WO2020187292A1 - Composé de formamide amino-5-pyrimidine substitué en position 4 par pyrazoleamino substitué en position 2, composition et utilisation associées - Google Patents

Composé de formamide amino-5-pyrimidine substitué en position 4 par pyrazoleamino substitué en position 2, composition et utilisation associées Download PDF

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WO2020187292A1
WO2020187292A1 PCT/CN2020/080203 CN2020080203W WO2020187292A1 WO 2020187292 A1 WO2020187292 A1 WO 2020187292A1 CN 2020080203 W CN2020080203 W CN 2020080203W WO 2020187292 A1 WO2020187292 A1 WO 2020187292A1
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alkyl
substituted
amino
methyl
membered heterocycloalkyl
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张强
王中祥
冯守业
李兰涛
张宏波
杨海龙
徐占强
周利凯
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北京赛特明强医药科技有限公司
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention belongs to the field of chemical medicine, and specifically relates to a class of compounds with JAK kinase inhibitory activity or their pharmaceutically acceptable salts, isomers, solvates or prodrugs, as well as pharmaceutical compositions containing these compounds and these compounds or combinations The application of substances in the preparation of drugs.
  • JAK kinase (Janus Kinase) and its downstream effectors, signal transduction and transcription activator proteins form an important cytokine signal transduction pathway-JAK-STAT pathway.
  • JAK-STAT pathway can be activated by a variety of cytokines, growth factors, and receptors, and participates in cell proliferation, differentiation, apoptosis, angiogenesis, and immune regulation.
  • JAK kinase is a key kinase in the JAK-STAT signaling pathway.
  • JAK kinase inhibitor (tofacitinib) was only approved for the treatment of rheumatoid arthritis in 2012 after the enzyme was discovered more than two decades [Norman P., Selective JAK inhibitors in development for rheumatoid arthritis, Expert Opin Investig Drugs, 2014, 23: 1067-1077].
  • JAK1 is the kinase domain, which is highly conserved in the JAK family
  • JH2 is the kinase-like domain or "pseudo" kinase domain, the pseudokinase domain It is the unique property of JAK protein that is different from other tyrosine proteins.
  • JH3-JH4 is the SH2 domain (Src homology 2domain), this domain contains about 100 amino acid residues, which can specifically recognize and bind phosphorylated tyrosine residues on the ligand ; JH5-JH7 are FERM domains, which are conserved and mainly regulate the binding of JAK to receptors.
  • JAK3 also contains the above-mentioned kinase domain structurally, and mutations of specific amino acids in its different domains will also cause changes in its kinase activity.
  • JAK-STAT signal pathway is an important intracellular signal transduction pathway in the growth, activation, differentiation, apoptosis and function of various cells.
  • STAT is a type of cytoplasmic protein that can bind to DNA in the regulatory region of target genes, and is a downstream substrate of JAK.
  • the STAT family includes 7 members including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6.
  • the interaction between JAKs and STATs plays an important role in the cytokine receptor signaling pathway [O'Sullivan LA et al., Cytokine receptor signaling through the JAK-Stat-Socs pathway in disease, Mol Immunol, 2007, 44: 2497-2506].
  • the JAK-STAT signal pathway is a signal transduction pathway stimulated by a variety of cytokine receptors.
  • JAK kinase mediates the signal transduction of most cytokines in cells, such as interleukin (IL), interferon (IFN), and Erythropoietin (EPO), granulocyte and macrophage colony stimulating factor (GMCSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), platelet derived factor (PDGF) and epidermal cells Growth factors (EGF), etc., and different receptors can activate different subtypes of JAK kinases, thereby exhibiting differentiated biological functions [Pesu M.et al.,Therapeutic targeting of Janus kinases,Immunol Rev,2008,223:132 -142].
  • IL interleukin
  • IFN interferon
  • EPO Erythropoietin
  • GMCSF granulocyte and macrophage colony stimulating factor
  • GH somatotropin
  • PRL prolactin
  • TPO
  • JAK1 and JAK2 are expressed in all tissue cells of the human body. JAK3 is mainly expressed in various hematopoietic tissue cells, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes. The deletion of JAK1 and JAK2 can cause fatal damage to the human body, and the deletion of JAK3 can avoid the toxic and adverse reactions that damage other tissues and cells [Yamaoka K., et al., JAK3 negatively regulates dendritic-cell cytokine production and survival, Blood, 2005, 106 :3227-3233].
  • JAK3 has become a popular target for the treatment of autoimmune diseases, and more and more clinical studies have focused the treatment of rheumatoid arthritis on blocking JAK3 signals On the transduction pathway.
  • Tofacitinib a selective JAK3 inhibitor, passed clinical trials and was approved for the treatment of rheumatoid arthritis.
  • the study of the stereochemical structure of Tofacitinib found that its chiral structure determines that it can specifically bind to JAK3 molecules, thereby inhibiting JAK3 phosphorylation, further leading to the hindrance of STAT phosphorylation, resulting in inhibition of downstream inflammatory cytokine synthesis. Tofacitinib has shown good clinical efficacy in clinical studies.
  • JAK-STAT signal pathway plays an important role in the process of cell differentiation and proliferation. Changes in JAK activity will also lead to changes in signal transmission in this pathway, which in turn affects cell functions. Based on the key role of JAK kinase in JAK-STAT signal transmission and the specific tissue cell distribution of JAK3 kinase, JAK3 becomes a good therapeutic target for diseases such as rheumatoid arthritis.
  • JAK3 inhibitors are mainly used for the treatment of patients with moderate to severe rheumatoid arthritis. These drugs have shown good therapeutic effects and good safety in the treatment, but their long-term safety needs to be further improved.
  • Tofacitinib it was found that the use of the drug will cause certain adverse reactions, including infection, tuberculosis, tumor and liver damage, so improving the efficacy of JAK3 inhibitors and reducing toxic side effects are key issues that need to be resolved in this research field. .
  • JAK kinase subtypes The ATP binding sites of several JAK kinase subtypes have high homology and small structural differences, which is an important reason for the low selectivity of JAK inhibitors. There is still room for improvement in the efficacy, selectivity and safety of a series of JAK kinase inhibitors that have been published. It is still necessary to develop JAK inhibitors with better efficacy and safety, among which highly selective JAK inhibitors The development is the key point.
  • the compound of the present application exhibits excellent biological activity and high selectivity, and can be used as a JAK kinase inhibitor in the treatment of related diseases.
  • this application provides a 2-(1-substituted pyrazole-4-)amino-4-substituted amino-5-pyrimidine carboxamide compound, and its use as a preparation treatment or prevention by tyrosine kinase (E.g. JAK1, JAK2, JAK3, TYK2) or the use of drugs for diseases caused by its variants.
  • tyrosine kinase E.g. JAK1, JAK2, JAK3, TYK2
  • a compound or an isomer, a solvate or a pharmaceutically acceptable salt thereof the compound having the structural formula (I):
  • n1 is an integer from 1 to 3
  • n2 is an integer from 1 to 2.
  • n1 is 3, n2 is 1 or n1 is 2, n2 is 2 or n1 is 2, and n2 is 1;
  • C 1 -C 10 alkyl halogen, halogenated C 1 -C 10 alkyl, cyano, hydroxy substituted C 1 -C 10 alkyl, C 1 -C 6 alkylthio, -SO 2 -R 5 , -SO-R 5 , -CO-R 5 ' , -OR 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl) -O-(C 1 -C 6 Alkyl), 4-7 membered heterocycloalkyl optionally substituted or unsubstituted by one or more A, 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl substituted C 1 -
  • A is C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, C 1 -C 3 acyl, cyano substituted C 1 -C 3 acyl, -( CH 2 )t-NR a R b ,
  • B is hydrogen, C 1 -C 6 alkyl
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, -(CH 2 )t-NR a R b , 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl,
  • R 5 ' is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 Alkyl, C 3 -C 8 cycloalkyl, 4-7 membered heterocycloalkyl, -NR a R b , 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl,
  • the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring, and the heteroaryl group contains 1-3 heteroatoms selected from N, O, S as ring atoms
  • the 4-7 membered heterocycloalkyl group is a 4-7 membered group containing 1-2 atoms selected from N, O, S as ring atoms Heterocycloalkyl,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-7 membered heterocycloalkyl, C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl, C 1 -C 3 alkylthio substituted C 1 -C 6 alkyl or mono- or di-C 1 -C 3 alkyl unsubstituted or substituted amino-substituted C 1 -C 6 alkyl;
  • R 2 or R 3 is each independently -(CH 2 )nR 4 , n is an integer from 0 to 8,
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy substituted C 1 -C 6 alkyl, or C 1- C 3 alkoxy substituted C 1- C 6 alkyl,
  • the 4-7 membered heterocycloalkyl group is a 4-7 membered heterocycloalkyl group containing 1-2 atoms selected from N, O, and S as ring atoms.
  • R 1 is C 3 -C 8 cycloalkyl, 4-7 membered heterocycloalkyl,
  • C 1 -C 6 alkyl halogen, halogenated C 1 -C 6 alkyl, cyano, C 1 -C 6 alkylthio, -SO 2 -R 5 , -SO- R 5 , -CO-R 5 ' , -OR 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, hydroxy substituted C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyl) -O-(C 1 -C 6 Alkyl), 4-7 membered heterocycloalkyl optionally substituted or unsubstituted by one or more A, 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl substituted C 1 -
  • A is C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, C 1 -C 3 acyl, cyano substituted C 1 -C 3 acyl, -( CH 2 )t-NR a R b ,
  • B is hydrogen, C 1 -C 3 alkyl
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, -(CH 2 )t-NR a R b , 4-7 membered heterocycloalkyl substituted C 1 -C 3 alkyl,
  • R 5 ' is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 Alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocycloalkyl, -NR a R b , 4-7 membered heterocycloalkyl substituted C 1 -C 3 alkyl,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl C 1 -C 3 alkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 3 alkyl, C 1 -C 3 alkylthio or C 1 -C 3 alkyl mono- or di-C 1 -C 3 alkyl unsubstituted or substituted amino-substituted C 1 -C 3 alkyl,
  • the aryl group is phenyl, naphthyl
  • the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isodihydro Indolyl, isoquinolinyl, indazinyl, isoxazolyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, oxazolyl, 1-phenyl-1H -Pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pterridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, Py
  • R 1 is C 3 -C 7 cycloalkyl, 4-6 membered heterocycloalkyl,
  • R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxy Methyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, sulfur Morpholinyl, oxetanyl, a
  • R 5 ' 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, morpholine Group, thiomorpholinyl, oxetanyl, a
  • R a and R b are each 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, ethyl Oxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyran-4-yl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, thiomorpholinyl
  • the aryl group is phenyl
  • the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, Pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
  • the 4-6 membered heterocycloalkyl group is a 4-6 membered heterocycloalkyl group containing 1-2 atoms selected from N, O, and S as ring atoms.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperidine
  • R 6 , R 7 , and R 8 are each 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, -SO 2 -R 5 , -SO-R 5 ,- CO-R 5 ' , -OR 5 , ethynyl, vinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl , Methoxypropyl, ethoxymethyl, ethoxyethyl, e
  • R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxy Methyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, sulfur Morpholinyl, oxetanyl, a
  • R 5 ' is hydrogen, hydroxy, pyrrolidinyl, piperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, or -NR a R b ,
  • R a and R b are each 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, ethyl Oxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, tetrahydropyran-4-yl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, thiomorpholinyl
  • R 2 or R 3 are each independently -(CH 2 )nR 4 , n is an integer from 0 to 6,
  • R 4 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy , Isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR c R d , or 1 to 3 selected from methyl, ethyl, propyl, isopropyl, Aldehyde, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, formamino, dimethylamino, methylsulfone, ethylsulfone, propylsulfone, isopropylsulfone, methylsulfonyl Sulfone, ethyl sulfoxide, propyl sulfoxide,
  • R c and R d are 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, ethoxypentyl, ethoxyhexyl, propoxyethyl Group, propoxypropyl, propoxybutyl, propoxypentyl, propoxy
  • the 4-6 membered heterocycloalkyl is pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, oxetanyl, nitrogen Etanyl.
  • R 2 or R 3 is each independently -(CH 2 )nR 4 , n is an integer from 0 to 3,
  • R 4 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy , Isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR c R d ,
  • R c and R d are 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, ethoxypentyl, ethoxyhexyl, propoxyethyl Group, propoxypropyl, propoxybutyl, propoxypentyl, propoxy
  • R 2 or R 3 are each independently hydrogen or dimethylaminomethyl.
  • a compound or an isomer, a solvate or a pharmaceutically acceptable salt thereof the compound having the structural formula (Ia):
  • C 1 -C 10 alkyl halogen, halogenated C 1 -C 10 alkyl, cyano, C 1 -C 6 alkylthio, -SO 2 -R 5 , -SO- R 5 , -CO-R 5 , -CONH-R 5 , -OR 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, hydroxy substituted C 1 -C 10 alkyl, C 1 -C 6 Alkoxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl) -O-( C 1 -C 6 alkyl), 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl, substituted or unsubstit
  • R 5 is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl,
  • the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring, and the heteroaryl group contains 1-3 heteroatoms selected from N, O, S as ring atoms
  • the 4-7 membered heterocycloalkyl group is a 4-7 membered group containing 1-2 atoms selected from N, O, S as ring atoms Heterocycloalkyl,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-7 membered heterocycloalkyl, C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl, C 1- C 3 alkylthio substituted C 1 -C 6 alkyl or mono or double C 1 -C 3 alkyl substituted or unsubstituted C 1 -C 6 alkyl substituted with amino;
  • R 2 or R 3 is each independently -(CH 2 )nR 4 , n is an integer from 0 to 8,
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy substituted C 1 -C 6 alkyl, or C 1- C 3 alkoxy substituted C 1- C 6 alkyl,
  • the 4-7 membered heterocycloalkyl group is a 4-7 membered heterocycloalkyl group containing 1-2 atoms selected from N, O, and S as ring atoms.
  • R 1 is C 3 -C 8 cycloalkyl, 4-7 membered heterocycloalkyl,
  • C 1 -C 6 alkyl halogen, halogenated C 1 -C 6 alkyl, cyano, C 1 -C 6 alkylthio, -SO 2 -R 5 , -SO- R 5 , -CO-R 5 , -CONH-R 5 , -OR 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, hydroxy substituted C 1 -C 6 alkyl, C 1 -C 3 Alkoxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyl) -O-( C 1 -C 6 alkyl), 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 6 alkyl, substituted or unsubstit
  • R 5 is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 3 alkyl,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl C 1 -C 3 alkyl, 4-7 membered heterocycloalkyl substituted C 1 -C 3 alkyl, C 1- C 3 alkylthio or C 1 -C 3 alkyl mono- or di-C 1 -C 3 alkyl unsubstituted or substituted amino-substituted C 1 -C 3 alkyl,
  • the aryl group is phenyl, naphthyl
  • the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl , Isoindolinyl, isoquinolinyl, inzinyl, isoxazolyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, oxazolyl, 1- Phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo[3,4-d ]Pyrimi
  • R 1 is C 3 -C 7 cycloalkyl, 4-6 membered heterocycloalkyl,
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4- 6-membered heterocycloalkyl, 4-6 membered heterocycloalkyl substituted C 1 -C 3 alkyl,
  • R a and R b are each 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, ethyl Oxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxa Cyclobutane, azetidiny
  • the aryl group is phenyl
  • the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyranyl, Pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
  • the 4-6 membered heterocycloalkyl group is a 4-6 membered heterocycloalkyl group containing 1-2 atoms selected from N, O, and S as ring atoms.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrofuranyl , Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl,
  • R 6 , R 7 , and R 8 are each 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, -SO 2 -CH 3 , -SO 2 -CH 2 CH 3 , -SO-CH 3 , -SO-CH 2 CH 3 , -COOH, -COCH 3 , -COCH 2 CH 3 , aldehyde group, -CONH 2 , -CONH-CH 3 , ethynyl, vinyl, hydroxymethyl Group, hydroxyethyl, hydroxypropyl, hydroxybutyl,
  • R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, hydroxy Methyl, hydroxyethyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, nitrogen Etanyl,
  • R a and R b are each 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, ethyl Oxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxa Cyclobutanyl, azetidiny
  • R 2 or R 3 are each independently -(CH 2 )nR 4 , and n is an integer from 0 to 6,
  • R 4 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy , Isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR c R d , or 1 to 3 selected from methyl, ethyl, propyl, isopropyl, Aldehyde, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, formamino, dimethylamino, methylsulfone, ethylsulfone, propylsulfone, isopropylsulfone, methylsulfonyl Sulfone, ethyl sulfoxide, propyl sulfoxide,
  • R c and R d are 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, ethoxypentyl, ethoxyhexyl, propoxyethyl Group, propoxypropyl, propoxybutyl, propoxypentyl, propoxy
  • the 4-6 membered heterocycloalkyl is pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, oxetanyl, nitrogen Etanyl.
  • R 2 or R 3 are each independently -(CH 2 )nR 4 , and n is an integer from 0 to 6,
  • R 4 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy , Isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR c R d , or 1 to 3 selected from methyl, ethyl, propyl, isopropyl, Aldehyde, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, formamino, dimethylamino, methylsulfone, ethylsulfone, propylsulfone, isopropylsulfone, methylsulfonyl Sulfone, ethyl sulfoxide, propyl sulfoxide,
  • R c and R d are 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, ethoxypentyl, ethoxyhexyl, propoxyethyl Group, propoxypropyl, propoxybutyl, propoxypentyl, propoxy
  • the 4-6 membered heterocycloalkyl is
  • R 2 or R 3 are each independently -(CH 2 )nR 4 , n is an integer from 0 to 3,
  • R 4 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy , Isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, -NR c R d ,
  • R c and R d are 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, ethoxypentyl, ethoxyhexyl, propoxyethyl Group, propoxypropyl, propoxybutyl, propoxypentyl, propoxy
  • R 2 or R 3 are each independently hydrogen or dimethylaminomethyl.
  • the pharmaceutically acceptable salt of the compound is selected from the hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, Phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, glucose Acid salt, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclic Hexasulfamate, salicylate, hexonate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt , One or more of magnesium salt, potassium salt, sodium salt and zinc salt.
  • Another aspect of the present invention relates to the preparation of the compound, its pharmaceutically acceptable salt, isomer, solvate, or prodrug for the treatment of autoimmune diseases related to tyrosine kinase JAK1, JAK2, JAK3, and TYK2
  • the autoimmune diseases and cancers related to tyrosine kinases JAK1, JAK2, JAK3, TYK2 include: fundus diseases, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, Rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer , Pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer,
  • Another aspect of the present invention relates to the use of the compound, its pharmaceutically acceptable salt, isomer, solvate, or prodrug in the preparation of a medicament for the treatment of autoimmune diseases and cancer related to tyrosine kinase JAK3 Application, wherein the autoimmune diseases and cancers related to 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, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma Cell tumor, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the pyrimidine carboxamide compound of the present application, its isomers, solvates, pharmaceutically acceptable salts or prodrugs, and one or A variety of pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition may also include one or more other therapeutic agents.
  • the present invention also relates to a method for treating diseases or disorders mediated by JAK1, JAK2, JAK3, and TYK2 tyrosine kinases, which comprises administering a therapeutically effective amount to a patient (human or other mammals, especially humans) in need
  • the JAK1, JAK2, JAK3, TYK2 tyrosine kinase-mediated diseases or conditions include those mentioned above.
  • the present invention also relates to a method for treating diseases or conditions mediated by JAK3 tyrosine kinase, which includes administering to a patient (human or other mammals, especially humans) in need a therapeutically effective amount of formula ( I) Compounds or salts thereof, the diseases or disorders mediated by JAK3 tyrosine kinase include those mentioned above.
  • alkyl refers to a saturated linear and branched hydrocarbon group with the specified number of carbon atoms.
  • the term C 1 -C 10 alkyl refers to an alkyl moiety containing 1 to 10 carbon atoms, similarly C 1 -C 3 Alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms.
  • C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl Base, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl Basepentyl and so on.
  • substituent terms such as “alkyl” are used in combination with other substituent terms, for example in the term “C 1 -C 3 alkoxy C 1 -C 6 alkylthio” or “hydroxy substituted C 1 -C 10 alkyl”
  • this linking substituent term e.g., alkyl or alkylthio
  • C 1 -C 3 alkoxy C 1 -C 6 alkylthio include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio and the like.
  • hydroxyl substituted C 1 -C 10 alkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxyisopropyl and the like.
  • the alkoxy group is an alkyl-O- group formed by the previously described linear or branched alkyl group and -O-, for example, a methoxy group, an ethoxy group, and the like.
  • the alkylthio group is an alkyl-S- group formed by the previously described linear or branched alkyl group and -S-, for example, methylthio, ethylthio and the like.
  • Alkenyl and alkynyl include straight chain, branched chain alkenyl or alkynyl, the term C 2 -C 6 alkenyl or C 2 -C 6 alkynyl means a straight or branched C 2 having at least one alkenyl or alkynyl group -C 6 hydrocarbon group.
  • halogenated C 1 -C 10 alkyl refers to a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkyl moiety including 1 to 10 carbon atoms.
  • halo C 1 -C 10 alkyl may include, but are not limited to, -CF 3 (trifluoromethyl), -CCl 3 (trichloromethyl), 1,1-difluoroethyl, 2,2 , 2-Trifluoroethyl and hexafluoroisopropyl, etc.
  • halo C 1 -C 10 alkoxy means a haloalkyl-O- group formed by the halogenated C 1 -C 10 alkyl group and -O-, which can be, for example, trifluoromethyl Oxy, trichloromethoxy, etc.
  • C 1 -C 3 acyl includes formyl (-CHO), acetyl (CH 3 CO-), and acetyl (C 2 H 5 CO-).
  • Cycloalkyl means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms.
  • the term “(C 3 -C 6 )cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having 3-6 ring carbon atoms.
  • Exemplary "(C 3 -C 6 )cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl means a group or part containing an aromatic monocyclic or bicyclic hydrocarbon atom group, which contains 6 to 12 carbon ring atoms and has at least one aromatic ring.
  • aryl are phenyl, naphthyl, indenyl and dihydroindenyl (indanyl).
  • the aryl group is phenyl.
  • heterocycloalkyl represents an unsubstituted or substituted stable 4- to 7-membered non-aromatic monocyclic saturated ring system consisting of carbon atoms and N, It is composed of 1 to 3 heteroatoms selected from O, S, among which N, S heteroatoms can be oxidized at will, and N heteroatoms can also be quaternized at will.
  • heterocyclic rings include, but are not limited to, azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazole Alkyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolane, piperidinyl, piperazinyl, tetrahydrofuranyl Hydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3 -Oxythiolanyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-ox
  • heteroaryl as used herein means a group or moiety containing an aromatic monocyclic or bicyclic atomic group (which may contain 5 to 10 ring atoms), which includes 1 to 3 independently selected from nitrogen, oxygen and sulfur Of heteroatoms.
  • 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, it represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system.
  • heteroaryl groups can be connected to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazole Group, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, iso Benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxolenyl, benzothienyl, indazinyl , Indolyl, isoindolyl, indoline, benzimidazolyl, di
  • carbonyl refers to a -C(O)- group.
  • halogen and “halo” refer to chlorine, fluorine, bromine or iodine substituents.
  • Hydroxo is intended to mean the -OH radical.
  • cyano as used herein refers to the group -CN.
  • 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.
  • the compounds, isomers, crystal forms or prodrugs of formula I and their pharmaceutically acceptable salts can exist in solvated and unsolvated forms.
  • the solvated form may be a water-soluble form.
  • the present invention includes all of these solvated and unsolvated forms.
  • isomers refers to different compounds with the same molecular formula, which may include various isomeric forms such as stereoisomers and tautomers.
  • “Stereoisomers” are isomers that differ only in the arrangement of their atoms in space. Certain compounds described herein contain one or more asymmetric centers, and therefore can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- based on absolute stereochemistry form.
  • the chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all these 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 compound can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation determination, and the degree of advantage of one stereoisomer over other isomers 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.
  • the resolution can be carried out as follows: (1) by forming diastereomeric salts, complexes or other derivatives; (2) by selective reaction with stereoisomer-specific reagents, for example, by enzyme Promote oxidation or reduction; or (3) by gas-liquid chromatography or liquid chromatography in a chiral environment, such as on a chiral carrier (such as silica gel bound with a chiral ligand) or in hand In the presence of sexual solvents.
  • a chiral carrier such as silica gel bound with a chiral ligand
  • stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or one enantiomer can be converted into another isomer by asymmetric transformation .
  • Tautomers are structurally different isomers that can be converted into each other through tautomerization.
  • Tautomerization is a form of isomerization and includes proton transfer or proton transfer tautomerization, which can be considered a subset of acid-base chemistry.
  • Proton transfer tautomerization or “proton transfer tautomerization” involves the migration of protons with bond-level changes, often the exchange of single bonds with adjacent double bonds. When tautomerization is possible (for example, in solution), a chemical equilibrium of tautomers can be reached.
  • An example of tautomerization is keto-enol tautomerization.
  • the compound of the present invention as the active ingredient and the method for preparing the compound are the content of the present invention.
  • the crystalline forms of some compounds may exist as polycrystals, and this form may also be included in the current invention.
  • some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included in the scope of this invention.
  • the compounds of the present invention can be used for therapy in free form, or in the form of pharmaceutically acceptable salts or other derivatives where appropriate.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compounds of the present invention. This salt is suitable for humans and lower animals, without excessive toxicity, irritation, allergic reactions, etc., and has reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting the compound of the present invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, Or by using methods well known in the art, such as ion exchange methods, these salts can be obtained.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconic acid Salt, hemisulfate, caproate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonates and aryl sulfonates. Amine cation formed by acid salt.
  • prodrug as used herein means that a compound can be converted into the compound represented by formula (I) of the present invention in vivo. This conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent compound in the blood or tissues.
  • the pharmaceutical composition of the present invention comprises a compound of structural formula (I) described herein or a pharmaceutically acceptable salt thereof, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer drugs, antiviral agents, and Inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • kinase inhibitors small molecules, polypeptides, antibodies, etc.
  • immunosuppressants anticancer drugs, antiviral agents, and Inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound
  • any pharmaceutically acceptable carrier, adjuvant or excipient any pharmaceutically acceptable carrier, adjuvant or excipient.
  • the compound of the present invention can be used alone, or in combination with one or more other compounds of the present invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • the so-called "combination therapy" refers to the use of the compound of the present invention together with another agent.
  • the mode of administration is simultaneous co-administration of each agent or sequential administration of each agent. In either case, the purpose is to To achieve the best effect of the drug.
  • Co-administration includes simultaneous delivery of dosage forms and separate separate dosage forms for each compound.
  • the administration of the compound of the present invention can be used simultaneously with other therapies known in the art, for example, the use of radiotherapy or cytostatic agents, cytotoxic agents, other anti-cancer agents and other additional therapies in cancer treatment to improve Cancer symptoms.
  • the present invention is not limited to the order of administration; the compounds of the present invention may be administered previously, concurrently, or after other anticancer agents or cytotoxic agents.
  • one or more other therapies can be used in combination, including surgery, radiotherapy (such as gamma-ray, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioisotopes, etc.), endocrine therapy, Biological response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia, cryotherapy, attenuation of any adverse effects (e.g., antiemetics), and other therapeutic drugs.
  • radiotherapy such as gamma-ray, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioisotopes, etc.
  • endocrine therapy such as gamma-ray, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioisotopes, etc.
  • Biological response modifiers e.g., interferons, interleukins, and tumor necrosis factor (TN
  • one or more compounds or salts of formula (I) as its active ingredient can be tightly mixed with the pharmaceutical carrier, which is carried out according to the traditional pharmaceutical ingredient technology.
  • the carrier can take various forms according to the preparation form designed according to different administration methods (for example, oral or parenteral administration).
  • Appropriate 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 jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention can have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsion; or for topical medicine such as ointment, cream; or as suppository for rectal administration.
  • the pharmaceutical ingredients can also be used in a unit dose form suitable for one-time administration of precise doses.
  • the pharmaceutical ingredient will include a traditional pharmaceutical carrier or excipient and a compound prepared according to the current invention as an active ingredient. In addition, it may also include other medical or pharmaceutical preparations, carriers, adjuvants, etc.
  • Therapeutic compounds can also be given to mammals instead of humans.
  • the dose of the drug used for a mammal will depend on the species of the animal and its disease or disorder.
  • Therapeutic compounds can be given to animals in the form of capsules, boluses, or tablet potions.
  • the therapeutic compound can also be injected or infused into the animal's body. We prepare these drug forms in a traditional way that meets the standards of veterinary practice.
  • the pharmacological compound can be mixed with animal feed and fed to animals. Therefore, concentrated feed additives or premixes can be prepared to mix with ordinary animal feed.
  • Another object of the present invention is to provide a method for treating autoimmune diseases and cancer, which comprises a method of administering to a subject a therapeutically effective amount of a composition containing the compound of the present invention.
  • Autoimmune diseases and cancers that can be treated in this way are indicated elsewhere in this document, including autoimmune diseases and cancers that are resistant to treatment with Tofacitinib, Peficitinib, Roxolitinib, Decernotinib or other kinase inhibitors.
  • the administration method of the present invention includes determining a therapeutically effective amount for a subject in need of the compound of the present invention.
  • the "therapeutically effective dose” varies according to the stage, progression or severity of the disease.
  • the daily dosage of the compounds and compositions of the present invention will depend on a variety of factors in the patient, including the condition being treated, the severity of the condition, the efficacy of the specific compound used, the specific composition, age, weight, general Health status, gender and diet, route and schedule of administration, metabolism and/or excretion rate of the compound, duration of treatment, etc.
  • the required dose of the compound of the present invention and a pharmaceutically acceptable carrier can be administered to humans and other animals after being formulated into a medicament.
  • the modes of administration include oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (such as through transdermal patches, powders, ointments, or drops), sublingual, buccal, or nasal spray.
  • the effective dose of the compound of the present invention is usually measured by the dose per kilogram of the patient's body weight, preferably 0.1-125 mg/kg body weight, and generally 0.01-500 mg/kg body weight.
  • Administration can be one or more times, daily, weekly, every other day or every other day, or an intermittent schedule.
  • the compound can be administered daily, weekly (e.g., every Monday), indefinitely, or over several weeks (e.g., 4-10 weeks).
  • the effective dose of the compound of the present invention will vary according to the compound used, the mode of administration, the severity of the disease, the condition to be treated, and various physical factors related to the patient. In most cases, when the daily dose of the preferred compound of the present invention is about 0.01-500 mg/kg, a satisfactory therapeutic effect can be achieved.
  • the preferred dose is 0.1-125 mg/kg, and the more preferred dose is 1-25 mg/kg.
  • the parenteral dosage is usually about 10%-20% of the oral dosage level.
  • each component of the composition will be administered during a desired treatment period. Whether as a separate dosage unit or as a single dosage form containing two components, the components in the composition can be administered simultaneously during the treatment period, or at different times during the treatment period, or one can be used as a pretreatment for the other Apply.
  • the present invention also provides methods for preparing corresponding compounds.
  • Various synthetic methods can be used to prepare the compounds described herein, including the methods involved in the following examples, the compounds of the present invention or their pharmaceutically acceptable salts, isomers
  • the body or hydrate can be synthesized using the following methods and synthetic methods known in the field of organic chemistry synthesis, or by those skilled in the art understanding of variations of these methods. Preferred methods include but are not limited to the following methods.
  • Step 2) The product obtained in step 1) (4-bromo-2-methoxy-6-methylaniline) 216 mg (1 mmol), pyridin-3-ol 95 mg (1 mmol), and cuprous bromide 14.3 mg (0.1 mmol) and 326 mg (1 mmol) of cesium carbonate were placed in a reaction flask, and 5 ml of N,N-dimethylformamide was added, protected by nitrogen, and heated and stirred until the reaction was completed. The solvent was evaporated, and the product was purified by column chromatography to obtain 108 mg of the product, with a yield of 47%. MS: 231 [M+H]+.
  • Step 2) Put 230 mg (1.4 mmol) of the product obtained in step 1) and 196 mg (1.4 mmol) of potassium carbonate in a reaction flask, add 3 ml of dimethyl sulfoxide, and 793 mg (7 mmol) of 30% hydrogen peroxide. Stir at no more than 20°C until the reaction is complete. Dilute with 15 ml of water, extract with ethyl acetate, spin-dry the organic phase, and purify by column chromatography to obtain 150 mg of product with a yield of 60%. MS: 181[M+H] + .
  • step 2 tert-butyl 4-(4-(dibenzylamino)-3-methoxy-5-methylphenyl)piperazine-1-carboxylate) 3.0 g (6 mmol) Place it in a reaction flask, add 12 ml of dichloromethane and 3 ml of trifluoroacetic acid, stir until the reaction is completed, and evaporate the solvent to obtain 2.4 g of the product with a yield of 100%. MS: 402[M+H] + .
  • Step 5) The product obtained in step 4) (3-(4-(4-(dibenzylamino)-3-methoxy-5-methylphenyl)piperazin-1-yl)-3-oxy 1.4 g (3 mmol) of propionitrile and 0.2 g of water-containing palladium carbon are placed in a reaction flask, 10 ml of methanol is added, and the reaction is completed by catalytic hydrogenation. After filtration, the filtrate was evaporated to dryness to obtain 800 mg of product with a yield of 92%. MS: 289 [M+H] + .
  • step 1) (4-chloro-6-vinylpyrimidine-5-amine) 450 mg (2.9 mmol), methyl boric acid 174 mg (2.9 mmol), palladium acetate 67 mg (0.3 mmol), tricyclohexyl Put 84 mg (0.3 mmol) of phosphine and 955 mg (4.5 mmol) of potassium phosphate in a reaction flask, add 10 ml of toluene/water (1:1, v/v), protect with nitrogen, heat and stir until the reaction is complete. The solvent was evaporated, and the obtained solid was purified by column chromatography to obtain 270 mg of product with a yield of 69%. MS: 136[M+H] + .
  • Step 3) Put 270 mg (2 mmol) of the product obtained in step 2) (4-methyl-6-vinylpyrimidin-5-amine) and 27 mg of water-containing palladium carbon in the reaction flask, add 5 ml of methanol, and catalytic hydrogenation Until the reaction is complete. After filtration, the filtrate was evaporated to dryness to obtain 185 mg of product with a yield of 67%. MS: 138[M+H] + .
  • the preparation of intermediate 11 refers to the preparation method of intermediate 10, wherein in step 2), methylboronic acid is replaced by cyclopropylboronic acid in an equimolar equivalent.
  • step 1) (1-fluoro-5-methoxy-3-methyl-2-nitrobenzene) 500 mg (2.7 mmol), dimethylamine in tetrahydrofuran solution (2M) 2 ml (4 mmol), Put 559 mg (4 mmol) of potassium carbonate in a reaction flask, add 2 ml of N,N-dimethylformamide, and heat and stir until the reaction is complete. The solvent was evaporated, and the obtained solid was purified by column chromatography to obtain 284 mg of product, with a yield of 50%. MS: 211 [M+H] + .
  • Step 3) Put 280 mg (1.3 mmol) of the product obtained in step 2) (5-methoxy-N,N,3-trimethyl-2-nitroaniline) and 280 mg of Raney nickel in the reaction flask , Add 5 ml of methanol, catalytic hydrogenation until the reaction is complete. After filtration, the filtrate was evaporated to dryness to obtain 220 mg of product with a yield of 91%. MS: 181[M+H] + .
  • the preparation of intermediate 13 refers to the preparation method of intermediate 12, wherein in step 2), the tetrahydrofuran solution of dimethylamine is replaced with an equimolar equivalent of phenol.
  • step 1) tert-butyl (4-bromo-2-methoxy-6-methylphenyl) carbamate) 632 mg (2 mmol), 4-methoxybenzyl mercaptan 308 Mg (2mmol), tris(dibenzylideneacetone) two palladium 183mg (0.2mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene 116mg (0.2mmol) 516 mg (4 mmol) of diisopropylethylamine is placed in a reaction flask, 10 ml of dioxane is added, protected by nitrogen, heated and stirred until the reaction is complete. Concentrate under reduced pressure, extract with ethyl acetate, spin-dry the organic phase, and purify by column chromatography to obtain 584 mg of product with a yield of 75%. MS: 390[M+H] + .
  • step 2 The product obtained in step 2) (tert-butyl(2-methoxy-4-((4-methoxybenzyl)sulfur)-6-methylphenyl)carbamate) 390 mg (1mmol ), 197 mg (1 mmol) of dichlorodimethylhydantoin was placed in a reaction flask, and 5 ml of acetonitrile was added, stirred until the reaction was completed, the solvent was evaporated, and the product was purified by column chromatography to obtain 202 mg, with a yield of 60%. MS: 336[M+H] + .
  • step 3 (tert-butyl (4-(chlorosulfonyl)-2-methoxy-6-methylphenyl) carbamate) 336 mg (1 mmol), methylamine hydrochloride Put 68 mg (1 mmol) and 112 mg (2 mmol) of potassium hydroxide in a reaction flask, add 5 ml of dichloromethane, stir until the reaction is complete, evaporate the solvent, and purify by column chromatography to obtain a product of 231 mg with a yield of 70%. MS: 331[M+H] + .
  • Step 5) The product obtained in step 4) (tert-butyl(2-methoxy-6-methyl-4-(N-methylsulfonyl)phenyl)carbamate) 231 mg (0.7 mmol ) Put in a reaction flask, add 4 ml of dichloromethane and 1 ml of trifluoroacetic acid, stir until the reaction is completed, and evaporate the solvent to obtain 160 mg of product with a yield of 100%. MS: 231[M+H] + .
  • the preparation of intermediate 16 refers to the preparation of intermediate 15, wherein in step 4), the methylamine hydrochloride is replaced by an equimolar equivalent of 2-aminoethane-1-ol.
  • step 1) (2-chloro-4-(cyclopropylamino)pyrimidine-5-carboxamide) 212 mg (1mmol), tert-butyl(R)-3-(4-amino-1H-pyridine) Azol-1-yl)piperidine-1-carboxylate (for the preparation method refer to WO 2014139465) 266 mg (1 mmol) was placed in the reaction flask, 2 ml of sec-butanol was added, and then 0.05 ml of trifluoroacetic acid was added dropwise, heated and stirred Until the reaction is complete.
  • step 2 The product obtained in step 2) (tert-butyl(R)-3-(4-((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-1H-pyrazole- 1-yl) piperidine-1-carboxylate) 221 mg (0.5 mmol) was placed in a reaction flask, 4 ml of dichloromethane and 1 ml of trifluoroacetic acid were added, stirred until the reaction was completed, and the solvent was evaporated to obtain product 171 Mg, the yield is 100%. MS: 343[M+H] + .
  • step 3 ((R)-4-(cyclopropylamino)-2-((1-(piperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5- Formamide) 171 mg (0.5 mmol) was placed in the reaction flask, 4 ml of tetrahydrofuran was added, 45 mg (0.5 mmol) of acryloyl chloride was added dropwise, and the reaction was completed. 99 mg of product was obtained by chromatography, and the yield was 50%.
  • step 1) (2-chloro-4-(cyclopropylamino)pyrimidine-5-carboxamide) 212 mg (1mmol), tert-butyl(S)-3-(4-amino-1H-pyridine) Azol-1-yl)piperidine-1-carboxylate (for the preparation method refer to WO 2014139465) 266 mg (1 mmol) was placed in the reaction flask, 2 ml of sec-butanol was added, and then 0.05 ml of trifluoroacetic acid was added dropwise, heated and stirred Until the reaction is complete.
  • step 2 The product obtained in step 2) (tert-butyl(S)-3-(4-((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-1H-pyrazole- 1-yl) piperidine-1-carboxylate) 221 mg (0.5 mmol) was placed in a reaction flask, 4 ml of dichloromethane and 1 ml of trifluoroacetic acid were added, stirred until the reaction was completed, and the solvent was evaporated to obtain product 171 Mg, the yield is 100%. MS: 343[M+H] + .
  • step 3 ((S)-4-(cyclopropylamino)-2-((1-(piperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5- Formamide) 171 mg (0.5 mmol) was placed in the reaction flask, 4 ml of tetrahydrofuran was added, 45 mg (0.5 mmol) of acryloyl chloride was added dropwise, and the reaction was completed. 99 mg of product was obtained by chromatography, and the yield was 50%.
  • the preparation method of Example 3 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), an equimolar equivalent of o-toluidine is substituted for cyclopropylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.42-11.06 (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, 3
  • the preparation method of Example 4 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), an equimolar equivalent of o-toluidine is substituted for cyclopropylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.40-11.00 (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
  • the preparation method of Example 5 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-fluoroaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.79-11.43 (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] + .
  • the preparation method of Example 6 refers to step 1) to step 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-fluoroaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.79-11.43(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).
  • the preparation method of Example 7 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclohexylamine is substituted with an equimolar equivalent of cyclohexylamine.
  • the preparation method of Example 8 refers to step 1) to step 4) of the preparation method of Example 2, wherein in step 1), cyclohexylamine is substituted with an equimolar equivalent of cyclohexylamine.
  • the preparation method of Example 9 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of aniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.54-11.41 (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).
  • the preparation method of Example 10 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of aniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.64-11.38 (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).
  • the preparation method of Example 11 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 3-fluoroaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.84-11.58 (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).
  • the preparation method of Example 12 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 3-fluoroaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.81-11.62 (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).
  • the preparation method of Example 13 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 4-fluoroaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.59-11.20(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) ] + .
  • the preparation method of Example 14 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-fluoroaniline is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.56-11.20(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[
  • the preparation method of Example 15 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1), 4-chloroaniline of equimolar equivalent is substituted for cyclopropylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.71-11.35 (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] + .
  • the preparation method of Example 16 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-chloroaniline of equimolar equivalent is substituted for cyclopropylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.69-11.38 (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).
  • the preparation method of Example 17 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 3-chloroaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.77-11.55(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(
  • the preparation method of Example 18 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 3-chloroaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.76-11.56 (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) ).
  • Example 19 (R)-2-((1-(1-acryloylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((2,4-difluorobenzene
  • the preparation method of Example 19 refers to the preparation method steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2,4-difluoroaniline is substituted for the ring Propylamine.
  • Example 20 (S)-2-((1-(1-acryloylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((2,4-difluorobenzene (Base) amino) pyrimidine-5-carboxamide.
  • the preparation method of Example 20 refers to the preparation method steps 1) to 4) of Example 2, wherein in step 1) an equimolar equivalent of 2,4-difluoroaniline is substituted for the ring Propylamine.
  • the preparation method of Example 21 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopentylamine is substituted with an equimolar equivalent of cyclopentylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 9.48 (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, 2
  • the preparation method of Example 22 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopentylamine is substituted with an equimolar equivalent of cyclopentylamine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.49(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 (
  • the preparation method of Example 23 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cycloheptylamine is substituted with an equimolar equivalent of cycloheptylamine.
  • the preparation method of Example 24 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cycloheptylamine is substituted with an equimolar equivalent of cycloheptylamine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.46(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.
  • Example 25 (R)-2-((1-(1-acryloylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((2-methoxyphenyl )Amino)pyrimidine-5-carboxamide
  • the preparation method of Example 25 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-methoxyaniline is substituted for cyclopropylamine.
  • Example 26 (S)-2-((1-(1-acryloylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((2-methoxyphenyl )Amino)pyrimidine-5-carboxamide
  • the preparation method of Example 26 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 2-methoxyaniline is substituted for cyclopropylamine.
  • the preparation method of Example 27 refers to the step 1) to step 4) of the preparation method of Example 1, wherein in step 1) equimolar equivalents of 2,3-dihydrobenzo[b][1,4]dioxin -6-Amine replaces cyclopropylamine.
  • the preparation method of Example 28 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1) equimolar equivalents of 2,3-dihydrobenzo[b][1,4]dioxin -6-Amine replaces cyclopropylamine.
  • the preparation method of Example 29 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), the cyclopropylamine is replaced by an equimolar equivalent of 3-methoxyprop-1-amine.
  • the preparation method of Example 30 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), the cyclopropylamine is replaced by an equimolar equivalent of 3-methoxyprop-1-amine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 9.48 (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),
  • the preparation method of Example 31 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethylaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.45-11.09(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] +
  • the preparation method of Example 32 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethylaniline.
  • the preparation method of Example 33 refers to the step 1) to step 4) of the preparation method of Example 1, wherein in step 1) equimolar equivalents of 2,3-dihydrobenzo[b][1,4]dioxin -5-amine replaces cyclopropylamine.
  • the preparation method of Example 34 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) equimolar equivalents of 2,3-dihydrobenzo[b][1,4]dioxin -5-amine replaces cyclopropylamine.
  • the preparation method of Example 35 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclohexylmethylamine is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.48(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.
  • the preparation method of Example 36 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclohexylmethylamine is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 9.48 (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(
  • the preparation method of Example 37 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclobutylamine is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 9.61 (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),
  • the preparation method of Example 38 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclobutylamine is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 9.50 (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] + .
  • the preparation method of Example 39 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethynylaniline.
  • the preparation method of Example 40 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethynylaniline.
  • the preparation method of Example 41 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-aminobenzonitrile.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 12.18-11.85 (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),
  • the preparation method of Example 42 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-aminobenzonitrile.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 12.17-11.86 (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
  • the preparation method of Example 43 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), 4-(trifluoromethyl)aniline is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.90-11.83 (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+
  • the preparation method of Example 44 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-(trifluoromethyl)aniline is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.89-11.84 (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,
  • the preparation method of Example 45 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-methoxyeth-1-amine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.49(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),
  • the preparation method of Example 46 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-methoxyeth-1-amine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.49(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] +
  • the preparation method of Example 47 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylmethylamine is replaced by an equimolar equivalent of cyclopropylmethylamine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.48(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,
  • the preparation method of Example 48 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylmethylamine is replaced by an equimolar equivalent of cyclopropylmethylamine.
  • the preparation method of Example 49 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by isoamylamine in an equimolar equivalent.
  • the preparation method of Example 50 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced with isoamylamine in an equimolar equivalent.
  • the preparation method of Example 51 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced with isopropylamine in an equimolar equivalent.
  • the preparation method of Example 52 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced with isopropylamine in an equimolar equivalent.
  • the preparation method of Example 53 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1), an equimolar equivalent of 1-amino-2-methylpropan-2-ol is substituted for cyclopropylamine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.47-9.13(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] + .
  • the preparation method of Example 54 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), an equimolar equivalent of 1-amino-2-methylpropan-2-ol is substituted for cyclopropylamine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.45(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.
  • the preparation method of Example 55 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of (tetrahydro-2H-pyran-4-yl)methylamine.
  • the preparation method of Example 56 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of (tetrahydro-2H-pyran-4-yl)methylamine.
  • the preparation method of Example 57 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 2-(tetrahydro-2H-pyran-4-yl)ethyl-1- Amine replaces cyclopropylamine.
  • the preparation method of Example 58 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-(tetrahydro-2H-pyran-4-yl)ethyl-1- Amine replaces cyclopropylamine.
  • the preparation method of Example 59 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethoxyaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.79-11.58(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
  • the preparation method of Example 60 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethoxyaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.79-11.58 (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(
  • the preparation method of Example 61 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1), 5-fluoro-2-methoxyaniline of equimolar equivalent is substituted for cyclopropylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.90-11.80 (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
  • the preparation method of Example 62 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), the cyclopropylamine is replaced by an equimolar equivalent of 5-fluoro-2-methoxyaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.90-11.80(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 (
  • the preparation method of Example 63 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-methoxy-6-methylaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 10.41 (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, 1
  • the preparation method of Example 64 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-methoxy-6-methylaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 10.41(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
  • the preparation method of Example 65 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-isopropoxyaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.77-11.63(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
  • the preparation method of Example 66 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-isopropoxyaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.77-11.63 (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.
  • the preparation method of Example 67 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), 4-fluoro-2-methoxyaniline of equimolar equivalent is substituted for cyclopropylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.64-11.13 (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
  • the preparation method of Example 68 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-fluoro-2-methoxyaniline of equimolar equivalent is substituted for cyclopropylamine.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.64-11.13 (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
  • the preparation method of Example 69 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-cyclopropylethyl-1-amine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.48(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),
  • the preparation method of Example 70 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-cyclopropylethyl-1-amine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.48(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
  • the preparation method of Example 71 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-amino-2-methylbutan-2-ol in an equimolar equivalent is substituted for cyclopropylamine.
  • the preparation method of Example 72 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), the cyclopropylamine is replaced by an equimolar equivalent of 4-amino-2-methylbutan-2-ol.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 9.48(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
  • the preparation method of Example 73 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-fluoro-6-methoxyaniline.
  • the preparation method of Example 74 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-fluoro-6-methoxyaniline is used instead of cyclopropylamine.
  • the preparation method of Example 75 refers to step 1) to step 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-chloro-6-methoxyaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 10.55 (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).
  • the preparation method of Example 76 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-chloro-6-methoxyaniline is substituted for cyclopropylamine.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 10.55(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,
  • the preparation method of Example 77 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-isobutoxyaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 11.71(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
  • the preparation method of Example 78 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-isobutoxyaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.71 (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,1
  • the preparation method of Example 79 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-(2-methoxyethoxy)aniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.78 (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
  • the preparation method of Example 80 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-(2-methoxyethoxy)aniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 11.74 (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 (
  • the preparation method of Example 81 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 2-isobutoxy-6-methylaniline is substituted for cyclopropylamine.
  • the preparation method of Example 82 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-isobutoxy-6-methylaniline.
  • the preparation method of Example 83 refers to the preparation method steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-(2-methoxyethoxy)-6-methylaniline is substituted Cyclopropylamine.
  • the preparation method of Example 84 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 2-(2-methoxyethoxy)-6-methylaniline is substituted Cyclopropylamine.
  • 1 H NMR (400MHz, DMSO-d6) ⁇ 10.45 (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
  • the preparation method of Example 85 refers to step 1) to step 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2,6-dimethoxyaniline.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 10.17 (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),
  • the preparation method of Example 86 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2,6-dimethoxyaniline.
  • 1 H NMR (400MHz, DMSO-d6) ⁇ 10.17 (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), 1.5
  • the preparation method of Example 87 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethoxy-6-methylaniline.
  • the preparation method of Example 88 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethoxy-6-methylaniline.
  • the preparation method of Example 89 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-isopropoxy-6-methylaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 10.49(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+
  • the preparation method of Example 90 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-isopropoxy-6-methylaniline.
  • 1 H NMR(400MHz,DMSO-d6) ⁇ 10.58(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] + .
  • the preparation method of Example 91 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2,6-dimethylaniline.
  • the preparation method of Example 92 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2,6-dimethylaniline.
  • the preparation method of Example 93 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2,6-dimethylaniline is used instead of cyclopropylamine, and in step 2) the equivalent is used.
  • step 1) an equimolar equivalent of 2,6-dimethylaniline is used instead of cyclopropylamine, and in step 2) the equivalent is used.
  • step 2) the equivalent is used
  • the preparation method of Example 94 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-chloro-6-methylaniline is used instead of cyclopropylamine, and in step 2), etc.
  • the preparation method of Example 95 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-chloro-6-methylaniline is used instead of cyclopropylamine.
  • the preparation method of Example 96 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-chloro-6-methylaniline.
  • the preparation method of Example 97 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-methoxy-6-methylaniline, in step 2) Replace tert-butyl(R)-3-(4-amino-1H- with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate Pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 98 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2,6-dimethoxyaniline is substituted for cyclopropylamine, and in step 2) An equivalent of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate instead of tert-butyl(R)-3-(4-amino-1H-pyridine) Azol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 99 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-methoxy-6-methylaniline, in step 4) Replace acryloyl chloride with equivalent (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride.
  • the preparation method of Example 100 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 2-methoxy-6-methylaniline is substituted for cyclopropylamine, in step 4) Replace acryloyl chloride with equivalent (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride.
  • the preparation method of Example 101 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-chloro-6-methoxyaniline is substituted for cyclopropylamine, and in step 4) An equivalent of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride replaces acryloyl chloride.
  • the preparation method of Example 102 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 2-chloro-6-methoxyaniline is substituted for cyclopropylamine, and in step 4) An equivalent of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride replaces acryloyl chloride.
  • the preparation method of Example 103 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1), 4-chloro-2-methoxy-6-methylaniline of equimolar equivalent is substituted for cyclopropylamine.
  • the preparation method of Example 104 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-chloro-2-methoxy-6-methylaniline of equimolar equivalent is substituted for cyclopropylamine.
  • Example 105 2-((1-(1-acryloylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((4-chloro-2-methoxy-6 -Methylphenyl)amino)pyrimidine-5-carboxamide
  • the preparation method of Example 105 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-chloro-2-methoxy-6-methylaniline is substituted for cyclopropylamine, In step 2), the equivalent of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate was used instead of tert-butyl(R)-3-(4- Amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 106 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2,6-dichloroaniline is used instead of cyclopropylamine, and in step 2) an equivalent of Tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate instead of tert-butyl(R)-3-(4-amino-1H-pyrazole-1 -Yl)piperidine-1-carboxylate.
  • the preparation method of Example 107 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2,6-dichloroaniline is substituted for cyclopropylamine.
  • the preparation method of Example 108 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2,6-dichloroaniline.
  • the preparation method of Example 109 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1), the ring is replaced by an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzonitrile. Propylamine.
  • the preparation method of Example 110 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzonitrile is substituted for the ring Propylamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.85-10.46 (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] + .
  • the preparation method of Example 111 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzonitrile is substituted for the ring Propylamine, in step 2) replace tert-butyl(R)-3-( with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate 4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 112 refers to the preparation method of Example 1 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-(pyridin-3-yl Oxy)aniline instead of cyclopropylamine.
  • step 2) the equivalent amount of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate was substituted for tert-butyl( R)-3-(4-Amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 113 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-(pyridin-3-yl (Oxy)aniline instead of cyclopropylamine.
  • the preparation method of Example 114 refers to the step 1) to step 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-(pyridin-3-yl (Oxy)aniline instead of cyclopropylamine.
  • the preparation method of Example 115 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-phenoxyaniline is substituted for the ring Propylamine, in step 2) replace tert-butyl(R)-3-( with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate 4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 116 refers to the preparation method steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-phenoxyaniline is substituted for the ring Propylamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.35 (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
  • the preparation method of Example 117 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-ethyl-6-methylaniline is substituted for cyclopropylamine, and in step 2) An equivalent of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate instead of tert-butyl(R)-3-(4-amino-1H-pyridine) Azol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 118 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-chloro-6-methoxyaniline is used instead of cyclopropylamine, and in step 2) An equivalent of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate instead of tert-butyl(R)-3-(4-amino-1H-pyridine) Azol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 119 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethyl-6-methylaniline.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.64-10.59 (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),1.7
  • the preparation method of Example 120 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethyl-6-methylaniline.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.63-10.60 (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
  • the preparation method of Example 121 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethyl-6-methoxyaniline.
  • 1 H NMR(400MHz, Methanol-d4) ⁇ 8.50(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) ] + .
  • the preparation method of Example 122 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-ethyl-6-methoxyaniline.
  • 1H NMR(400MHz, Methanol-d4) ⁇ 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] + .
  • the preparation method of Example 123 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-cyclopropyl-6-methoxyaniline.
  • 1 H NMR(400MHz,Methanol-d4) ⁇ 8.50(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
  • the preparation method of Example 124 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), cyclopropylamine is replaced by an equimolar equivalent of 2-cyclopropyl-6-methoxyaniline.
  • 1H NMR(400MHz,Methanol-d4) ⁇ 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
  • the preparation method of Example 125 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-cyclopropyl-6-methoxyaniline is used instead of cyclopropylamine, step 2)
  • step 1) an equimolar equivalent of 2-cyclopropyl-6-methoxyaniline is used instead of cyclopropylamine
  • step 2) The equivalent 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.
  • the preparation method of Example 126 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-ethoxy-6-methylaniline is substituted for cyclopropylamine, in step 2) Replace tert-butyl(R)-3-(4-amino-1H- with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate Pyrazol-1-yl)piperidine-1-carboxylate.
  • step 1) cyclopropylamine is replaced by an equimolar equivalent of 2-isopropoxy-6-methylaniline
  • step 2) The equivalent 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.
  • the preparation method of Example 128 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-methoxy-6-methyl-5-pyrimidinamine is substituted for cyclopropylamine, In step 2), the equivalent of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate was used instead of tert-butyl(R)-3-(4- Amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 129 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), 4-methoxy-6-methyl-5-pyrimidinamine is substituted for cyclopropylamine with an equimolar equivalent.
  • the preparation method of Example 130 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-methoxy-6-methyl-5-pyrimidinamine is substituted for cyclopropylamine in an equimolar equivalent.
  • step 1) cyclopropylamine is replaced by an equimolar equivalent of 2-ethyl-6-methoxyaniline
  • step 2) Replace tert-butyl(R)-3-(4-amino-1H- with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate Pyrazol-1-yl)piperidine-1-carboxylate.
  • Step 1) 4-ethyl-6-methylpyrimidin-5-amine in an equimolar equivalent is substituted for cyclopropylamine.
  • step 2) Replace tert-butyl(R)-3-(4-amino) with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate -1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 133 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), 4-ethyl-6-methylpyrimidin-5-amine is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.79 (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
  • the preparation method of Example 134 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-ethyl-6-methylpyrimidin-5-amine is substituted for cyclopropylamine with an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.81-10.72 (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.
  • the preparation method of Example 135 refers to the steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzamide is substituted for the ring Propylamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.60-10.55 (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),1.6
  • Example 136 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), the ring is replaced with an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzamide. Propylamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.60-10.54 (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(
  • the preparation method of Example 137 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzamide is substituted for the ring Propylamine, in step 2) replace tert-butyl(R)-3-( with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate 4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzoic acid is substituted for cyclopropylamine, step 2)
  • step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzoic acid is substituted for cyclopropylamine
  • step 2) The equivalent 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;
  • the preparation method of Example 139 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzoic acid is substituted for cyclopropylamine .
  • the preparation method of Example 140 refers to the preparation method of Example 2 steps 1) to 4), wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzoic acid is substituted for cyclopropylamine .
  • Example 143 refers to the preparation method of Example 141, in which an equimolar equivalent of dimethylamine in tetrahydrofuran (2M) is substituted for methylamine hydrochloride.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.51 (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 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of dimethylamine in tetrahydrofuran (2M).
  • 2M tetrahydrofuran
  • Example 145 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of ethylamine in tetrahydrofuran (2M).
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.58 (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
  • Example 146 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of ethylamine in tetrahydrofuran (2M).
  • Example 147 refers to the preparation method of Example 141, wherein isopropylamine is used in place of methylamine hydrochloride in an equimolar equivalent.
  • 1 H NMR(400MHz,DMSO-d 6 ) ⁇ 10.55(s,1H),9.60(s,1H),8.60(s,1H),8.44-8.39(m,3H),8.20(d,J 7.8 Hz, 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 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by isopropylamine in an equimolar equivalent.
  • 1 H NMR(400MHz,DMSO-d 6 ) ⁇ 10.56(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,
  • Example 149 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of cyclobutylamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.55 (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
  • Example 150 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of cyclobutylamine.
  • Example 151 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by cyclopentylamine in an equimolar equivalent.
  • 1 H NMR(400MHz,DMSO-d 6 ) ⁇ 10.55(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
  • Example 152 refers to the preparation method of Example 142, in which the methylamine hydrochloride is replaced by an equimolar equivalent of cyclopentylamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.55 (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,
  • Example 153 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by cyclohexylamine in an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.55 (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
  • Example 154 refers to the preparation method of Example 142, in which the methylamine hydrochloride is replaced by an equimolar equivalent of cyclohexylamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.56 (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,
  • Example 155 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of azetidine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.51 (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 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of azetidine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.55-10.48 (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),
  • Example 157 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of tetrahydropyrrole.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.50-10.46 (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 refers to the preparation method of Example 142, in which methylamine hydrochloride is replaced by an equimolar equivalent of tetrahydropyrrole.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.50-10.45 (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(
  • Example 159 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by piperidine in an equimolar equivalent.
  • Example 160 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by piperidine in an equimolar equivalent.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.49 (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(
  • Example 161 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of morpholine.
  • Example 162 refers to the preparation method of Example 142, in which the methylamine hydrochloride is replaced by an equimolar equivalent of morpholine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.49 (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.
  • Example 163 refers to the preparation method of Example 141, in which the methylamine hydrochloride is replaced by an equimolar equivalent of 2-methoxyeth-1-amine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.62 (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, 1
  • Example 164 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of 2-methoxyeth-1-amine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.60 (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
  • Example 165 refers to the preparation method of Example 141, in which the methylamine hydrochloride is replaced by an equimolar equivalent of 2-aminoethane-1-ol.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.56 (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.
  • Example 166 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of 2-aminoethane-1-ol.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.56 (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),
  • Example 167 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of tetrahydro-2H-pyran-4-amine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.56 (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
  • Example 168 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of tetrahydro-2H-pyran-4-amine.
  • Example 169 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of aminoacetonitrile.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.61 (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 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of aminoacetonitrile.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.61 (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
  • Example 171 refers to the preparation method of Example 138, in which the methylamine hydrochloride is replaced by an equimolar equivalent of aminoacetonitrile in the last step.
  • the preparation method of Example 172 refers to the step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 1-(4-(4-amino-3-methoxy-5-methyl) (Phenyl)piperazin-1-yl)ethan-1-one replaces cyclopropylamine.
  • the preparation method of Example 173 refers to the preparation method of Example 2 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 1-(4-(4-amino-3-methoxy-5-methyl) (Phenyl)piperidin-1-yl)ethan-1-one replaced cyclopropylamine.
  • the preparation method of Example 174 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 3-methoxy-5-methyl-[1,1'-biphenyl Yl]-4-amine replaces cyclopropylamine.
  • the preparation method of Example 175 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 3-methoxy-5-methyl-[1,1'-biphenyl Yl]-4-amine replaces cyclopropylamine.
  • 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
  • the preparation method of Example 176 refers to the preparation method of Example 1 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 3-methoxy-5-methyl-[1,1'-biphenyl Yl]-4-amine instead of cyclopropylamine, in step 2) the equivalent of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate was used instead of tert-butyl (R)-3-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 177 refers to the preparation method of Example 1 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-(pyridin-3-yl ) Aniline replaces cyclopropylamine.
  • step 2) the equivalent 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.
  • the preparation method of Example 178 refers to the step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-(pyridin-3-yl ) Aniline replaces cyclopropylamine.
  • the preparation method of Example 179 refers to the preparation method of Example 2 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-(pyridin-3-yl ) Aniline replaces cyclopropylamine.
  • the preparation method of Example 180 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 5-methoxy-N 1 ,N 1 ,3-trimethylbenzene- 1,2-Diamine replaces cyclopropylamine.
  • the preparation method of Example 181 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 5-methoxy-N 1 ,N 1 ,3-trimethylbenzene- 1,2-Diamine replaces cyclopropylamine.
  • the preparation method of Example 182 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 5-methoxy-N 1 ,N 1 ,3-trimethylbenzene- 1,2-diamine replaces cyclopropylamine, in step 2) replace tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate with an equivalent amount (R)-3-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 183 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), the ring is replaced by an equimolar equivalent of 4-methoxy-2-methyl-6-phenoxyaniline.
  • Propylamine, in step 2) replace tert-butyl(R)-3-( with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate 4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 184 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-cyclopropyl-6-methoxypyrimidin-5-amine is substituted for cyclopropylamine .
  • Example 185 refers to the preparation method of Example 2 from step 1) to step 4), wherein in step 1), 4-cyclopropyl-6-methoxypyrimidin-5-amine is substituted for cyclopropylamine in step 1) .
  • the preparation method of Example 186 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-cyclopropyl-6-methoxypyrimidin-5-amine is substituted for cyclopropylamine , In step 2) replace tert-butyl (R)-3-(4) with equivalent tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate -Amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 187 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1), 4-cyclopropyl-6-ethylpyrimidine-5-amine is substituted for cyclopropylamine with an equimolar equivalent, In step 2), the equivalent of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate was used instead of tert-butyl(R)-3-(4- Amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 188 refers to step 1) to step 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-cyclopropyl-6-ethylpyrimidin-5-amine is substituted for cyclopropylamine.
  • the preparation method of Example 189 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1), 4-cyclopropyl-6-ethylpyrimidine-5-amine is substituted for cyclopropylamine with an equimolar equivalent.
  • the preparation method of Example 190 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) equimolar equivalents of 2-methoxy-6-methyl-4-(methylsulfonyl) Aniline replaces cyclopropylamine.
  • the preparation method of Example 191 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) equimolar equivalents of 2-methoxy-6-methyl-4-(methylsulfonyl) Aniline replaces cyclopropylamine.
  • the preparation method of Example 192 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 2-methoxy-6-methyl-4-(ethylsulfonyl) Aniline replaces cyclopropylamine.
  • the preparation method of Example 193 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) equimolar equivalents of 2-methoxy-6-methyl-4-(ethylsulfonyl) Aniline replaces cyclopropylamine.
  • the preparation method of Example 194 refers to the preparation method of Example 1 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 3-(4-(4-amino-3-methoxy-5-methyl) (Phenyl)piperazin-1-yl)-3-oxopropionitrile replaces cyclopropylamine.
  • the preparation method of Example 195 refers to the preparation method of Example 2 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 3-(4-(4-amino-3-methoxy-5-methyl) (Phenyl)piperazin-1-yl)-3-oxopropionitrile replaces cyclopropylamine.
  • Example 196 refers to the preparation method of Example 141, in which the methylamine hydrochloride is replaced by an equimolar equivalent of 3-aminopropan-1-ol.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.56 (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),
  • Example 197 refers to the preparation method of Example 142, in which the methylamine hydrochloride is replaced by an equimolar equivalent of 3-aminoprop-1-ol.
  • Example 198 refers to the preparation method of Example 141, in which the methylamine hydrochloride is replaced by an equimolar equivalent of N 1 ,N 1 -dimethylethylene-1,2-diamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.56 (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),
  • Example 199 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of N 1 ,N 1 -dimethylethylene-1,2-diamine.
  • Example 200 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of 2-(methylamino)acetonitrile.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.53 (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 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of 2-(methylamino)acetonitrile.
  • Example 202 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of 3-aminopropionitrile.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.58 (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
  • Example 203 refers to the preparation method of Example 142, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of 3-aminopropionitrile.
  • Example 204 refers to the preparation method of Example 141, in which the methylamine hydrochloride is replaced by an equimolar equivalent of 2-(methylamino)ethan-1-ol.
  • Example 205 (S)-2-((1-(1-acryloylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((4-((2-hydroxyl (Ethyl)(methyl)carbamoyl)-2-methoxy-6-methylphenyl)amino)pyrimidine-5-carboxamide
  • Example 205 refers to the preparation method of Example 142, in which the methylamine hydrochloride is replaced by an equimolar equivalent of 2-(methylamino)ethan-1-ol.
  • the preparation method of Example 206 refers to steps 1) to 4) of the preparation method of Example 1, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzoic acid is substituted for cyclopropylamine , In step 2) replace tert-butyl (R) with equimolar equivalent of tert-butyl (R)-3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate -3-(4-Amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • the preparation method of Example 207 refers to the steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-5-methylbenzoic acid is substituted for cyclopropylamine
  • step 2) the tert-butyl (S)-3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate is substituted for the tert-butyl (S) with equimolar equivalent -3-(4-Amino-1H-pyrazol-1-yl)piperidine-1-carboxylate.
  • Example 210 refers to the preparation method of Example 208, in which an equimolar equivalent of 2-aminoethane-1-ol is substituted for aminoacetonitrile.
  • Example 211 refers to the preparation method of Example 209, in which an equimolar equivalent of 2-aminoethane-1-ol is substituted for aminoacetonitrile.
  • Example 212 refers to the preparation method of Example 141, wherein the methylamine hydrochloride is replaced by an equimolar equivalent of N 1 ,N 1 -dimethylpropane-1,3-diamine.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.55 (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),
  • the preparation method of Example 213 refers to steps 1) to 4) of the preparation method of Example 2, wherein in step 1) an equimolar equivalent of 4-amino-3-methoxy-N,5-dimethylbenzenesulfonate Amide replaces cyclopropylamine.
  • the preparation method of Example 214 refers to the preparation method of Example 2 from step 1) to step 4), wherein in step 1) an equimolar equivalent of 4-amino-N-(2-hydroxyethyl)-3-methoxy is used. -5-methylbenzenesulfonamide replaces cyclopropylamine.
  • Test Example 1 The compound of the present invention inhibits JAK1, JAK2, JAK3, TYK2 kinase activity test
  • JAK3 The following will take JAK3 as an example.
  • JAK1, JAK2, JAK3, and TYK2 The specific experimental conditions of JAK1, JAK2, JAK3, and TYK2 are shown in the appendix.
  • EDTA (0.5M pH8.0) solution preparation accurately weigh 14.612g EDTA powder, add ultrapure water and dilute to 100mL (if insoluble, heat to 37°C, adjust pH to 8.0 with 1N NaOH solution)
  • 1 ⁇ Kinase Assay Buffer Add 25mL HEPES solution (1M), 190.175mg EGTA, 5mL MgCl 2 solution (1M), 1mL DTT, 50 ⁇ L Tween-20 into the reagent bottle, and add ultrapure water to make the volume to 500mL (adjust pH To 7.5).
  • 1 ⁇ Detection Buffer Take 1mL 10 ⁇ Detection Buffer and add 9mL water to mix.
  • 4 ⁇ stop solution mix 0.8 mL of the above EDTA (0.5M, pH 8.0) solution, 1 mL 10 ⁇ Detection Buffer and 8.2 mL ultrapure water.
  • 4 ⁇ JAK3 kinase solution Dilute the kinase stock solution with 1 ⁇ Kinase Assay Buffer to a concentration of 0.36nM, mix well, and store on ice.
  • 4 ⁇ Substrate solution Dilute the substrate ULight TM -labeled JAK-1 (Tyr1023) Peptide stock solution to 200 nM with 1 ⁇ Kinase Assay Buffer, and mix well.
  • 4 ⁇ ATP solution Dilute the ATP stock solution with 1 ⁇ Kinase Assay Buffer to a concentration of 40 ⁇ M, and mix.
  • 4 ⁇ Detection Solution Dilute the detection antibody Europium-anti-phospho-tyrosine antibody (PT66) with 1 ⁇ Detection Buffer to a concentration of 8nM, and mix.
  • PT66 Europium-anti-phospho-tyrosine antibody
  • 2 ⁇ substrate/ATP mixture 4 ⁇ substrate solution and 600 ⁇ l 4 ⁇ ATP solution are mixed in equal amounts (prepared before use).
  • the compound solution diluted with ultrapure water in the above 96-well plate is transferred to the corresponding well of the 384-well plate according to the standard two-well turntable.
  • Add 2 ⁇ substrate/ATP mixture Take 5 ⁇ l of the above 2 ⁇ substrate/ATP mixture into the corresponding reaction wells of a 384-well plate with a discharge gun.
  • Negative control set a negative control well in a 384-well plate, add 2.5 ⁇ l/well 4 ⁇ substrate, 2.5 ⁇ l 4 ⁇ enzyme solution, 2.5 ⁇ l 1 ⁇ Kinase Assay Buffer, and 2.5 ⁇ l 4% DMSO super Pure water.
  • Inhibition rate [1-(reading value of experimental well-reading value of negative control well)/(reading value of positive control well-reading value of negative control well)]*100%
  • JAK1 kinase activity test JAK1 kinase activity test
  • JAK1 final concentration 10 nM
  • ATP final concentration 10 ⁇ M
  • ULight TM -labeled JAK-1 (Tyr1023) Peptide (final concentration 100 nM); enzymatic reaction time is 2 hours.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and there were 11 concentrations after 3-fold dilution, and the minimum final concentration was 0.042nM.
  • the final concentration of DMSO is 1%.
  • JAK2 final concentration 0.25nM
  • ATP final concentration 5 ⁇ M
  • ULight TM- labeled JAK-1 (Tyr1023) Peptide (final concentration 50nM); enzymatic reaction time is 1 hour.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and there were 11 concentrations after 3-fold dilution, and the minimum final concentration was 0.042nM.
  • the final concentration of DMSO is 1%.
  • JAK3 final concentration 0.36 nM
  • ATP final concentration 10 ⁇ M
  • ULight TM -labeled JAK-1 (Tyr1023) Peptide
  • enzymatic reaction time is 1 hour.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and there were 11 concentrations after 3-fold dilution, and the minimum final concentration was 0.042nM.
  • the final concentration of DMSO is 1%.
  • TYK2 final concentration 8nM
  • ATP final concentration 20 ⁇ M
  • ULight TM -labeled JAK-1 (Tyr1023) Peptide final concentration 100 nM
  • enzymatic reaction time is 2 hours.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and there were 11 concentrations after 3-fold dilution, and the minimum final concentration was 0.042nM.
  • the final concentration of DMSO is 1%.
  • Table 2 lists the determination results of the inhibitory activity of some compounds of the present invention on tyrosine kinases JAK1, JAK2, JAK3, and TYK2, where A means IC 50 is less than or equal to 50 nM, B means IC 50 is greater than 50 nM but less than or equal to 500 nM, C indicates that IC 50 is greater than 500 nM but less than or equal to 5000 nM, D indicates that IC 50 is greater than 5000 nM, and NT indicates that no corresponding kinase was tested.
  • the compounds of the present application have shown certain inhibitory activity against tyrosine kinases JAK1, JAK2, JAK3, and TYK2, and especially have a strong inhibitory effect on the activity of JAK3 kinase. 165 and 166 as examples), compared to JAK1, JAK2 and TYK2, it shows high selectivity to JAK3 and can be a safe and effective JAK3 inhibitor.

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  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
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Abstract

L'invention concerne une classe de nouveaux composés servant d'inhibiteur de kinase JAK, une composition et une utilisation associées. En particulier, l'invention concerne une classe de composés ayant une forte activité inhibitrice de kinase JAK (tel que représenté dans la formule (1)), ou un stéréoisomère, un isomère géométrique, un tautomère, un sel pharmaceutiquement acceptable, un promédicament, un produit métabolique, un dérivé isotopique et un solvate de ceux-ci, ainsi qu'une composition pharmaceutique contenant le composé. L'invention concerne également l'utilisation du composé ou de la composition pharmaceutique selon l'invention dans la préparation de produits pharmaceutiques utilisés pour le traitement de maladies auto-immunes ou de cancers.
PCT/CN2020/080203 2019-03-19 2020-03-19 Composé de formamide amino-5-pyrimidine substitué en position 4 par pyrazoleamino substitué en position 2, composition et utilisation associées WO2020187292A1 (fr)

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CN112500354A (zh) * 2020-12-08 2021-03-16 烟台凯博医药科技有限公司 一种4-氯-6-环丙基嘧啶-5-胺的合成方法
WO2022253333A1 (fr) * 2021-06-02 2022-12-08 南京明德新药研发有限公司 Composés amides et leur application

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102066340A (zh) * 2008-04-16 2011-05-18 波托拉医药品公司 作为syk或jak蛋白激酶抑制剂的2,6-二氨基-嘧啶-5-基甲酰胺类化合物
WO2013043962A1 (fr) * 2011-09-22 2013-03-28 Merck Sharp & Dohme Corp. Carboxamides de cyanométhylpyrazole en tant qu'inhibiteurs de janus kinase
CN103492370A (zh) * 2011-04-22 2014-01-01 西格诺药品有限公司 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
WO2014058921A2 (fr) * 2012-10-08 2014-04-17 Portola Pharmaceuticals, Inc. Inhibiteurs substitués de pyrimidinyl kinase
CN104169272A (zh) * 2011-12-23 2014-11-26 赛尔佐姆有限公司 作为激酶抑制剂的嘧啶-2,4-二胺衍生物
CN104262328A (zh) * 2013-09-18 2015-01-07 北京韩美药品有限公司 抑制btk和/或jak3激酶活性的化合物
WO2017198050A1 (fr) * 2016-05-16 2017-11-23 浙江予川医药科技有限公司 Dérivé de 5-aminopyrazole carboxamide en tant qu'inhibiteur de la btk, son procédé de préparation et composition pharmaceutique associée
WO2019057112A1 (fr) * 2017-09-21 2019-03-28 北京赛特明强医药科技有限公司 Composé 2-substitué pyrazole amino-4-substitué amino-5-pyrimidine formamide, composition, et application associée
WO2019233891A1 (fr) * 2018-06-04 2019-12-12 Glaxosmithkline Intellectual Property Development Limited Composés inhibiteurs de tbk1

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2844652B1 (fr) * 2012-05-03 2019-03-13 Genentech, Inc. Dérivés de pyrazole aminopyrimidine en tant que modulateurs de lrrk2
WO2013174895A1 (fr) * 2012-05-24 2013-11-28 Cellzome Limited Analogues hétérocyclyle de pyrimidine comme inhibiteurs de tyk2
SG11201601119XA (en) * 2013-08-20 2016-03-30 Incyte Corp Survival benefit in patients with solid tumors with elevated c-reactive protein levels

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102066340A (zh) * 2008-04-16 2011-05-18 波托拉医药品公司 作为syk或jak蛋白激酶抑制剂的2,6-二氨基-嘧啶-5-基甲酰胺类化合物
CN103492370A (zh) * 2011-04-22 2014-01-01 西格诺药品有限公司 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
WO2013043962A1 (fr) * 2011-09-22 2013-03-28 Merck Sharp & Dohme Corp. Carboxamides de cyanométhylpyrazole en tant qu'inhibiteurs de janus kinase
CN104169272A (zh) * 2011-12-23 2014-11-26 赛尔佐姆有限公司 作为激酶抑制剂的嘧啶-2,4-二胺衍生物
WO2014058921A2 (fr) * 2012-10-08 2014-04-17 Portola Pharmaceuticals, Inc. Inhibiteurs substitués de pyrimidinyl kinase
CN104262328A (zh) * 2013-09-18 2015-01-07 北京韩美药品有限公司 抑制btk和/或jak3激酶活性的化合物
WO2017198050A1 (fr) * 2016-05-16 2017-11-23 浙江予川医药科技有限公司 Dérivé de 5-aminopyrazole carboxamide en tant qu'inhibiteur de la btk, son procédé de préparation et composition pharmaceutique associée
WO2019057112A1 (fr) * 2017-09-21 2019-03-28 北京赛特明强医药科技有限公司 Composé 2-substitué pyrazole amino-4-substitué amino-5-pyrimidine formamide, composition, et application associée
WO2019233891A1 (fr) * 2018-06-04 2019-12-12 Glaxosmithkline Intellectual Property Development Limited Composés inhibiteurs de tbk1

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MICHAEL L CURTIN; ROBIN HEYMAN H; ROBIN R FREY; PATRICK A MARCOTTE; KEITH B GLASER; JAMES R JANKOWSKI; TERRANCE J MAGOC; DANIEL H : "Pyrazole Diaminopyrimidines as Dual Inhibitors of KDR and Aurora B kinases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, 15 July 2012 (2012-07-15), pages 4750 - 4755, XP028504439, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2012.05.067 *
YIN YUAN , ZHANG TIAN-TAI , ZHANG DA-YONG: "Research Progress of JAK-3 Kinase and Its Inhibitors", ACTA PHARMACEUTICA SINICA, vol. 51, no. 10, 31 October 2016 (2016-10-31), pages 1520 - 1529, XP055734145, ISSN: 0513-4870, DOI: 10.16438/j.0513-4870.2016-0087 *

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