin-1-yl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinyl methyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, cyclobutyl-methyl, cyclopentyl-methyl, cyclohexyl-1-yl, cyclopentylmethyl, piperidinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, etc, Aryl or heteroaryl substituted or unsubstituted with a substituent selected from azetidinylmethyl, dimethylamino, diethylamino, dipropylamino, methylamino, ethylamino, propylamino, methylethylamino, methylpropylamino or ethylpropylamino,

R₅is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazolyl, pyrazinyl, thiazolyl, neopentyl, or neopentyl, Pyrimidinyl, pyridazinyl, or- (CH)₂)t-NR^aR^b，

-(CH₂)t-NR^aR^bWherein t is an integer of 0 to 3,

R₅' is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentylHexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, or-NR^aR^b，

R^aAnd R^bEach independently of the others hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyran-4-yl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylaminopropyl,

the aryl is phenyl, and the heteroaryl is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, thiazolyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, and the like,

The 4-6 membered heterocycloalkyl group is a 4-6 membered heterocycloalkyl group containing 1-2 atoms selected from N, O, S as ring atoms.

In some preferred embodiments of the present application, R₁Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl,Ethoxyethyl, ethoxypropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylethyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, methyl-2-hydroxy-propyl, methyl-3-hydroxy-butyl, methyl-2-methyl-ethyl, methyl-3-methyl-ethyl, methyl-2-propyl, methyl-3-propyl, methyl-4-propyl, methyl-2-propyl, ethyl-ethyl, methyl-4-ethyl, methyl-2-ethyl, methyl-ethyl, ethyl-2-methyl-ethyl, ethyl-methyl-4-ethyl, methyl-2-ethyl, ethyl-methyl-2-propyl, ethyl-methyl-3-butyl, ethyl-methyl-4-ethyl, ethyl-4-methyl, ethyl-methyl-4-methyl, ethyl, butyl, ethyl, butyl, ethyl, butyl, ethyl, butyl, ethyl, butyl, ethyl, butyl, ethyl, butyl, ethyl, butyl, ethyl, etc,

Or is that

R₆、R₇、R₈Each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluorine, chlorine, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂- R₅、-SO-R₅、-CO-R₅’、-O-R₅Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazin-1-yl, 4-hydroxyethylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4- (2-cyanoacetyl) piperazin-1-yl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, t-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-2-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-2-methyl, n-butyl, n-ethyl, n-butyl, n-methyl, n-butyl, n-methyl, n-ethyl, n-methyl, n-butyl, n-methyl, n-2-methyl, n-ethyl, n-methyl, n-butyl, n-p-ethyl, n-p-methyl, n-butyl, n-methyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, azetidinylmethyl, dimethylamino, diethylamino, dipropylamino, methylamino, ethylamino, propylamino, methylethylamino, methylpropylamino or ethylpropylamino,

R₅is hydrogen, methyl, ethyl, propylIsopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, or- (CH).₂)t-NR^aR^b，

-(CH₂)t-NR^aR^bWherein t is an integer of 0 to 3,

R₅' is hydrogen, hydroxy, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, or-NR^aR^b，

R^aAnd R^bEach independently is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyran-4-yl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylaminopropyl.

In some embodiments of the present application, R₂Or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 6,

R₄is hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutylCyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR^cR^dOr a 4-6 membered heterocycloalkyl group which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, aldehyde, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylaminoacyl, dimethylaminoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, methylsulfinylidene, ethylsulfoxidyl, propylsulfoxidyl, isopropylsulfoxidyl, hydroxyl, fluorine, chlorine, hydroxymethyl, hydroxyethyl, hydroxypropyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, methylpropylamino, methylisopropylamino, oxo (═ O), trifluoromethyl;

R^cand R^dEach independently hydrogen, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, tert-butyl, 1-ethylpropyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxyhexyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, isopropoxyethyl, isopropoxypropyl, isopropoxybutyl, isopropoxypentyl or isopropoxyhexyl,

the 4-6 membered heterocycloalkyl group is pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, oxetanyl, azetidinyl.

In some embodiments of the present application, R₂Or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 3,

R₄is hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a combination thereof,Isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR^cR^d，

R^cAnd R^dEach independently hydrogen, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, tert-butyl, 1-ethylpropyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxyhexyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, isopropoxyethyl, isopropoxypropyl, isopropoxybutyl, isopropoxypentyl or isopropoxyhexyl.

In some preferred embodiments of the present application, R₂Or R₃Each independently hydrogen, dimethylaminomethyl.

According to one aspect of the present invention, there is provided a compound, or an isomer, solvate or pharmaceutically acceptable salt thereof, having the structural formula (Ia):

wherein R is₁Is selected from 1 to 3 of C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio radical, C₁-C₃Acyl, hydroxy, halogen, halogeno C₁-C₃Alkyl, cyano, -CONH₂Oxo (═ O) or-NR^aR^bC substituted or unsubstituted by the substituent in (1)₃-C₈A cycloalkyl group,

or from 1 to 3 selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio radical, C₁-C₃Acyl, hydroxy, halogen, halogeno C₁-C₃Alkyl, cyano, or,-CONH₂Oxo (═ O) or-NR^aR^bA 4-7 membered heterocycloalkyl group which is substituted or unsubstituted with the substituent(s) in (1),

or from 1 to 3 selected from C₁-C₁₀Alkyl, halogen, halogeno C₁-C₁₀Alkyl, cyano, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、 -CO-R₅、-CONH-R₅、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl, hydroxy substituted C₁-C₁₀Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl radical C₁-C₆Alkyl, (C)₃-C₈Cycloalkyl) -O- (C₁-C₆Alkyl), 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, -NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

R₅is hydrogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-7 membered heterocycloalkyl substituted C₁-C₆An alkyl group, a carboxyl group,

R^aand R^bEach independently is hydrogen, C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 4-7 membered heterocycloalkyl, C₁-C₆Alkoxy substituted C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical C₁-C₆Alkyl, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₆Alkyl or mono-or di-C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₆An alkyl group;

R₂or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 8,

In some embodiments of the present application, in formula (Ia), R₁Is C₃-C₈Cycloalkyl, 4-7 membered heterocycloalkyl,

or from 1 to 3 selected from C₁-C₆Alkyl, halogen, halogeno C₁-C₆Alkyl, cyano, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、- CO-R₅、-CONH-R₅、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl, hydroxy substituted C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyl radical C₁-C₆Alkyl, (C)₃-C₆Cycloalkyl) -O- (C₁-C₆Alkyl), 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, -NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

R₅is hydrogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl, 4-7 membered heterocycloalkyl substituted C₁-C₃An alkyl group, a carboxyl group,

R^aand R^bEach independently is hydrogen, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 4-7 membered heterocycloalkyl, C₁-C₃Alkoxy substituted C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl radical C₁-C₃Alkyl, 4-7 membered heterocycloalkyl substituted C₁-C₃Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₃Alkyl or mono-or di-C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₃An alkyl group, a carboxyl group,

the aryl is phenyl, naphthyl,

The heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinonyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo [3,4-d ] group]Pyrimidinyl, pyridinyl, pyrido [3,2-d ]]Pyrimidinyl, pyrido [3,4-d ]]Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, pyridazinyl, quinazolinyl, quinolyl, and quinolyl,

In some embodiments of the present application, in formula (Ia), preferably R₁Is C₃-C₇Cycloalkyl, 4-6 membered heterocycloalkyl,

or from 1 to 3 substituents selected from methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, formyl, acetyl, hydroxy, fluoro, chloro, trifluoromethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyano, -CONH₂Cyclopropyl, cyclobutyl, cyclopentylCyclohexyl or-NR^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₆An alkyl group, a carboxyl group,

or from 1 to 3 substituents selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluoro, chloro, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂-CH₃、-SO₂- CH₂CH₃、-SO-CH₃、-SO-CH₂CH₃、-COOH、-COCH₃、-COCH₂CH₃Aldehyde group, -CONH₂、-CONH-CH₃Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, azetidinylmethyl, -O-R₅or-NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

R₅is hydrogen, C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl, 4-6 membered heterocycloalkyl substituted C₁-C₃An alkyl group, a carboxyl group,

R^aand R^bEach independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylA group, methoxymethyl group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, ethoxyethyl group, ethoxypropyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, tetrahydropyranyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, oxetanyl group, azetidinyl group,

In some embodiments of the present application, in formula (Ia), more preferably, R₁Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl,

or is that

R₆、R₇、R₈Each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluorine, chlorine, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂- CH₃、-SO₂-CH₂CH₃、-SO-CH₃、-SO-CH₂CH₃、-COOH、-COCH₃、-COCH₂CH₃Aldehyde group, -CONH₂、-CONH- CH₃Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, azetidinylmethyl, -O-R₅or-NR^aR^b，

R₅Is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl,

R^aand R^bEach independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylMethoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl.

According to some embodiments of the application, in formula (Ia), R₂Or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 6,

R₄is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR^cR^dOr a 4-6 membered heterocycloalkyl group which is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, aldehyde, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylaminoacyl, dimethylaminoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, methylsulfinylidene, ethylsulfoxidyl, propylsulfoxidyl, isopropylsulfoxidyl, hydroxyl, fluorine, chlorine, hydroxymethyl, hydroxyethyl, hydroxypropyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, methylpropylamino, methylisopropylamino, oxo (═ O), trifluoromethyl;

R^cand R^dEach independently is hydrogen, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, tert-butyl, 1-ethylpropyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxyhexyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, isopropoxyethyl, isopropoxypropyl, isopropoxybutyl, isopropoxypentyl, tert-butyl, 1-ethylpropyl, neopentyl, and neopentylA group or an isopropoxyhexyl group,

According to some embodiments of the present application, in formula (Ia), preferably R₂Or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 6,

said 4-6 membered heterocycloalkyl group is

In some embodiments of the present application, in formula (Ia), R₂Or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 3,

R₄is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR^cR^d，

In some preferred embodiments herein, in formula (Ia), R₂Or R₃Each independently hydrogen, dimethylaminomethyl.

According to some embodiments of the application, the pharmaceutically acceptable salt of the compound is one or more selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, gluconate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium salt, and zinc salt of the compound.

Another aspect of the present invention relates to the use of the compound, a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof for the manufacture of a medicament for the treatment of autoimmune diseases and cancers associated with the tyrosine kinases JAK1, JAK2, JAK3, TYK2, wherein the autoimmune diseases and cancers associated with the tyrosine kinases JAK1, JAK2, JAK3, TYK2 include: fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract cancer sarcoma, bile duct cancer.

Another aspect of the present invention relates to the use of the compound, a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof for the manufacture of a medicament for the treatment of autoimmune diseases and cancers associated with the tyrosine kinase JAK3, wherein the autoimmune diseases and cancers associated with the tyrosine kinase JAK3 include: fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract cancer sarcoma, bile duct cancer.

In yet another aspect, the present invention provides a pharmaceutical composition comprising a pyrimidinecarboxamide compound of the present application, an isomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.

According to some embodiments of the present application, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

The present invention also relates to a method of treating a JAK1, JAK2, JAK3, TYK2 tyrosine kinase mediated disease or disorder, including those mentioned above, comprising administering to a patient (human or other mammal, especially human) in need thereof a therapeutically effective amount of a compound of formula (I) or a salt thereof, said JAK1, JAK2, JAK3, TYK2 tyrosine kinase mediated disease or disorder including those mentioned above.

In particular, the present invention also relates to a method of treating a JAK3 tyrosine kinase mediated disease or disorder which comprises administering to a patient (human or other mammal, especially human) in need thereof a therapeutically effective amount of a compound of formula (I) or a salt thereof, said JAK3 tyrosine kinase mediated disease or disorder including those mentioned previously.

Detailed Description

Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "including", "comprising", and "having", are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Detailed Description

Unless otherwise specified, alkyl represents a saturated straight-chain, branched-chain hydrocarbon radical having the indicated number of carbon atoms, the term C₁-C₁₀Alkyl represents an alkyl moiety containing from 1 to 10 carbon atoms, as with C₁-C₃Alkyl represents an alkyl moiety containing 1 to 3 carbon atoms, e.g. C₁-C₆Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl groups and the like.

When substituent terms such as "alkyl" are used in combination with other substituent terms, for example, in the term "C₁-C₃Alkoxy radical C₁-C₆Alkylthio "or" hydroxy-substituted C₁-C₁₀In alkyl, "the linking substituent term (e.g., alkyl or alkylthio) is intended to encompass divalent moieties wherein the point of attachment is through the linking substituent. "C₁-C₃Alkoxy radical C₁-C₆Examples of alkylthio "include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio, and the like. "hydroxy substituted C₁-C₁₀Examples of alkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, and the like.

Alkoxy is an alkyl-O-group formed from a straight or branched chain alkyl group previously described with-O-, for example, methoxy, ethoxy, and the like. Similarly, an alkylthio group is an alkyl-S-group formed from a straight or branched chain alkyl group previously described with-S-, for example, methylthio, ethylthio, and the like.

Alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups, the term C₂-C₆Alkenyl or C₂-C₆Alkynyl denotes straight-chain or branched C with at least one alkenyl or alkynyl group₂-C₆A hydrocarbyl group.

The term "halo C₁-C₁₀Alkyl is represented by the group consisting ofGroups having one or more halogen atoms which may be the same or different on one or more carbon atoms of the alkyl moiety of 1 to 10 carbon atoms. "halo C₁-C₁₀Examples of alkyl groups "may include, but are not limited to, -CF₃(trifluoromethyl), -CCl₃(trichloromethyl), 1-difluoroethyl, 2,2, 2-trifluoroethyl, hexafluoroisopropyl, and the like. Similarly, the term "halo C₁-C₁₀Alkoxy "denotes a group consisting of said halo C₁-C₁₀The haloalkyl-O-group formed by alkyl and-O-may be, for example, trifluoromethoxy, trichloromethoxy and the like.

The term "C₁-C₃Acyl includes formyl (-CHO), acetyl (CH)₃CO-), acetyl (C)₂H₅CO-)。

The term "-CO-R₅、-SO₂-R₅、-SO-R₅、-CONH-R₅Respectively represent

"cycloalkyl" means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term "(C)₃-C₆) Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon ring having from 3 to 6 ring carbon atoms. Exemplary "(C)₃-C₆) Cycloalkyl "includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "aryl" denotes a group or moiety comprising an aromatic monocyclic or bicyclic hydrocarbon radical containing from 6 to 12 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" are phenyl, naphthyl, indenyl and indanyl (indanyl). Typically, in the compounds of the present invention, aryl is phenyl.

The term "heterocycloalkyl", as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 4 to 7 membered non-aromatic monocyclic saturated ring system consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatoms may be optionally oxidized and the N heteroatoms may be optionally quaternized. Examples of such heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-oxathiolanyl, 1, 3-oxathianyl, 1, 3-dithianyl, 1, 4-oxathianyl, 1, 4-dithianyl, morpholinyl, thiomorpholinyl.

The term "heteroaryl" as used herein denotes a group or moiety comprising an aromatic monocyclic or bicyclic radical (which may contain 5 to 10 ring atoms) comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term also includes bicyclic heterocyclic aryl groups containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise specified, represents an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9-or 10-ring atom fused-benzene heteroaromatic ring system or bicyclic heteroaromatic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, where the N, S heteroatom may be oxidized and the N heteroatom may also be quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom to form a stable structure. Illustrative examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzisothiazolyl, dihydrobenzisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridyl, and the like, Benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, and pteridinyl.

The term "carbonyl" refers to the group-C (O) -. The terms "halogen" and "halo" represent a chloro, fluoro, bromo, or iodo substituent. "oxo" represents the oxygen moiety of a double bond; for example, if directly attached to a carbon atom, a carbonyl moiety (C ═ O) is formed. "hydroxyl" is intended to mean the radical-OH. The term "cyano" as used herein refers to the group-CN.

The term "each independently" means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

It is clear that the compounds of formula I, isomers, crystalline forms or prodrugs, and pharmaceutically acceptable salts thereof, may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.

The term "isomer" in this application is a different compound having the same molecular formula and may include various isomeric forms such as stereoisomers, tautomers and the like. "stereoisomers" are isomers that differ only in the arrangement of the atoms in space. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms which can be defined as (R) -or (S) -in terms of absolute stereochemistry. The chemical entities, pharmaceutical compositions and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other can be determined.

The individual isomers (or isomer-enriched mixtures) of the present invention can be resolved using methods known to those skilled in the art. For example, the splitting can be performed as follows: (1) by forming diastereomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support (e.g., silica gel with bound chiral ligand) or in the presence of a chiral solvent. One skilled in the art will appreciate that when the desired stereoisomer is converted to another chemical entity by one of the separation methods described above, additional steps are required to release the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or one enantiomer may be converted to the other by asymmetric transformation.

When a compound described herein contains an olefinic double bond, it is meant that the compound includes various cis-trans isomers, unless otherwise specified.

"tautomers" are structurally different isomers that can be interconverted by tautomerization. "tautomerization" is a form of isomerization and includes proton shift or proton shift tautomerization, which can be considered a subset of acid-base chemistry. "proton shift tautomerization" or "proton shift tautomerization" involves the migration of protons with a shift in the bond order, often an interchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. One example of tautomerization is keto-enol tautomerization.

The compounds of the present invention as active ingredients, as well as methods for preparing the compounds, are the subject of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and as such may be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

The compounds of the invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salts may be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, caproates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoate, pectinates, persulfates, per3-phenylpropionates, phosphates, picrates, propionates, stearates, sulfates, thiocyanates, P-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include the appropriate non-toxic ammonium, quaternary ammonium, and amine-based cations formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

In addition, the term "prodrug" as used herein means a compound which can be converted in vivo to a compound of the formula (I) of the present invention. This conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent compound in the blood or tissue.

The pharmaceutical compositions of the invention comprise a compound of structural formula (I) as described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, or an additional active agent that is an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.

The compounds of the present invention may be used alone or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or for sequential administration at different times, or the therapeutic agents may be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent, either by co-administration of each agent simultaneously or by sequential administration of each agent, in either case, for the purpose of achieving optimal effect of the drug. Co-administration includes simultaneous delivery dosage forms, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention may be used concurrently with other therapies known in the art, for example, radiation therapy or adjunctive therapies such as cytostatic agents, cytotoxic agents, other anti-cancer agents, etc. in the treatment of cancer to ameliorate the symptoms of the cancer. The present invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anti-cancer or cytotoxic agents. Alternatively, one or more other therapies may be used in combination, including surgery, radiation therapy (e.g., gamma-rays, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes, etc.), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, and Tumor Necrosis Factor (TNF)), hyperthermia, cryotherapy, attenuating any adverse effects (e.g., antiemetics), and other therapeutic agents.

To prepare the pharmaceutical compositions of this invention, one or more compounds or salts of formula (I) as the active ingredient may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation designed for administration by any convenient route, e.g. oral or parenteral. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the handbook of pharmaceutical excipients, which is published by the United states society of pharmacy and British pharmaceutical society.

The pharmaceutical compositions of the invention may be in a form, for example, suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injection such as clear solutions, suspensions, emulsions; or for topical application such as creams; or as suppositories for rectal administration. The pharmaceutical compositions may also be in unit dosage form suitable for single use administration of the precise dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound as an active ingredient prepared in accordance with the present invention, and may also include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.

Therapeutic compounds may also be administered to mammals other than humans. The dosage of the drug administered to a mammal will depend on the species of the animal and its disease state or disorder in which it is suffering. The therapeutic compound may be administered to the animal in the form of a capsule, bolus, tablet or solution. Therapeutic compounds may also be administered into the animal by injection or infusion. We prepared these pharmaceutical forms according to conventional means which meet the criteria of veterinary practice. Alternatively, the pharmaceutical composition may be mixed with animal feed for feeding to the animal, and thus, the concentrated feed supplement or premix may be prepared for mixing with conventional animal feed.

It is a further object of the present invention to provide a method for treating autoimmune diseases and cancer comprising administering to a subject a therapeutically effective amount of a composition comprising a compound of the present invention. Autoimmune diseases, cancers that can be so treated are noted elsewhere herein, including autoimmune diseases, cancers, etc. that are resistant to treatment with Tofacitinib, Pefitinib, Roxolitinib, Decernotinib, or other kinase inhibitors.

The methods of administration of the present invention comprise determining a therapeutically effective amount of a compound of the present invention to a subject in need thereof. The "therapeutically effective dose" will vary depending on the stage, progression or severity of the disease. The daily dosage of the compounds and compositions of the present invention will depend upon a variety of factors including the condition being treated, the severity of the condition, the pharmaceutical efficacy of the particular compound employed, the particular composition, the age, body weight, general health, sex and diet, the route and schedule of administration, the rate of metabolism and/or excretion of the compound, the duration of treatment, and the like. In addition, the compounds of the invention can be administered to humans and other animals in dosages and in dosages with a pharmaceutically acceptable carrier. Modes of administration include oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (e.g., via transdermal patches, powders, ointments, or drops), sublingual, buccal, or nasal spray, and the like. The effective dose of the compounds of the present invention is generally measured in terms of the amount administered per kg of body weight of the patient, preferably 0.1 to 125 mg/kg of body weight, and generally 0.01 to 500 mg/kg of body weight. Administration may be one or more times, daily, weekly, every other day or every other day, or on an intermittent schedule. For example, the compound may be administered daily, weekly (e.g., monday), indefinitely or over a period of weeks (e.g., 4-10 weeks). The effective dosage of the compounds of the present invention will vary depending upon the compound employed, the mode of administration, the severity of the disease, the condition being treated and the various physical factors of the patient involved. In most cases, satisfactory therapeutic results are achieved when the preferred compounds of the invention are administered at a daily dosage of about 0.01 to about 500 mg/kg. The dosage is preferably 0.1-125 mg/kg, and the dosage is more preferably 1-25 mg/kg. Parenteral dosages are generally at an oral dosage level of about 10% to 20%. When the compounds of the present invention are used as part of a combination treatment regimen, the components of each composition will be administered during a desired treatment period. Whether comprising the two components as separate dosage units or as a single dosage form, the components of the composition may be administered simultaneously during the treatment period, may be administered at different times during the treatment period, or may be administered as a pre-treatment of the other.

The present invention also provides methods for preparing the corresponding compounds, and the compounds described herein can be prepared using a variety of synthetic methods, including those referred to in the examples below, and the compounds of the present invention, or pharmaceutically acceptable salts, isomers, or hydrates thereof, can be synthesized using the methods described below, and synthetic methods known in the art of organic chemical synthesis, or by variations on these methods as understood by those skilled in the art, with preferred methods including, but not limited to, the methods described below.

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. The examples provided below are intended to better illustrate the invention, all temperatures being in degrees Celsius unless otherwise indicated. The final compound name in this application was generated by the naming program in Chemdraw and translated into chinese.

Synthesis of partial intermediates

Intermediate 1.2 preparation of methoxy-6-methyl-4- (pyridin-3-yloxy) aniline

Step 1) preparation of 4-bromo-2-methoxy-6-methylaniline

20 g (0.145mol) of 2-methoxy-6-methylaniline and 31 g (0.175mol) of N-bromosuccinimide are placed in a reaction bottle, 100ml of N, N-dimethylformamide is added, the mixture is stirred until the reaction is finished, 500ml of water is added, the mixture is filtered by suction, and the obtained solid is purified by column chromatography to obtain 24 g of a product with the yield of 76%. MS:216[ M + H]⁺。

Step 2): 216 mg (1mmol) of the product (4-bromo-2-methoxy-6-methylaniline) obtained in the step 1), 95 mg (1mmol) of pyridine-3-alcohol, 14.3 mg (0.1mmol) of cuprous bromide and 326 mg (1mmol) of cesium carbonate are placed in a reaction bottle, 5ml of N, N-dimethylformamide is added, nitrogen is used for protection, and the reaction is heated and stirred until the reaction is finished. The solvent was evaporated and purified by column chromatography to give 108 mg of product in 47% yield. MS 231[ M + H ] +.

Intermediate 2.4-amino-3-methoxy-5-methylbenzamide preparation

Step 1) preparation of 4-amino-3-methoxy-5-methylbenzonitrile

Placing 7.5 g (34.7mmol) of 4-bromo-2-methoxy-6-methylaniline, 16.1 g (38.2mmol) of potassium ferrocyanide, 786 mg (3.5mmol) of palladium acetate and 5.5 g (52mmol) of sodium carbonate in a reaction bottle, adding 50 ml of N, N-dimethylacetamide under the protection of nitrogen, and heating and stirring until the reaction is finished. Adding 300 ml of water for dilution, carrying out suction filtration, and carrying out chromatographic purification on the obtained solid column to obtain 5 g of the product with the yield of 88%. MS 163[ M + H]⁺。

Step 2): putting 230 mg (1.4mmol) of the product obtained in the step 1) and 196 mg (1.4mmol) of potassium carbonate into a reaction bottle, adding 3 ml of dimethyl sulfoxide and 793 mg (7mmol) of 30% hydrogen peroxide, and stirring at the temperature of no more than 20 ℃ until the reaction is finished. Diluting with 15 ml of water, extracting with ethyl acetate, spin-drying the organic phase, and purifying by column chromatography to obtain 150 mg of productThe rate was 60%. MS:181[ M + H ]]⁺。

Intermediate 3.1 preparation of (4- (4-amino-3-methoxy-5-methylphenyl) piperazin-1-yl) ethan-1-one

1.1 g (5mmol) of 4-bromo-2-methoxy-6-methylaniline, 653 mg (5mmol) of 1- (piperazin-1-yl) ethan-1-one, 458 mg (0.5mmol) of tris (dibenzylideneacetone) dipalladium, 197 mg (0.5mmol) of 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl and 2.1 g (10mmol) of potassium phosphate are placed in a reaction flask, 20 ml of dioxane is added, nitrogen is used for protection, and the mixture is heated and stirred until the reaction is finished. The solvent is evaporated to dryness, and the product is purified by column chromatography to obtain 800 mg of the product with the yield of 60 percent. MS 264[ M + H ]]⁺。

Intermediate 4.3 preparation of methoxy-5-methyl- [1,1' -biphenyl ] -4-amine

2.16 g (10mmol) of (4-bromo-2-methoxy-6-methylaniline), 1.22 g (10mmol) of phenylboronic acid, 449 mg (2mmol) of palladium acetate, 561 mg (2mmol) of tricyclohexylphosphine and 3.18 g (15mmol) of potassium phosphate are placed in a reaction bottle, 50 ml of toluene/water (10: 1, v/v) are added, nitrogen is used for protection, and the mixture is heated and stirred until the reaction is finished. The solvent was evaporated to dryness and the resulting solid was purified by column chromatography to give 1.6 g of product with 75% yield. MS:214[ M + H]⁺。

Intermediate 5.2-methoxy-6-methyl-4- (pyridin-3-yl) aniline

2.16 g (10mmol) of (4-bromo-2-methoxy-6-methylaniline), 1.23 g (10mmol) of pyridine-3-boronic acid, 1463 mg (2mmol) of 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride and 3.18 g (15mmol) of potassium phosphate are placed in a reaction bottle, and 50 ml of methyl methacrylate is addedBenzene/water (10: 1, v/v), under nitrogen protection, heating and stirring until the reaction is finished. The solvent was evaporated to dryness and the resulting solid was purified by column chromatography to give 1.6 g of product with 75% yield. MS:215[ M + H]⁺。

Intermediate 6/7.2 preparation of 6-methoxy-6-methyl-4- (methylsulfonyl) aniline, 2-methoxy-6-methyl-4- (ethylsulfonyl) aniline

Putting 1.1 g (5mmol) of (4-bromo-2-methoxy-6-methylaniline), 520 mg (5mmol) of sodium methanesulfinate, 95 mg (0.5mmol) of cuprous iodide and 69 mg (0.5mmol) of L-sodium proline in a reaction bottle, adding 5ml of dimethyl sulfoxide, protecting with nitrogen, and heating and stirring until the reaction is finished. Diluting with 25ml of water, extracting with ethyl acetate, spin-drying the organic phase, and purifying the obtained solid by column chromatography to obtain 700 mg of the product with the yield of 63%. MS:216[ M + H]⁺。

The same procedure was used for the preparation of 2-methoxy-6-methyl-4- (ethylsulfonyl) aniline, except that sodium methanesulfinate was replaced by an equivalent amount of sodium ethylsulfinate.

Intermediate 8.preparation of 3- (4- (4-amino-3-methoxy-5-methylphenyl) piperazin-1-yl) -3-oxopropanenitrile

Step 1): preparation of N, N-dibenzyl-4-bromo-2-methoxy-6-methylaniline

4.32 g (20mmol) of 4-bromo-2-methoxy-6-methylaniline, 2.53 g (20mmol) of benzyl chloride and 5.52 g (40mmol) of potassium carbonate are placed in a reaction bottle, 20 ml of N, N-dimethylformamide is added, and the mixture is heated and stirred until the reaction is finished. Diluting with 100ml of water, extracting with ethyl acetate, spin-drying the organic phase, and purifying the obtained solid by column chromatography to obtain 5.9 g of the product with the yield of 75%. MS 396[ M + H ]]⁺。

Step 2) preparation of tert-butyl 4- (4- (dibenzylamino) -3-methoxy-5-methylphenyl) piperazine-1-carboxylate

3.96 g (10mmol) of the product (N, N-dibenzyl-4-bromo-2-methoxy-6-methylaniline) obtained in step 1), 1.86 g (10mmol) of tert-butyl-piperazine-1-carboxylate, 916 mg (1mmol) of tris (dibenzylideneacetone) dipalladium, 394 mg (1mmol) of 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl, and 3.18 g (15mmol) of potassium phosphate were placed in a reaction flask, 50 ml of dioxane was added, nitrogen was used for protection, and heating and stirring were carried out until the reaction was completed. The solvent is evaporated to dryness, and the product is purified by column chromatography to obtain 3.0 g of product with 60 percent of yield. MS 502[ M + H ]]⁺。

Step 3) preparation of N, N-dibenzyl-2-methoxy-6-methyl-4- (piperazin-1-yl) aniline

3.0 g (6mmol) of the product (tert-butyl 4- (4- (dibenzylamino) -3-methoxy-5-methylphenyl) piperazine-1-formate) obtained in the step 2) is placed in a reaction bottle, 12 ml of dichloromethane and 3 ml of trifluoroacetic acid are added, the reaction is stirred until the reaction is finished, and the solvent is evaporated to obtain 2.4 g of the product with the yield of 100%. MS:402[ M + H]⁺。

Step 4) preparation of 3- (4- (4- (dibenzylamino) -3-methoxy-5-methylphenyl) piperazin-1-yl) -3-oxopropanenitrile 425 mg (5mmol) of 2-cyanoacetic acid was placed in a reaction flask, 15 ml of N, N-dimethylformamide was added, followed by addition of 2281 mg (6mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 774 mg (6mmol) of N, N-diisopropylethylamine, after stirring for 0.5 h, 2.0 g (5mmol) of the product obtained in step 4) (N, N-dibenzyl-2-methoxy-6-methyl-4- (piperazin-1-yl) aniline), stirring until the reaction is finished. After being diluted by adding 75 ml of water, the mixture is extracted by ethyl acetate, organic phase is dried by spinning under reduced pressure, and the obtained solid is purified by column chromatography to obtain 1.4 g of a product with the yield of 60 percent. MS 469[ M + H]⁺。

Step 5): putting 1.4 g (3mmol) of the product (3- (4- (4- (dibenzylamino) -3-methoxy-5-methylphenyl) piperazine-1-yl) -3-oxopropanenitrile) obtained in the step 4) and 0.2 g of palladium-carbon containing water into a reaction bottle, adding 10 ml of methanol, and carrying out catalytic hydrogenation until the reaction is finished. Filtering, evaporating the filtrate to dryness to obtain 800 mg of the product with the yield of 92 percent. MS:289[ M + H ]]⁺。

Preparation of intermediate 9.2-cyclopropyl-6-methoxyaniline

2.02 g (10mmol) of 2-bromo-6-methoxyaniline, 0.86 g (10mmol) of cyclopropylboronic acid, 224 mg (1mmol) of palladium acetate, 280 mg (1mmol) of tricyclohexylphosphine and 3.18 g (15mmol) of potassium phosphate are placed in a reaction flask, 20 ml of toluene/water (1: 1, v/v) are added, nitrogen is used for protection, and the mixture is heated and stirred until the reaction is finished. The solvent was evaporated to dryness and the resulting solid was purified by column chromatography to give 1.3 g of product with 80% yield. MS:164[ M + H]⁺。

Intermediate 10.4-Ethyl-6-methylpyrimidin-5-amine preparation

Step 1) preparation of 4-chloro-6-vinylpyrimidin-5-amine

4.0 g (24.4mmol) of 4, 6-dichloropyrimidine-5-amine, 4.2 g (24.4mmol) of vinyl boronic acid pinacol ester, 2.2 g (2.4mmol) of tris (dibenzylideneacetone) dipalladium, 684 mg (2.4mmol) of tricyclohexylphosphine and 7.7 g (36.6mmol) of potassium phosphate are placed in a reaction bottle, 100ml of dioxane/water (1: 1, v/v) is added, nitrogen is used for protection, and the mixture is heated and stirred until the reaction is finished. Concentrating under reduced pressure, extracting with ethyl acetate, spin-drying the organic phase, and purifying by column chromatography to obtain 900 mg of product with a yield of 23%. MS 156[ M + H ]]⁺。

Step 2) preparation of 4-methyl-6-vinylpyrimidin-5-amine

450 mg (2.9mmol) of the product (4-chloro-6-vinylpyrimidin-5-amine) obtained in step 1), 174 mg (2.9mmol) of methylboronic acid, 67 mg (0.3mmol) of palladium acetate, 84 mg (0.3mmol) of tricyclohexylphosphine, 955 mg (4.5mmol) of potassium phosphate were placed in a reaction flask, and 10 ml of toluene/water (1: 1, v/v) and under the protection of nitrogen, and heating and stirring until the reaction is finished. The solvent was evaporated and the resulting solid was purified by column chromatography to give 270 mg of product in 69% yield. MS 136[ M + H ]]⁺。

Step 3): step 2)270 mg (2mmol) of the obtained product (4-methyl-6-vinyl pyrimidine-5-amine) and 27 mg of palladium-carbon containing water are placed in a reaction bottle, 5ml of methanol is added, and catalytic hydrogenation is carried out until the reaction is finished. Filtering, evaporating the filtrate to dryness to obtain 185 mg of the product, wherein the yield is 67%. MS 138[ M + H ]]⁺。

Intermediate 11.4-cyclopropyl-6-ethylpyrimidin-5-amine preparation

Preparation of intermediate 11 reference is made to the preparation of intermediate 10, wherein in step 2) the methyl boronic acid is replaced by an equimolar amount of cyclopropylboronic acid.

Intermediate 12.5-methoxy-N¹,N¹Preparation of 3-trimethylbenzene-1, 2-diamine

Step 1) preparation of 1-fluoro-5-methoxy-3-methyl-2-nitrobenzene

Placing 3.5 g (25mmol) of 1-fluoro-3-methoxy-5-methylbenzene into a reaction bottle, adding 15 ml of acetic acid, dropwise adding 3.2 g (35 mmol) of 70% nitric acid, stirring until the reaction is finished, adding 100ml of water, extracting with ethyl acetate, spin-drying an organic phase, and purifying by column chromatography to obtain 2.5 g of a product with the yield of 54%. MS:186[ M + H ]]⁺。

Step 2) preparation of 5-methoxy-N, N, 3-trimethyl-2-nitroaniline

500 mg (2.7mmol) of the product (1-fluoro-5-methoxy-3-methyl-2-nitrobenzene) obtained in step 1), 2ml (4mmol) of a tetrahydrofuran solution of dimethylamine (2M), and 559 mg (4mmol) of potassium carbonate were put in a reaction flask, 2ml of N, N-dimethylformamide was added, and the mixture was heated and stirred until the reaction was completed. The solvent was evaporated and the resulting solid was purified by column chromatography to give 284 mg of product in 50% yield. MS 211[ M + H ]]⁺。

Step 3): 280 mg (1.3mmol) of the product (5-methoxy-N, N, 3-trimethyl-2-nitroaniline) obtained in the step 2) and 280 mg of raney nickelPlacing the mixture into a reaction bottle, adding 5ml of methanol, and carrying out catalytic hydrogenation until the reaction is finished. Filtering, evaporating the filtrate to dryness to obtain 220 mg of the product, wherein the yield is 91%. MS:181[ M + H ]]⁺。

Intermediate 13.4-methoxy-2-methyl-6-phenoxyaniline

Preparation of intermediate 13 reference is made to the preparation of intermediate 12, wherein in step 2) an equimolar amount of phenol is substituted for dimethylamine in tetrahydrofuran.

Intermediate 14.4-cyclopropyl-6-methoxypyrimidin-5-amine preparation

1.1 g (6.9mmol) of 4-chloro-6-methoxypyrimidine-5-amine, 592 mg (6.9mmol) of cyclopropylboronic acid, 512 mg (0.7mmol) of 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium and 2.2 g (10.3mmol) of potassium phosphate are placed in a reaction bottle, 20 ml of toluene/water (10: 1, v/v) are added, nitrogen is protected, and the mixture is heated and stirred until the reaction is finished. The solvent was evaporated to dryness and the resulting solid was purified by column chromatography to give 170 mg of product in 35% yield. MS 166[ M + H ]]⁺。

Intermediate 15.4-amino-3-methoxy-N, 5-dimethylbenzenesulfonamide

Step 1) preparation of tert-butyl (4-bromo-2-methoxy-6-methylphenyl) carbamate

Putting 2.16 g (10mmol) of 4-bromo-2-methoxy-6-methylaniline and 2.18 g (10mmol) of di-tert-butyl dicarbonate in a reaction bottle, adding 20 ml of tert-butyl alcohol, heating and stirring until the reaction is finished, evaporating the solvent to dryness, and purifying by column chromatography to obtain 2.53 g of a product with the yield of 80%. MS:316[ M + H ]]⁺. Step 2) tert-butyl (2-methoxy-4-, (Preparation of (4-methoxybenzyl) thio) -6-methylphenyl) carbamate the product obtained in step 1) (tert-butyl (4-bromo-2-methoxy-6-methylphenyl) carbamate) 632 mg (2mmol), 4-methoxybenzyl mercaptan 308 mg (2mmol), tris (dibenzylideneacetone) dipalladium 183 mg (0.2mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene 116 mg (0.2mmol), diisopropylethylamine 516 mg (4mmol) were placed in a reaction flask, 10 ml dioxane was added, nitrogen was blanketed, and heating and stirring were carried out until the reaction was complete. Vacuum concentrating, extracting with ethyl acetate, spin drying the organic phase, and purifying by column chromatography to obtain 584 mg of product with 75% yield. MS 390[ M + H ]]⁺。

Step 3) preparation of tert-butyl (4- (chlorosulfonyl) -2-methoxy-6-methylphenyl) carbamate

Putting 390 mg (1mmol) of the product (tert-butyl (2-methoxy-4- ((4-methoxybenzyl) thio) -6-methylphenyl) carbamate) obtained in the step 2) and 197 mg (1mmol) of dichlorodimethylhydantoin in a reaction bottle, adding 5ml of acetonitrile, stirring until the reaction is finished, evaporating the solvent to dryness, and purifying by column chromatography to obtain 202 mg of the product, wherein the yield is 60%. MS 336[ M + H ]]⁺。

Step 4) preparation of tert-butyl (2-methoxy-6-methyl-4- (N-methylsulfonyl) phenyl) carbamate

336 mg (1mmol) of the product (tert-butyl (4- (chlorosulfonyl) -2-methoxy-6-methylphenyl) carbamate) obtained in the step 3), 68 mg (1mmol) of methylamine hydrochloride and 112 mg (2mmol) of potassium hydroxide are placed in a reaction bottle, 5ml of dichloromethane is added, the reaction is stirred until the reaction is finished, the solvent is evaporated, and the product 231 mg is obtained through column chromatography purification, wherein the yield is 70%. MS:331[ M + H]⁺。

Step 5): 231 mg (0.7mmol) of the product obtained in the step 4) (tert-butyl (2-methoxy-6-methyl-4- (N-methylsulfonyl) phenyl) carbamate) was placed in a reaction flask, 4 ml of dichloromethane and 1ml of trifluoroacetic acid were added, the reaction was stirred until the reaction was completed, and the solvent was distilled off to obtain 160 mg of the product with a yield of 100%. MS 231[ M + H ]]⁺。

Intermediate 16.preparation of 4-amino-N- (2-hydroxyethyl) -3-methoxy-5-methylbenzenesulfonamide

Preparation of intermediate 16 reference is made to the preparation of intermediate 15, wherein the methylamine hydrochloride is replaced with an equimolar amount of 2-aminoethyl-1-ol in step 4).

Examples

EXAMPLE 1 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclopropylamino) pyrimidine-5-carboxamide

Step 1) preparation of 2-chloro-4- (cyclopropylamino) pyrimidine-5-carboxamide

Cyclopropylamine 570 mg (10mmol), 2, 4-dichloropyrimidine-5-carboxamide 1910 mg (10mmol), 10 ml of tetrahydrofuran and 2580 mg (20mmol) of diisopropylethylamine were added to a reaction flask, and after completion of the reaction, 200 ml of water was added, and the product 1484 mg was obtained by suction filtration in 70% yield. MS 213[ M + H]⁺。

Step 2) preparation of tert-butyl (R) -3- (4- ((5-carbamoyl-4- (cyclopropylamino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) piperidine-1-carboxylate

212 mg (1mmol) of the product (2-chloro-4- (cyclopropylamino) pyrimidine-5-carboxamide) obtained in step 1), 266 mg (1mmol) of tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate (preparation method is referred to WO 2014139465), and 2ml of sec-butyl alcohol was added to a reaction flask, followed by dropwise addition of 0.05 ml of trifluoroacetic acid, followed by heating and stirring until the reaction was completed. Adding 5ml of water for dilution, adding saturated sodium bicarbonate water solution to adjust the reaction system to be neutral, performing suction filtration, and performing column chromatography purification on the obtained solid to obtain 221 mg of a product with the yield of 50%. MS:443[ M + H]⁺。

Step 3 preparation of) (R) -4- (cyclopropylamino) -2- ((1- (piperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide the product obtained in step 2) (tert-butyl (R) -3- (4- ((5-carbamoyl-4- (cyclo-C-l) amino)Propylamino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) piperidine-1-carboxylate) 221 mg (0.5mmol) was placed in a reaction flask, 4 ml of dichloromethane and 1ml of trifluoroacetic acid were added, stirring was performed until the reaction was completed, and the solvent was evaporated to obtain 171 mg of a product in 100% yield. MS:343[ M + H]⁺。

Step 4) (preparation of R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclopropylamino) pyrimidine-5-carboxamide 171 mg (0.5mmol) of the product obtained in step 3 ((R) -4- (cyclopropylamino) -2- ((1- (piperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide) was placed in a reaction flask, adding 4 ml tetrahydrofuran, dripping 45 mg (0.5mmol) of acryloyl chloride, stirring until the reaction is finished, extracting ethyl acetate and sodium carbonate aqueous solution, concentrating an organic phase, and carrying out column chromatography to obtain 99 mg of a product, wherein the yield is 50%.¹H NMR(400MHz,DMSO- d6)δ9.72(s,1H),9.31(s,1H),8.46(s,1H),8.12(s,1H),8.01-7.74(m,1H),7.68(s,1H),7.33-7.02(m,1H), 6.94-6.69(m,1H),6.19-5.98(m,1H),5.81-5.58(m,1H),4.67-4.23(m,1H),4.23-3.95(m,2H),3.17-2.98(m, 1H),2.98-2.80(m,2H),2.20-1.91(m,2H),1.90-1.75(m,1H),1.62-1.38(m,1H),0.95-0.69(m,2H),0.61-0.42 (m,2H).MS:397[M+H]⁺。

EXAMPLE 2 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclopropylamino) pyrimidine-5-carboxamide

Step 1) preparation of 2-chloro-4- (cyclopropylamino) pyrimidine-5-carboxamide

Step 2) preparation of tert-butyl (S) -3- (4- ((5-carbamoyl-4- (cyclopropylamino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) piperidine-1-carboxylate

212 mg (1mmol) of the product (2-chloro-4- (cyclopropylamino) pyrimidine-5-carboxamide) obtained in step 1), 266 mg (1mmol) of tert-butyl (S) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate (preparation method is referred to WO 2014139465), and 2ml of sec-butyl alcohol was added to a reaction flask, followed by dropwise addition of 0.05 ml of trifluoroacetic acid, followed by heating and stirring until the reaction was completed. Adding 5ml of water for dilution, adding saturated sodium bicarbonate water solution to adjust the reaction system to be neutral, performing suction filtration, and performing column chromatography purification on the obtained solid to obtain 221 mg of a product with the yield of 50%. MS:443[ M + H]⁺。

Step 3) preparation of (S) -4- (cyclopropylamino) -2- ((1- (piperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide 221 mg (0.5mmol) of the product obtained in step 2) (tert-butyl (S) -3- (4- ((5-carbamoyl-4- (cyclopropylamino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) piperidine-1-carboxylate) was placed in a reaction flask, 4 ml of dichloromethane and 1ml of trifluoroacetic acid were added, stirring was performed until the reaction was completed, and the solvent was evaporated to give 171 mg of the product in 100% yield. MS:343[ M + H]⁺。

Step 4) (preparation of S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclopropylamino) pyrimidine-5-carboxamide 171 mg (0.5mmol) of the product obtained in step 3 ((S) -4- (cyclopropylamino) -2- ((1- (piperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide) was placed in a reaction flask, adding 4 ml tetrahydrofuran, dripping 45 mg (0.5mmol) of acryloyl chloride, stirring until the reaction is finished, extracting ethyl acetate and sodium carbonate aqueous solution, concentrating an organic phase, and carrying out column chromatography to obtain 99 mg of a product, wherein the yield is 50%.¹H NMR(400MHz,DMSO- d6)δ9.57(s,1H),9.19(s,1H),8.46(s,1H),8.12(s,1H),7.74-7.66(m,2H),7.21-6.94(m,1H),6.93-6.71(m, 1H),6.21-6.00(m,1H),5.74-5.60(m,1H),4.66-4.22(m,1H),4.21-3.98(m,2H),3.57-3.39(m,1H),3.16-2.93 (m,1H),2.93-2.82(m,1H),2.12(s,1H),2.02(s,1H),1.86-1.76(m,1H),1.59-1.35(m,1H),0.95-0.76(m,2H), 0.58-0.48(m,2H).MS:397[M+H]⁺。

EXAMPLE 3 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (o-tolylamino) pyrimidine-5-carboxamide

Preparation method reference of example 3The preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of o-toluidine.¹H NMR(400MHz,DMSO-d6)δ11.42-11.06(m,1H),9.67-9.43(m,1H),8.78-8.61(m, 1H),8.46-8.12(m,1H),8.11-7.83(m,1H),7.73-7.54(m,1H),7.51-7.41(m,1H),7.39-7.30(m,2H),7.30-7.08 (m,2H),7.06-6.69(m,1H),6.21-6.05(m,1H),5.76-5.63(m,1H),4.61-4.20(m,1H),4.19-3.77(m,2H),3.11- 2.70(m,1H),2.36-2.10(m,4H),2.09-1.68(m,3H),1.57-1.42(m,1H).MS:447[M+H]⁺。

EXAMPLE 4 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (o-tolylamino) pyrimidine-5-carboxamide

The preparation of example 4 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of o-toluidine.¹H NMR(400MHz,DMSO-d6)δ11.40-11.00(m,1H),9.65-9.45(m,1H),8.78-8.65(m, 1H),8.48-7.74(m,2H),7.74-7.53(m,1H),7.53-7.41(m,1H),7.41-7.18(m,3H),7.18-6.94(m,1H),6.92-6.69 (m,1H),6.24-6.00(m,1H),5.76-5.60(m,1H),4.60-4.25(m,1H),4.17-3.75(m,2H),3.29-2.96(m,1H),2.92- 2.62(m,1H),2.46-2.14(m,3H),2.14-1.69(m,3H),1.60-1.36(m,1H).MS:447[M+H]⁺。

EXAMPLE 5 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-fluorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 5 refers to the preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced by an equimolar amount of 2-fluoroaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.79-11.43(m,1H),9.64(s,1H),8.75(s,1H),8.67(s, 1H),8.12-7.91(m,2H),7.59(s,1H),7.40(s,1H),7.38-7.15(m,3H),6.91-6.71(m,1H),6.20-6.03(m,1H), 5.74-5.62(m,1H),4.61-3.86(m,3H),3.19-2.98(m,1H),2.96-2.77(m,1H),2.19-1.72(m,3H),1.58-1.41(m, 1H).MS:451[M+H]⁺。

EXAMPLE 6 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-fluorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 6 the preparation of example 2, steps 1) to 4), was referenced, wherein cyclopropylamine was replaced with an equimolar amount of 2-fluoroaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.79-11.43(m,1H),9.66(s,1H),8.76(s,1H),8.70-7.75 (m,3H),7.60(s,1H),7.45-7.03(m,4H),6.91-6.69(m,1H),6.22-6.02(m,1H),5.76-5.61(m,1H),4.57-3.85 (m,3H),3.21-2.96(m,1H),2.96-2.75(m,1H),2.22-1.70(m,3H),1.58-1.39(m,1H).MS:451[M+H]⁺。

EXAMPLE 7 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclohexylamino) pyrimidine-5-carboxamide

The preparation of example 7 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of cyclohexylamine.¹H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.24(s,1H),8.45(s,1H),7.87(s,1H),7.79- 7.47(m,2H),7.04(s,1H),6.89-6.74(m,1H),6.10(t,J＝17.5Hz,1H),5.78-5.59(m,1H),4.69-4.22(m,1H), 4.19-3.85(m,3H),3.00-2.82(m,1H),2.20-2.10(m,1H),2.09-1.90(m,3H),1.86-1.76(m,1H),1.75-1.65(m, 2H),1.62-1.48(m,2H),1.48-1.36(m,2H),1.36-1.13(m,4H).MS:439[M+H]⁺。

EXAMPLE 8 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclohexylamino) pyrimidine-5-carboxamide

The preparation of example 8 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of cyclohexylamine.¹H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.25(s,1H),8.46(s,1H),7.88(s,1H),7.82- 7.45(m,2H),7.04(s,1H),6.90-6.72(m,1H),6.11(t,J＝17.5Hz,1H),5.78-5.59(m,1H),4.70-3.88(m,4H), 3.58-3.06(m,1H),3.04-2.83(m,1H),2.24-1.87(m,4H),1.87-1.55(m,4H),1.55-1.07(m,6H).MS: 439[M+H]⁺。

EXAMPLE 9 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (phenylamino) pyrimidine-5-carboxamide

The preparation of example 9 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of aniline.¹H NMR(400MHz,DMSO-d6)δ11.54-11.41(m,1H),9.59(s,1H),8.75-8.65(m,1H),8.14- 7.64(m,3H),7.64-7.28(m,5H),7.19-7.01(m,1H),6.91-6.70(m,1H),6.18-6.05(m,1H),5.76-5.61(m,1H), 4.63-3.89(m,3H),3.24-2.75(m,2H),2.16-1.70(m,3H),1.58-1.39(m,1H).MS:433[M+H]⁺。

EXAMPLE 10 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (phenylamino) pyrimidine-5-carboxamide

The preparation of example 10 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of aniline.¹H NMR(400MHz,DMSO-d6)δ11.64-11.38(m,1H),9.74-9.55(m,1H),8.78-8.56(m,1H), 8.16-7.65(m,3H),7.62-7.32(m,5H),7.23-7.03(m,1H),6.99-6.70(m,1H),6.20-6.04(m,1H),5.77-5.58(m, 1H),4.65-4.22(m,1H),4.22-3.92(m,2H),3.41-2.78(m,2H),2.17-1.72(m,3H),1.59-1.40(m,1H).MS: 433[M+H]⁺。

EXAMPLE 11 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-fluorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 11 refers to the preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced by an equimolar amount of 3-fluoroaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.84-11.58(m,1H),9.80-9.52(m,1H),8.81-8.61(m, 1H),8.22-7.92(m,2H),7.86-7.29(m,4H),7.30-7.18(m,1H),6.99-6.68(m,2H),6.21-6.01(m,1H),5.79-5.58 (m,1H),4.67-3.90(m,3H),3.23-2.98(m,1H),2.98-2.74(m,1H),2.17-1.73(m,3H),1.59-1.39(m,1H).MS: 451[M+H]⁺。

EXAMPLE 12 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-fluorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 12 the preparation of example 2, steps 1) to 4), was referenced, wherein cyclopropylamine was replaced with an equimolar amount of 3-fluoroaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.81-11.62(m,1H),9.77-9.58(m,1H),8.80-8.62(m, 1H),8.24-7.87(m,2H),7.86-7.48(m,2H),7.48-7.19(m,3H),6.98-6.69(m,2H),6.20-6.02(m,1H),5.76-5.60 (m,1H),4.60-3.98(m,3H),3.21-2.98(m,1H),2.97-2.71(m,1H),2.14-1.76(m,3H),1.59-1.39(m,1H).MS: 451[M+H]⁺。

EXAMPLE 13 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-fluorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 13 refers to the preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced with an equimolar amount of 4-fluoroaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.59-11.20(m,1H),9.68-9.50(m,1H),8.77-8.60(m, 1H),7.98(s,1H),7.80(s,1H),7.71-7.31(m,4H),7.30-7.12(m,2H),6.92-6.71(m,1H),6.19-6.02(m,1H), 5.74-5.60(m,1H),4.63-3.82(m,3H),3.22-2.95(m,1H),2.96-2.73(m,1H),2.17-1.68(m,3H),1.58-1.40(m, 1H).MS:451[M+H]⁺。

EXAMPLE 14 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-fluorophenyl) amino) pyrimidine-5-carboxamide

Preparation of example 14 reference is made to preparation of example 2, steps 1) to 4), where in step 1)The cyclopropylamine was replaced with an equimolar amount of 4-fluoroaniline.¹H NMR(400MHz,DMSO-d6)δ11.56-11.20(m,1H),9.66-9.55(m,1H),8.74-8.57(m, 1H),8.02-7.77(m,2H),7.65-7.47(m,3H),7.45-7.37(m,1H),7.30-7.13(m,2H),6.92-6.70(m,1H),6.21-6.01 (m,1H),5.78-5.59(m,1H),4.74-3.83(m,3H),3.21-2.96(m,1H),2.89-2.76(m,1H),2.08-1.97(m,1H),1.86- 1.69(m,2H),1.54-1.42(m,1H).MS:451[M+H]⁺。

EXAMPLE 15 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-chlorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 15 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 4-chloroaniline.¹H NMR(400MHz,DMSO-d6)δ11.71-11.35(m,1H),9.74-9.57(m,1H),8.78-8.62(m, 1H),8.14-7.78(m,2H),7.72-7.29(m,6H),6.96-6.71(m,1H),6.27-6.00(m,1H),5.78-5.58(m,1H),4.68-3.86 (m,3H),3.24-2.97(m,1H),2.96-2.75(m,1H),2.18-1.71(m,3H),1.59-1.41(m,1H).MS:467[M+H]⁺。

EXAMPLE 16 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-chlorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 16 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 4-chloroaniline.¹H NMR(400MHz,DMSO-d6)δ11.69-11.38(m,1H),9.79-9.56(m,1H),8.77-8.61(m, 1H),8.10-7.81(m,2H),7.69-7.47(m,3H),7.47-7.36(m,3H),6.91-6.72(m,1H),6.23-6.02(m,1H),5.77-5.61 (m,1H),4.57-4.01(m,3H),3.17-3.00(m,1H),2.95-2.77(m,1H),2.14-1.76(m,3H),1.60-1.40(m,1H).MS: 467[M+H]⁺。

EXAMPLE 17 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-chlorophenyl) amino) pyrimidine-5-carboxamide

Preparation of example 17 reference is made to the preparation process of example 11) To step 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 3-chloroaniline.¹H NMR(400MHz,DMSO-d6)δ11.77-11.55(m,1H),9.67(s,1H),8.79-8.63(m,1H), 8.35-7.83(m,2H),7.81-7.67(m,1H),7.65-7.52(m,1H),7.51-7.44(m,1H),7.43-7.30(m,2H),7.22-7.06(m, 1H),6.91-6.66(m,1H),6.18-6.02(m,1H),5.76-5.59(m,1H),4.64-3.93(m,3H),3.27-2.97(m,1H),2.96-2.73 (m,1H),2.16-1.74(m,3H),1.59-1.38(m,1H).MS:467[M+H]⁺。

EXAMPLE 18 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-chlorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 18 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 3-chloroaniline.¹H NMR(400MHz,DMSO-d6)δ11.76-11.56(m,1H),9.67(s,1H),8.79-8.62(m,1H), 8.02(s,2H),7.82-7.70(m,1H),7.69-7.56(m,1H),7.53-7.31(m,3H),7.20-7.07(m,1H),6.90-6.68(m,1H), 6.20-6.03(m,1H),5.76-5.58(m,1H),4.65-3.96(m,3H),3.22-2.95(m,1H),2.95-2.75(m,1H),2.21-1.71(m, 3H),1.60-1.38(m,1H).MS:467[M+H]⁺。

EXAMPLE 19 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 4-difluorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 19 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2, 4-difluoroaniline.¹H NMR(400MHz,DMSO-d6)δ11.78-11.10(m,1H),9.78-9.61(m,1H),8.75-8.66 (m,1H),8.19-7.79(m,2H),7.79-7.43(m,2H),7.43-7.24(m,2H),7.23-7.03(m,1H),6.93-6.70(m,1H),6.24- 6.01(m,1H),5.76-5.60(m,1H),4.58-3.84(m,3H),3.23-2.97(m,1H),2.96-2.72(m,1H),2.14-1.71(m,3H), 1.57-1.40(m,1H).MS:469[M+H]⁺。

EXAMPLE 20 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 4-difluorophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 20 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2, 4-difluoroaniline.¹H NMR(400MHz,DMSO-d6)δ11.72-11.10(m,1H),9.73-9.62(m,1H),8.75-8.65 (m,1H),8.10-7.78(m,2H),7.62-7.42(m,2H),7.42-7.22(m,2H),7.21-7.03(m,1H),6.91-6.71(m,1H),6.21- 6.03(m,1H),5.75-5.62(m,1H),4.60-3.83(m,3H),3.23-2.97(m,1H),2.96-2.69(m,1H),2.15-1.76(m,3H), 1.56-1.37(m,1H).MS:469[M+H]⁺。

EXAMPLE 21 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclopentylamino) pyrimidine-5-carboxamide

The preparation of example 21 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of cyclopentylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.28-9.03(m,1H),8.45(s,1H),7.95(s,1H), 7.88-7.62(m,1H),7.59(s,1H),7.29-6.92(m,1H),6.91-6.71(m,1H),6.23-6.00(m,1H),5.79-5.58(m,1H), 4.69-4.21(m,2H),4.21-3.96(m,2H),3.55-3.34(m,1H),3.11-2.87(m,1H),2.27-2.10(m,1H),2.09-1.91(m, 3H),1.88-1.76(m,1H),1.75-1.66(m,2H),1.65-1.55(m,2H),1.54-1.31(m,3H).MS:425[M+H]⁺。

EXAMPLE 22 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclopentylamino) pyrimidine-5-carboxamide

The preparation of example 22 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of cyclopentylamine.¹H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.30-9.02(m,1H),8.45(s,1H),7.95(s,1H), 7.87-7.52(m,2H),7.23-6.93(m,1H),6.90-6.74(m,1H),6.17-6.01(m,1H),5.75-5.62(m,1H),4.69-4.21(m, 2H),4.21-3.99(m,2H),3.53-3.34(m,1H),3.12-2.89(m,1H),2.22-2.04(m,2H),2.03-1.91(m,2H),1.87-1.75 (m,1H),1.75-1.67(m,2H),1.66-1.57(m,2H),1.55-1.41(m,3H).MS:425[M+H]⁺。

EXAMPLE 23 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cycloheptylamino) pyrimidine-5-carboxamide

The preparation of example 23 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of cycloheptylamine.¹H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.34-9.06(m,1H),8.44(s,1H),7.98-7.86 (m,1H),7.85-7.48(m,2H),7.44-6.93(m,1H),6.89-6.75(m,1H),6.10(t,J＝18.1Hz,1H),5.77-5.61(m,1H), 4.65-4.22(m,1H),4.17-4.01(m,2H),3.54-3.34(m,1H),3.32-2.99(m,1H),2.99-2.79(m,1H),2.21-2.09(m, 1H),2.09-2.00(m,1H),1.99-1.86(m,2H),1.86-1.78(m,1H),1.64-1.46(m,11H).MS:453[M+H]⁺。

EXAMPLE 24 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cycloheptylamino) pyrimidine-5-carboxamide

The preparation of example 24 the preparation of example 2 is referred to in steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of cycloheptylamine.¹H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.35-9.04(m,1H),8.54-8.40(m,1H),7.90 (s,1H),7.83-7.62(m,1H),7.61-7.49(m,1H),7.20-6.93(m,1H),6.90-6.74(m,1H),6.17-6.02(m,1H),5.72- 5.61(m,1H),4.68-4.22(m,1H),4.16-3.93(m,2H),3.55-3.34(m,1H),3.12-2.86(m,1H),2.20-2.09(m,1H), 2.09-1.99(m,1H),1.98-1.86(m,2H),1.86-1.75(m,1H),1.70-1.41(m,12H).MS:453[M+H]⁺。

Example 25 preparation of (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxyphenyl) amino) pyrimidine-5-carboxamide example 25 reference is made to preparation method of example 1, steps 1) to 4), where in step 1) is equalMolar equivalents of 2-methoxyaniline in place of cyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ11.73-11.32(m,1H),9.56(s,1H),8.79-8.62(m, 1H),8.12-7.96(m,1H),7.95-7.76(m,1H),7.75-7.54(m,1H),7.44(s,1H),7.30-7.13(m,1H),7.12-7.00(m, 2H),7.00-6.91(m,1H),6.91-6.70(m,1H),6.18-6.04(m,1H),5.76-5.61(m,1H),4.61-3.95(m,3H),3.84(s, 3H),3.31-2.97(m,1H),2.96-2.76(m,1H),2.14-1.74(m,3H),1.59-1.38(m,1H).MS:463[M+H]⁺。

EXAMPLE 26 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 26 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ11.76-11.31(m,1H),9.56(s,1H),8.82-8.62(m, 1H),8.10-7.96(m,1H),7.96-7.77(m,1H),7.76-7.54(m,1H),7.54-7.31(m,1H),7.31-7.10(m,1H),7.10-6.91 (m,3H),6.90-6.71(m,1H),6.24-6.03(m,1H),5.78-5.60(m,1H),4.64-3.94(m,3H),3.84(s,3H),3.19-2.96 (m,1H),2.96-2.75(m,1H),2.17-1.71(m,3H),1.58-1.37(m,1H).MS:463[M+H]⁺。

EXAMPLE 27 (R) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) amino) pyrimidine-5-carboxamide

Preparation of example 27 reference is made to preparation of example 1, steps 1) to 4), wherein 2, 3-dihydrobenzo [ b ] is present in step 1) in equimolar amounts][1,4]Dioxin-6-amine is used for replacing cyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ11.40-11.11(m,1H),9.67-9.44 (m,1H),8.74-8.54(m,1H),8.07-7.89(m,1H),7.80-7.58(m,1H),7.57-7.26(m,2H),7.13(s,1H),7.00-6.69 (m,3H),6.21-6.02(m,1H),5.75-5.59(m,1H),4.61-4.20(m,4H),4.17-3.86(m,2H),3.55-3.34(m,1H),3.32- 2.99(m,1H),2.98-2.78(m,1H),2.18-1.74(m,3H),1.64-1.38(m,1H).MS:491[M+H]⁺。

EXAMPLE 28 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) amino) pyrimidine-5-carboxamide

Preparation of example 28 preparation of example 2 reference is made to steps 1) to 4) of the preparation of example 2, wherein 2, 3-dihydrobenzo [ b ] is present in step 1) in equimolar amounts][1,4]Dioxin-6-amine is used for replacing cyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ11.43-11.10(m,1H),9.66-9.47 (m,1H),8.72-8.55(m,1H),8.03-7.84(m,1H),7.80-7.09(m,4H),7.00-6.69(m,3H),6.18-6.03(m,1H),5.77- 5.53(m,1H),4.61-4.16(m,6H),4.05-3.89(m,1H),3.18-2.94(m,1H),2.94-2.79(m,1H),2.12-1.75(m,3H), 1.59-1.38(m,1H).MS:491[M+H]⁺。

EXAMPLE 29 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-methoxypropyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 29 refers to the preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) with an equimolar amount of 3-methoxypropan-1-amine.¹H NMR(400MHz,DMSO-d6)δ9.56-9.27(m,1H),9.26-8.97(m,1H),8.55- 8.39(m,1H),8.01-7.78(m,1H),7.77-7.31(m,2H),7.26-6.92(m,1H),6.90-6.73(m,1H),6.19-6.01(m,1H), 5.75-5.59(m,1H),4.67-3.96(m,3H),3.63-3.44(m,2H),3.40(t,J＝6.1Hz,2H),3.22(s,3H),3.20-3.00(m, 1H),2.99-2.84(m,1H),2.22-1.93(m,2H),1.93-1.71(m,3H),1.57-1.43(m,1H).MS:429[M+H]⁺。

EXAMPLE 30 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-methoxypropyl) amino) pyrimidine-5-carboxamide

Preparation of example 30 reference is made to preparation of example 2, steps 1) to 4), wherein 3-methoxy-3 is present in step 1) in equimolar amountsPhenylprop-1-amine instead of cyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.27-8.99(m,1H),8.45(s,1H), 8.01-7.89(m,1H),7.87-7.61(m,1H),7.57(s,1H),7.25-6.93(m,1H),6.91-6.75(m,1H),6.17-6.03(m,1H), 5.75-5.60(m,1H),4.67-3.98(m,3H),3.61-3.45(m,2H),3.45-3.41(m,1H),3.40-3.38(m,1H),3.22(s,3H), 3.16-2.99(m,1H),2.99-2.83(m,1H),2.21-1.95(m,2H),1.87-1.73(m,3H),1.60-1.45(m,1H).MS:429[M+H]⁺。

EXAMPLE 31 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 31 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-ethylaniline.¹H NMR(400MHz,DMSO-d6)δ11.45-11.09(m,1H),9.71-9.41(m,1H),8.77-8.56 (m,1H),8.35-7.59(m,2H),7.59-7.20(m,5H),7.20-6.99(m,1H),6.93-6.66(m,1H),6.23-6.04(m,1H),5.79- 5.61(m,1H),4.60-3.75(m,3H),3.31-2.96(m,1H),2.95-2.65(m,1H),2.65-2.54(m,2H),2.17-1.66(m,3H), 1.58-1.38(m,1H),1.20-1.07(m,3H).MS:461[M+H]⁺。

EXAMPLE 32 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 32 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-ethylaniline.¹H NMR(400MHz,DMSO-d6)δ11.44-11.13(m,1H),9.61-9345(m,1H),8.75-8.62 (m,1H),7.97(s,1H),7.68-7.55(m,1H),7.46-7.39(m,1H),7.38-7.19(m,4H),7.17(t,J＝7.4Hz,1H),6.91- 6.69(m,1H),6.20-6.06(m,1H),5.74-5.64(m,1H),4.57-4.03(m,2H),3.90-3.80(m,1H),3.16-2.95(m,1H), 2.87-2.69(m,1H),2.68-2.55(m,2H),1.91(s,1H),1.86-1.70(m,2H),1.55-1.43(m,1H),1.13(t,J＝7.5Hz, 3H).MS:461[M+H]⁺。

EXAMPLE 33 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) pyrimidine-5-carboxamide

Preparation of example 33 reference is made to preparation of example 1, steps 1) to 4), wherein 2, 3-dihydrobenzo [ b ] is present in step 1) in equimolar amounts][1,4]Dioxin-5-amine is used for replacing cyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ11.72-11.18(m,1H),9.56(s, 1H),8.79-8.56(m,1H),8.48-7.97(m,1H),7.97-7.81(m,1H),7.79-7.57(m,1H),7.56-7.42(m,1H),7.25(s, 1H),6.93-6.70(m,2H),6.68-6.51(m,1H),6.27-6.00(m,1H),5.78-5.58(m,1H),4.65-4.27(m,3H),4.27-4.08 (m,3H),4.08-3.90(m,1H),3.21-2.92(m,1H),2.91-2.74(m,1H),2.18-1.69(m,3H),1.57-1.41(m,1H).MS: 491[M+H]⁺。

EXAMPLE 34 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) amino) pyrimidine-5-carboxamide

Preparation of example 34 reference is made to preparation of example 2, steps 1) to 4), wherein 2, 3-dihydrobenzo [ b ] is present in step 1) in equimolar amounts][1,4]Dioxin-5-amine is used for replacing cyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ11.56-11.28(m,1H),9.56(s, 1H),8.72-8.62(m,1H),8.10-7.91(m,1H),7.74(s,1H),7.64-7.51(m,1H),7.45(s,1H),7.25(s,1H),6.90-6.72 (m,2H),6.67-6.55(m,1H),6.18-6.05(m,1H),5.74-5.63(m,1H),4.39-4.11(m,6H),4.09-3.96(m,1H),3.20- 3.00(m,1H),2.96-2.78(m,1H),2.16-1.99(m,2H),1.94-1.75(m,2H).MS:491[M+H]⁺。

EXAMPLE 35 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((cyclohexylmethyl) amino) pyrimidine-5-carboxamide

The preparation of example 35 reference is made to the preparation of example 1, steps 1) to 4), wherein cyclohexylmethylamine is replaced with equimolar amounts in step 1) for cyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.40-9.05(m,1H),8.45(s,1H),7.99- 7.89(m,1H),7.86-7.65(m,1H),7.57(s,1H),7.27-6.92(m,1H),6.91-6.74(m,1H),6.18-6.01(m,1H),5.75- 5.59(m,1H),4.65-3.99(m,3H),3.58-3.35(m,1H),3.28-3.05(m,1H),3.03-2.82(m,1H),2.21-2.11(m,1H), 2.09-1.94(m,1H),1.90-1.74(m,2H),1.74-1.69(m,2H),1.69-1.60(m,3H),1.59-1.34(m,2H),1.26-1.11(m, 3H),1.04-0.93(m,2H).MS:453[M+H]⁺。

EXAMPLE 36 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((cyclohexylmethyl) amino) pyrimidine-5-carboxamide

The preparation of example 36 reference is made to the preparation of example 2, steps 1) to 4), wherein cyclohexylmethylamine in step 1) is replaced by an equimolar amount.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.35-9.06(m,1H),8.54-8.41(m,1H), 8.00-7.89(m,1H),7.87-7.50(m,2H),7.26-6.75(m,2H),6.20-6.02(m,1H),5.77-5.54(m,1H),4.68-3.98(m, 3H),3.55-3.36(m,1H),3.29-3.03(m,1H),3.02-2.80(m,1H),2.20-1.89(m,2H),1.88-1.78(m,1H),1.78-1.74 (m,1H),1.74-1.69(m,2H),1.69-1.66(m,1H),1.66-1.59(m,2H),1.59-1.41(m,2H),1.28-1.07(m,3H),1.05- 0.90(m,2H).MS:453[M+H]⁺。

EXAMPLE 37 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclobutylamino) pyrimidine-5-carboxamide

The preparation of example 37 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of cyclobutylamine.¹H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.44(s,1H),8.46(s,1H),7.99(s,1H), 7.91-7.70(m,1H),7.60(s,1H),7.25-7.08(m,1H),6.87-6.77(m,1H),6.16-6.05(m,1H),5.72-5.64(m,1H), 4.57-4.50(m,1H),4.22-4.16(m,1H),4.08-4.00(m,1H),3.55-3.48(m,1H),3.18-3.07(m,1H),3.04-2.87(m, 1H),2.39-2.33(m,2H),2.23-2.16(m,1H),2.09-2.01(m,1H),1.96-1.90(m,2H),1.83-1.74(m,3H),1.58-1.50 (m,1H).MS:411[M+H]⁺。

EXAMPLE 38 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (cyclobutylamino) pyrimidine-5-carboxamide

The preparation of example 38 reference is made to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of cyclobutylamine.¹H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.38-9.15(m,1H),8.53-8.42(m,1H), 7.98(s,1H),7.74(s,1H),7.58(s,1H),7.08(s,1H),6.89-6.77(m,1H),6.17-6.03(m,1H),5.75-5.63(m,1H), 4.73-4.50(m,2H),4.28-4.02(m,3H),3.02-2.87(m,1H),2.45-2.29(m,3H),2.24-2.02(m,2H),1.94-1.71(m, 5H).MS:411[M+H]⁺。

Example 39.(R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethynylphenyl) amino) pyrimidine-5-carboxamide the preparation of example 39 references the preparation of example 1 steps 1) to 4) where cyclopropylamine is replaced with an equimolar equivalent of 2-ethynylaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.93-11.76(m,1H),9.67-9.62(m,1H),8.88- 8.74(m,1H),8.69(s,1H),8.12(d,J＝6.6Hz,1H),8.03-7.96(m,1H),7.74-7.59(m,1H),7.55-7.51(m,1H), 7.46(s,1H),7.44-7.38(m,1H),7.14-7.04(m,1H),6.91-6.78(m,1H),6.18-6.05(m,1H),5.73-5.64(m,1H), 4.62-4.48(m,2H),4.24-4.13(m,1H),4.07-4.00(m,1H),3.08-2.82(m,1H),2.18-1.98(m,2H),1.90-1.75(m, 2H),1.50(s,1H).MS:457[M+H]⁺。

EXAMPLE 40 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethynylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 40 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-ethynylaniline.¹H NMR(400MHz,DMSO-d6)δ11.91-11.77(m,1H),9.63(s,1H),8.75(s,1H), 8.69(s,1H),8.13(d,J＝8.1Hz,1H),7.99(s,1H),7.72(s,1H),7.64-7.52(m,1H),7.50-7.37(m,2H),7.15- 6.99(m,1H),6.92-6.74(m,1H),6.18-6.05(m,1H),5.73-5.63(m,1H),4.64-4.45(m,2H),4.28-4.15(m,1H), 4.09-3.95(m,1H),3.07(s,1H),2.87(s,1H),2.18-2.01(m,2H),1.84-1.78(m,2H).MS:457[M+H]⁺。

EXAMPLE 41 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-cyanophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 41 reference is made to the preparation of example 1, steps 1) to 4), where in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-aminobenzonitrile.¹H NMR(400MHz,DMSO-d6)δ12.18-11.85(m,2H),9.76-9.73(m,1H),8.73(s, 1H),8.04-8.02(m,1H),7.90-7.87(m,1H),7.78-7.72(m,1H),7.54-7.51(m,1H),7.39(s,1H),7.34-7.31(m, 1H),6.90-6.82(m,1H),6.58(s,1H),6.15-6.10(m,1H),5.73-5.67(m,1H),4.63-4.49(m,1H),4.24-4.10(m, 2H),2.15-2.10(m,2H),1.98-1.96(m,1H),1.82-1.80(m,2H),1.50-1.46(m,1H).MS:458[M+H]⁺。

EXAMPLE 42 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-cyanophenyl) amino) pyrimidine-5-carboxamide

The preparation of example 42 reference is made to the preparation of example 2, steps 1) to 4), where in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-aminobenzonitrile.¹H NMR(400MHz,DMSO-d6)δ12.17-11.86(m,1H),9.75-9.69(m,1H),8.80- 8.77(m,1H),8.15-7.96(m,2H),7.93-7.68(m,2H),7.64-7.42(m,2H),7.42-7.19(m,2H),6.90-6.73(m,1H), 6.20-6.05(m,1H),5.75-5.64(m,1H),4.30-3.87(m,3H),3.20-2.99(m,1H),2.82(s,1H),2.13-1.97(m,1H), 1.91-1.74(m,2H),1.55-1.42(m,1H).MS:458[M+H]⁺。

EXAMPLE 43 (R) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-trifluoromethyl) phenyl) amino) pyrimidine-5-carboxamide

Preparation of example 43 reference exampleThe preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4- (trifluoromethyl) aniline.¹H NMR(400MHz,DMSO-d6)δ11.90-11.83(m,1H),9.72(s,1H),8.79-8.70 (m,1H),8.09-7.99(m,2H),7.85-7.74(m,2H),7.74-7.56(m,3H),7.52-7.46(m,1H),6.90-6.68(m,1H),6.19- 6.02(m,1H),5.75-5.59(m,1H),4.61-3.98(m,3H),3.52-3.38(m,1H),3.14-2.84(m,1H),2.15-2.04(m,1H), 1.99-1.63(m,2H),1.55-1.38(m,1H).MS:501[M+H]⁺。

EXAMPLE 44 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-trifluoromethyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 44 reference is made to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 4- (trifluoromethyl) aniline.¹H NMR(400MHz,DMSO-d6)δ11.89-11.84(m,1H),9.72(s,1H),8.80-8.69 (m,1H),8.18-8.07(m,1H),8.06-7.94(m,2H),7.87-7.76(m,2H),7.70-7.67(m,2H),7.48(s,1H),6.85-6.81 (m,1H),6.18-6.05(m,1H),5.78-5.61(m,1H),4.33-3.98(m,3H),3.55-3.48(m,1H),3.18-2.94(m,1H),2.23- 2.02(m,2H),1.86-1.73(m,1H),1.55-1.43(m,1H).MS:501[M+H]⁺。

Example 45 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxyethyl) amino) pyrimidine-5-carboxamide the preparation of example 45 refers to preparation of example 1 step 1) to step 4) where cyclopropylamine is replaced with an equimolar amount of 2-methoxyethyl-1-amine in step 1).¹H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.25(s,1H),8.46(s,1H),7.94- 7.91(m,1H),7.81-7.61(m,1H),7.56(s,1H),7.06(s,1H),6.88-6.76(m,1H),6.15-6.04(m,1H),5.72-5.64(m, 1H),4.63-4.50(m,1H),4.22-4.12(m,2H),4.12-3.99(m,1H),3.65-3.62(m,1H),3.55-3.53(m,1H),3.51-3.45 (m,1H),3.29(s,3H),3.16-2.86(m,2H),2.17-2.12(m,1H),2.06-1.98(m,1H),1.86-1.79(m,1H),1.57-1.48 (m,1H).MS:415[M+H]⁺。

EXAMPLE 46 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxyethyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 46 refers to the procedure of example 2, steps 1) to 4), wherein cyclopropylamine is replaced with an equimolar amount of 2-methoxyethyl-1-amine in step 1).¹H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.25(s,1H),8.46(s,1H),7.93- 7.92(m,1H),7.71(s,1H),7.56(s,1H),7.06(s,1H),6.90-6.75(m,1H),6.17-6.04(m,1H),5.73-5.62(m,1H), 4.60-4.01(m,3H),3.66-3.49(m,4H),3.29(s,3H),3.19-2.83(m,2H),2.18-1.98(m,2H),1.88-1.77(m,1H), 1.58-1.46(m,1H).MS:415[M+H]⁺。

EXAMPLE 47 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((cyclopropylmethyl) amino) pyrimidine-5-carboxamide

The preparation of example 47 refers to the preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) with an equimolar amount of cyclopropylmethylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.25(s,1H),8.46(s,1H),7.97(s,1H), 7.82-7.63(m,1H),7.58-7.56(m,1H),7.16-6.97(m,1H),6.86-6.78(m,1H),6.15-6.05(m,1H),5.72-5.65(m, 1H),4.63(s,1H),4.21-4.13(m,2H),4.07-4.00(m,1H),3.18-3.05(m,1H),3.01-2.92(m,1H),2.18-2.13(m, 1H),2.05-2.00(m,1H),1.87-1.81(m,1H),1.56-1.50(m,1H),1.24-1.18(m,1H),1.17-1.10(m,1H),0.49-0.47 (d,J＝7.8Hz,2H),0.27-0.26(s,2H).MS:411[M+H]⁺。

EXAMPLE 48 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((cyclopropylmethyl) amino) pyrimidine-5-carboxamide

Preparation of example 48 reference is made to preparation of example 2, steps 1) to 4), where in step 1)The cyclopropylamine was replaced with an equimolar amount of cyclopropylmethylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.25(s,1H),8.46(s,1H),7.98(s,1H), 7.71(s,1H),7.57(s,1H),7.07(s,1H),6.90-6.75(m,1H),6.15-6.03(m,1H),5.75-5.63(m,1H),4.61-4.02(m, 3H),3.56-3.37(m,2H),3.21-3.00(m,1H),3.03-2.85(m,1H),2.22-1.98(m,2H),1.82(s,1H),1.52(s,1H), 1.21-1.08(m,1H),0.49-0.47(t,J＝7.9Hz,2H),0.27-0.26(m,2H).MS:411[M+H]⁺。

EXAMPLE 49 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (isopentylamino) pyrimidine-5-carboxamide

The preparation of example 49 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of isoamylamine.¹H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.19(s,1H),8.45(s,1H),7.93(d,J＝7.4 Hz,1H),7.80-7.65(m,1H),7.62-7.59(m,1H),7.22-6.97(m,1H),6.88-6.78(m,1H),6.15-6.05(m,1H),5.72- 5.64(m,1H),4.65-4.55(m,1H),4.20-4.15(m,1H),4.10-3.99(m,1H),3.52-3.45(m,3H),3.14-2.86(m,2H), 2.16-2.11(m,1H),2.05-1.99(m,1H),1.85-1.79(m,1H),1.68-1.62(m,1H),1.51-1.48(m,2H),0.93(s,3H), 0.91(s,3H).MS:427[M+H]⁺。

EXAMPLE 50 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (isopentylamino) pyrimidine-5-carboxamide

The preparation of example 50 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of isoamylamine.¹H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.19(s,1H),8.45(s,1H),7.93(d,J＝7.1 Hz,1H),7.81-7.64(m,1H),7.60(s,1H),7.15-6.96(m,1H),6.89-6.75(m,1H),6.17-6.04(m,1H),5.73-5.63 (m,1H),4.28-3.97(m,3H),3.53-3.46(m,2H),3.17-2.99(m,1H),2.99-2.82(m,1H),2.17-2.09(m,1H),2.07- 1.98(m,1H),1.86-1.77(m,1H),1.73-1.60(m,1H),1.56-1.44(m,3H),0.92(d,J＝6.6Hz,6H).MS:427[M+H]⁺。

EXAMPLE 51 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (isopropylamino) pyrimidine-5-carboxamide

The preparation of example 51 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of isopropylamine.¹H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.13-9.09(m,1H),8.45(s,1H),7.91(s,1H), 7.77-7.64(m,1H),7.61-7.58(m,1H),7.13-6.97(m,1H),6.87-6.79(m,1H),6.15-6.05(m,1H),5.71-5.64(m, 1H),4.67-4.56(m,1H),4.17-4.11(m,2H),4.06-3.99(m,1H),3.12(t,J＝12.8,12.8Hz,1H),3.00-2.92(m,1H), 2.16-2.13(m,1H),2.04-1.99(m,1H),1.85-1.80(m,1H),1.55-1.51(m,1H),1.25(s,6H).MS:399[M+H]⁺。

EXAMPLE 52 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (isopropylamino) pyrimidine-5-carboxamide

The preparation of example 52 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of isopropylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.11(s,1H),8.45(s,1H),7.91(s,1H),7.70 (s,1H),7.59(s,1H),7.06(s,1H),6.91-6.74(m,1H),6.17-6.04(m,1H),5.73-5.63(m,1H),4.61(s,1H),4.27- 4.10(m,3H),4.03(d,J＝13.9Hz,1H),3.17-3.06(m,1H),3.03-2.87(m,1H),2.18-1.99(m,1H),1.87-1.79(m, 1H),1.59-1.47(m,1H),1.25(s,6H).MS:399[M+H]⁺。

EXAMPLE 53 (R) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-hydroxy-2-methylpropyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 53 refers to the procedure of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 1-amino-2-methylpropan-2-ol.¹H NMR(400MHz,DMSO-d6)δ9.47-9.13(m,2H),8.46(s,1H),7.97(s, 1H),7.83-7.53(m,2H),7.31-6.70(m,2H),6.16-6.04(m,1H),5.73-5.63(m,1H),4.64(s,1H),4.26-4.12(m, 2H),4.12-3.98(m,1H),3.52-3.37(m,3H),3.13-2.88(m,1H),2.18-2.00(m,2H),1.86-1.76(m,1H),1.58-1.45 (m,1H),1.15(s,6H).MS:429[M+H]⁺。

EXAMPLE 54 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-hydroxy-2-methylpropyl) amino) pyrimidine-5-carboxamide

The procedure of example 54 is as in example 2, step 1) to step 4) of the procedure, wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 1-amino-2-methylpropan-2-ol.¹H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.40-9.16(m,1H),8.46(s, 1H),7.97(s,1H),7.69(s,1H),7.56(s,1H),7.19-6.91(m,1H),6.88-6.76(m,1H),6.17-6.04(m,1H),5.73-5.63 (m,1H),4.64(s,1H),4.25-4.10(m,2H),4.09-4.00(m,1H),3.48-3.39(m,2H),3.16-3.01(m,1H),3.00-2.86 (m,1H),2.21-2.00(m,2H),1.86-1.76(m,1H),1.57-1.46(m,1H),1.16(s,6H).MS:429[M+H]⁺。

EXAMPLE 55 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 55 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of (tetrahydro-2H-pyran-4-yl) methylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.34(s,1H),8.52-8.44 (m,1H),7.93(d,J＝4.5Hz,1H),7.73(s,1H),7.59(s,1H),7.23-6.97(m,1H),6.89-6.76(m,1H),6.16-6.04 (m,1H),5.73-5.63(m,1H),4.59-4.01(m,3H),3.89-3.83(m,2H),3.45-3.36(m,2H),3.28(t,J＝11.6Hz,2H), 3.16-3.03(m,1H),3.03-2.87(m,1H),2.20-1.99(m,2H),1.90-1.75(m,2H),1.64-1.47(m,3H),1.32-1.21(m, 2H).MS:455[M+H]⁺。

EXAMPLE 56 (R) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) pyrimidine-5-carboxamide

Preparation of example 56 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) cyclopropylamine is replaced with an equimolar amount of (tetrahydro-2H-pyran-4-yl) methylamine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.34(s,1H),8.46(s,1H), 7.96-7.90(m,1H),7.80-7.71(m,1H),7.59(s,1H),7.06(s,1H),6.89-6.75(m,1H),6.16-6.04(m,1H),5.73- 5.63(m,1H),4.59-4.02(m,3H),3.89-3.84(m,2H),3.44-3.36(m,2H),3.31-3.26(m,2H),3.17-3.04(m,1H), 3.03-2.86(m,1H),2.16-1.99(m,2H),1.82(s,2H),1.64-1.56(m,2H),1.52(s,1H),1.31-1.22(m,2H).MS: 455[M+H]⁺。

EXAMPLE 57 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (tetrahydro-2H-pyran-4-yl) ethyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 57 reference is made to the procedure of example 2, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) by an equimolar amount of 2- (tetrahydro-2H-pyran-4-yl) ethan-1-amine.¹H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.20(s,1H),8.45 (s,1H),7.93(s,1H),7.71(s,1H),7.57(s,1H),7.07(s,1H),6.89-6.77(m,1H),6.16-6.04(m,1H),5.73-5.63 (m,1H),4.60-4.01(m,3H),3.86-3.78(m,2H),3.49(s,2H),3.25(t,J＝11.6Hz,2H),3.18-2.86(m,2H),2.19- 1.97(m,2H),1.87-1.76(m,1H),1.64-1.50(m,6H),1.27-1.14(m,2H).MS:469[M+H]⁺。

EXAMPLE 58 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (tetrahydro-2H-pyran-4-yl) ethyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 58 reference is made to the preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) by an equimolar amount of 2- (tetrahydro-2H-pyran-4-yl) ethan-1-amine.¹H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.20(s,1H),8.45 (s,1H),7.93(s,1H),7.71(s,1H),7.57(s,1H),7.06(s,1H),6.89-6.76(m,1H),6.17-6.04(m,1H),5.74-5.63 (m,1H),4.60-4.02(m,3H),3.86-3.79(m,2H),3.49(s,2H),3.29-3.20(m,2H),3.17-3.04(m,1H),3.01-2.84 (m,1H),2.18-1.97(m,2H),1.82(s,1H),1.62-1.48(m,6H),1.25-1.16(m,2H).MS:469[M+H]⁺。

EXAMPLE 59 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 59 reference is made to preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-ethoxyaniline.¹H NMR(400MHz,DMSO-d6)δ11.79-11.58(m,1H),9.55(s,1H),8.90-8.69(m, 1H),8.64(s,1H),8.15-8.00(m,1H),7.95-7.76(m,1H),7.62-7.45(m,1H),7.45-7.19(m,1H),7.10-6.92(m, 3H),6.91-6.71(m,1H),6.18-6.05(m,1H),5.74-5.62(m,1H),4.32-3.97(m,5H),3.20-3.00(m,1H),2.97-2.81 (m,1H),2.19-2.05(m,1H),2.01-1.89(m,1H),1.88-1.76(m,1H),1.58-1.37(m,4H).MS:477[M+H]⁺。

Example 60 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethoxyphenyl) amino) pyrimidine-5-carboxamide the preparation of example 60 refers to the preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced with an equimolar amount of 2-ethoxyaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.79-11.58(m,1H),9.55(s,1H),8.85-8.69(m, 1H),8.67-8.62(m,1H),8.20-7.98(m,1H),7.97-7.76(m,1H),7.66-7.47(m,1H),7.49-7.29(m,1H),7.12-6.93 (m,3H),6.91-6.77(m,1H),6.18-6.05(m,1H),5.75-5.63(m,1H),4.28-4.04(m,5H),3.18-3.02(m,1H),3.00- 2.82(m,1H),2.08-2.06(s,1H),2.00-1.89(m,1H),1.86-1.78(m,1H),1.61-1.40(m,4H).MS:477[M+H]⁺。

EXAMPLE 61 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((5-fluoro-2-methoxyphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 61Reference example 1, preparation method steps 1) to 4), wherein cyclopropylamine is replaced with equimolar amounts of 5-fluoro-2-methoxyaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.90-11.80(m,1H),9.73-9.55(m,1H), 8.86-8.64(m,2H),8.18-7.87(m,2H),7.67-7.26(m,2H),7.03(s,1H),6.90-6.75(m,2H),6.18-6.04(m,1H), 5.75-5.62(m,1H),4.33-4.12(m,2H),4.08-3.99(m,1H),3.85(s,3H),3.33-3.30(m,1H),3.18-2.90(m,1H), 2.20-1.96(m,2H),1.87-1.77(m,1H),1.57-1.44(m,1H).MS:481[M+H]⁺。

EXAMPLE 62 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((5-fluoro-2-methoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 62 the preparation of example 2, steps 1) to 4), was referenced, wherein in step 1) the cyclopropylamine was replaced with an equimolar amount of 5-fluoro-2-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ11.90-11.80(m,1H),9.74-9.55(m,1H), 8.81-8.65(m,2H),8.15-7.89(m,2H),7.65-7.49(m,1H),7.33(s,1H),7.09-7.01(m,1H),6.94-6.73(m,2H), 6.18-6.03(m,1H),5.78-5.62(m,1H),4.33-4.00(m,3H),3.85(s,3H),3.76-3.51(m,1H),3.18-2.90(m,1H), 2.18-2.03(m,2H),1.87-1.76(m,1H),1.57-1.44(m,1H).MS:481[M+H]⁺。

EXAMPLE 63 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 63 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-methoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.58(s,1H),8.58(s,1H), 7.88(s,1H),7.32-7.14(m,3H),7.08-7.03(m,1H),7.03-6.80(m,3H),6.20-6.08(m,1H),5.77-5.65(m,1H), 4.55-4.22(m,1H),4.14-3.97(m,1H),3.76-3.71(m,4H),3.27-3.04(m,1H),2.86-2.61(m,1H),2.13(s,3H), 1.92-1.80(m,2H),1.79-1.70(m,1H),1.54-1.44(m,1H).MS:477[M+H]⁺。

EXAMPLE 64 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 64 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-methoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.41(d,J＝3.5Hz,1H),9.58(s,1H), 8.58(s,1H),7.89(s,1H),7.32-7.14(m,3H),7.10-7.03(m,1H),7.02-6.89(m,2H),6.90-6.72(m,1H),6.21- 6.09(m,1H),5.77-5.65(m,1H),4.59-4.26(m,1H),4.14-3.96(m,1H),3.76-3.71(m,4H),3.34-3.31(m,1H), 3.28-3.03(m,1H),2.13(s,3H),1.91-1.71(m,3H),1.56-1.42(m,1H).MS:477[M+H]⁺。

Example 65 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isopropoxyphenyl) amino) pyrimidine-5-carboxamide the preparation of example 65 refers to preparation of example 1, steps 1) to 4), where cyclopropylamine is replaced with an equimolar amount of 2-isopropoxyaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.77-11.63(m,1H),9.57-9.51(m,1H),8.87- 8.69(m,1H),8.63(s,1H),8.20-8.01(m,1H),7.94-7.81(m,1H),7.60-7.49(m,1H),7.38-7.30(m,1H),7.08(s, 1H),7.04-6.77(m,3H),6.17-6.05(m,1H),5.74-5.63(m,1H),4.66-4.59(m,1H),4.29-3.98(m,3H),3.21-2.79 (m,2H),2.18-1.90(m,2H),1.87-1.75(m,1H),1.57-1.45(m,1H),1.31(s,6H).MS:491[M+H]⁺。

EXAMPLE 66 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isopropoxyphenyl) amino) pyrimidine-5-carboxamide the preparation of example 66 refers to preparation of example 2, steps 1) to 4), where in step 1) an equimolar amount of 2-isopropoxyaniline is substituted for the equimolar amount of 2-isopropoxyanilineCyclopropylamine.¹H NMR(400MHz,DMSO-d6)δ11.77-11.63(m,1H),9.61-9.48(m,1H),8.92- 8.68(m,1H),8.68-8.60(m,1H),8.25-7.97(m,1H),7.94-7.80(m,1H),7.60-7.49(m,1H),7.45-7.23(m,1H), 7.08(s,1H),7.05-6.90(m,2H),6.91-6.74(m,1H),6.18-6.05(m,1H),5.74-5.63(m,1H),4.67-4.59(m,1H), 4.34-3.99(m,3H),3.20-2.97(m,1H),2.96-2.78(m,1H),2.15-1.93(m,2H),1.89-1.76(m,1H),1.58-1.45(m, 1H),1.31(s,6H).MS:491[M+H]⁺。

EXAMPLE 67 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-fluoro-2-methoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 67 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-fluoro-2-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ11.64-11.13(m,1H),9.58(s,1H),8.78-8.61 (m,2H),8.03-7.81(m,2H),7.63-7.59(m,1H),7.28(s,1H),7.07-6.95(m,1H),6.93-6.70(m,2H),6.18-6.05 (m,1H),5.74-5.63(m,1H),4.58-4.03(m,3H),3.88-3.83(m,3H),3.16-3.00(m,1H),2.95-2.77(m,1H),2.09- 1.99(m,1H),1.93-1.73(m,2H),1.55-1.44(m,1H).MS:481[M+H]⁺。

EXAMPLE 68 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-fluoro-2-methoxyphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 68 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-fluoro-2-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ11.64-11.13(m,1H),9.58(s,1H),8.81-8.68 (m,1H),8.68-8.59(m,1H),8.05-7.83(m,2H),7.64-7.59(m,1H),7.41-7.28(m,1H),7.08-6.98(m,1H),6.92- 6.74(m,2H),6.19-6.05(m,1H),5.74-5.63(m,1H),4.62-4.01(m,3H),3.88-3.83(m,3H),3.23-3.00(m,1H), 2.94-2.78(m,1H),2.16-2.04(m,1H),1.94-1.71(m,2H),1.57-1.43(m,1H).MS:481[M+H]⁺。

EXAMPLE 69 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-cyclopropylethyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 69 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-cyclopropylethan-1-amine.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.33-9.19(m,1H),8.52-8.43(m, 1H),7.98-7.92(m,1H),7.72(s,1H),7.67-7.53(m,1H),7.07(s,1H),6.90-6.75(m,1H),6.16-6.03(m,1H), 5.73-5.62(m,1H),4.64-4.00(m,3H),3.56-3.45(m,2H),3.18-2.83(m,2H),2.19-1.98(m,2H),1.87-1.76(m, 1H),1.56-1.46(m,3H),0.78-0.68(m,1H),0.44-0.38(m,2H),0.14-0.07(m,2H).MS:425[M+H]⁺。

Example 70 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-cyclopropylethyl) amino) pyrimidine-5-carboxamide the preparation of example 70 refers to preparation of example 1, steps 1) to 4), where cyclopropylamine is replaced with an equimolar amount of 2-cyclopropylethan-1-amine in step 1).¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.28(s,1H),8.45(s,1H),7.96- 7.90(m,1H),7.82-7.66(m,1H),7.61(s,1H),7.07(s,1H),6.89-6.76(m,1H),6.15-6.04(m,1H),5.73-5.62(m, 1H),4.64-3.99(m,3H),3.52-3.46(m,2H),3.18-3.02(m,1H),3.03-2.86(m,1H),2.19-1.98(m,2H),1.87-1.76 (m,1H),1.52-1.51(m,3H),0.78-0.68(m,1H),0.45-0.39(m,2H),0.13-0.08(m,2H).MS:425[M+H]⁺。

EXAMPLE 71 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-hydroxy-3-methylbutyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 71 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-2-methylbutan-2-ol.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.18(s,1H),8.44(s,1H), 8.07-7.92(m,1H),7.71(s,1H),7.56(d,J＝4.4Hz,1H),7.06(s,1H),6.89-6.77(m,1H),6.17-6.04(m,1H), 5.72-5.62(m,1H),4.65-4.51(m,1H),4.41(s,1H),4.27-4.19(m,1H),4.18-4.11(m,1H),4.11-3.99(m,1H), 3.58-3.54(m,1H),3.51-3.43(m,1H),3.15-2.93(m,1H),2.14-2.01(m,2H),1.85-1.77(m,1H),1.71-1.66(m, 2H),1.54-1.45(m,1H),1.15(s,6H).MS:443[M+H]⁺。

EXAMPLE 72 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-hydroxy-3-methylbutyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 72 reference is made to the procedure of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-2-methylbutan-2-ol.¹H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.18(s,1H),8.44(s,1H), 8.06-8.00(m,1H),7.70(s,1H),7.57-7.54(m,1H),7.05(s,1H),6.89-6.77(m,1H),6.17-6.04(m,1H),5.73- 5.63(m,1H),4.63-4.54(m,1H),4.41(s,1H),4.27-4.18(m,1H),4.17-4.02(m,2H),3.60-3.53(m,2H),3.47(t, J＝11.4Hz,1H),3.14-2.94(m,1H),2.13-2.00(m,2H),1.84-1.77(m,1H),1.71-1.68(m,1H),1.54-1.46(m, 1H),1.15(s,6H).MS:443[M+H]⁺。

EXAMPLE 73 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-fluoro-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 73 the preparation of example 2, steps 1) to 4), was referenced, wherein in step 1) the cyclopropylamine was replaced with an equimolar amount of 2-fluoro-6-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ10.46-10.42(m,1H),9.65(s,1H),8.60(s, 1H),7.93(s,1H),7.35-7.28(m,2H),7.24(s,1H),7.19(d,J＝11.0Hz,1H),7.06-6.99(m,2H),6.92-6.78(m, 1H),6.20-6.09(m,1H),5.74-5.67(m,1H),4.52-4.25(m,1H),4.10-4.01(m,1H),3.79(s,3H),3.78-3.67(m, 1H),3.29-3.03(m,1H),2.83-2.68(m,1H),1.91-1.76(m,3H),1.49-1.48(m,1H).MS:481[M+H]⁺。

EXAMPLE 74 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-fluoro-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 74 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-fluoro-6-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ10.44-10.43(m,1H),9.65(s,1H),8.61(s, 1H),7.93(s,1H),7.35-7.27(m,2H),7.24(s,1H),7.21-7.16(m,1H),7.06-7.00(m,2H),6.91-6.77(m,1H), 6.20-6.08(m,1H),5.75-5.67(m,1H),4.52-4.25(m,1H),4.11-4.00(m,1H),3.79(s,3H),3.78-3.69(m,1H), 3.29-3.02(m,1H),2.86-2.67(m,1H),1.90-1.76(m,3H),1.51-1.44(m,1H).MS:481[M+H]⁺。

EXAMPLE 75 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-chloro-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 75 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-chloro-6-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.63(s,1H),8.60(s,1H),7.93 (s,1H),7.40-7.27(m,3H),7.24-7.20(m,2H),7.12-7.05(m,1H),6.93-6.72(m,1H),6.22-6.07(m,1H),5.76- 5.67(m,1H),4.50-4.25(m,1H),4.10-4.04(m,1H),3.75(s,3H),3.74-3.73(m,1H),3.32(s,2H),1.88-1.77(m, 3H),1.52-1.46(m,1H).MS:497[M+H]⁺。

EXAMPLE 76 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-chloro-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 76 reference is made to the procedure of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-chloro-6-methoxyaniline.¹H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.63(s,1H),8.60(s,1H),7.93 (s,1H),7.38-7.28(m,3H),7.25-7.22(m,1H),7.21-7.20(m,1H),7.12-7.06(m,1H),6.93-6.73(m,1H),6.21- 6.08(m,1H),5.75-5.67(m,1H),4.51-4.24(m,1H),4.10-4.01(m,1H),3.75(s,3H),3.74(s,1H),3.33-3.03(m, 1H),2.86-2.69(m,1H),1.88-1.77(m,3H),1.51-1.45(m,1H).MS:497[M+H]⁺。

Example 77 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isobutoxyphenyl) amino) pyrimidine-5-carboxamide the preparation of example 77 refers to preparation method step 1) to step 4) of example 2, where cyclopropylamine is replaced by an equimolar equivalent of 2-isobutoxyaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.71(s,1H),11.52(s,1H),9.58-9.54(m,1H), 8.86-8.63(m,2H),8.12-7.99(m,1H),7.90-7.78(m,1H),7.60-7.47(m,1H),7.37(s,1H),7.05-7.03(m,1H), 6.96-6.92(m,1H),6.89-6.81(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.62-4.19(m,2H),4.17-4.01(m, 2H),3.82-3.79(m,2H),3.16-3.00(m,1H),2.92-2.79(m,1H),2.06-1.83(m,3H),1.50(s,1H),1.07(d,J＝6.8 Hz,3H),1.01(d,J＝6.6Hz,3H).MS:505[M+H]⁺。

EXAMPLE 78 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isobutoxyphenyl) amino) pyrimidine-5-carboxamide the preparation of example 78 refers to preparation method step 1) to step 4) of example 1, where cyclopropylamine is replaced by an equimolar equivalent of 2-isobutoxyaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ11.71(s,1H),11.52(s,1H),9.57-9.54(m,1H), 8.87-8.63(m,2H),8.13-7.99(m,1H),7.90-7.77(m,1H),7.61-7.47(m,1H),7.39(s,1H),7.05-7.03(m,1H), 6.96-6.92(m,1H),6.89-6.81(m,1H),6.17-6.06(m,1H),5.72-5.64(m,1H),4.61-4.20(m,1H),4.18-3.97(m, 2H),3.82-3.79(m,2H),3.21-2.98(m,1H),2.96-2.77(m,1H),2.12-2.03(m,2H),1.92-1.75(m,2H),1.49(s, 1H),1.09-1.05(m,3H),1.03-1.00(m,3H).MS:505[M+H]⁺。

EXAMPLE 79 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (2-methoxyethoxy) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 79 reference is made to preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2- (2-methoxyethoxy) aniline.¹H NMR(400MHz,DMSO-d6)δ11.78(s,1H),11.55(s,1H),9.64(s, 1H),8.83-8.66(m,1H),8.63(s,1H),8.07-7.93(m,2H),7.79-7.59(m,1H),7.48-7.36(m,1H),7.10-7.06(m, 1H),6.99-6.96(m,1H),6.90-6.82(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.62-4.22(m,2H),4.16(s, 2H),4.07-4.01(m,1H),3.78-3.70(m,2H),3.30(s,3H),3.18-3.04(m,1H),2.93-2.77(m,1H),2.12-1.81(m, 3H),1.55-1.46(m,1H).MS:507[M+H]⁺。

EXAMPLE 80 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (2-methoxyethoxy) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 80 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2- (2-methoxyethoxy) aniline.¹H NMR(400MHz,DMSO-d6)δ11.74(s,1H),11.48(s,1H),9.58-9.53 (m,1H),8.83-8.63(m,2H),8.09-7.99(m,1H),7.90-7.76(m,1H),7.60-7.46(m,1H),7.35(s,1H),7.08-7.05 (m,1H),6.99-6.95(m,1H),6.90-6.82(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.62-4.20(m,2H),4.18- 4.15(m,2H),4.08-4.02(m,1H),3.79-3.70(m,2H),3.35(s,3H),3.17-3.02(m,1H),2.92-2.81(m,1H),2.10- 1.90(m,2H),1.91-1.79(m,1H),1.50(s,1H).MS:507[M+H]⁺。

EXAMPLE 81 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isobutoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 81 reference is made to preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-isobutoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.53(s,1H),8.58(s,1H), 7.86(s,1H),7.21(s,2H),7.18-7.07(m,2H),7.02-6.82(m,3H),6.21-6.07(m,1H),5.76-5.65(m,1H),4.54- 4.22(m,1H),4.10-3.99(m,1H),3.71-3.63(m,3H),3.33-3.18(m,2H),2.17(s,3H),1.94-1.66(m,5H),0.79(d, J＝7.6Hz,6H).MS:519[M+H]⁺。

EXAMPLE 82 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isobutoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 82 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-isobutoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.53(s,1H),8.58(s,1H), 7.86(s,1H),7.31-7.17(m,2H),7.17-7.06(m,2H),7.05-6.82(m,3H),6.21-6.06(m,1H),5.75-5.64(m,1H), 4.51-4.26(m,1H),4.13-3.99(m,1H),3.80-3.59(m,3H),3.28-3.02(m,1H),2.86-2.64(m,1H),2.17(s,3H), 1.92-1.70(m,4H),1.55-1.42(m,1H),0.79(d,J＝7.1Hz,6H).MS:519[M+H]⁺。

EXAMPLE 83 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (2-methoxyethoxy) -6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 83 refers to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2- (2-methoxyethoxy) -6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.55(s,1H), 8.58(s,1H),7.86(s,1H),7.20-7.17(m,3H),7.09(s,1H),7.05-6.94(m,2H),6.92-6.83(m,1H),6.20-6.07(m, 1H),5.76-5.66(m,1H),4.54-4.21(m,1H),4.06-4.04(m,3H),3.81-3.64(m,1H),3.50(s,2H),3.33-3.31(d,J ＝6.3Hz,1H),3.23-3.20(m,1H),3.15(s,3H),2.15(s,3H),1.90-1.70(m,3H),1.50-1.48(s,1H).MS: 521[M+H]⁺。

EXAMPLE 84 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (2-methoxyethoxy) -6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 84 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2- (2-methoxyethoxy) -6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.55(s,1H), 8.58(s,1H),7.86(s,1H),7.20(s,2H),7.16-7.15(m,1H),7.09-7.08(m,1H),7.05-6.95(m,2H),6.93-6.84(m, 1H),6.21-6.07(m,1H),5.81-5.66(m,1H),4.50-4.28(m,1H),4.15-3.96(m,4H),3.75-3.71(m,1H),3.51-3.49 (m,3H),3.15(s,3H),2.15(s,3H),1.91-1.70(m,3H),1.57-1.42(m,1H).MS:521[M+H]⁺。

EXAMPLE 85 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dimethoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 85 reference is made to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2, 6-dimethoxyaniline.¹H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.50(s,1H),8.55(s,1H),7.86 (s,1H),7.28-7.23(m,1H),7.22(s,1H),7.15-7.12(m,1H),6.93-6.73(m,4H),6.21-6.09(m,1H),5.76-5.68(m, 1H),4.52-4.27(m,1H),4.12-3.99(m,1H),3.83-3.74(m,1H),3.72-3.69(m,6H),3.28-3.04(m,1H),2.85-2.67 (m,1H),1.91-1.82(m,2H),1.81-1.74(m,1H),1.54-1.45(m,1H).MS:493[M+H]⁺。

EXAMPLE 86 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dimethoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 86 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2, 6-dimethoxyaniline.¹H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.50(s,1H),8.55(s,1H),7.86 (s,1H),7.28-7.23(m,1H),7.22(s,1H),7.15-7.11(m,1H),6.91-6.73(m,4H),6.21-6.09(m,1H),5.75-5.67(m, 1H),4.52-4.27(m,1H),4.11-3.99(m,1H),3.81-3.73(m,1H),3.72-3.69(m,6H),3.26-3.04(m,1H),2.84-2.67 (m,1H),1.90-1.82(m,2H),1.81-1.75(m,1H),1.53-1.45(m,1H).MS:493[M+H]⁺。

EXAMPLE 87 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for preparation of example 87 refers to the procedure of example 2, steps 1) to 4), wherein cyclopropylamine is replaced with an equimolar amount of 2-ethoxy-6-methylaniline in step 1).¹H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.57(s,1H),8.59(s,1H), 7.88(s,1H),7.21-7.14(m,3H),7.12-7.07(m,1H),7.03-6.81(m,3H),6.20-6.06(m,1H),5.75-5.66(m,1H), 4.53-4.25(m,1H),4.13-3.92(m,3H),3.78-3.71(m,1H),3.27-3.04(m,1H),2.84-2.61(m,1H),2.15(s,3H), 1.89-1.68(m,3H),1.54-1.42(m,1H),1.16(t,J＝6.9Hz,3H).MS:491[M+H]⁺。

EXAMPLE 88 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 88 reference is made to the procedure of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) by an equimolar amount of 2-ethoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.55(s,1H),8.58(s,1H), 7.88(s,1H),7.29-7.07(m,4H),7.04-6.82(m,3H),6.21-6.07(m,1H),5.76-5.66(m,1H),4.53-4.24(m,1H), 4.10-3.99(m,3H),3.76-3.71(m,1H),3.29-3.03(m,1H),2.86-2.67(m,1H),2.15(s,3H),1.89-1.68(m,3H), 1.48(s,1H),1.16(t,J＝7.0Hz,3H).MS:491[M+H]⁺。

EXAMPLE 89 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isopropoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 89 the procedure of example 2 is referenced from step 1) to step 4) of the procedure, wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-isopropoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.59(s,1H),8.59(s,1H), 7.90(s,1H),7.35-7.07(m,4H),7.06-6.71(m,3H),6.21-6.06(m,1H),5.76-5.64(m,1H),4.54-4.23(m,2H), 4.14-3.96(m,1H),3.85-3.68(m,1H),3.25-3.02(m,1H),2.86-2.63(m,1H),2.14(s,3H),1.91-1.65(m,3H), 1.56-1.41(m,1H),1.16-1.07(m,6H).MS:505[M+H]⁺。

EXAMPLE 90 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isopropoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 90 reference is made to the procedure of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-isopropoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d6)δ10.58(s,1H),9.71(s,1H),8.58(s,1H), 7.93(s,1H),7.23(s,2H),7.17-7.06(m,2H),7.05-6.70(m,3H),6.21-6.06(m,1H),5.77-5.63(m,1H),4.53- 4.26(m,2H),4.15-3.93(m,2H),3.24-3.03(m,1H),2.90-2.64(m,1H),2.15(s,3H),1.89-1.69(m,3H),1.48(s, 1H),1.17-1.08(m,6H).MS:505[M+H]⁺。

Example 91 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dimethylphenyl) amino) pyrimidine-5-carboxamide the preparation of example 91 refers to preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced by an equimolar equivalent of 2, 6-dimethylaniline in step 1).¹H NMR(400MHz,DMSO-d₆)δ10.58(s,1H),9.59(s,1H),8.60(s,1H),7.90(s, 1H),7.32-7.09(m,5H),6.98(s,1H),6.94-6.71(m,1H),6.21-6.07(m,1H),5.76-5.67(m,1H),4.51-4.23(m, 1H),4.04(dd,J＝31.5,13.6Hz,1H),3.70(d,J＝16.0Hz,1H),3.27-3.02(m,1H),2.85-2.61(m,1H),2.15(d, J＝6.2Hz,6H),1.90-1.66(m,3H),1.48(s,1H).MS:461[M+H]⁺.

Example 92 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dimethylphenyl) amino) pyrimidine-5-carboxamide the preparation of example 92 refers to preparation 1) to 4) of example 2, where cyclopropylamine is replaced by an equimolar amount of 2, 6-dimethylaniline in step 1).¹H NMR(400MHz,DMSO-d₆)δ10.58(s,1H),9.59(s,1H),8.60(s,1H),7.90(s, 1H),7.33-7.10(m,5H),6.98(s,1H),6.91-6.72(m,1H),6.20-6.08(m,1H),5.75-5.66(m,1H),4.38(dd,J＝ 75.6,12.7Hz,1H),4.13-3.97(m,1H),3.69(s,1H),3.14(d,J＝61.1Hz,1H),2.70-2.63(m,1H),2.15(d,J＝ 6.2Hz,6H),1.89-1.65(m,3H),1.54-1.41(m,1H).MS:461[M+H]⁺.

Example 93.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dimethylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 93 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equivalent molar equivalent of 2, 6-dimethylaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate (preparation reference WO 2014139465).¹H NMR(400MHz, DMSO-d₆)δ10.59(s,1H),9.58(s,1H),8.60(s,1H),7.89(s,1H),7.15(d,J＝9.7Hz,5H),7.01-6.92(m,2H), 6.21(dd,J＝16.6,2.5Hz,1H),5.76(dd,J＝10.4,2.4Hz,1H),4.56(d,J＝13.2Hz,1H),4.19(d,J＝13.8Hz, 1H),4.08-3.99(m,1H),3.19(t,J＝13.0Hz,1H),2.76(t,J＝12.7Hz,1H),2.13(s,6H),1.83-1.74(m,2H), 1.52-1.34(m,2H).MS:461[M+H]⁺.

Example 94.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-chloro-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 94 referring to preparation of example 1, steps 1) to 4), wherein in step 1) cyclopropylamine is replaced with an equivalent molar equivalent of 2-chloro-6-methylaniline and in step 2) tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.76(s,1H),9.65(s, 1H),8.63(s,1H),7.93(s,1H),7.42(d,J＝7.2Hz,2H),7.33-7.27(m,2H),7.15(s,1H),7.01-6.91(m,2H),6.21 (dd,J＝16.6,2.5Hz,1H),5.76(dd,J＝10.4,2.4Hz,1H),4.55(d,J＝13.4Hz,1H),4.23-4.02(m,2H),3.21(t, J＝12.9Hz,1H),2.78(t,J＝12.8Hz,1H),2.20(s,3H),1.85-1.75(m,2H),1.52-1.34(m,2H).MS:481[M+H]⁺.

EXAMPLE 95 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-chloro-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 95 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-chloro-6-methylaniline.¹H NMR(400MHz,DMSO-d₆)δ10.76(s,1H),9.66(s,1H),8.63(s,1H),7.93 (s,1H),7.54-7.25(m,4H),7.18(s,1H),7.01(d,J＝12.6Hz,1H),6.93-6.71(m,1H),6.21-6.07(m,1H),5.73 (d,J＝12.2Hz,1H),4.37(d,J＝94.5Hz,1H),4.07(d,J＝16.1Hz,1H),3.74(d,J＝34.6Hz,1H),3.27-3.01 (m,1H),2.87-2.65(m,1H),2.21(d,J＝4.9Hz,3H),1.91-1.66(m,3H),1.49(s,1H).MS:481[M+H]⁺.

EXAMPLE 96 preparation of (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-chloro-6-methylphenyl) amino) pyrimidine-5-carboxamide example 96 reference is made to preparation of example 2, steps 1) to 4), where 2-chloro equivalent is used in step 1) in equimolar amounts-6-methylaniline instead of cyclopropylamine.¹H NMR(400MHz,DMSO-d₆)δ10.76(s,1H),9.66(s,1H),8.63(s,1H),7.93 (s,1H),7.55-7.29(m,3H),7.29-7.17(m,2H),7.06-6.98(m,1H),6.91-6.71(m,1H),6.14(dd,J＝26.9,16.4 Hz,1H),5.73(d,J＝12.2Hz,1H),4.37(dd,J＝88.0,13.1Hz,1H),4.07(d,J＝16.1Hz,1H),3.74(d,J＝34.3 Hz,1H),3.28-3.01(m,1H),2.87-2.63(m,1H),2.21(d,J＝4.9Hz,3H),1.91-1.67(m,3H),1.49(s,1H).MS: 481[M+H]⁺.

Example 97.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 97 the preparation of example 1 is referred to as step 1) to step 4) of the preparation of example 1, wherein in step 1) the cyclopropylamine is replaced by an equivalent molar equivalent of 2-methoxy-6-methylaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.42(s,1H), 9.56(s,1H),8.57(s,1H),7.87(s,1H),7.32-7.19(m,2H),7.16(s,1H),7.03(s,1H),6.99-6.89(m,3H),6.22 (dd,J＝16.6,2.5Hz,1H),5.76(dd,J＝10.4,2.5Hz,1H),4.56(d,J＝13.2Hz,1H),4.20(d,J＝13.7Hz,1H), 4.10-4.01(m,1H),3.70(s,3H),3.25-3.15(m,1H),2.83-2.72(m,1H),2.12(s,3H),1.78(d,J＝14.0Hz,2H), 1.55-1.33(m,2H).MS:477[M+H]⁺.

Example 98.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dimethoxyphenyl) amino) pyrimidine-5-carboxamide the preparation of example 98 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equivalent molar amount of 2, 6-dimethoxyaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.16(s,1H), 9.49(s,1H),8.54(s,1H),7.85(s,1H),7.33-7.20(m,2H),7.17(s,1H),7.10(s,1H),7.00-6.91(m,1H),6.75(d, J＝8.4Hz,2H),6.21(dd,J＝16.7,2.5Hz,1H),5.76(dd,J＝10.4,2.5Hz,1H),4.56(d,J＝13.2Hz,1H),4.19 (d,J＝13.8Hz,1H),4.12-4.02(m,1H),3.69(s,6H),3.27-3.16(m,1H),2.83-2.74(m,1H),1.80(s,2H),1.56- 1.39(m,2H).MS:493[M+H]⁺.

EXAMPLE 99 (R, E) -2- ((1- (1- (4- (dimethylamino) but-2-enoyl) piperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 99 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-methoxy-6-methylaniline and in step 4) the acryloyl chloride is replaced with an equivalent amount of (E) -4- (dimethylamino) but-2-enoyl chloride hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.40(s,1H),9.55(s,1H),8.58(s,1H),7.99–7.74(m,1H),7.29–7.11 (m,3H),7.08–6.93(m,3H),6.67–6.52(m,2H),4.51–4.19(m,1H),4.10–3.93(m,1H),3.71(s,3H),3.12–2.94 (m,3H),2.24–2.04(m,11H),1.89–1.69(m,3H),1.53–1.42(m,1H).MS:534[M+H]⁺.

EXAMPLE 100 (S, E) -2- ((1- (1- (4- (dimethylamino) but-2-enoyl) piperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 100 reference is made to preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equivalent molar amount of 2-methoxy-6-methylaniline and in step 4) the acryloyl chloride is replaced with an equivalent amount of (E) -4- (dimethylamino) but-2-enoyl chloride hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.40(s,1H),9.55(s,1H),8.58(s,1H),7.96-7.75(m,1H),7.30-7.13 (m,3H),7.08-7.04(m,1H),7.01-6.92(m,2H),6.67-6.63(m,1H),6.59–6.49(m,1H),4.56-4.17(m,1H),4.09- 3.95(m,1H),3.71(s,3H),3.09-2.94(m,3H),2.18-2.08(m,11H),1.90-1.81(m,2H),1.78-1.70(m,1H),1.52- 1.44(m,1H).MS:534[M+H]⁺.

EXAMPLE 101 (R, E) -4- ((2-chloro-6-methoxyphenyl) amino) -2- ((1- (1- (4- (dimethylamino) but-2-enoyl) piperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide

Preparation of example 101 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-chloro-6-methoxyaniline and in step 4) the acryloyl chloride is replaced with an equivalent amount of (E) -4- (dimethylamino) but-2-enoyl chloride hydrochloride.¹H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.60(s,1H),8.60(s,1H),8.02-7.80(m,1H),7.59-7.28(m, 2H),7.28-7.20(m,2H),7.19-7.03(m,2H),6.72-6.48(m,2H),4.54-4.17(m,1H),4.11-3.97(m,1H),3.84-3.66 (m,4H),3.27-2.96(m,3H),2.84–2.63(m,1H),2.21-2.09(m,6H),2.02-1.66(m,3H),1.55-1.38(m,1H).MS: 554[M+H]⁺.

EXAMPLE 102 (S, E) -4- ((2-chloro-6-methoxyphenyl) amino) -2- ((1- (1- (4- (dimethylamino) but-2-enoyl) piperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide

The preparation of example 102 reference is made to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equivalent molar amount of 2-chloro-6-methoxyaniline and in step 4) the acryloyl chloride is replaced by an equivalent amount of (E) -4- (dimethylamino) but-2-enoyl chloride hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.54(s,1H),9.60(s,1H),8.60(s,1H),8.03–7.79(m,1H),7.39–7.26(m, 2H),7.26–7.19(m,2H),7.19–7.03(m,2H),6.72–6.44(m,2H),4.56–4.14(m,1H),4.12–3.95(m,1H),3.88– 3.61(m,4H),3.27–2.92(m,3H),2.91–2.65(m,1H),2.21–2.09(m,6H),1.92–1.67(m,3H),1.56–1.43(m,1H). MS:554[M+H]⁺.

EXAMPLE 103 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-chloro-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 103 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 4-chloro-2-methoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d₆)δ10.48-10.22(m,1H),9.63(s,1H), 8.59(s,1H),7.90(s,1H),7.54-6.96(m,5H),6.86(m,1H),6.24-5.99(m,1H),5.83-5.55(m,1H),4.60-4.26(m, 1H),4.19-4.01(m,1H),3.79-3.62(m,4H),3.17-2.61(m,2H),2.12(s,3H),2.00-1.69(m,3H),1.63-1.39(m, 1H).MS:511[M+H]⁺.

EXAMPLE 104 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-chloro-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for preparation of example 104 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-chloro-2-methoxy-6-methylaniline.¹H NMR(400MHz,DMSO-d₆)δ10.51-10.27(m,1H),9.63(s,1H), 8.59(s,1H),7.90(s,1H),7.49-6.94(m,5H),6.94-6.71(m,1H),6.31-5.99(m,1H),5.71(t,J＝12.6Hz,1H), 4.64-4.23(m,1H),4.18-3.94(m,1H),3.75(s,3H),3.65(s,1H),3.30-2.59(m,2H),2.12(s,3H),2.03-1.68(m, 3H),1.66-1.45(m,1H).MS:511[M+H]⁺.

Example 105.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-chloro-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 105 referring to preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced with an equivalent molar equivalent of 4-chloro-2-methoxy-6-methylaniline in step 1) and tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate in step 2).¹H NMR(400MHz,DMSO-d₆)δ10.38(s, 1H),9.59(s,1H),8.58(s,1H),8.01-7.77(m,1H),7.40-7.22(m,1H),7.20(s,1H),7.10(s,2H),7.05(s,1H), 6.94-6.79(m,1H),6.19-6.06(m,1H),5.73-5.64(m,1H),4.53(d,J＝13.2Hz,1H),4.18(d,J＝13.8Hz,1H), 4.04-3.85(m,1H),3.74(s,3H),3.23(t,J＝12.9Hz,1H),2.83(t,J＝12.7Hz,1H),2.12(s,3H),1.95-1.79(m, 2H),1.79-1.49(m,2H).MS:511[M+H]⁺.

Example 106.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dichlorophenyl) amino) pyrimidine-5-carboxamide

Preparation of example 106 the preparation of example 1 is referred to as step 1) to step 4) of the preparation of example 1, wherein in step 1) the cyclopropylamine is replaced with an equivalent molar equivalent of 2, 6-dichloroaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.92(s,1H),9.70(s, 1H),8.65(s,1H),7.97(s,1H),7.66-7.60(m,2H),7.47-7.33(m,2H),7.16(s,1H),7.05-6.90(m,2H),6.21(dd, J＝16.7,2.4Hz,1H),5.76(dd,J＝10.3,2.4Hz,1H),4.58-4.50(m,1H),4.13(d,J＝37.2Hz,2H),3.22(t,J＝ 13.2Hz,1H),2.80(t,J＝12.8Hz,1H),1.87-1.78(m,2H),1.53-1.37(m,2H).MS:501[M+H]⁺.

Example 107.(R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dichlorophenyl) amino) pyrimidine-5-carboxamide the preparation of example 107 refers to preparation 1) to 4) of example 1, where cyclopropylamine is replaced with an equimolar amount of 2, 6-dichloroaniline in step 1).¹H NMR(400MHz,DMSO-d₆)δ10.90(s,1H),9.71(s,1H),8.66(s,1H),7.97(s, 1H),7.77-7.63(m,2H),7.39(d,J＝7.9Hz,2H),7.19(s,1H),7.07(d,J＝22.0Hz,1H),6.92-6.71(m,1H), 6.22-6.05(m,1H),5.76-5.65(m,1H),4.54-4.19(m,1H),4.06(s,1H),3.77(d,J＝43.5Hz,1H),3.20-3.02(m, 1H),2.88-2.66(m,1H),1.92-1.70(m,3H),1.55-1.42(m,1H).MS:501[M+H]⁺.

Example 108 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2, 6-dichlorophenyl) amino) pyrimidine-5-carboxamide the preparation of example 108 refers to preparation of example 2, steps 1) to 4), wherein cyclopropylamine is replaced with an equimolar equivalent of 2, 6-dichloroaniline in step 1).¹H NMR(400MHz,DMSO-d₆)δ10.91(s,1H),9.71(s,1H),8.66(s,1H),7.97(s, 1H),7.69(dt,J＝20.6,10.2Hz,2H),7.39(s,2H),7.21-6.99(m,2H),6.93-6.71(m,1H),6.21-6.06(m,1H), 5.76-5.65(m,1H),4.53-4.18(m,1H),4.07(d,J＝14.6Hz,1H),3.77(d,J＝43.1Hz,1H),3.14-2.96(m,1H), 2.86-2.66(m,1H),1.93-1.70(m,3H),1.55-1.42(m,1H).MS:501[M+H]⁺.

EXAMPLE 109 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyano-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 109 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-3-methoxy-5-methylbenzonitrile.¹H NMR(400MHz,DMSO-d₆)δ10.81-10.47(m,1H),9.69(s, 1H),8.62(s,1H),7.94(s,1H),7.65-7.45(m,2H),7.44-7.15(m,2H),7.13-6.94(m,1H),6.91-6.65(m,1H), 6.24-5.96(m,1H),5.84-5.55(m,1H),4.62-4.17(m,1H),4.17-4.02(m,1H),3.80(s,4H),3.27-2.59(m,2H), 2.18(s,3H),2.05-1.43(m,4H).MS:502[M+H]⁺.

EXAMPLE 110 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyano-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 110 reference is made to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-3-methoxy-5-methylbenzonitrile.¹H NMR(400MHz,DMSO-d₆)δ10.85-10.46(m,1H),9.68(s, 1H),8.62(s,1H),7.93(s,1H),7.63-7.15(m,4H),7.14-6.95(m,1H),6.93-6.64(m,1H),6.32-5.99(m,1H), 5.84-5.51(m,1H),4.58-4.18(m,1H),4.15-3.95(m,1H),3.93-3.42(m,4H),3.30-2.66(m,2H),2.18(s,3H), 1.99-1.40(m,4H).MS:502[M+H]⁺.

Example 111.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyano-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 111 the preparation of example 1 is referred to as step 1) to step 4) of preparation of example 1, wherein in step 1) the cyclopropylamine is replaced by an equivalent molar equivalent of 4-amino-3-methoxy-5-methylbenzonitrile and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ 10.63(s,1H),9.63(s,1H),8.61(s,1H),8.09-7.83(m,1H),7.62-7.24(m,3H),7.18(s,1H),7.00(s,1H),6.92- 6.80(m,1H),6.13(dd,J＝16.7,2.4Hz,1H),5.70(dd,J＝10.4,2.4Hz,1H),4.63-4.04(m,2H),4.02-3.85(m, 1H),3.78(s,3H),3.25(t,J＝13.2Hz,1H),2.86(t,J＝12.7Hz,1H),2.17(s,3H),1.94-1.48(m,4H).MS:502 [M+H]⁺.

Example 112.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyridin-3-yloxy) phenyl) amino) pyrimidine-5-carboxamide

Preparation of example 112 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-methoxy-6-methyl-4- (pyridin-3-yloxy) aniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equimolar amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO- d₆)δ10.35(s,1H),9.54(s,1H),8.57(s,1H),8.46-8.44(m,1H),8.35-8.31(m,1H),7.92-7.71(m,1H),7.52- 7.49(m,1H),7.43-7.40(m,1H),7.21(d,J＝10.5Hz,3H),6.87-6.80(m,2H),6.73(s,1H),6.13-6.09(m,1H), 5.69-5.65(m,1H),4.53-4.47(m,1H),4.17-4.08(m,2H),3.68(s,3H),3.18-3.11(m,1H),2.79-2.71(m,1H), 2.12(s,3H),1.94-1.88(m,2H),1.72-1.63(m,2H).MS:570[M+H]⁺.

EXAMPLE 113 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyridin-3-yloxy) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 113 the preparation of example 1, steps 1) to 4), was referenced, wherein in step 1) the cyclopropylamine was replaced with an equimolar amount of 2-methoxy-6-methyl-4- (pyridin-3-yloxy) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.36(s,1H),9.58 (s,1H),8.58(s,1H),8.40-8.33(m,2H),7.99-7.76(m,1H),7.44-7.40(m,2H),7.28-7.18(m,3H),6.84-6.71(m, 3H),6.09-6.03(m,1H),5.67-5.62(m,1H),4.63-4.19(m,1H),4.12-4.05(m,1H),3.92-3.75(m,1H),3.69(s, 3H),3.11-2.73(m,1H),2.11(s,3H),1.97-1.82(m,3H),1.50-1.31(m,2H).MS:570[M+H]⁺.

EXAMPLE 114 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyridin-3-yloxy) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 114 reference is made to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-methoxy-6-methyl-4- (pyridin-3-yloxy) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.36(s,1H),9.59 (s,1H),8.58(s,1H),8.42-8.32(m,2H),7.99-7.73(m,1H),7.46-7.40(m,2H),7.35-7.16(m,3H),6.84-6.64(m, 3H),6.11-6.03(m,1H),5.68-5.62(m,1H),4.58-4.30(m,1H),4.12-4.03(m,1H),3.91-3.75(m,1H),3.69(s, 3H),3.28-3.00(m,1H),2.83-2.70(m,1H),2.11(s,3H),2.00-1.95(m,1H),1.88-1.77(m,2H),1.49-1.38(m, 1H).MS:570[M+H]⁺.

Example 115.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4-phenoxyphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 115 the preparation of example 1 is referred to as step 1) to step 4) of preparation of example 1, wherein in step 1) the cyclopropylamine is replaced with an equivalent molar equivalent of 2-methoxy-6-methyl-4-phenoxyaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ 10.33(s,1H),9.53(s,1H),8.72-8.27(m,2H),7.93-7.74(m,1H),7.42-7.37(m,2H),7.23-7.20(m,2H),7.11- 7.07(m,3H),6.86-6.79(m,1H),6.76-6.72(m,1H),6.69-6.64(m,1H),6.14-6.08(m,1H),5.69-5.64(m,1H), 4.52-4.46(m,1H),4.15-4.05(m,2H),3.67(s,3H),3.17-3.08(m,1H),2.78-2.71(m,1H),2.11(s,3H),1.93- 1.86(m,2H),1.72-1.61(m,2H).MS:569[M+H]⁺.

EXAMPLE 116 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4-phenoxyphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 116 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 2-methoxy-6-methyl-4-phenoxyaniline.¹H NMR(400MHz,DMSO-d₆)δ10.35(s,1H),9.58(s,1H), 8.71-8.29(m,2H),7.94-7.82(m,1H),7.39-7.37(m,2H),7.25-7.24(m,1H),7.21-7.19(m,1H),7.12-7.09(m, 1H),7.04-7.00(m,2H),6.79-6.63(m,3H),6.11-6.06(m,1H),5.68-5.64(m,1H),4.53-4.30(m,1H),4.10-4.05 (m,1H),3.90-3.80(m,1H),3.67(s,3H),3.14-3.00(m,1H),2.83-2.75(m,1H),2.10(s,3H),2.02-1.93(m,2H), 1.83-1.78(m,2H).MS:569[M+H]⁺.

EXAMPLE 117.2- ((1- (1-Acrylopiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-methylphenyl) amino) pyrimidine-5-carboxamide the preparation of example 117 reference is made to the preparation of example 1, steps 1) to 4), where step 1) is carried out in equimolar amounts of 2-Ethyl-6-methylaniline instead of cyclopropylamine, tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate was replaced in step 2) with an equivalent amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.48(s,1H),9.44 (s,1H),8.44(s,1H),7.76(s,1H),7.09-6.97(m,5H),6.85-6.78(m,1H),6.77(s,1H),6.09-6.03(m,1H),5.63- 5.59(m,1H),4.44-4.37(m,1H),4.07-4.00(m,1H),3.91-3.83(m,1H),3.10-2.95(m,1H),2.65-2.56(m,1H), 2.38-2.36(m,1H),2.33-2.30(m,1H),1.95(s,3H),1.64-1.56(m,2H),1.30-1.16(m,2H),0.89(t,J＝7.6,7.6 Hz,3H).MS:475[M+H]⁺.

Example 118.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-chloro-6-methoxyphenyl) amino) pyrimidine-5-carboxamide the preparation of example 118 refers to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equivalent molar amount of 2-chloro-6-methoxyaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H), 9.61(s,1H),8.60(s,1H),7.92(s,1H),7.41-7.26(m,2H),7.18-7.07(m,4H),7.01-6.92(m,1H),6.22(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.3,2.4Hz,1H),4.56(d,J＝13.3Hz,1H),4.14(d,J＝44.4Hz,2H),3.74(s, 3H),3.28-3.18(m,1H),2.85-2.75(m,1H),1.88-1.77(m,2H),1.56-1.35(m,2H).MS:497[M+H]⁺.

EXAMPLE 119 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 119 refers to the procedure of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) with an equimolar amount of 2-ethyl-6-methylaniline.¹H NMR(400MHz,DMSO-d₆)δ10.64-10.59(m,1H),9.59(s,1H),8.61(s, 1H),7.90(s,1H),7.28-7.16(m,5H),6.97-6.70(m,2H),6.20-6.09(m,1H),5.75-5.67(m,1H),4.49-4.25(m, 1H),4.12-3.95(m,1H),3.76-3.63(m,1H),3.24-3.01(m,1H),2.84-2.59(m,1H),2.55-2.52(m,1H),2.49(s, 1H),2.14-2.11(m,3H),1.87-1.78(m,2H),1.73-1.60(m,1H),1.54-1.42(m,1H),1.09-1.03(m,3H).MS:475 [M+H]⁺.

EXAMPLE 120 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 120 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-ethyl-6-methylaniline.¹H NMR(400MHz,DMSO-d₆)δ10.63-10.60(m,1H),9.59(s,1H),8.61(s, 1H),7.90(s,1H),7.28-7.16(m,5H),6.98-6.92(m,1H),6.92-6.72(m,1H),6.20-6.08(m,1H),5.75-5.66(m, 1H),4.50-4.24(m,1H),4.10-3.96(m,1H),3.75-3.61(m,1H),3.28-3.00(m,2H),2.86-2.54(m,2H),2.14-2.11 (m,3H),1.87-1.79(m,2H),1.69-1.44(m,2H),1.09-1.05(m,3H).MS:475[M+H]⁺.

EXAMPLE 121 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 121 reference is made to the procedure of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) by an equimolar amount of 2-ethyl-6-methoxyaniline.¹H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.36-7.20(m,2H),7.20 –6.90(m,3H),6.90-6.68(m,1H),6.34-6.16(m,1H),5.88-5.69(m,1H),4.63-4.38(m,1H),4.23-4.02(m,1H), 3.75(s,3H),3.21-2.69(m,2H),2.67–2.54(m,2H),2.32-1.85(m,3H),1.84-1.62(m,1H),1.61-1.21(m,1H), 1.21-1.04(m,3H).MS:491[M+H]⁺.

EXAMPLE 122 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 122 refers to the procedure of example 2, steps 1) to 4), wherein cyclopropylamine is replaced with an equimolar amount of 2-ethyl-6-methoxyaniline in step 1). 1H NMR (400MHz, Methanol-d4) delta 8.50(s,1H),7.36-7.22(M,2H), 7.21-6.94 (M,3H),6.93-6.69(M,1H),6.33-6.19(M,1H),5.85-5.74(M,1H),4.64-4.40(M,1H),4.22-4.02(M,1H), 3.76(s,3H),3.02-2.55(M,4H),2.03-1.74(M,3H),1.69-1.55(M,1H),1.32-1.27(M,1H),1.21-1.05(M,3H). MS:491[ M + H ], [ M + H ]]⁺.

EXAMPLE 123 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-cyclopropyl-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 123 reference is made to the procedure of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-cyclopropyl-6-methoxyaniline.¹H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.31(s,1H),7.28- 7.13(m,2H),7.08-6.92(m,1H),6.89-6.74(m,1H),6.74-6.64(m,1H),6.33-6.20(m,1H),5.85-5.73(m,1H), 4.64-4.40(m,1H),4.20-4.04(m,1H),3.86–3.71(m,4H),3.27-3.04(m,1H),2.96-2.77(m,1H),2.02-1.84(m, 4H),1.66–1.56(m,1H),0.92-0.84(m,1H),0.83-0.75(m,1H),0.70-0.53(m,2H).MS:503[M+H]⁺.

EXAMPLE 124 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-cyclopropyl-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 124 refers to the procedure of example 2, steps 1) to 4), wherein cyclopropylamine is replaced with an equimolar amount of 2-cyclopropyl-6-methoxyaniline in step 1). 1H NMR (400MHz, Methanol-d4) delta 8.50(s,1H),7.31(s,1H), 7.27-7.11 (m,2H),7.10-6.91(m,1H),6.90-6.74(m,1H),6.74-6.61(m,1H),6.33-6.20(m,1H),5.85-5.74(m,1H), 4.68-4.39(m,1H),4.23-4.02(m,1H),3.90-3.63(m,4H),3.18-3.11(m,1H),2.93-2.78(m,1H),2.04-1.82(m, 4H),1.67-1.56(m,1H),0.92-0.85(m,1H),0.83-0.72(m,1H),0.71-0.51(m,2H).MS:503[M+H]⁺.

Example 125.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-cyclopropyl-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 125 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equivalent molar equivalent of 2-cyclopropyl-6-methoxyaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.45(s, 1H),9.52(s,1H),8.57(s,1H),7.87(s,1H),7.31-7.20(m,2H),7.16(s,1H),7.06(s,1H),6.99-6.89(m,2H), 6.56(d,J＝7.9Hz,1H),6.25-6.18(m,1H),5.76(dd,J＝10.4,2.5Hz,1H),4.56(d,J＝13.2Hz,1H),4.19(d, J＝13.8Hz,1H),4.04(s,1H),3.68(s,3H),3.24-3.15(m,1H),2.82-2.72(m,1H),1.86(q,J＝4.9,3.1Hz,1H), 1.76(s,2H),1.49-1.34(m,2H),0.88-0.73(m,2H),0.66-0.47(m,2H).MS:503[M+H]⁺.

Example 126.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 126 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equivalent molar equivalent of 2-ethoxy-6-methylaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.46(s,1H), 9.54(s,1H),8.57(s,1H),8.01-7.67(m,1H),7.32-7.10(m,3H),7.06(s,1H),6.99-6.87(m,3H),6.26-6.16(m, 1H),5.79-5.73(m,1H),4.59-4.50(m,1H),4.23-4.14(m,1H),4.09-3.91(m,3H),3.19(t,J＝13.0Hz,1H),2.76 (t,J＝12.7Hz,1H),2.13(s,3H),1.85-1.74(m,2H),1.56-1.32(m,2H),1.15(t,J＝6.9Hz,3H).MS:491 [M+H]⁺.

Example 127.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-isopropoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 127 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-isopropoxy-6-methylaniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equimolar amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.46(s, 1H),9.53(s,1H),8.57(s,1H),7.99-7.74(m,1H),7.30-7.14(m,3H),7.07(s,1H),6.98-6.87(m,3H),6.26-6.17 (m,1H),5.79-5.72(m,1H),4.60-4.51(m,1H),4.45-4.39(m,1H),4.22-4.13(m,1H),4.12-4.01(m,1H),3.19 (t,J＝13.0Hz,1H),2.76(t,J＝12.8Hz,1H),2.12(s,3H),1.84-1.74(m,2H),1.52-1.32(m,2H),1.17-1.02(m, 6H).MS:505[M+H]⁺.

Example 128.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-methoxy-6-methylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

Preparation of example 128 the preparation of example 1 is referred to as step 1) to step 4) of the preparation of example 1, wherein in step 1) the cyclopropylamine is replaced by an equivalent molar equivalent of 4-methoxy-6-methyl-5-pyrimidinamine and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.58(s, 1H),9.68(s,1H),8.61(d,J＝9.7Hz,2H),8.00-7.86(m,1H),7.45-7.29(m,1H),7.17(s,1H),7.01(s,1H), 6.96-6.88(m,1H),6.22-6.15(m,1H),5.73(dd,J＝10.4,2.4Hz,1H),4.55(d,J＝13.3Hz,1H),4.24-4.09(m, 2H),3.88(s,3H),3.26-3.19(m,1H),2.84-2.75(m,1H),2.27(s,3H),1.88(s,2H),1.68-1.45(m,2H).MS:479 [M+H]⁺.

EXAMPLE 129 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-methoxy-6-methylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 129 reference is made to the procedure of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-methoxy-6-methyl-5-pyrimidinamine.¹H NMR(400MHz,DMSO-d₆)δ10.59(s,1H),9.70(s,1H),8.64(d, J＝10.9Hz,2H),7.94(s,1H),7.35(m,1H),7.19(s,1H),7.11(s,1H),6.92-6.76(m,1H),6.19-6.04(m,1H), 5.75-5.63(m,1H),4.57-4.17(m,1H),4.10-4.07(m,1H),3.89(s,4H),3.30-3.05(m,1H),2.87-2.79(m,1H), 2.29(s,3H),1.96(s,1H),1.72(s,2H),1.50(s,1H).MS:479[M+H]⁺.

EXAMPLE 130 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-methoxy-6-methylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 130 refers to the preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-methoxy-6-methyl-5-pyrimidinamine.¹H NMR(400MHz,DMSO-d₆)δ10.59(s,1H),9.70(s,1H),8.64(d, J＝8.7Hz,2H),7.93(s,1H),7.35(s,1H),7.19(s,1H),7.11(s,1H),6.91-6.76(m,1H),6.18-6.05(m,1H), 5.75-5.64(m,1H),4.57-4.21(m,1H),4.13-4.04(m,1H),3.90(d,J＝4.5Hz,4H),3.32-3.06(m,1H),2.92-2.74 (m,1H),2.29(s,3H),2.03-1.63(m,3H),1.51(s,1H).MS:479[M+H]⁺.

Example 131.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-ethyl-6-methoxyphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 131 reference is made to preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced by an equivalent molar amount of 2-ethyl-6-methoxyaniline in step 1) and an equivalent amount of tert-butyl-aniline in step 2)4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylic acid ester instead of tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylic acid ester.¹H NMR(400MHz,DMSO-d₆)δ10.39(s,1H), 9.53(s,1H),8.56(s,1H),8.00-7.67(m,1H),7.32-7.26(m,1H),7.26-7.15(m,1H),7.14(s,1H),7.00-6.91(m, 4H),6.27-6.17(m,1H),5.79-5.74(m,1H),4.61-4.52(m,1H),4.24-4.15(m,1H),4.09-3.98(m,1H),3.67(s, 3H),3.19(t,J＝12.9Hz,1H),2.77(t,J＝12.8Hz,1H),2.46-2.41(m,1H),1.81-1.72(m,2H),1.49-1.34(m, 2H),1.27-1.19(m,1H),1.04(t,J＝7.5Hz,3H).MS:491[M+H]⁺.

Example 132.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-ethyl-6-methylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

Preparation of example 132 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equivalent molar equivalent of 4-ethyl-6-methylpyrimidin-5-amine and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.77(s, 1H),9.70(s,1H),8.89(s,1H),8.65(s,1H),8.03-7.86(m,1H),7.48-7.31(m,1H),7.13(s,1H),6.96-6.89(m, 1H),6.84(s,1H),6.22-6.15(m,1H),5.76-5.72(m,1H),4.59-4.52(m,1H),4.22-4.15(m,1H),4.13-4.04(m, 1H),3.26-3.18(m,1H),2.83-2.77(m,1H),2.68-2.64(m,2H),2.31(s,3H),1.88-1.82(m,2H),1.58-1.41(m, 2H),1.10(t,J＝7.5,7.5Hz,3H).MS:477[M+H]⁺.

EXAMPLE 133 (R) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-ethyl-6-methylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

The procedure for preparation of example 133 reference is made to the procedure of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-ethyl-6-methylpyrimidin-5-amine.¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),9.82-9.25(m,1H), 8.95-8.83(m,1H),8.73-8.64(m,1H),8.09-7.86(m,1H),7.52-7.29(m,1H),7.14(s,1H),6.97(s,1H),6.89- 6.76(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.54-4.21(m,1H),4.11-4.01(m,1H),3.92-3.79(m,1H), 3.25-3.09(m,1H),2.92-2.78(m,1H),2.70-2.65(m,2H),2.33(s,3H),1.94-1.79(m,2H),1.60-1.51(m,2H), 1.15-1.09(m,3H).MS:477[M+H]⁺.

EXAMPLE 134 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-ethyl-6-methylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 134 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-ethyl-6-methylpyrimidin-5-amine.¹H NMR(400MHz,DMSO-d₆)δ10.81-10.72(m,1H),9.72(s,1H), 8.96-8.92(m,1H),8.71-8.65(m,1H),8.02-7.89(m,1H),7.46-7.30(m,1H),7.14(s,1H),6.96(s,1H),6.89- 6.76(m,1H),6.17-6.06(m,1H),5.74-5.64(m,1H),4.54-4.21(m,1H),4.12-4.04(m,1H),3.92-3.79(m,1H), 3.27-3.08(m,1H),2.89-2.72(m,1H),2.69-2.65(m,2H),2.33(s,3H),1.94-1.89(m,1H),1.86-1.77(m,1H), 1.73-1.58(m,1H),1.55-1.47(m,1H),1.14-1.10(m,3H).MS:477[M+H]⁺.

EXAMPLE 135 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-carbamoyl-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 135 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-3-methoxy-5-methylbenzamide.¹H NMR(400MHz,DMSO-d₆)δ10.60-10.55(m,1H),9.61 (s,1H),8.60(s,1H),8.03-7.87(m,2H),7.57-7.48(m,2H),7.45-7.28(m,2H),7.22(s,1H),7.08(s,1H),6.87- 6.61(m,1H),6.14-6.00(m,1H),5.71-5.60(m,1H),4.48-4.12(m,1H),4.01-3.92(m,1H),3.78(s,3H),3.09- 2.78(m,1H),2.18(s,3H),1.85-1.72(m,2H),1.63-1.44(m,2H),1.31-1.21(m,2H).MS:520[M+H]⁺.

EXAMPLE 136 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-carbamoyl-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for preparation of example 136 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-3-methoxy-5-methylbenzamide.¹H NMR(400MHz,DMSO-d₆)δ10.60-10.54(m,1H),9.61 (s,1H),8.60(s,1H),8.03-7.90(m,2H),7.56-7.47(m,2H),7.42-7.28(m,2H),7.22(s,1H),7.08(s,1H),6.84- 6.63(m,1H),6.14-6.00(m,1H),5.71-5.60(m,1H),4.48-4.12(m,1H),4.01-3.93(m,1H),3.78(s,3H),3.44- 3.36(m,1H),3.31-3.18(m,1H),3.07-2.82(m,1H),2.18(s,3H),1.85-1.74(m,2H),1.63-1.48(m,2H).MS: 520[M+H]⁺.

Example 137.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-carbamoyl-2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 137 the preparation of example 1 was referenced to steps 1) to 4) of the preparation of example 1, wherein in step 1) the cyclopropylamine was replaced with an equivalent molar equivalent of 4-amino-3-methoxy-5-methylbenzamide and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate was replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ 10.44(s,1H),9.58(s,1H),8.59(s,1H),8.14(s,1H),7.89(s,1H),7.58(s,2H),7.52(s,1H),7.43-7.24(m,1H), 7.19(s,1H),6.90(s,1H),6.88-6.82(m,1H),6.12(dd,J＝16.6,2.4Hz,1H),5.70(dd,J＝10.4,2.4Hz,1H), 4.49-4.38(m,2H),4.16-4.08(m,1H),3.77(s,3H),3.43-3.35(m,1H),3.31-3.16(m,2H),2.82(s,1H),2.17(s, 3H),1.68(s,2H).MS:520[M+H]⁺.

Example 138.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (methylcarbamoyl) phenyl) amino) pyrimidine-5-carboxamide

Preparation of one) 4- ((2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid

Preparation method reference example 1 preparation method steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equivalent molar equivalent of 4-amino-3-methoxy-5-methylbenzoic acid and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate;

preparation of 2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (methylcarbamoyl) phenyl) amino) pyrimidine-5-carboxamide

104 mg (0.2mmol) of (4- ((2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid) was placed in a reaction flask, 1ml of N, N-dimethylformamide was added, followed by 114 mg (0.3mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 52 mg (0.4mmol) of N, N-diisopropylethylamine, and after stirring for 0.5 hour, 14 mg (0.2mmol) of methylamine hydrochloride was added, and the reaction was stirred until completion. After diluting with 5ml of water, ethyl acetate is used for extraction, organic phase is dried by spinning under reduced pressure, and the obtained solid is purified by column chromatography to obtain 53 mg of product with 50% yield.¹H NMR(400MHz,DMSO- d₆)δ10.47(s,1H),9.58(s,1H),8.62-8.58(m,2H),7.89(s,1H),7.53-7.46(m,2H),7.35-7.23(m,1H),7.19(s, 1H),6.96(s,1H),6.89-6.82(m,1H),6.15-6.10(m,1H),5.72-5.68(m,1H),4.49-4.41(m,1H),4.15-4.07(m, 1H),3.78(s,3H),3.26-3.06(m,2H),2.82(d,J＝4.4Hz,3H),2.77-2.66(m,1H),2.17(s,3H),1.76-1.59(m, 4H).MS:534[M+H]⁺.

EXAMPLE 139 (R) -4- ((2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid

The preparation of example 139 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 4-amino-3-methoxy-5-methylbenzoic acid.¹H NMR(400MHz,DMSO-d₆)δ10.59(s,1H),9.60(s,1H),8.60 (s,1H),8.00–7.83(m,1H),7.57(s,1H),7.47(s,1H),7.22(s,2H),7.11(s,1H),6.85–6.61(m,1H),6.14–6.02(m, 1H),5.69–5.59(m,1H),4.11–3.96(m,1H),3.77(s,3H),3.41–3.19(m,4H),2.17(s,3H),1.78–1.48(m,4H). MS:521[M+H]⁺.

EXAMPLE 140 (S) -4- ((2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid

The preparation of example 140 reference is made to preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced by an equimolar amount of 4-amino-3-methoxy-5-methylbenzoic acid.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.58(s,1H),8.59 (s,1H),7.94–7.87(m,1H),7.55(s,1H),7.46(s,1H),7.21(s,2H),7.11(s,1H),6.88–6.59(m,1H),6.11–6.03(m, 1H),5.68–5.61(m,1H),3.96–3.93(m,1H),3.75(s,3H),3.17–2.83(m,4H),2.15(s,3H),1.73–1.52(m,4H). MS:521[M+H]⁺.

EXAMPLE 141 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (methylcarbamoyl) phenyl) amino) pyrimidine-5-carboxamide

104 mg (0.2mmol) of ((R) -4- ((2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid) was placed in a reaction flask, and 1ml ofN, N-dimethylformamide, 114 mg (0.3mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 52 mg (0.4mmol) of N, N-diisopropylethylamine were added, and after stirring for 0.5 hour, 14 mg (0.2mmol) of methylamine hydrochloride was added, and the reaction was stirred until completion. Adding 5ml of water for dilution, extracting by ethyl acetate, carrying out vacuum spin drying on the organic phase, and carrying out column chromatography purification on the obtained solid to obtain the product.¹H NMR(400MHz,DMSO-d₆)δ10.53(s,1H), 9.61(s,1H),8.60(s,1H),8.48-8.43(m,1H),7.90(s,1H),7.51-7.43(m,2H),7.35-7.20(m,2H),7.02(s,1H), 6.88-6.64(m,1H),6.17-6.02(m,1H),5.73-5.61(m,1H),4.48-4.20(m,1H),4.06-3.93(m,1H),3.78(s,3H), 3.73-3.61(m,1H),3.33-3.31(m,1H),3.21-2.93(m,1H),2.78-2.75(m,3H),2.17(s,3H),1.84-1.69(m,2H), 1.65-1.47(m,2H).MS:534[M+H]⁺.

EXAMPLE 142 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (methylcarbamoyl) phenyl) amino) pyrimidine-5-carboxamide

104 mg (0.2mmol) of ((S) -4- ((2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid) was placed in a reaction flask, 1ml of N, N-dimethylformamide was added, followed by 114 mg (0.3mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 52 mg (0.4mmol) of N, N-diisopropylethylamine, and after stirring for 0.5 hour, 14 mg (0.2mmol) of methylamine hydrochloride was added, and the reaction was stirred until completion. Adding 5ml of water for dilution, extracting by ethyl acetate, carrying out vacuum spin drying on the organic phase, and carrying out column chromatography purification on the obtained solid to obtain the product.¹H NMR(400MHz,DMSO-d₆)δ10.52(s,1H), 9.60(s,1H),8.59(s,1H),8.47(s,1H),7.91(s,1H),7.50-7.42(m,2H),7.36-7.21(m,2H),7.02(s,1H),6.87- 6.62(m,1H),6.17-6.01(m,1H),5.73-5.61(m,1H),4.51-4.39(m,1H),4.26-4.13(m,1H),4.06-3.99(m,1H), 3.98-3.90(m,1H),3.78(s,3H),3.04-2.93(m,1H),2.78-2.74(m,3H),2.17(s,3H),1.84-1.68(m,2H),1.65- 1.47(m,2H).MS:534[M+H]⁺.

EXAMPLE 143 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (dimethylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 143 the preparation of example 141 was referenced wherein methylamine hydrochloride was replaced with an equimolar amount of dimethylamine in tetrahydrofuran (2M).¹H NMR(400MHz,DMSO-d₆)δ10.51(s,1H),9.59(s,1H),8.59(s,1H),7.96-7.88(m, 1H),7.23-7.21(m,2H),7.12-7.08(m,2H),6.98-6.95(m,1H),6.86-6.73(m,1H),6.24-5.97(m,1H),5.76-5.71 (m,1H),3.75(s,3H),3.30-3.30(m,2H),3.02-2.97(m,7H),2.95-2.92(m,6H),2.16(s,3H).MS:548[M+H]⁺.

EXAMPLE 144 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (dimethylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 144 the procedure of example 142 is referenced wherein an equimolar amount of dimethylamine in tetrahydrofuran (2M) is substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.54(s,1H),9.64(s,1H),8.59(s,1H),7.91(s,1H), 7.33-7.21(m,2H),7.16-7.07(m,2H),6.97(s,1H),6.91-6.82(m,1H),6.20-6.05(m,1H),5.75-5.64(m,1H), 4.48-4.22(m,1H),4.11-4.03(m,1H),4.01-3.87(m,1H),3.78-3.74(m,3H),3.34-3.26(m,1H),3.08-3.00(m, 1H),2.98(s,3H),2.95(s,3H),2.82-2.66(m,1H),2.17(s,3H),1.94-1.89(m,1H),1.82-1.73(m,1H),1.64-1.50 (m,1H).MS:548[M+H]⁺.

EXAMPLE 145 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (ethylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 145 reference is made to the preparation of example 141 wherein methylamine is replaced with an equimolar amount of ethylamine in tetrahydrofuran (2M)A hydrochloride salt.¹H NMR(400MHz,DMSO-d₆)δ10.58(s,1H),9.65(s,1H),8.63(s,1H),8.50(s,1H),7.94 (s,1H),7.54(s,1H),7.49(s,1H),7.30-7.20(m,2H),7.10(s,1H),6.89-6.68(m,1H),6.20-6.04(m,1H),5.76- 5.65(m,1H),4.55-4.19(m,1H),4.08-3.99(m,1H),3.81(s,3H),3.31-3.24(m,3H),3.21-3.00(m,1H),2.78- 2.63(m,1H),2.15(s,3H),1.86-1.70(m,2H),1.65-1.45(m,2H),1.18-1.10(m,3H).MS:548[M+H]⁺.

EXAMPLE 146 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (ethylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 146 reference is made to the procedure for the preparation of example 142, where methylamine hydrochloride is replaced with an equimolar amount of ethylamine in tetrahydrofuran (2M).¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.47(s,1H),7.91 (s,1H),7.51(s,1H),7.45(s,1H),7.31-7.22(m,2H),7.06(s,1H),6.87-6.65(m,1H),6.16-6.00(m,1H),5.72- 5.60(m,1H),4.50-4.17(m,1H),4.04-3.94(m,1H),3.79(s,3H),3.31-3.24(m,3H),3.21-2.99(m,1H),2.78- 2.66(m,1H),2.18(s,3H),1.83-1.71(m,2H),1.61-1.47(m,2H),1.15-1.12(m,3H).MS:548[M+H]⁺.

EXAMPLE 147 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (isopropylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 147 is as in example 141, substituting an equimolar amount of isopropylamine for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.60(s,1H),8.60(s,1H),8.44-8.39(m,3H),8.20(d,J＝7.8Hz, 1H),7.52(s,1H),7.44(s,1H),7.22(s,1H),7.09(s,1H),6.13-6.02(m,1H),5.70-5.62(m,1H),4.09-3.95(m, 3H),3.79(s,3H),2.18(s,3H),1.75-1.49(m,4H),1.24-1.23(m,3H),1.18-1.16(m,6H).MS:562[M+H]⁺.

EXAMPLE 148 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (isopropylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 148 the procedure of example 142 is referenced wherein an equimolar amount of isopropylamine is substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.21(d,J＝7.6Hz,1H),7.91(s,1H), 7.52(s,1H),7.44(s,1H),7.33-7.21(m,2H),7.10(s,1H),6.86-6.65(m,1H),6.14-5.99(m,1H),5.71-5.60(m, 1H),4.51-4.15(m,1H),4.14-4.06(m,2H),4.03-3.92(m,1H),3.79(s,3H),3.23-3.00(m,1H),2.84-2.66(m, 1H),2.18(s,3H),1.85-1.72(m,2H),1.62-1.49(m,2H),1.19-1.16(m,6H).MS:562[M+H]⁺.

EXAMPLE 149 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (cyclobutylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 149 the preparation of example 141 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of cyclobutylamine.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.59(s,1H),8.62-8.27(m,3H),7.98-7.79(m,1H),7.53-7.51(m, 1H),7.45-7.42(m,1H),7.23-7.21(m,1H),7.06(s,1H),6.85-6.63(m,1H),6.14-6.01(m,1H),5.71-5.61(m, 1H),4.49-4.38(m,2H),4.17-3.93(m,2H),3.79(s,3H),2.28-2.20(m,3H),2.18(s,3H),2.11-2.02(m,3H), 1.77-1.66(m,4H),1.55-1.44(m,2H).MS:574[M+H]⁺.

EXAMPLE 150 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (cyclobutylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Example 150 preparation method reference exampleThe method of example 142, wherein methylamine hydrochloride is replaced with an equimolar amount of cyclobutylamine.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.61(s,1H),8.63-8.59(m,2H),7.91(s,1H),7.52(s,1H),7.44(s, 1H),7.31-7.21(m,2H),7.06(s,1H),6.87-6.67(m,1H),6.15-6.00(m,1H),5.72-5.60(m,1H),4.49-4.39(m, 2H),4.22-4.08(m,1H),4.01-3.94(m,1H),3.79(s,3H),3.19-2.97(m,1H),2.77-2.67(m,1H),2.24-2.21(m, 2H),2.18(s,3H),2.10-2.04(m,2H),1.82-1.77(m,1H),1.72-1.66(m,3H),1.59-1.48(m,2H).MS:574[M+H]⁺.

EXAMPLE 151 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (cyclopentylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 151 reference is made to the procedure for the preparation of example 141, where the methylamine hydrochloride is replaced with an equimolar amount of cyclopentylamine.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.59(s,1H),8.60(s,1H),8.46(s,1H),8.27(d,J＝7.3Hz,1H), 7.96-7.79(m,1H),7.53-7.51(m,1H),7.43(s,1H),7.23-7.21(m,1H),7.09-7.06(m,1H),6.86-6.63(m,1H), 6.14-6.04(m,1H),5.71-5.62(m,1H),4.26-4.14(m,2H),4.13-3.88(m,2H),3.79(s,3H),2.18(s,3H),1.94- 1.86(m,3H),1.79-1.67(m,5H),1.57-1.51(m,6H).MS:588[M+H]⁺.

EXAMPLE 152 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (cyclopentylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 152 the procedure of example 142 is referenced wherein an equimolar amount of cyclopentylamine is substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.29-8.26(m,1H),7.91(s,1H),7.53(s, 1H),7.43(s,1H),7.31-7.22(m,2H),7.08(s,1H),6.86-6.65(m,1H),6.15-6.01(m,1H),5.71-5.61(m,1H), 4.53-4.42(m,1H),4.25-4.14(m,2H),4.03-3.95(m,1H),3.79(s,3H),3.21-3.00(m,1H),2.80-2.68(m,1H), 2.18(s,3H),1.93-1.88(m,2H),1.82-1.78(m,1H),1.73-1.68(m,3H),1.57-1.52(m,6H).MS:588[M+H]⁺.

EXAMPLE 153 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (cyclohexylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 153 the preparation of example 141 was referenced wherein an equimolar amount of cyclohexylamine was used in place of methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.59(s,1H),8.60(s,1H),8.28-8.17(m,1H),7.98-7.79(m,1H), 7.54-7.50(m,1H),7.44-7.40(m,1H),7.37-7.21(m,2H),7.12-7.08(m,1H),6.84-6.63(m,1H),6.14-6.01(m, 1H),5.70-5.58(m,1H),4.49-3.95(m,2H),3.78(s,3H),2.18(s,3H),1.85-1.71(m,8H),1.62-1.44(m,4H), 1.35-1.26(m,6H).MS:602[M+H]⁺.

EXAMPLE 154 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (cyclohexylcarbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 154 the preparation of example 142 was referenced wherein an equimolar amount of cyclohexylamine was substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.22-8.16(m,1H),7.90(s,1H),7.52(s, 1H),7.43(s,1H),7.31-7.21(m,2H),7.10(s,1H),6.86-6.65(m,1H),6.14-6.00(m,1H),5.71-5.59(m,1H), 4.50-4.11(m,1H),4.04-3.94(m,1H),3.79(s,3H),3.25-2.99(m,1H),2.84-2.63(m,1H),2.18(s,3H),1.86- 1.79(m,4H),1.78-1.70(m,4H),1.64-1.56(m,2H),1.34-1.27(m,5H),1.17-1.09(m,1H).MS:602[M+H]⁺.

EXAMPLE 155 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (azetidine-1-carbonyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 155 the preparation of example 141 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of azetidine.¹H NMR(400MHz,DMSO-d₆)δ10.51(s,1H),9.60(s,1H),8.59(s,1H),7.98-7.83(m,1H),7.27-7.16(m, 4H),7.06-7.00(m,1H),6.96-6.74(m,1H),6.29-6.06(m,1H),5.76-5.66(m,1H),4.45-4.27(m,3H),4.08-4.00 (m,3H),3.77(s,3H),3.31-3.29(m,2H),2.27-2.21(m,3H),2.17(s,3H),1.85-1.73(m,3H),1.55-1.49(m,1H). MS:560[M+H]⁺.

EXAMPLE 156 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (azetidine-1-carbonyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 156 the preparation of example 142 was referenced wherein an equimolar amount of azetidine was substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.55-10.48(m,1H),9.60(s,1H),8.60(s,1H),7.90(s,1H),7.25-7.14(m, 4H),7.07-7.00(m,1H),6.98-6.86(m,1H),6.27-6.08(m,1H),5.78-5.66(m,1H),4.47-4.28(m,3H),4.12-4.07 (m,1H),4.05-4.01(m,2H),3.77(s,3H),3.72-3.60(m,1H),3.24-3.00(m,1H),2.74-2.65(m,1H),2.27-2.22 (m,2H),2.18(s,3H),1.90-1.84(m,1H),1.81-1.72(m,2H),1.58-1.46(m,1H).MS:560[M+H]⁺.

EXAMPLE 157 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyrrolidine-1-carbonyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 157 the preparation of example 141 was referenced wherein an equimolar amount of pyrrolidine was substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.50-10.46(m,1H),9.58(s,1H),8.59(s,1H),8.02-7.75(m,1H),7.20(s,2H), 7.13-7.01(m,3H),6.91-6.74(m,1H),6.19-6.06(m,1H),5.73-5.66(m,1H),3.76(s,3H),3.51-3.42(m,6H), 3.31-3.30(m,1H),2.86-2.86(m,3H),2.16(s,3H),1.90-1.81(m,7H).MS:574[M+H]⁺.

EXAMPLE 158 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyrrolidine-1-carbonyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 158 the preparation of example 142 was referenced wherein an equimolar amount of pyrrolidine was substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.50-10.45(m,1H),9.59(s,1H),8.59(s,1H),7.89(s,1H),7.30-7.21(m,1H), 7.20(s,1H),7.12-6.98(m,3H),6.91-6.80(m,1H),6.19-6.04(m,1H),5.76-5.65(m,1H),4.50-4.22(m,1H), 4.09-3.85(m,2H),3.78-3.74(m,3H),3.50-3.43(m,4H),3.22-2.98(m,1H),2.75-2.64(m,1H),2.17(s,3H), 1.90-1.79(m,7H),1.66-1.51(m,1H).MS:574[M+H]⁺.

EXAMPLE 159 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (piperidine-1-carbonyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 159 the preparation of example 141 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of piperidine.¹H NMR (400MHz,DMSO-d₆)δ10.48(s,1H),9.58(s,1H),8.59(s,1H),7.98-7.80(m,1H),7.32-7.19(m,2H),7.10(s, 1H),6.99-6.70(m,3H),6.19-6.06(m,1H),5.75-5.65(m,1H),4.33-3.81(m,3H),3.75(s,3H),3.61-3.41(m, 3H),3.31-3.30(m,1H),2.16(s,3H),1.94-1.90(m,1H),1.80-1.75(m,1H),1.63-1.47(m,8H),1.27-1.18(m, 2H).MS:588[M+H]⁺.

EXAMPLE 160 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (piperidine-1-carbonyl) phenyl) amino) pyrimidine-5-carboxamide

The procedure of example 160 the procedure of example 142 is referenced wherein an equimolar amount of piperidine is substituted for methylamine hydrochloride.¹H NMR (400MHz,DMSO-d₆)δ10.49(s,1H),9.59(s,1H),8.59(s,1H),7.90(s,1H),7.29-7.20(m,2H),7.12-7.09(m, 1H),6.95-6.90(m,1H),6.89-6.65(m,2H),6.19-6.05(m,1H),5.75-5.64(m,1H),4.50-4.22(m,1H),4.09-4.00 (m,1H),3.99-3.79(m,2H),3.75(s,3H),3.62-3.43(m,3H),3.18-2.98(m,1H),2.82-2.66(m,1H),2.17(s,3H), 1.99-1.88(m,2H),1.84-1.71(m,2H),1.64-1.60(m,2H),1.55-1.48(m,4H).MS:588[M+H]⁺.

EXAMPLE 161 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (morpholine-4-carbonyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 161 the preparation of example 141 was referenced wherein morpholine was substituted for methylamine hydrochloride in equimolar amounts.¹H NMR (400MHz,DMSO-d₆)δ10.50(s,1H),9.60(s,1H),8.60(s,1H),8.00-7.78(m,1H),7.25-7.16(m,2H),7.15(s, 1H),7.05-6.95(m,2H),6.93-6.82(m,1H),6.20–6.05(m,1H),5.75-5.66(m,1H),4.48-4.25(m,1H),4.10-4.00 (m,1H),4.00-3.84(m,2H),3.80-3.74(m,4H),3.65(s,3H),3.50-3.40(m,3H),3.08-3.00(m,1H),2.78-2.71 (m,1H),2.15(s,3H),2.00-1.90(m,2H),1.80-1.75(m,1H),1.68-1.56(m,1H).MS:590[M+H]⁺.

EXAMPLE 162 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (morpholine-4-carbonyl) phenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 162 the procedure for the preparation of example 142 is referenced, wherein morpholine is substituted for methylamine hydrochloride in equimolar amounts.¹H NMR (400MHz,DMSO-d₆)δ10.49(s,1H),9.59(s,1H),8.59(s,1H),7.98-7.79(m,1H),7.25-7.18(m,2H),7.13(s, 1H),7.03-6.93(m,2H),6.90-6.81(m,1H),6.18-6.05(m,1H),5.74-5.66(m,1H),4.49-4.24(m,1H),4.08-4.01 (m,1H),3.99-3.84(m,2H),3.78-3.74(m,4H),3.62(s,3H),3.50-3.42(m,3H),3.08-2.99(m,1H),2.78-2.70 (m,1H),2.17(s,3H),1.97-1.90(m,2H),1.81-1.76(m,1H),1.66-1.54(m,1H).MS:590[M+H]⁺.

EXAMPLE 163 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-4- ((2-methoxyethyl) carbamoyl) -6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 163 the procedure of example 141 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of 2-methoxyethyl-1-amine.¹H NMR(400MHz,DMSO-d₆)δ10.62(s,1H),9.65(s,1H),8.61(s,1H),8.56(s,1H),7.90(s,1H), 7.52(s,1H),7.47(s,1H),7.40-7.29(m,1H),7.23(s,1H),7.05(s,1H),6.89-6.76(m,1H),6.15-6.00(m,1H), 5.70-5.60(m,1H),4.50-4.13(m,1H),4.04-3.91(m,1H),3.79(s,3H),3.48-3.45(m,4H),3.43-3.42(m,1H), 3.28(s,3H),3.18-3.00(m,1H),2.84-2.67(m,1H),2.19(s,3H),1.85-1.76(m,2H),1.62-1.50(m,2H).MS: 578[M+H]⁺.

EXAMPLE 164 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-4- ((2-methoxyethyl) carbamoyl) -6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 164 the procedure of example 142 is referenced wherein an equimolar amount of 2-methoxyethyl-1-amine is substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.60(s,1H),9.65(s,1H),8.60(s,1H),8.56(s,1H),7.92(s,1H), 7.53(s,1H),7.47(s,1H),7.41-7.28(m,1H),7.23(s,1H),7.07(s,1H),6.88-6.77(m,1H),6.16-6.01(m,1H), 5.72-5.60(m,1H),4.49-4.13(m,1H),4.04-3.91(m,1H),3.79(s,3H),3.48-3.45(m,4H),3.43-3.42(m,1H), 3.28(s,3H),3.18-2.98(m,1H),2.83-2.67(m,1H),2.18(s,3H),1.84-1.74(m,2H),1.61-1.48(m,2H).MS:578 [M+H]⁺.

EXAMPLE 165 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-hydroxyethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 165 the preparation of example 141 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of 2-aminoethyl-1-ol.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.60(s,1H),8.60(s,1H),8.49-8.46(m,1H),7.94-7.86 (m,1H),7.54-7.52(m,1H),7.47-7.46(m,1H),7.37-7.26(m,1H),7.22(s,1H),7.06(s,1H),6.87-6.58(m,1H), 6.13-6.01(m,1H),5.71-5.64(m,1H),4.75-4.73(m,1H),4.21-3.99(m,2H),3.79(s,3H),3.74-3.65(m,1H), 3.53-3.50(m,3H),3.31-3.30(m,3H),2.18(s,3H),1.76-1.46(m,4H).MS:564[M+H]⁺.

EXAMPLE 166 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-hydroxyethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 166 the preparation of example 142 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of 2-aminoethyl-1-ol.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.50-8.46(m,1H),7.91(s,1H), 7.53(s,1H),7.47(s,1H),7.31-7.22(m,2H),7.07(s,1H),6.86-6.64(m,1H),6.16-6.01(m,1H),5.72-5.61(m, 1H),4.76-4.73(m,1H),4.49-4.13(m,1H),4.04-3.95(m,1H),3.79(s,3H),3.77-3.67(m,1H),3.53-3.50(m, 2H),3.22-2.98(m,1H),2.80-2.65(m,1H),2.18(s,3H),1.84-1.67(m,3H),1.63-1.41(m,3H).MS:564[M+H]⁺.

EXAMPLE 167 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- ((tetrahydro-2H-pyran-4-yl) carbamoyl) phenyl) amino) pyrimidine-5-carboxamide

The procedure of example 167 reference the procedure of example 141 wherein methylamine hydrochloride is replaced with an equimolar amount of tetrahydro-2H-pyran-4-amine.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.31-8.29(m,1H),7.92- 7.87(m,1H),7.52(s,1H),7.44(s,1H),7.33-7.27(m,1H),7.22(s,1H),7.08(s,1H),6.90-6.76(m,1H),6.11- 6.05(m,1H),5.69-5.63(m,1H),4.50-4.14(m,1H),4.01-3.98(m,2H),3.91-3.87(m,2H),3.79(s,3H),3.39- 3.38(m,2H),3.30-3.30(m,1H),3.24-2.96(m,1H),2.83-2.69(m,1H),2.18(s,3H),1.79-1.74(m,4H),1.59- 1.54(m,4H).MS:604[M+H]⁺.

EXAMPLE 168 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- ((tetrahydro-2H-pyran-4-yl) carbamoyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 168 the preparation of example 142 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of tetrahydro-2H-pyran-4-amine.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.61(s,1H),8.61(s,1H),8.32-8.29(m,1H),7.91(s, 1H),7.53(s,1H),7.44(s,1H),7.32-7.21(m,2H),7.09(s,1H),6.87-6.67(m,1H),6.15-6.01(m,1H),5.72-5.61 (m,1H),4.50-4.14(m,1H),4.05-3.98(m,2H),3.91-3.87(m,2H),3.79(s,3H),3.43-3.36(m,3H),3.24-2.96 (m,1H),2.83-2.69(m,1H),2.19(s,3H),1.81-1.74(m,4H),1.61-1.53(m,4H).MS:604[M+H]⁺.

EXAMPLE 169 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((cyanomethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 169 the preparation of example 141 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of aminoacetonitrile.¹H NMR(400MHz,DMSO-d₆)δ10.61(s,1H),9.63(s,1H),9.24(s,1H),8.61(s,1H),7.99-7.87(m,1H),7.56- 7.46(m,3H),7.43-7.25(m,1H),7.22(s,1H),7.10-7.06(m,1H),6.24-5.97(m,1H),5.73-5.63(m,1H),4.39- 4.28(m,3H),4.15-3.96(m,2H),3.80(s,3H),3.75-3.68(m,1H),2.19(s,3H),1.81-1.43(m,5H).MS:559 [M+H]⁺.

EXAMPLE 170 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((cyano) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 170 the preparation of example 142 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of aminoacetonitrile.¹H NMR(400MHz,DMSO-d₆)δ10.61(s,1H),9.63(s,1H),9.24(s,1H),8.61(s,1H),7.91(s,1H),7.56-7.47(m, 2H),7.36-7.24(m,1H),7.22(s,1H),7.11-7.06(m,1H),6.85-6.58(m,1H),6.16-6.01(m,1H),5.74-5.59(m, 1H),4.47-4.35(m,1H),4.34-4.29(m,2H),4.02-3.91(m,1H),3.80(s,3H),3.79-3.74(m,1H),3.22-2.95(m, 1H),2.83-2.61(m,1H),2.19(s,3H),1.86-1.71(m,2H),1.61-1.45(m,2H).MS:559[M+H]⁺.

Example 171.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((cyanomethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 171 the preparation of example 138 was referenced wherein the final step was an equimolar amount of aminoacetonitrile instead of methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.59(s,1H),9.33(t,J＝5.4,5.4Hz,1H),8.60(s, 1H),7.90(s,1H),7.57-7.49(m,2H),7.37-7.23(m,1H),7.19(s,1H),7.01(s,1H),6.87-6.79(m,1H),6.11(dd, J＝16.6,2.4Hz,1H),5.69(dd,J＝10.4,2.4Hz,1H),4.47-4.41(m,1H),4.39-4.37(m,2H),4.12-4.05(m,1H), 3.84-3.81(m,1H),3.80(s,3H),3.22-3.12(m,1H),2.84-2.73(m,1H),2.19(s,3H),1.78-1.70(m,2H),1.66- 1.57(m,2H).MS:559[M+H]⁺.

EXAMPLE 172 (R) -4- ((4- (4-acetylpiperazin-1-yl) -2-methoxy-6-methylphenyl) amino) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide

The preparation of example 172 refers to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 1- (4- (4-amino-3-methoxy-5-methylphenyl) piperazin-1-yl) ethan-1-one.¹H NMR(400MHz,DMSO-d₆)δ10.21(s, 1H),9.54(s,1H),8.55(s,1H),7.95-7.46(m,1H),7.29-7.08(m,3H),6.99-6.76(m,1H),6.61-6.45(m,2H), 6.26-6.08(m,1H),5.79-5.69(m,1H),4.53-3.76(m,2H),3.73-3.63(m,4H),3.59-3.49(m,4H),3.31(s,1H), 3.16-3.00(m,5H),2.09-2.01(m,6H),1.96-1.73(m,4H).MS:603[M+H]⁺.

EXAMPLE 173 (S) -4- ((4- (4-acetylpiperazin-1-yl) -2-methoxy-6-methylphenyl) amino) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) pyrimidine-5-carboxamide

The preparation of example 173 the preparation of example 2, steps 1) to 4), wherein 1- (4- (4-amino-3-methoxy-5-methylphenyl) piperidin-1-yl) ethan-1-one in step 1) is replaced by equimolar amounts.¹H NMR(400MHz,DMSO-d₆)δ10.24- 10.19(m,1H),9.54(s,1H),8.55(s,1H),7.85(s,1H),7.24(s,1H),7.21-7.16(m,1H),6.96-6.77(m,1H),6.65- 6.40(m,3H),6.28-6.09(m,1H),5.80-5.66(m,1H),4.57-4.28(m,1H),4.17-3.97(m,1H),3.77-3.73(m,1H), 3.70(s,3H),3.58-3.50(m,4H),3.15-3.06(m,4H),2.17-2.10(m,2H),2.07(s,3H),2.04(s,3H),1.93-1.80(m, 3H),1.49-1.41(m,1H).MS:603[M+H]⁺.

EXAMPLE 174 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-methoxy-5-methyl- [1,1' -biphenyl ] -4-yl) amino) pyrimidine-5-carboxamide

Preparation of example 174 reference is made to preparation of example 1, steps 1) to 4), wherein 3-methoxy-5-methyl- [1,1' -biphenyl ] is present in step 1) in equimolar amounts]-4-amine instead of cyclopropylamine.¹H NMR(400MHz,DMSO-d₆)δ10.44(s,1H),9.59(s,1H), 8.59(s,1H),7.83-7.64(m,3H),7.44-7.34(m,4H),7.32-7.27(m,1H),7.25-7.21(m,2H),7.13-7.07(m,1H), 6.76-6.64(m,1H),6.23-6.08(m,1H),5.77-5.66(m,1H),4.49-4.30(m,1H),4.00-3.90(m,1H),3.82(s,3H), 3.60-3.49(m,1H),3.28-3.21(m,1H),2.36-2.26(m,1H),2.21(s,3H),2.10-0.93(m,4H).MS:553[M+H]⁺.

EXAMPLE 175 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((3-methoxy-5-methyl- [1,1' -biphenyl ] -4-yl) amino) pyrimidine-5-carboxamide

Preparation of example 175 reference is made to preparation of example 2, steps 1) to 4), wherein 3-methoxy-5-methyl- [1,1' -biphenyl ] is present in step 1) in equimolar amounts]-4-amine instead of cyclopropylamine.¹H NMR(400MHz,DMSO-d₆)δ10.44(s,1H),9.59(s,1H), 8.59(s,1H),7.76-7.66(m,3H),7.47-7.34(m,5H),7.25-7.21(m,2H),7.13-7.05(m,1H),6.81-6.66(m,1H), 6.24-6.07(m,1H),5.78-5.68(m,1H),4.54-4.19(m,1H),3.82(s,3H),3.76-3.61(m,1H),3.58-3.49(m,1H), 3.31-3.31(m,1H),2.31-2.25(m,1H),2.20(s,3H),1.88-1.01(m,4H).MS:553[M+H]⁺.

Example 176.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((3-methoxy-5-methyl- [1,1' -biphenyl ] -4-yl) amino) pyrimidine-5-carboxamide

Preparation of example 176 reference is made to preparation of example 1, steps 1) to 4), wherein 3-methoxy-5-methyl- [1,1' -biphenyl ] is present in step 1) in equimolar amounts]-4-amine instead of cyclopropylamine, step 2) replacing tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate with an equivalent amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ 10.38(s,1H),9.54(s,1H),8.59(s,1H),7.94-7.82(m,3H),7.51(t,2H),7.40-7.36(m,2H),7.34-7.21(m,2H), 7.17(s,1H),7.04(s,1H),6.68-6.57(m,1H),6.08-6.01(m,1H),5.66-5.62(m,1H),4.22-4.08(m,1H),3.82(s, 3H),3.80-3.63(m,1H),3.61-3.53(m,1H),3.31(m,1H),2.20(s,3H),2.01-1.87(m,1H),1.65-1.47(m,4H). MS:553[M+H]⁺.

Example 177.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyridin-3-yl) phenyl) amino) pyrimidine-5-carboxamide

Preparation of example 177 the preparation of example 1 is referred to as step 1) to step 4) of example 1, wherein in step 1) the cyclopropylamine is replaced by an equivalent molar equivalent of 2-methoxy-6-methyl-4- (pyridin-3-yl) aniline and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced by an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ 10.42(s,1H),9.56(s,1H),9.12(s,1H),8.60-8.58(m,2H),8.31-8.25(m,1H),8.10-7.73(m,1H),7.55-7.52(m, 1H),7.45(s,1H),7.38(s,1H),7.32-7.21(m,1H),7.18(s,1H),7.06(s,1H),6.73-6.58(m,1H),6.09-6.02(m, 1H),5.67-5.63(m,1H),4.22-4.12(m,1H),3.83(s,3H),3.61(s,1H),2.21(s,3H),2.04-1.88(m,1H),1.67-1.47 (m,4H),1.29-1.20(m,2H).MS:554[M+H]⁺.

EXAMPLE 178 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyridin-3-yl) phenyl) amino) pyrimidine-5-carboxamide

Preparation of example 178 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-methoxy-6-methyl-4- (pyridin-3-yl) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.52-10.44(m,1H),9.60 (s,1H),9.02-8.95(m,1H),8.61-8.54(m,2H),8.13-8.05(m,1H),8.01-7.77(m,1H),7.53-7.28(m,4H),7.24- 7.21(m,1H),7.15-7.06(m,1H),6.75-6.57(m,1H),6.17-5.92(m,1H),5.73-5.59(m,1H),4.54-4.14(m,1H), 3.94-3.81(m,4H),3.79-3.58(m,1H),3.54-3.36(m,1H),2.76-2.63(m,1H),2.63-2.53(m,1H),2.28-2.17(m, 3H),1.84-1.59(m,2H),1.56-1.32(m,1H).MS:554[M+H]⁺.

EXAMPLE 179 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (pyridin-3-yl) phenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 179 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 2-methoxy-6-methyl-4- (pyridin-3-yl) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.51-10.41(m,1H),9.60 (s,1H),9.02-8.94(m,1H),8.62-8.54(m,2H),8.13-8.05(m,1H),7.98-7.75(m,1H),7.49-7.26(m,4H),7.24- 7.21(m,1H),7.15-7.04(m,1H),6.76-6.57(m,1H),6.19-6.02(m,1H),5.74-5.62(m,1H),4.46-4.08(m,1H), 3.94-3.79(m,4H),3.76-3.52(m,1H),3.51-3.36(m,1H),2.80-2.64(m,1H),2.64-2.54(m,1H),2.29-2.17(m, 3H),1.84-1.58(m,2H),1.44-1.24(m,1H).MS:554[M+H]⁺.

EXAMPLE 180 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (dimethylamino) -4-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 180 reference is made to preparation of example 1, steps 1) to 4), wherein 5-methoxy-N is present in step 1) in equimolar amounts¹,N¹3-trimethylbenzene-1, 2-diamine instead of cyclopropylamine.¹H NMR(400MHz,DMSO-d₆)δ10.50-10.21(m,1H), 9.58(s,1H),8.58(s,1H),7.87(s,1H),7.54-6.98(m,3H),6.94-6.65(m,1H),6.65-6.29(m,2H),6.25-5.91(m, 1H),5.80-5.52(m,1H),4.62-4.17(m,1H),4.15-3.95(m,1H),3.81-3.62(m,4H),3.21-2.93(m,1H),2.86-2.65 (m,1H),2.62-2.53(m,6H),2.15-1.98(m,3H),1.95-1.56(m,3H),1.55-1.32(m,1H).MS:520[M+H]⁺.

EXAMPLE 181 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (dimethylamino) -4-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 181 reference is made to preparation of example 2, steps 1) to 4), where in step 1) the 5-methoxy-N is present in equimolar amounts¹,N¹3-trimethylbenzene-1, 2-diamine instead of cyclopropylamine.¹H NMR(400MHz,DMSO-d₆)δ10.43-10.14(m,1H), 9.58(s,1H),8.58(s,1H),7.87(s,1H),7.28-7.12(m,3H),6.97-6.64(m,1H),6.65-6.35(m,2H),6.18-6.07 (m,1H),5.80-5.59(m,1H),4.61-4.16(m,1H),4.16-3.91(m,1H),3.79-3.58(m,4H),3.23-2.93(m,1H),2.89- 2.62(m,1H),2.62-2.53(m,6H),2.15-1.98(m,3H),1.94-1.57(m,3H),1.54-1.35(m,1H).MS:520[M+H]⁺.

Example 182.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((2- (dimethylamino) -4-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 182 reference is made to preparation of example 1, steps 1) to 4), wherein 5-methoxy-N is present in step 1) in equimolar amounts¹,N¹3-trimethylbenzene-1, 2-diamine instead of cyclopropylamine, tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate was replaced in step 2) with an equivalent amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆) δ10.29(s,1H),9.54(s,1H),8.57(s,1H),7.85(s,1H),7.40-6.98(m,3H),6.93-6.73(m,1H),6.60-6.32(m,2H), 6.13(dd,J＝16.6,2.4Hz,1H),5.71(d,J＝10.4Hz,1H),4.55-4.34(m,1H),4.13(d,J＝13.6Hz,1H),3.92(t, J＝11.7Hz,1H),3.79(s,3H),3.21-3.11(m,1H),2.82-2.70(m,1H),2.57(s,6H),2.03(s,3H),1.91-1.71(m, 2H),1.67-1.37(m,2H).MS:520[M+H]⁺.

Example 183.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-methoxy-2-methyl-6-phenoxyphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 183 reference is made to preparation of example 1, steps 1) to 4), where1) Wherein an equimolar amount of 4-methoxy-2-methyl-6-phenoxyaniline is used instead of cyclopropylamine, and an equimolar amount of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is used instead of tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate in step 2).¹H NMR(400MHz,DMSO-d₆)δ 10.26(s,1H),9.52(s,1H),8.49(s,1H),7.87-7.65(m,1H),7.24(s,1H),7.22-7.11(m,4H),7.00-6.97(m,1H), 6.87-6.80(m,4H),6.49-6.40(m,1H),6.13-6.08(m,1H),5.70-5.67(m,1H),4.53-4.44(m,1H),4.16-4.09(m, 1H),3.96-3.89(m,1H),3.76(s,3H),3.19-3.07(m,1H),2.79-2.71(m,1H),2.17(s,3H),1.91-1.83(m,1H), 1.81-1.58(m,3H).MS:569[M+H]⁺.

EXAMPLE 184 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyclopropyl-6-methoxypyrimidin-5-yl) amino) pyrimidine-5-carboxamide

The preparation of example 184 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-cyclopropyl-6-methoxypyrimidin-5-amine.¹H NMR(400MHz,DMSO-d₆)δ10.60(s,1H),9.68(s,1H),8.70- 8.51(m,2H),7.94(s,1H),7.36(s,1H),7.22(s,1H),7.15(s,1H),6.91-6.72(m,1H),6.18-6.05(m,1H),5.74- 5.63(m,1H),4.57-4.20(m,1H),4.11-3.99(m,1H),3.86(s,4H),3.28-3.02(m,1H),2.88-2.65(m,1H),2.09- 1.72(m,4H),1.57-1.43(m,1H),0.97(s,4H).MS:505[M+H]⁺.

EXAMPLE 185 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyclopropyl-6-methoxypyrimidin-5-yl) amino) pyrimidine-5-carboxamide

Preparation of example 185 the preparation of example 2, steps 1) to 4), was referenced wherein the cyclopropylamine was replaced with an equimolar amount of 4-cyclopropyl-6-methoxypyrimidin-5-amine in step 1).¹H NMR(400MHz,DMSO-d₆)δ10.60(s,1H),9.68(s,1H),8.70- 8.51(m,2H),7.94(s,1H),7.35(s,1H),7.22(s,1H),7.15(s,1H),6.90-6.74(m,1H),6.18-6.05(m,1H),5.74- 5.63(m,1H),4.53-4.26(m,1H),4.07(d,J＝14.1Hz,1H),3.86(s,4H),3.29-3.02(m,1H),2.91-2.68(m,1H), 2.07(d,J＝5.7Hz,1H),1.98-1.65(m,3H),1.55-1.43(m,1H),0.97(s,4H).MS:505[M+H]⁺.

Example 186.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyclopropyl-6-methoxypyrimidin-5-yl) amino) pyrimidine-5-carboxamide

Preparation of example 186 reference is made to preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equivalent molar equivalent of 4-cyclopropyl-6-methoxypyrimidin-5-amine and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.58 (s,1H),9.66(s,1H),8.62(s,1H),8.56(s,1H),7.94(s,1H),7.34(s,1H),7.18(s,1H),7.05(s,1H),6.95-6.86 (m,1H),6.17(dd,J＝16.7,2.5Hz,1H),5.73(dd,J＝10.5,2.4Hz,1H),4.53(d,J＝13.2Hz,1H),4.24-4.04 (m,2H),3.85(s,3H),3.25-3.17(m,1H),2.84-2.75(m,1H),2.10-2.03(m,1H),1.86(d,J＝12.4Hz,2H),1.62- 1.40(m,2H),1.02-0.88(m,4H).MS:505[M+H]⁺.

Example 187.2- ((1- (1-acryloylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyclopropyl-6-ethylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

Preparation of example 187 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equivalent molar equivalent of 4-cyclopropyl-6-ethylpyrimidin-5-amine and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate is replaced with an equivalent of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ10.84- 10.78(m,1H),9.71(s,1H),8.83-8.65(m,1H),8.02-7.85(m,1H),7.49-7.30(m,1H),7.23-7.14(m,1H),7.13- 7.08(m,1H),6.98-6.93(m,1H),6.91-6.87(m,1H),6.21-6.14(m,1H),5.75-5.71(m,1H),4.58-4.48(m,1H), 4.21-4.14(m,1H),4.10-4.02(m,1H),3.44-3.34(m,2H),3.30-3.17(m,2H),2.83-2.75(m,1H),2.64-2.59(m, 2H),2.10-2.05(m,1H),1.84-1.81(m,1H),1.50-1.40(m,1H),1.09(t,J＝7.4,7.4Hz,3H),1.00-0.96(m,2H), 0.88-0.77(m,1H).MS:503[M+H]⁺.

EXAMPLE 188 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyclopropyl-6-ethylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

The preparation of example 188 reference is made to preparation of example 1, steps 1) to 4), where in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-cyclopropyl-6-ethylpyrimidin-5-amine.¹H NMR(400MHz,DMSO-d₆)δ10.86-10.79(m,1H),9.71(s,1H), 9.01-8.83(m,1H),8.65(s,1H),8.02-7.89(m,1H),7.53-7.33(m,1H),7.18-7.12(m,1H),7.02-6.92(m,1H), 6.88-6.76(m,1H),6.17-6.06(m,1H),5.74-5.64(m,1H),4.55-4.21(m,1H),4.11-4.02(m,1H),3.89-3.76(m, 1H),3.25-3.06(m,1H),2.86-2.67(m,1H),2.65-2.61(m,2H),2.12-2.04(m,1H),1.92-1.79(m,2H),1.65-1.60 (m,1H),1.54-1.45(m,1H),1.14-1.09(m,3H),1.03-0.96(m,2H),0.85-0.77(m,2H).MS:503[M+H]⁺.

EXAMPLE 189 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4-cyclopropyl-6-ethylpyrimidin-5-yl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 189 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-cyclopropyl-6-ethylpyrimidin-5-amine.¹H NMR(400MHz,DMSO-d₆)δ10.85-10.79(m,1H),9.71(s,1H), 9.01-8.85(m,1H),8.71-8.64(m,1H),8.01-7.90(m,1H),7.53-7.35(m,1H),7.18-7.12(m,1H),7.01-6.92(m, 1H),6.89-6.77(m,1H),6.17-6.05(m,1H),5.73-5.64(m,1H),4.54-4.27(m,1H),4.11-4.02(m,1H),3.84(s, 1H),3.15-3.01(m,1H),2.90-2.77(m,1H),2.66-2.63(m,2H),2.13-2.07(m,1H),1.89-1.79(m,2H),1.65-1.60 (m,1H),1.51(s,1H),1.17-1.13(m,2H),1.12-1.09(m,3H),1.01-0.97(m,1H),0.82-0.79(m,1H).MS:503 [M+H]⁺.

EXAMPLE 190 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (methylsulfonyl) phenyl) amino) pyrimidine-5-carboxamide

Preparation of example 190 reference is made to preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) by an equimolar amount of 2-methoxy-6-methyl-4- (methylsulfonyl) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.72(s,1H),9.65(s, 1H),8.62(s,1H),7.99-7.88(m,1H),7.54-7.44(m,2H),7.39-7.27(m,1H),7.20-7.12(m,2H),6.93-6.59(m, 1H),6.16-6.03(m,1H),5.72-5.63(m,1H),4.13-3.94(m,2H),3.89-3.85(m,3H),3.83-3.76(m,1H),3.32-3.30 (m,2H),3.26-3.22(m,3H),3.05-2.76(m,1H),2.24(s,3H),1.95-1.91(m,1H),1.81-1.76(m,1H),1.62-1.47 (m,1H).MS:555[M+H]⁺.

EXAMPLE 191 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (methylsulfonyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 191 reference is made to preparation of example 2, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) by an equimolar amount of 2-methoxy-6-methyl-4- (methylsulfonyl) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.75-10.66(m,1H), 9.68-9.63(m,1H),8.69-8.61(m,1H),7.99-7.89(m,1H),7.54-7.44(m,2H),7.36-7.18(m,2H),7.16-7.13(m, 1H),6.87-6.65(m,1H),6.16-6.01(m,1H),5.72-5.60(m,1H),4.56-4.42(m,1H),4.24-4.07(m,1H),4.06-3.99 (m,1H),3.86(s,3H),3.84-3.81(m,1H),3.27-3.23(m,3H),3.14-3.03(m,1H),2.95-2.72(m,1H),2.27-2.23 (m,3H),1.94-1.90(m,1H),1.82-1.76(m,1H),1.62-1.51(m,1H).MS:555[M+H]⁺.

EXAMPLE 192 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (ethylsulfonyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 192 refers to preparation of example 1, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) with an equimolar amount of 2-methoxy-6-methyl-4- (ethylsulfonyl) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.74(s,1H),9.65(s, 1H),8.62(s,1H),7.99-7.89(m,1H),7.58-7.47(m,1H),7.46-7.22(m,3H),7.19-7.16(m,1H),6.89-6.56(m, 1H),6.17-6.04(m,1H),5.73-5.63(m,1H),4.51-3.91(m,3H),3.85-3.81(m,4H),3.31-3.26(m,2H),3.05-2.75 (m,1H),2.30-2.21(m,4H),1.94-1.90(m,1H),1.81-1.76(m,1H),1.62-1.49(m,1H),1.17-1.14(m,3H).MS: 569[M+H]⁺.

EXAMPLE 193 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (ethylsulfonyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 193 reference is made to preparation of example 2, steps 1) to 4), wherein cyclopropylamine is replaced in step 1) by an equimolar amount of 2-methoxy-6-methyl-4- (ethylsulfonyl) aniline.¹H NMR(400MHz,DMSO-d₆)δ10.75(s,1H),9.67– 9.63(m,1H),8.68–8.62(m,1H),7.94(s,1H),7.51–7.44(m,1H),7.41–7.29(m,2H),7.20–7.15(m,2H), 6.87–6.66(m,1H),6.17–6.01(m,1H),5.72–5.61(m,1H),4.56–4.43(m,1H),4.21–4.07(m,1H),4.06– 3.98(m,1H),3.85(s,3H),3.83–3.82(m,1H),3.38–3.35(m,1H),3.32–3.28(m,1H),3.14–3.01(m,1H), 2.91–2.72(m,1H),2.28–2.24(m,3H),1.95–1.90(m,1H),1.82–1.76(m,1H),1.62–1.47(m,1H),1.17– 1.14(m,3H).MS:569[M+H]⁺.

EXAMPLE 194 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (4- (2-cyanoacetyl) piperazin-1-yl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 194 the preparation of example 1, steps 1) to 4), wherein 3- (4- (4-amino-3-methoxy-5-methylphenyl) piperazin-1-yl) -3-oxopropanenitrile is replaced with an equimolar amount of 3- (4-amino-3-methoxy-5-methylphenyl) piperazin-1-yl) -3-oxopropanenitrile.¹H NMR(600MHz,DMSO-d₆)δ 10.22(s,1H),9.54(s,1H),8.55(s,1H),7.93-7.75(m,1H),7.28-7.18(m,3H),6.93-6.77(m,1H),6.60-6.44(m, 2H),6.27-6.07(m,1H),5.78-5.70(m,1H),4.55-4.31(m,1H),4.15-4.09(m,3H),4.08-3.97(m,1H),3.78-3.73 (m,1H),3.70(s,3H),3.59-3.50(m,2H),3.46-3.45(m,1H),3.30-3.30(m,1H),3.20-3.07(m,5H),2.14-2.07 (m,3H),1.93-1.82(m,3H),1.47-1.43(m,1H).MS:628[M+H]⁺.

EXAMPLE 195 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (4- (2-cyanoacetyl) piperazin-1-yl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 195 refers to preparation of example 2, steps 1) to 4), wherein 3- (4- (4-amino-3-methoxy-5-methylphenyl) piperazin-1-yl) -3-oxopropanenitrile is replaced with an equimolar amount of 3- (4-amino-3-methoxy-5-methylphenyl) piperazin-1-yl) -3-oxopropanenitrile in step 1).¹H NMR(600MHz,DMSO-d₆)δ 10.21(s,1H),9.53(s,1H),8.55(s,1H),7.93-7.69(m,1H),7.25-7.14(m,3H),6.91-6.72(m,1H),6.59-6.47(m, 2H),6.26-6.13(m,1H),5.76-5.68(m,1H),4.56-4.43(m,1H),4.16-4.09(m,3H),4.07-3.96(m,1H),3.77-3.73 (m,1H),3.70(s,3H),3.59-3.50(m,2H),3.46-3.44(m,1H),3.30-3.29(m,1H),3.18-3.07(m,4H),2.82-2.67 (m,1H),2.12-2.04(m,3H),1.96-1.82(m,3H),1.48-1.42(m,1H).MS:628[M+H]⁺.

EXAMPLE 196 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((3-hydroxypropyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 196 the preparation of example 141 was followed, wherein 3-aminopropan-1-ol was replaced by an equimolar amountMethylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.62(s,1H),8.60(s,1H),8.48(s,1H),7.91(s,1H),7.51 (s,1H),7.45(s,1H),7.37–7.25(m,1H),7.22(s,1H),7.07(s,1H),6.88–6.63(m,1H),6.15–6.01(m,1H), 5.71–5.61(m,1H),4.51–4.45(m,1H),4.21–4.07(m,1H),4.02–3.93(m,1H),3.79(s,3H),3.71–3.61(m, 1H),3.48–3.46(m,2H),3.31–3.22(m,2H)，2.18(s,3H),1.84–1.78(m,1H),1.76–1.62(m,4H),1.62– 1.21(m,3H).MS:578[M+H]⁺.

EXAMPLE 197 (S) -2- ((1- (1-Acrylopiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((3-hydroxypropyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 197 is as in example 142, wherein the methylamine hydrochloride is replaced with an equimolar amount of 3-aminopropan-1-ol.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.47(s,1H),7.91(s,1H),7.51 (s,1H),7.44(s,1H),7.36–7.24(m,1H),7.22(s,1H),7.06(s,1H),6.86–6.64(m,1H),6.16–6.02(m,1H), 5.71–5.61(m,1H),4.52–4.47(m,1H),4.19–3.92(m,2H),3.78(s,3H),3.75–3.64(m,1H),3.49–3.45(m, 2H),3.30–3.23(m,2H),2.17(s,3H),1.87–1.45(m,8H).MS:578[M+H]⁺.

EXAMPLE 198 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2- (dimethylamino) ethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 198 reference is made to the preparation of example 141 wherein the N is present in equimolar amounts¹,N¹-dimethylethyl-1, 2-diamine instead of methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.42(s,1H),8.08– 7.78(m,1H),7.51(s,1H),7.44(s,1H),7.36–7.26(m,1H),7.22(s,1H),7.06(s,1H),6.99–6.42(m,-1H), 6.16–6.05(m,1H),5.77–5.63(m,1H),4.51–4.14(m,1H),4.12–3.84(m,2H),3.78(s,3H),3.31–3.30(m, 4H),3.24–2.75(m,2H),2.42–2.37(m,4H),2.18(s,9H).MS:591[M+H]⁺.

EXAMPLE 199 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2- (dimethylamino) ethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 199 reference is made to the preparation of example 142 where N is present in equimolar amounts¹,N¹-dimethylethyl-1, 2-diamine instead of methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.42(s,1H),8.26(s, 1H),7.96–7.85(m,1H),7.50(s,1H),7.44(s,1H),7.22(s,1H),7.06(s,1H),6.86–6.62(m,1H),6.15–6.01 (m,1H),5.71–5.61(m,1H),4.57–4.13(m,1H),4.13–3.81(m,2H),3.78(s,3H),3.30–3.15(m,4H),3.13 –2.61(m,2H),2.43–2.35(m,4H),2.19(s,9H).MS:591[M+H]⁺.

EXAMPLE 200 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((cyanomethyl) (methyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 200 the preparation of example 141 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of 2- (methylamino) acetonitrile.¹H NMR(400MHz,DMSO-d₆)δ10.53(s,1H),9.61(s,1H),8.60(s,1H),7.96–7.82(m,1H),7.38– 6.93(m,6H),6.88–6.72(m,1H),6.17–6.04(m,1H),5.76–5.67(m,1H),4.53–4.44(m,2H),4.21–4.02 (m,2H),3.80–3.74(m,4H),3.31–3.31(m,1H),3.11–3.04(m,4H),2.79–2.73(m,1H),2.18(s,3H),1.92 –1.78(m,2H).MS:573[M+H]⁺.

EXAMPLE 201 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((cyanomethyl) (methyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 201 the preparation of example 142 was referenced wherein an equimolar amount of 2- (methylamino) acetonitrile was substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.54(s,1H),9.61(s,1H),8.60(s,1H),7.90(s,1H),7.39–6.96(m, 6H),6.89–6.70(m,1H),6.18–6.06(m,1H),5.73–5.65(m,1H),4.55–4.45(m,2H),4.24–3.95(m,2H), 3.81–3.75(m,4H),3.32–3.28(m,1H),3.11–3.03(m,4H),2.81–2.70(m,1H),2.18(s,3H),1.91–1.77(m, 2H).MS:573[M+H]⁺.

EXAMPLE 202 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-cyanoethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 202 the procedure of example 141 was followed, wherein 3-aminopropionitrile was used in place of methylamine hydrochloride in an equimolar amount.¹H NMR(400MHz,DMSO-d₆)δ10.58(s,1H),9.62(s,1H),8.88(s,1H),8.60(s,1H),7.94–7.69(m,1H), 7.58–7.41(m,3H),7.36–7.20(m,2H),7.11–6.70(m,1H),6.17–6.02(m,1H),5.75–5.61(m,1H),4.17– 3.89(m,2H),3.79(s,3H),3.75–3.66(m,1H),3.51–3.46(m,2H),3.31–3.30(m,2H),2.80–2.77(m,2H), 2.19(s,3H),1.81–1.50(m,4H).MS:573[M+H]⁺.

EXAMPLE 203 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-cyanoethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure of example 203 the procedure of example 142 is followed, wherein an equimolar amount of 3-aminopropionitrile is substituted for methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.58(s,1H),9.62(s,1H),8.89(s,1H),8.60(s,1H),7.91(s,1H),7.53–7.45 (m,2H),7.36–7.20(m,2H),7.06(s,1H),6.89–6.61(m,1H),6.15–6.01(m,1H),5.71–5.60(m,1H),4.19 –3.94(m,2H),3.79(s,3H),3.74–3.67(m,1H),3.51–3.46(m,2H),3.35–3.31(m,2H),2.80–2.77(m,2H), 2.18(s,3H),1.82–1.49(m,4H).MS:573[M+H]⁺.

EXAMPLE 204 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-hydroxyethyl) (methyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 204 the procedure of example 141 is referenced wherein the methylamine hydrochloride is replaced with an equimolar amount of 2- (methylamino) ethan-1-ol.¹H NMR(400MHz,DMSO-d₆)δ10.51(s,1H),9.60(s,1H),8.59(s,1H),7.96–7.83(m,1H),7.45 –7.22(m,2H),7.22–7.11(m,2H),7.11–6.93(m,2H),6.93–6.72(m,1H),6.18–6.04(m,1H),5.76–5.65 (m,1H),4.90–4.78(m,1H),4.48–4.22(m,1H),4.04–3.85(m,2H),3.75(s,3H),3.63–3.52(m,3H),3.31 –3.31(m,1H),3.01–2.92(m,4H),2.89–2.69(m,1H),2.16(s,3H),1.93–1.89(m,1H),1.84–1.68(m,2H). MS:578[M+H]⁺.

EXAMPLE 205 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-hydroxyethyl) (methyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The preparation of example 205 the preparation of example 142 was referenced wherein the methylamine hydrochloride was replaced with an equimolar amount of 2- (methylamino) ethan-1-ol.¹H NMR(400MHz,DMSO-d₆)δ10.50(s,1H),9.60(s,1H),8.59(s,1H),7.90(s,1H),7.56–7.21 (m,2H),7.21–7.08(m,2H),7.08–6.89(m,2H),6.87–6.64(m,1H),6.18–6.03(m,1H),5.75–5.64(m, 1H),4.99–4.73(m,1H),4.59–4.16(m,1H),4.10–3.83(m,2H),3.75(s,3H),3.66–3.51(m,3H),3.32– 3.28(m,1H),3.03–2.92(m,4H),2.91–2.68(m,1H),2.16(s,3H),1.93–1.89(m,1H),1.85–1.67(m,2H). MS:578[M+H]⁺.

EXAMPLE 206 (R) -4- ((2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid

Preparation of example 206 reference is made to the preparation of example 1, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-3-methoxy-5-methylbenzoic acid and in step 2) the tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) pyrrolidine-1-carboxylate is replaced with an equimolar amount of tert-butyl (R) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO- d₆)δ10.39(s,1H),9.56(s,1H),8.59(s,1H),8.52–8.38(m,1H),8.03–7.78(m,1H),7.56–7.47(m,1H), 7.33–7.22(m,1H),7.19(d,J＝2.8Hz,1H),6.97(s,1H),6.70–6.40(m,1H),6.24–6.00(m,1H),5.66(s, 1H),4.55–4.44(m,1H),3.74(s,3H),3.68–3.38(m,4H),2.14(s,3H),2.05–1.82(m,1H),1.58–1.26(m, 1H).MS:507[M+H]⁺.

EXAMPLE 207 (S) -4- ((2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid

The preparation of example 207 the preparation of example 2 is referenced to the preparation of example 2, steps 1) to 4), wherein in step 1) an equimolar amount of 4-amino-3-methoxy-5-methylbenzoic acid is substituted for cyclopropylamine and in step 2) an equimolar amount of tert-butyl (S) -3- (4-amino-1H-pyrazol-1-yl) pyrrolidine-1-carboxylate is substituted for tert-butyl (S) -3- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate.¹H NMR(400MHz,DMSO- d₆)δ10.38(s,1H),9.56(s,1H),8.59(s,1H),8.49–8.42(m,1H),7.90(s,1H),7.62–7.51(m,1H),7.36–7.22 (m,1H),7.19(s,1H),6.98(s,1H),6.70–6.42(m,1H),6.22–6.02(m,1H),5.83–5.57(m,1H),4.49(s,1H), 3.74(s,3H),3.71–3.29(m,4H),2.13(s,3H),2.07–1.82(m,1H),1.54–1.28(m,1H).MS:507[M+H]⁺.

EXAMPLE 208 (R) -2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((cyanomethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

101 mg (0.2mmol) of ((R) -4- ((2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid) was placed in a reaction flask, 1ml of N, N-dimethylformamide was added, followed by 114 mg (0.3mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 52 mg (0.4mmol) of N, N-diisopropylethylamine were added, and after stirring for 0.5 hour, 11 mg (0.2mmol) of aminoacetonitrile was added, and the reaction was stirred until completion. Adding 5ml of water for dilution, extracting by ethyl acetate, carrying out vacuum spin drying on the organic phase, and carrying out column chromatography purification on the obtained solid to obtain the product.¹H NMR(400MHz,DMSO-d₆)δ10.51 (s,1H),9.76–9.52(m,1H),9.31(s,1H),8.61(s,1H),7.91(s,1H),7.67–7.47(m,2H),7.42–7.25(m,1H), 7.20(s,1H),6.98(d,J＝5.4Hz,1H),6.64–6.38(m,1H),6.24–6.06(m,1H),5.76–5.57(m,1H),4.50–4.37 (m,1H),4.34(t,J＝4.8Hz,2H),3.80(s,3H),3.70–3.39(m,4H),2.19(s,3H),2.12–1.85(m,1H),1.58– 1.32(m,1H).MS:545[M+H]⁺.

EXAMPLE 209 (S) -2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((cyanomethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

101 mg (0.2mmol) of ((S) -4- ((2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -5-carbamoylpyrimidin-4-yl) amino) -3-methoxy-5-methylbenzoic acid) was placed in a reaction flask, 1ml of N, N-dimethylformamide was added, followed by 114 mg (0.3mmol) of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 52 mg (0.4mmol) of N, N-diisopropylethylamine were added, and after stirring for 0.5 hour, 11 mg (0.2mmol) of aminoacetonitrile was added, and the reaction was stirred until completion. Adding 5ml of water for dilution, extracting by ethyl acetate,and (4) carrying out decompression spin-drying on the organic phase, and carrying out column chromatography purification on the obtained solid to obtain the product.¹H NMR(400MHz,DMSO-d₆)δ10.51 (s,1H),9.61(s,1H),9.32(s,1H),8.61(s,1H),7.91(s,1H),7.67–7.45(m,2H),7.44–7.21(m,1H),7.25– 7.16(m,1H),6.98(d,J＝5.3Hz,1H),6.67–6.43(m,1H),6.21–6.07(m,1H),5.72–5.58(m,1H),4.53– 4.37(m,1H),4.34(t,J＝4.8Hz,2H),3.80(s,3H),3.69–3.39(m,4H),2.19(s,3H),2.11–1.85(m,1H),1.68 –1.38(m,1H).MS:545[M+H]⁺.

EXAMPLE 210 (R) -2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-hydroxyethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure in example 210 the procedure in example 208 was followed, substituting the aminoacetonitrile with an equimolar amount of 2-aminoethan-1-ol.¹H NMR(400MHz,DMSO-d₆)δ10.46(s,1H),9.60(s,1H),8.78–8.51(m,2H),8.08–7.79(m,1H),7.63– 7.45(m,2H),7.38–7.23(m,1H),7.20(d,J＝3.9Hz,1H),6.96(d,J＝6.6Hz,1H),6.66–6.35(m,1H),6.25 –6.03(m,1H),5.77–5.55(m,1H),4.82–4.71(m,1H),4.43(d,J＝31.4Hz,1H),3.79(s,3H),3.69–3.58 (m,2H),3.56–3.48(m,3H),3.48–3.36(m,2H),2.17(s,3H),2.11–1.83(m,2H),1.52–1.30(m,1H).MS: 550[M+H]⁺.

EXAMPLE 211 (S) -2- ((1- (1-acryloylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((2-hydroxyethyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure in example 211 was as in example 209, except that the aminoacetonitrile was replaced with 2-aminoethan-1-ol in equimolar amount.¹H NMR(400MHz,DMSO-d₆)δ10.46(s,1H),9.60(s,1H),8.60(s,1H),8.58–8.53(m,1H),7.90(s,1H), 7.64–7.42(m,2H),7.35–7.23(m,1H),7.20(d,J＝3.9Hz,1H),6.96(d,J＝6.7Hz,1H),6.68–6.44(m,1H), 6.22–6.02(m,1H),5.73–5.50(m,1H),4.82–4.68(m,1H),4.43(d,J＝31.3Hz,1H),3.78(s,3H),3.71– 3.60(m,2H),3.60–3.49(m,3H),3.48–3.37(m,2H),2.17(s,3H),2.16–1.84(m,2H),1.55–1.32(m,1H). MS:550[M+H]⁺.

EXAMPLE 212 (R) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- ((3- (dimethylamino) propyl) carbamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

Preparation of example 212 reference is made to the preparation of example 141 where N is present in equimolar amounts¹,N¹-dimethylpropan-1, 3-diamine instead of methylamine hydrochloride.¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.55–8.52(m,1H), 7.94–7.84(m,1H),7.50(s,1H),7.43(s,1H),7.38–7.27(m,1H),7.22(s,1H),7.06(s,1H),6.88–6.59(m, 1H),6.15–6.01(m,1H),5.71–5.60(m,1H),4.47–3.93(m,2H),3.78(s,3H),3.27–3.23(m,2H),2.29– 2.24(m,3H),2.17(s,3H),2.14(s,6H),1.74–1.49(m,8H).MS:605[M+H]⁺.

EXAMPLE 213 (S) -2- ((1- (1-Acrylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((2-methoxy-6-methyl-4- (N-methylsulfamoyl) phenyl) amino) pyrimidine-5-carboxamide

The preparation of example 213 reference is made to preparation of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-3-methoxy-N, 5-dimethylbenzenesulfonamide.¹H NMR(400MHz,DMSO-d₆)δ10.67(s,1H), 9.63(s,1H),8.61(s,1H),7.93–7.89(m,1H),7.40–7.37(m,2H),7.33–7.31(m,2H),7.21–7.16(m,2H), 6.94–6.54(m,1H),6.11–6.05(m,1H),5.70–5.67(m,1H),4.05–3.99(m,2H),3.81(s,3H),3.30–3.30(m, 2H),3.02–2.81(m,3H),2.44(s,3H),2.22(s,3H),1.89–1.81(m,2H).MS:570[M+H]⁺.

EXAMPLE 214 (S) -2- ((1- (1-acryloylpiperidin-3-yl) -1H-pyrazol-4-yl) amino) -4- ((4- (N- (2-hydroxyethyl) sulfamoyl) -2-methoxy-6-methylphenyl) amino) pyrimidine-5-carboxamide

The procedure for the preparation of example 214 reference is made to the procedure of example 2, steps 1) to 4), wherein in step 1) the cyclopropylamine is replaced with an equimolar amount of 4-amino-N- (2-hydroxyethyl) -3-methoxy-5-methylbenzenesulfonamide.¹H NMR(400MHz,DMSO-d₆)δ10.67(s, 1H),9.63(s,1H),8.61(s,1H),7.92(s,1H),7.63–7.47(m,2H),7.39–7.32(m,2H),7.22–7.13(m,2H),6.91 –6.62(m,1H),6.15–6.04(m,1H),5.72–5.63(m,1H),4.73(s,1H),4.60–4.20(m,1H),4.19–3.89(m,3H), 3.81(s,3H),3.43–3.38(m,3H),3.30–3.30(m,2H),3.16–3.00(m,1H),2.87–2.81(m,3H),2.22(s,3H). MS:600[M+H]⁺.

Test example 1. test of inhibition of kinase activity of JAK1, JAK2, JAK3, TYK2 with the compound of the present invention in an enzymatic reaction assembled in vitro, compounds of different concentrations were added to detect the inhibition of the specific enzymatic reaction by the compound, and the specific test method was as follows:

TABLE 1 test instruments, materials and reagents

Second, testing method

The following will be exemplified by JAK3, and specific experimental conditions for JAK1, JAK2, JAK3, TYK2 are shown in the appendix.

1. Preparing a reagent:

preparation of EDTA (0.5M pH8.0) solution by accurately weighing 14.612g of EDTA powder, adding ultrapure water, and adjusting the volume to 100mL (if insoluble, heating to 37 deg.C, adjusting pH to 8.0 with 1N NaOH solution)

1 × Kinase Assay Buffer: into a reagent bottle were added 25mL of HEPES solution (1M), 190.175mg of EGTA, and 5mL of MgCl₂The solution (1M), 1mL DTT, 50. mu.L Tween-20, and ultrapure water were added to make a volume of 500mL (pH adjusted to 7.5).

1 × Detection Buffer 1mL of 10 × Detection Buffer was added to 9mL of water and mixed.

4 × stop solution: 0.8mL of the above EDTA (0.5M, pH8.0) solution, 1mL of 10 XDetection Buffer, and 8.2mL of ultrapure water were mixed together. 4 XJAK 3 Kinase solution A Kinase stock solution was diluted with 1 XKinase Assay Buffer to a concentration of 0.36nM, mixed well and stored on ice.

4 × substrate solution: substrate ULight was diluted with 1 × Kinase Assay Buffer^TM-Labeled JAK-1(Tyr1023) Peptide stock solution to 200nM and mixed well.

4 × ATP solution: the ATP stock was diluted with 1 XKinase Assay Buffer to a concentration of 40. mu.M and mixed well.

4 × detection solution: the Detection antibody Europium-anti-phosphorus-tyrosine antibody (PT66) was diluted with 1 XDeprotection Buffer to a concentration of 8nM and mixed well.

2 × substrate/ATP mixture: the 4 Xsubstrate solution and 600. mu.l of 4 XATP solution were mixed in equal amounts (prepared before use).

2. Experimental procedure

1) The dilution of the compound is carried out,

in a 96-well plate, compounds were diluted with DMSO solutions at 3-fold ratios to form 11 gradients, and another pure DMSO solution served as a positive control; a new 96-well plate was prepared, and the solution was diluted 25-fold with ultrapure water (DMSO concentration: 4%)

2) Rotating Compounds to 384 well plates

The compound solution diluted with ultrapure water in the above 96-well plate was transferred to the corresponding well of a 384-well plate according to a standard 2-well carousel.

3) Add 4 × kinase solution: mu.l of the 4 Xkinase solution was added to the corresponding reaction well of the 384-well plate using a line gun, and pre-reacted at room temperature for 5 minutes.

4) Add 2 Xsubstrate/ATP mix 5. mu.l of the above 2 Xsubstrate/ATP mix to the corresponding reaction well of a 384 well plate using a discharge gun.

5) Negative control: a negative control well was set in a 384-well plate, and 2.5. mu.l/well of 4 Xsubstrate, 2.5. mu.l of 4 Xenzyme solution, 2.5. mu.l of 1 XKinase Assay Buffer, and 2.5. mu.l of ultrapure water containing 4% DMSO were added to the well.

6) And (4) centrifuging, mixing uniformly, and reacting for 60min at room temperature in the dark.

7) Termination of the enzymatic reaction:

5. mu.l of the 4 Xstop solution was pipetted into the corresponding well of 384-well plate, centrifuged and mixed, and reacted at room temperature for 5 minutes.

8) And (3) color development reaction:

5. mu.l of the 4 × detection solution was pipetted into the mesopores of 384-well plate, centrifuged and mixed, and reacted at room temperature for 60 min.

9) The 384 well plate is placed in a plate reader, and a corresponding program detection signal is called.

10) Inhibition rate and IC₅₀And (3) calculating:

pore reading 10000 × EU 665/EU 615 values

Inhibition rate [1- (experimental well reading-negative control well reading)/(positive control well reading-negative control well reading) ]. 100%

Inputting the drug concentration and the corresponding inhibition rate into GraphPad Prism5 for processing and calculating the corresponding IC₅₀The value is obtained.

Test conditions:

JAK1 kinase activity assay:

JAK1 (final concentration 10 nM); ATP (final concentration 10 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 100 nM); the enzymatic reaction time was 2 hours. The maximum final concentration of the compound was 2.5. mu.M, and after 3-fold gradient dilution, the minimum final concentration was 0.042 nM. The final concentration of DMSO is 1%.

JAK2 kinase activity assay:

JAK2 (final concentration 0.25 nM); ATP (final concentration 5 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 50 nM); the enzymatic reaction time was 1 hour. The maximum final concentration of the compound was 2.5. mu.M, and after 3-fold gradient dilution, the minimum final concentration was 0.042 nM. The final concentration of DMSO is 1%.

JAK3 kinase activity assay:

JAK3 (final concentration 0.36 nM); ATP (final concentration 10 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 50 nM); the enzymatic reaction time was 1 hour. The maximum final concentration of the compound was 2.5. mu.M, and after 3-fold gradient dilution, the minimum final concentration was 0.042 nM.The final concentration of DMSO is 1%.

TYK2 kinase activity assay:

TYK2 (final concentration 8 nM); ATP (final concentration 20 μ M); ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 100 nM); the enzymatic reaction time was 2 hours. The maximum final concentration of the compound was 2.5. mu.M, and after 3-fold gradient dilution, the minimum final concentration was 0.042 nM. The final concentration of DMSO is 1%.

Table 2 shows the results of measurement of inhibitory activity of partial compounds of the present invention on tyrosine kinases JAK1, JAK2, JAK3 and TYK2, wherein A represents IC₅₀Less than or equal to 50nM, B represents IC₅₀Greater than 50nM but less than or equal to 500nM, C represents IC₅₀Greater than 500nM but less than or equal to 5000nM, D represents IC₅₀Above 5000nM, NT indicates that the corresponding kinase was not tested.

The test results in the following table show that the compounds of the present invention exhibit certain inhibitory activities against tyrosine kinases JAK1, JAK2, JAK3 and TYK2, and particularly have potent inhibitory effects against the activity of JAK3 kinase, and some of the compounds of the present invention (exemplified by 165 and 166) exhibit high selectivity against JAK3, JAK2 and TYK2, compared to JAK1, and thus can be safe and effective JAK3 inhibitors.

TABLE 2 results of determination of inhibitory Activity of partial Compounds of the present invention against JAK1, JAK2, JAK3 and TYK2 tyrosine kinases

The foregoing is a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various improvements and modifications can be made to the embodiment of the present invention without departing from the principle of the present invention, and these improvements and modifications should also be construed as the protection scope of the present invention.

Claims

1. A compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,

wherein n1 is an integer from 1 to 3, and n2 is an integer from 1 to 2;

R₁is selected from 1 to 3 of C₁-C₁₀Alkyl, halogen, halogeno C₁-C₁₀Alkyl, cyano, hydroxy-substituted C₁-C₁₀Alkyl radical, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、-CO-R₅’、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl radical C₁-C₆Alkyl, 4-7 membered heterocycloalkyl optionally substituted or unsubstituted with one or more A, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, aryl or heteroaryl optionally substituted with one or more B, -NR^aR^bAryl substituted or unsubstituted by the substituent in (1)A group or a heteroaryl group, or a pharmaceutically acceptable salt thereof,

a is C₁-C₆Alkyl, cyano-substituted C₁-C₆Alkyl radical, C₁-C₃Acyl, cyano-substituted C₁-C₃The acyl group,

b is hydrogen, C₁-C₆An alkyl group, a carboxyl group,

R₅is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl, cyano-substituted C₁-C₆Alkyl, aryl or heteroaryl, - (CH)₂)t-NR^aR^b4-7 membered heterocycloalkyl substituted C₁-C₆An alkyl group, a carboxyl group,

-(CH₂)t-NR^aR^bwherein t is an integer of 0 to 6,

R₂or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 8,

R₄is hydrogen, -NR^cR^d，

R^cAnd R^dIndependently of each other are hydrogen and C₁-C₆An alkyl group, a carboxyl group,

2. A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₁Is composed of

From 1 to 3 selected from C₁-C₆Alkyl, halogen, halogeno C₁-C₆Alkyl, cyano, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、-CO-R₅’、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl, hydroxy substituted C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyl radical C₁-C₆Alkyl, 4-7 membered heterocycloalkyl optionally substituted or unsubstituted with one or more A, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, aryl or heteroaryl optionally substituted with one or more B, -NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

a is C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl radical, C₁-C₃Acyl, cyano-substituted C₁-C₃The acyl group,

b is hydrogen, C₁-C₃An alkyl group, a carboxyl group,

R₅is hydrogen, C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₃Alkyl, hydroxy substituted C₁-C₃Alkyl, cyano-substituted C₁-C₃Alkyl, aryl or heteroaryl, - (CH)₂)t-NR^aR^b4-7 membered heterocycloalkyl substituted C₁-C₃An alkyl group, a carboxyl group,

-(CH₂)t-NR^aR^bwherein t is an integer of 0 to 3,

the aryl is phenyl, and the heteroaryl is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyranyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, pyridyl, etc,

3. A compound according to claim 2, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₁Is composed of

From 1 to 3 substituents selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluorine, chlorine, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂-R₅、-SO-R₅、-CO-R₅’、-O-R₅Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazin-1-yl, 4-hydroxyethylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4- (2-cyanoacetyl) piperazin-1-yl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, t-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-2-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-2-methyl, n-butyl, n-ethyl, n-butyl, n-methyl, n-butyl, n-methyl, n-ethyl, n-methyl, n-butyl, n-methyl, n-2-methyl, n-ethyl, n-methyl, n-butyl, n-p-ethyl, n-p-methyl, n-butyl, n-methyl, aryl or heteroaryl substituted or unsubstituted with a substituent selected from tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, azetidinylmethyl, dimethylamino, diethylamino, dipropylamino, methylamino, ethylamino, propylamino, methylethylamino, methylpropylamino or ethylpropylamino,

R₅is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isopentyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or neopentyl,Hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, phenyl, pyridin 2-yl, pyridin-3-yl, pyridin-4-yl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, or- (CH)₂)t-NR^aR^b，

-(CH₂)t-NR^aR^bWherein t is an integer of 0 to 3,

R₅' is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, or-NR^aR^b，

4. A compound according to claim 3, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₁Is composed of

R₆、R₇、R₈Each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluorine, chlorine, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂-R₅、-SO-R₅、-CO-R₅’、-O-R₅Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazin-1-yl, 4-hydroxyethylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4- (2-cyanoacetyl) piperazin-1-yl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, t-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-methyl, n-2-butyl, n-methyl, n-butyl, n-methyl, n-butyl, n-2-methyl, n-butyl, n-ethyl, n-butyl, n-methyl, n-butyl, n-methyl, n-ethyl, n-methyl, n-butyl, n-methyl, n-2-methyl, n-ethyl, n-methyl, n-butyl, n-p-ethyl, n-p-methyl, n-butyl, n-methyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, azetidinylmethyl, dimethylamino, diethylamino, dipropylamino, methylamino, ethylamino, propylamino, methylethylamino, methylpropylamino or ethylpropylamino,

R₅is hydrogen, methyl,Ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, phenyl, pyridin 2-yl, pyridin-3-yl, pyridin-4-yl, pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, or- (CH)₂)t-NR^aR^b，

-(CH₂)t-NR^aR^bWherein t is an integer of 0 to 3,

5. A compound according to any one of claims 1 to 4, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₂Or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 6,

R₄is hydrogen, -NR^cR^d；

R^cAnd R^dEach independently is hydrogen, methyl, ethyl,Propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, tert-butyl, 1-ethylpropyl, neopentyl.

6. A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the compound is of formula (Ia):

wherein R is₁Is selected from 1 to 3 of C₁-C₁₀Alkyl, halogen, halogeno C₁-C₁₀Alkyl, cyano, hydroxy-substituted C₁-C₁₀Alkyl radical, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、-CO-R₅、-CONH-R₅、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Cycloalkyl radical C₁-C₆Alkyl, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, -NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

R₂or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 8,

R₄is hydrogen, -NR^cR^d，

7. A compound according to claim 6, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₁Is selected from 1 to 3 of C₁-C₆Alkyl, halogen, halogeno C₁-C₆Alkyl, cyano, C₁-C₆Alkylthio, -SO₂-R₅、-SO-R₅、-CO-R₅、-CONH-R₅、-O-R₅、C₂-C₆Alkynyl, C₂-C₆Alkenyl, hydroxy substituted C₁-C₆Alkyl radical, C₁-C₃Alkoxy radical C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyl radical C₁-C₆Alkyl, 4-7 membered heterocycloalkyl substituted C₁-C₆Alkyl, -NR^aR^bAryl substituted or unsubstituted with the substituent(s) in (1) or(ii) a heteroaryl group, wherein,

8. A compound according to claim 7, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₁Is selected from 1 to 3 of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluorine, chlorine, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂-CH₃、-SO₂-CH₂CH₃、-SO-CH₃、-SO-CH₂CH₃、-COOH、-COCH₃、-COCH₂CH₃Aldehyde group, -CONH₂、-CONH-CH₃Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, azetidinylmethyl, -O-R₅or-NR^aR^bAryl or heteroaryl substituted or unsubstituted with the substituent(s) in (1),

R^aand R^bEach independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl,

the aryl is phenyl, and the heteroaryl is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazolyl, pyrazinyl, pyrazolyl, pyridyl, thienyl, thiazolyl, or the like,Pyrimidinyl, pyridazinyl,

9. A compound according to claim 8, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₁Is composed of

R₆、R₇、R₈Each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, fluorine, chlorine, trifluoromethyl, cyano, methylthio, ethylthio, propylthio, isopropylthio, -SO₂-CH₃、-SO₂-CH₂CH₃、-SO-CH₃、-SO-CH₂CH₃、-COOH、-COCH₃、-COCH₂CH₃Aldehyde group, -CONH₂、-CONH-CH₃Ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, oxetanylmethyl, azetidinylmethyl, -O-R₅Or is or-NR^aR^b，

R^aand R^bEach independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl.

10. A compound according to any one of claims 6 to 9, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein R₂Or R₃Each independently is- (CH)₂)n-R₄N is an integer of 0 to 6,

R₄is hydrogen, NR^cR^d；

R^cAnd R^dEach independently hydrogen, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, tert-butyl, 1-ethylpropyl, neopentyl.

11. A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the compound is selected from:

12. a pharmaceutical composition comprising a compound of any one of claims 1 to 11, a stereoisomer, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.

14. The use of a compound according to any one of claims 1-11, or a stereoisomer, pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of autoimmune diseases and cancer associated with the tyrosine kinases JAK1, JAK2, JAK3, TYK 2.

15. The use of claim 14, wherein the autoimmune diseases and cancers associated with the tyrosine kinases JAK1, JAK2, JAK3, TYK2 are selected from the group consisting of: fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, nasopharyngeal cancer, esophageal cancer, brain tumor, lymphoma, multiple myeloma, biliary tract cancer sarcoma, bile duct cancer.

16. Use according to claim 15, wherein the leukemia is selected from: chronic myelocytic leukemia, acute myelocytic leukemia.

17. The use of claim 15, wherein the lymphoma is selected from: non-hodgkin lymphoma, B cell or T cell lymphoma.