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WO2020187292A1 - 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用 - Google Patents

2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用 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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PCT/CN2020/080203
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French (fr)
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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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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D—HETEROCYCLIC COMPOUNDS
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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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Abstract

本发明提供了作为JAK激酶抑制剂的一类新化合物、组合物及其应用。具体地，本发明提供了一类具有强力JAK激酶抑制活性的化合物（如式（1）所示）或其立体异构体、几何异构体、互变异构体、在药学上可接受的盐、前药、代谢产物、同位素衍生物和溶剂化物，及其包含所述化合物的药物组合物。本发明还公开了本发明化合物或药物组合物在制备药物中的应用，该药物用于治疗自身免疫疾病或癌症。

Description

2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用 技术领域
本发明属于化学医药领域，具体涉及一类具有JAK激酶抑制活性的化合物或其药学上可接受的盐、异构体、溶剂化物或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。
背景技术
JAK激酶(Janus kinase)和其下游的效应器、信号转导及转录激活蛋白形成了重要的细胞因子信号传导途径——JAK-STAT通路。研究发现JAK-STAT通路可由多种细胞因子、生长因子以及受体激活，参与细胞增殖、分化、凋亡、血管生成以及免疫调节等过程。JAK激酶是JAK-STAT信号通路中的关键激酶，该酶被发现二十多年后，第一种JAK激酶抑制剂(tofacitinib)于2012年才被批准用于类风湿性关节炎的治疗[Norman P.，Selective JAK inhibitors in development for rheumatoid arthritis，Expert Opin Investig Drugs,2014,23:1067-1077]。
在哺乳动物体内，JAK激酶家族中的四成员：JAK1、JAK2、JAK3和TYK2由超过1100个氨基酸组成，相对分子质量可达120000-140000，同源性达40％-70％，这些JAK激酶家族成员从C端到N端依次可分为7个同源结构域(JH)：JH1为激酶区，在JAK家族中高度保守；JH2为激酶样区或“假”激酶区，该假激酶结构域是JAK蛋白区别于其他酪氨酸蛋白的独特属性，该激酶区虽不具有催化活性，但对JH1的活性起调节作用，该结构域内的突变常可导致JAK激酶活性的增强或者减弱，并进而导致某些疾病的发生；JH3-JH4为SH2结构域(Src homology 2domain)，该结构域含有约100个氨基酸残基，其可以特异性地识别和结合配基上磷酸化的酪氨酸残基；JH5-JH7为FERM结构域，该结构域保守，主要调节JAK与受体的结合。JAK3作为JAK激酶家族成员之一，在结构上，同样含有上述的激酶区，其不同结构域内特定氨基酸的突变也会造成其激酶活性的改变。
JAK-STAT信号通路是多种细胞生长、活化、分化、凋亡及其功能发挥过程中重要的一条细胞内信号转导途径。STAT是一类能与靶基因调控区DNA结合的胞质蛋白，是JAK的下游底物。STAT家族中包括STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B及STAT6等7个成员。JAKs与STATs之间的相互作用在细胞因子受体信号通路中起着重要作用[O'Sullivan LA et al.，Cytokine receptor signaling through the JAK-Stat-Socs pathway in disease，Mol Immunol,2007,44:2497-2506]。当细胞表面的细胞因子受体与其各自的细胞因子配体结合后引起受体分子的二聚化，使得与受体偶联的JAK激酶相互靠近并通过交互的酪氨酸磷酸化作用而活化。JAK-STAT信号通路是一条由多种细胞因子受体刺激的信号转导通路，JAK激酶介导细胞内大多数细胞因子的信号传导，如白介素(IL)类、干扰素(IFN)类、促红细胞生成素(EPO)、粒细胞和巨噬细胞集落刺激因子(GMCSF)、促生长素(GH)、催乳素(PRL)、促血 小板生成素(TPO)、血小板衍生因子(PDGF)以及表皮细胞生长因子(EGF)等，而且不同受体可激活不同亚型的JAK激酶，从而表现差异化的生物学功能[Pesu M.et al.,Therapeutic targeting of Janus kinases,Immunol Rev,2008,223:132-142]。
JAK1和JAK2在人体各组织细胞中均有表达，JAK3主要表达于各造血组织细胞中，主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。JAK1和JAK2等缺失会造成人体致死性损伤，JAK3缺失则可避免损伤其他组织细胞的毒性不良反应[Yamaoka K.,et al.,JAK3 negatively regulates dendritic-cell cytokine production and survival,Blood,2005,106:3227-3233]。基于JAK激酶家族中各亚型的功能特点和特殊的组织分布，JAK3已成为治疗自身免疫性疾病的热门靶标，越来越多临床研究也将类风湿性关节炎的治疗聚焦于阻断JAK3信号转导通路上。2012年，选择性JAK3抑制剂Tofacitinib通过了临床试验，被批准用于类风湿性关节炎的治疗。
Tofacitinib(CP690550)是Pfizer公司研发的一种吡咯并嘧啶类选择性JAK3激酶抑制剂，对JAK3的抑制活性(IC 50＝1nmol/L)是JAK2(IC 50＝20nmol/L)的20倍及JAK1(IC 50＝112nmol/L)的100倍。研究Tofacitinib的立体化学结构发现其手性结构决定其能够特异性地结合到JAK3分子上，从而抑制JAK3磷酸化，进一步导致STAT磷酸化受阻，造成下游炎性细胞因子合成受到抑制。Tofacitinib在临床研究中表现出良好的临床疗效，在类风湿性关节炎临床试验研究中，5mg或10mg Tofacitinib计量组与等量安慰剂组对比呈现出显著的统计学差异，但临床试验研究中发现使用Tofacitinib与严重感染风险增高相关，其长期安全性有待进一步研究。
JAK-STAT信号通路在细胞分化及增殖过程中起到了重要的作用，JAK活性的改变也将导致该通路信号传递的改变，进而影响细胞功能。基于JAK激酶在JAK-STAT信号传递中的关键作用，以及JAK3激酶特定的组织细胞分布，使得JAK3成为类风湿性关节炎等疾病良好的治疗靶点。
目前JAK3抑制剂主要用于中重度类风湿性关节炎患者的治疗，该类药物在治疗中表现出良好的治疗效果和较好的安全性，但其长期安全性仍有待进一步提高。Tofacitinib临床研究过程中发现，使用该药物后会导致一定的不良反应，包括感染、结核、肿瘤和肝损伤等，所以提高JAK3抑制剂的药效、减少毒副作用是该研究领域亟待解决的关键问题。
JAK激酶几个亚型的ATP结合位点同源性较高，结构差异性较小，这是导致JAK抑制剂选择性不高的重要原因。目前已公开的一系列JAK激酶抑制剂在疗效、选择性和安全性方面还有改进的空间，仍需要开发出药效更佳和安全性更好的JAK抑制剂，其中高选择性JAK抑制剂的开发是关键点。本申请的化合物表现出极佳的生物活性和高选择性，可以作为JAK激酶抑制剂应用于相关疾病的治疗中。
发明内容
鉴于上述问题，本申请提供了一种2-(1-取代吡唑-4-)氨基-4-取代氨基-5-嘧啶甲酰胺类化合物，以及其用作制备治疗或预防由酪氨酸激酶(例如JAK1、JAK2、JAK3、TYK2)或其变种引起的疾病的药物的用途。
根据本发明的一方面，提供了一种化合物或其异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式(I)：
Figure PCTCN2020080203-appb-000001
其中，n1为1至3的整数，n2为1至2的整数，优选地，n1为3，n2为1或者n1为2，n2为2或者n1为2，n2为1；
R 1为由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8环烷基，
或由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的4-7元杂环烷基，
或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 8环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 10烷基，
或由1至3个选自C 1-C 10烷基、卤素、卤代C 1-C 10烷基、氰基、羟基取代C 1-C 10烷基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5 ’、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 6烷氧基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基C 1-C 6烷基、(C 3-C 8环烷基)-O-(C 1-C 6烷基)、任选被一个或多个A取代或非取代的4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、任选被一个或多个B取代的芳基或杂芳基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
A为C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 1-C 3酰基、氰基取代C 1-C 3酰基、-(CH 2)t-NR aR b，
B为氢、C 1-C 6烷基，
R 5为氢、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、芳基或杂芳基、-(CH 2)t-NR aR b、4-7元杂环烷基取代C 1-C 6烷基，
-(CH 2)t-NR aR b中t为0至6的整数，
R 5 ’为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、-NR aR b、4-7元杂环烷基取代C 1-C 6烷基，
所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-7元杂环烷基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至8的整数，
R 4为氢、羟基、C 1-C 3烷基、C 3-C 7环烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、-NR cR d，或者被1至3个选自C 1-C 3烷基、醛基、C 1-C 4烷基酰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、羟基、卤素、氧代(＝O)、羟基C 1-C 3烷基、氨基、单或双C 1-C 3烷基取代氨基、卤代C 1-C 3烷基中的取代基所取代或者未取代的4-7元杂环烷基，
R c和R d分别独立的为氢、C 1-C 6烷基、C 3-C 6环烷基、羟基取代C 1-C 6烷基或C 1-C 3烷氧基取代C 1-C 6烷基，
所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
在本申请的一些实施方案中，R 1为C 3-C 8环烷基，4-7元杂环烷基，
或由1至3个选自C 1-C 3烷氧基、C 1-C 3烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 6环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
或由1至3个选自C 1-C 6烷基、卤素、卤代C 1-C 6烷基、氰基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5 ’、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、羟基取代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 6烷基、C 3-C 6环烷基、C 3-C 6环烷基C 1-C 6烷基、(C 3-C 6环烷基)-O-(C 1-C 6烷基)、任选被一个或多个A取代或非取代的4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、任选被一个或多个B取代的芳基或杂芳基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
A为C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 1-C 3酰基、氰基取代C 1-C 3酰基、-(CH 2)t-NR aR b，
B为氢、C 1-C 3烷基，
R 5为氢、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 3-C 6环烷基、4-7元杂环烷基、芳基或杂芳基、-(CH 2)t-NR aR b、4-7元杂环烷基取代C 1-C 3烷基，
-(CH 2)t-NR aR b中t为0至3的整数，
R 5 ’为氢、羟基、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 3-C 6环烷基、4-7元杂环烷基、-NR aR b、4-7元杂环烷基取代C 1-C 3烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、4-7元杂环烷基、C 1-C 3烷氧基取代C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 3-C 6环烷基C 1-C 3烷基、4-7元杂环烷基取代C 1-C 3烷基、C 1-C 3烷硫基取代C 1-C 3烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 3烷基，
所述芳基为苯基、萘基、
Figure PCTCN2020080203-appb-000002
所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、异噻唑基、吲唑基、吲哚基、异吲哚基、二氢吲哚基、异二氢吲哚基、异喹啉基、吲嗪基、异噁唑基、1,5-萘啶基、1,6-萘啶酮基、噁二唑基、噁唑基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡喃基、吡唑基、吡唑并[3,4-d]嘧啶基、吡啶并[3,2-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、
Figure PCTCN2020080203-appb-000003
所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
在本申请的一些优选实施方案中，R 1为C 3-C 7环烷基，4-6元杂环烷基，
或由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、三氟甲基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、氰基、-CONH 2、环丙基、环丁基、环戊基、环己 基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
或由1至3个选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、-SO 2-R 5、-SO-R 5、-CO-R 5 ’、-O-R 5、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、4-甲基哌嗪-1-基、4-羟乙基哌嗪-1-基、4-乙基哌嗪-1-基、4-乙酰基哌嗪-1-基、4-(2-氰基乙酰基)哌嗪-1-基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、二甲氨基、二乙氨基、二丙氨基、甲氨基、乙氨基、丙氨基、甲基乙基氨基、甲基丙基氨基、或者乙基丙基氨基中的取代基所取代或者非取代的芳基或者杂芳基，
R 5为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、苯基、吡啶2-基、吡啶-3-基、吡啶-4-基、吡咯基、呋喃基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、或者-(CH 2)t-NR aR b，
-(CH 2)t-NR aR b中t为0至3的整数，
R 5 ’为氢、羟基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、或-NR aR b，
R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃-4-基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基，
所述芳基为苯基，所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、
Figure PCTCN2020080203-appb-000004
所述4-6元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-6元杂环烷基。
在本申请的一些优选实施方案中，R 1为环丙基、环丁基、环戊基、环己基、环庚基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基甲基、环丙基乙基、 环丁基甲基、环丁基乙基、环戊基甲基、环戊基乙基、环己基甲基、环己基乙基、四氢吡喃-4-基甲基、四氢吡喃-4-基乙基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、
或者为
Figure PCTCN2020080203-appb-000005
Figure PCTCN2020080203-appb-000006
R 6、R 7、R 8各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、-SO 2-R 5、-SO-R 5、-CO-R 5 ’、-O-R 5、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、4-甲基哌嗪-1-基、4-羟乙基哌嗪-1-基、4-乙基哌嗪-1-基、4-乙酰基哌嗪-1-基、4-(2-氰基乙酰基)哌嗪-1-基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、二甲氨基、二乙氨基、二丙氨基、甲氨基、乙氨基、丙氨基、甲基乙基氨基、甲基丙基氨基、或者乙基丙基氨基，
R 5为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、苯基、吡啶2-基、吡啶-3-基、吡啶-4-基、吡咯基、呋喃基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、或者-(CH 2)t-NR aR b，
-(CH 2)t-NR aR b中t为0至3的整数，
R 5 ’为氢、羟基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氮杂环丁烷基、或者-NR aR b，
R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃-4-基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基。
在本申请的一些实施方案中，R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至6的整数，
R 4为氢、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、环庚基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、-NR cR d，或者被1至3个选自甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、丁酰基、异丁酰基、氨基酰基、甲氨基酰基、二甲氨基酰基、甲砜基、乙砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜 基、羟基、氟、氯、羟甲基、羟乙基、羟丙基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、甲基乙基氨基、甲基丙基氨基、甲基异丙基氨基、氧代(＝O)、三氟甲基中的取代基所取代或者未取代的4-6元杂环烷基；
R c和R d分别独立地为氢、甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、仲丁基、叔丁基、1-乙基丙基、新戊基、环丙基、环丁基、环戊基、环己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、丙氧基乙基、丙氧基丙基、丙氧基丁基、丙氧基戊基、丙氧基己基、异丙氧基乙基、异丙氧基丙基、异丙氧基丁基、异丙氧基戊基或异丙氧基己基，
所述4-6元杂环烷基为吡咯烷基、四氢呋喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡喃基、氧杂环丁烷基、氮杂环丁烷基。
在本申请的一些实施方案中，R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至3的整数，
R 4为氢、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、环庚基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、-NR cR d，
R c和R d分别独立地为氢、甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、仲丁基、叔丁基、1-乙基丙基、新戊基、环丙基、环丁基、环戊基、环己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、丙氧基乙基、丙氧基丙基、丙氧基丁基、丙氧基戊基、丙氧基己基、异丙氧基乙基、异丙氧基丙基、异丙氧基丁基、异丙氧基戊基或异丙氧基己基。
在本申请的一些优选实施方案中，R 2或者R 3各自独立地为氢、二甲氨基甲基。
根据本发明的一方面，提供了一种化合物或其异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式(Ia)：
Figure PCTCN2020080203-appb-000007
其中，R 1为由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8环烷基，
或由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的4-7元杂环烷基，
或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 8环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 10烷基，
或由1至3个选自C 1-C 10烷基、卤素、卤代C 1-C 10烷基、氰基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5、-CONH-R 5、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、羟基取代C 1-C 10烷基、C 1-C 6烷氧基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基C 1-C 6烷基、(C 3-C 8环烷基)-O-(C 1-C 6烷基)、4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-7元 杂环烷基、4-7元杂环烷基取代C 1-C 6烷基，
所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-7元杂环烷基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至8的整数，
R 4为氢、羟基、C 1-C 3烷基、C 3-C 7环烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、-NR cR d，或者被1至3个选自C 1-C 3烷基、醛基、C 1-C 4烷基酰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、羟基、卤素、氧代(＝O)、羟基C 1-C 3烷基、氨基、单或双C 1-C 3烷基取代氨基、卤代C 1-C 3烷基中的取代基所取代或者未取代的4-7元杂环烷基，
R c和R d分别独立的为氢、C 1-C 6烷基、C 3-C 6环烷基、羟基取代C 1-C 6烷基或C 1-C 3烷氧基取代C 1-C 6烷基，
所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
在本申请的一些实施方案中，在式(Ia)中，R 1为C 3-C 8环烷基，4-7元杂环烷基，
或由1至3个选自C 1-C 3烷氧基、C 1-C 3烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 6环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
或由1至3个选自C 1-C 6烷基、卤素、卤代C 1-C 6烷基、氰基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5、-CONH-R 5、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、羟基取代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 6烷基、C 3-C 6环烷基、C 3-C 6环烷基C 1-C 6烷基、(C 3-C 6环烷基)-O-(C 1-C 6烷基)、4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
R 5为氢、羟基、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、C 3-C 6环烷基、4-7元杂环烷基、4-7元杂环烷基取代C 1-C 3烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、4-7元杂环烷基、C 1-C 3烷氧基取代C 1-C 3烷基、羟基取代C 1-C 3烷基、C 3-C 6环烷基C 1-C 3烷基、4-7元杂环烷基取代C 1-C 3烷基、C 1-C 3烷硫基取代C 1-C 3烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 3烷基，
所述芳基为苯基、萘基、
Figure PCTCN2020080203-appb-000008
所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、异噻唑基、吲唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、异喹啉基、吲嗪基、异噁唑基、1,5-萘啶基、1,6-萘啶酮基、噁二唑基、噁唑基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡喃基、吡唑基、吡唑并[3,4-d]嘧啶基、吡啶基、吡啶并[3,2-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基、
Figure PCTCN2020080203-appb-000009
所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
在本申请的一些实施方案中，在式(Ia)中，优选地，R 1为C 3-C 7环烷基，4-6元杂环烷基，
或由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、三氟甲基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、氰基、-CONH 2、环丙基、环丁基、环戊基、环己基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
或由1至3个选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、-SO 2-CH 3、-SO 2-CH 2CH 3、-SO-CH 3、-SO-CH 2CH 3、-COOH、-COCH 3、-COCH 2CH 3、醛基、-CONH 2、-CONH-CH 3、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、哌嗪基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、-O-R 5、或者-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
R 5为氢、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环烷基、4-6元杂环烷基取代C 1-C 3烷基，
R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基，
所述芳基为苯基，所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、
Figure PCTCN2020080203-appb-000010
所述4-6元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-6元杂环烷基。
在本申请的一些实施方案中，在式(Ia)中，更优选地，R 1为环丙基、环丁基、环戊基、环己基、环庚基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基，
或者为由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、三氟甲基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、氰基、-CONH 2、环丙基、环丁基、环戊基、环己基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
或者为
Figure PCTCN2020080203-appb-000011
Figure PCTCN2020080203-appb-000012
R 6、R 7、R 8各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、-SO 2-CH 3、-SO 2-CH 2CH 3、-SO-CH 3、-SO-CH 2CH 3、-COOH、-COCH 3、-COCH 2CH 3、醛基、-CONH 2、-CONH-CH 3、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、哌嗪基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、-O-R 5、或者-NR aR b，
R 5为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基，
R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基。
根据本申请的一些实施方案，在式(Ia)中，R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至6的整数，
R 4为氢、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、环庚基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、-NR cR d，或者被1至3个选自甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、丁酰基、异丁酰基、氨基酰基、甲氨基酰基、二甲氨基酰基、甲砜基、乙砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、羟基、氟、氯、羟甲基、羟乙基、羟丙基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、甲基乙基氨基、甲基丙基氨基、甲基异丙基氨基、氧代(＝O)、三氟甲基中的取代基所取代或者未取代的4-6元杂环烷基；
R c和R d分别独立地为氢、甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、仲丁基、叔丁基、1-乙基丙基、新戊基、环丙基、环丁基、环戊基、环己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、丙氧基乙基、丙氧基丙基、丙氧基丁基、丙氧基戊基、丙氧基己基、异丙氧基乙基、异丙氧基丙基、异丙氧基丁基、异丙氧基戊基或异丙氧基己基，
所述4-6元杂环烷基为吡咯烷基、四氢呋喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡喃基、氧杂环丁烷基、氮杂环丁烷基。
根据本申请的一些实施方案，在式(Ia)中，优选地，R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至6的整数，
R 4为氢、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、环庚基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、-NR cR d，或者被1至3个选自甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、丁酰基、异丁酰基、氨基酰基、甲氨基酰基、二甲氨基酰基、甲砜基、乙砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、羟基、氟、氯、羟甲基、羟乙基、羟丙基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、甲基乙基氨基、甲基丙基氨基、甲基异丙基氨基、氧代(＝O)、三氟甲基中的取代基所取代或者未取代的4-6元杂环烷基；
R c和R d分别独立地为氢、甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、仲丁基、叔丁基、1-乙基丙基、新戊基、环丙基、环丁基、环戊基、环己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、丙氧基乙基、丙氧基丙基、丙氧基丁基、丙氧基戊基、丙氧基己基、异丙氧基乙基、异丙氧基丙基、异丙氧基丁基、异丙氧基戊基或异丙氧基己基，
所述4-6元杂环烷基为
Figure PCTCN2020080203-appb-000013
Figure PCTCN2020080203-appb-000014
在本申请的一些实施方案中，在式(Ia)中，R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至3的整数，
R 4为氢、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、环庚基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、-NR cR d，
R c和R d分别独立地为氢、甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、仲丁基、叔丁基、1-乙基丙基、新戊基、环丙基、环丁基、环戊基、环己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、丙氧基乙基、丙氧基丙基、丙氧基丁基、丙氧基戊基、丙氧基己基、异丙氧基乙基、异丙氧基丙基、异丙氧基丁基、异丙氧基戊基或异丙氧基己基。
在本申请的一些优选实施方案中，在式(Ia)中，R 2或者R 3各自独立地为氢、二甲氨基甲基。
根据本申请的一些实施方案，所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
本发明的另一方面涉及所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药在制备治疗与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症的药物中的应用，其中，所述与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症包括：眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、 白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
本发明的另一方面涉及所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药在制备治疗与酪氨酸激酶JAK3相关的自身免疫疾病以及癌症的药物中的应用，其中，所述与酪氨酸激酶JAK3相关的自身免疫疾病以及癌症包括：眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
本发明的又一方面提供了一种药物组合物，该药物组合物包括本申请的嘧啶甲酰胺类化合物、其异构体、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。
根据本申请的一些实施方案，该药物组合物还可以包括一种或多种其他治疗剂。
本发明还涉及一种治疗JAK1、JAK2、JAK3、TYK2酪氨酸激酶介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的式(I)化合物或其盐，所述JAK1、JAK2、JAK3、TYK2酪氨酸激酶介导的疾病或病症包括前述提及的那些。
尤其是，本发明还涉及一种治疗JAK3酪氨酸激酶介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的式(I)化合物或其盐，所述JAK3酪氨酸激酶介导的疾病或病症包括前述提及的那些。
具体实施方式
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
发明详述
除非有特殊说明，烷基表示具有指定数目碳原子的饱和直链、支链烃基，术语C 1-C 10烷基表示含有1至10个碳原子的烷基部分，同理C 1-C 3烷基表示含有1至3个碳原子的烷基部分，比如，C 1-C 6烷基包括甲基、乙基、丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、n-戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、n-己基、2-己基和2-甲基戊基等。
当取代基术语例如“烷基”与其它取代基术语组合使用时，例如在术语“C 1-C 3烷氧基C 1-C 6烷硫基”或“羟基取代C 1-C 10烷基”中，该连接取代基术语(例如烷基或烷硫基)旨在包含二价的部分，其中连接点通过所述连接取代基。“C 1-C 3烷氧基C 1-C 6烷硫基”的实例包括但不限于甲氧基甲硫基、甲氧基乙硫基和乙氧基丙硫基等。“羟基取代C 1-C 10烷基”的实例包括但不限于羟基甲基、羟基乙基和羟基异丙基等。
烷氧基由先前描述的直链或支链烷基与-O-形成的烷基-O-基团，例如，甲氧基、乙氧基等等。类似的，烷硫基由先前描述的直链或支链烷基与-S-形成的烷基-S-基团，例如，甲硫基，乙硫基等等。
烯基和炔基包括直链、支链烯基或炔基，术语C 2-C 6烯基或者C 2-C 6炔基表示具有至少一个烯基或炔基的直链或支链C 2-C 6烃基。
术语“卤代C 1-C 10烷基”表示在包括1到10个碳原子的烷基部分的一个或多个碳原子上具有一个或多个可以相同或不同的卤素原子的基团。“卤代C 1-C 10烷基”的实例可以包括但不限于-CF 3(三氟甲基)、-CCl 3(三氯甲基)、1,1-二氟乙基、2,2,2-三氟乙基和六氟异丙基等。类似的，术语“卤代C 1-C 10烷氧基”表示由所述的卤代C 1-C 10烷基与-O-形成的卤代烷基-O-基团，可以为例如三氟甲氧基、三氯甲氧基等等。
术语“C 1-C 3酰基”包括甲酰基(-CHO)、乙酰基(CH 3CO-)、乙酰基(C 2H 5CO-)。
术语“-CO-R 5、-SO 2-R 5、-SO-R 5、-CONH-R 5”分别表示
Figure PCTCN2020080203-appb-000015
“环烷基”表示含有指定数目碳原子的非芳香的、饱和的、环状的烃基。例如，术语“(C 3-C 6)环烷基”指的是具有3-6个环碳原子的非芳香的环状烃环。示例性的“(C 3-C 6)环烷基”包括环丙基、环丁基、环戊基和环己基。
术语“芳基”表示包含芳香的单环或双环烃原子团的基团或部分，其含有6到12个碳环原子且具有至少一个芳香环。“芳基”的实例为苯基、萘基、茚基和二氢茚基(茚满基)。通常，在本发明化合物中，芳基为苯基。
在这里使用的术语“杂环烷基”，除非有特殊说明，代表未被取代的或已被取代的稳定的4至7元非芳香的单环饱和环体系，它们由碳原子以及从N，O，S中选的1至3个杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。这类杂环的例子包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑烷基、吡唑啉基、咪唑烷基、咪唑啉基、噁唑啉基、噻唑啉基、四氢呋喃基、二氢呋喃基、四氢噻吩基、1,3-二氧杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、二氢吡喃基、四氢噻喃基、1,3-二噁烷基、1,4-二噁烷基、1,3-氧硫杂环戊烷基、1,3-氧硫杂环己烷基、1,3-二噻烷基、1,4-氧硫杂环戊烷基、1,4-氧硫杂环己烷基、1,4-二噻烷基、吗啉基、硫吗啉基。
在这里使用的术语“杂芳基”表示包含芳香的单环或双环原子团(可以含有5到10个环原子)的基团或部分，其包括1到3个独立地选自氮、氧和硫的杂原子。该术语还包括双环杂环芳基，其中含有与杂环烷基环部分稠合的芳基环部分，或者含有与环烷基环部分稠合的杂芳基环部分。除非有特别说明，代表未被取代或已被取代的稳定的5或6元单环芳香环体系，也可以代表未被取代或已被取代的9或10个环原子的苯稠杂芳环体系或二环杂芳环体系，它们由碳原子和由1至3个从N，O，S中选择的杂原子组成，其中N、S杂原子可以被氧化，N杂原子还可以被季铵化。杂芳基可以和任何杂原子或碳原子连接组成一个稳定的结构。杂芳基的示例性实例包括但不限于呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、异噻唑基、吡啶基、氧代-吡啶基(吡啶基-N-氧化物)、哒嗪基、吡嗪基、嘧啶基、三嗪基、苯并呋喃基、异苯并呋喃基、2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、二氢苯并二氧杂环己烯基、苯并噻吩基、吲嗪基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、二氢苯并咪唑基、苯并噁唑基、二氢苯并噁唑基、苯并噻唑基、苯并异噻唑基、二氢苯并异噻唑基、吲唑基、咪唑并吡啶基、吡唑并吡啶基、苯并三唑基、三唑并吡啶基、嘌呤基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、噌啉基、酞嗪基、喹唑啉基、1,5-二氮杂萘基、1,6-二氮杂萘基、1,7-二氮杂萘基、1,8-二氮杂萘基和蝶啶基。
术语“羰基”指的是-C(O)-基。术语“卤素”和“卤”表示氯、氟、溴或碘取代基。“氧代”表示双键的氧部分；例如，如果直接连接到碳原子上形成一个羰基部分(C＝O)。“羟基”旨在表示-OH原子团。本文所用术语“氰基”是指基团-CN。
术语“各自独立地”是指当一个以上的取代基选自许多可能的取代基时，那些取代基可以相同或不同。
很清楚，式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本申请中术语“异构体”为具有相同分子式的不同化合物，可以包括立体异构、互变异构等各种异构形式。“立体异构体”是仅原子在空间的排列方式不同的异构体。本文描述的某些化合物含有一个或多个不对称中心，且因此可以产生对映体、非对映体和其他依据绝对立体化学可以被定义为(R)-或(S)-的立体异构形式。本发明的化学实体、药物组合物和方法旨在包括所有这些可能的异构体，包括外消旋混合物、光学纯形式和中间的混合物。旋光(R)-和(S)-异构体可以使用手性合成子或手性试剂来制备，或使用常规技术来拆分。化合物的光学活性可以通过任何合适的方法进行分析，包括但不限于手性色谱法和旋光测定法，且可确定一种立体异构体超越其他异构体的优势程度。
可使用本领域技术人员已知的方法拆分本发明单独的异构体(或异构体富集的混合物)。例如，可如下进行所述拆分：(1)通过形成非对映异构体盐、复合物或其他衍生物；(2)通过与立体异构体特异性试剂的选择性反应，例如通过酶促氧化或还原；或(3)通过在手性环境中的气-液色谱或液相色谱，所述手性环境例如在手性载体上(例如结合有手性配体的硅胶)或在手性溶剂存在下。本领域技术人员将会理解，当将所需立体异构体通过上述分离方法之一转化成另一化学实体时，需要其他步骤来释放所需形式。或者，特异性立体异构体可通过使用光学活性试剂、底物、催化剂或溶剂的不对称合成法来合成，或通过不对称转化将一种对映异构体转化成另一种异构体。
当本文所述的化合物含有烯烃双键时，除非另有说明，其意指该化合物包括各种顺反异构体。
“互变异构体”是可通过互变异构化互相转换的结构上不同的异构体。“互变异构化”是异构化的一种形式，且包括质子移变或质子转移互变异构化，可认为它是酸碱化学的子集。“质子移变互变异构化”或“质子转移互变异构化”涉及伴有键级变换的质子迁移，往往是单键与相邻的双键的互换。当可能发生互变异构化时(例如，在溶液中)，可达到互变异构体的化学平衡。互变异构化的一个实例为酮-烯醇互变异构化。
作为活性成分的本发明的化合物，以及制备该化合物的方法，都是本发明的内容。而且，一些化合物的晶型形式可以作为多晶体存在，这种形式也可以被包括在目前的发明里。另外，一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物，这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹 果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化受前体药物在血液中水解或在血液或组织中经酶转化为母体化合物的影响。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。或者，可以组合使用一个或多个其他疗法，包括手术、放疗(如γ-射线、中子束放射疗法、电子束放射治疗、质子治疗、近距离放射治疗和全身放射性同位素等)、内分泌疗法、生物应答调节剂(例如，干扰素、白介素和肿瘤坏死因子(TNF))、热疗、冷冻疗法、减弱任何不良影响(例如，止吐剂)以及其他的治疗药物。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗自身免疫疾病和癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。可被这样治疗的自身免疫疾病、癌症在本文别处会 注明，包括具有对Tofacitinib、Peficitinib、Roxolitinib、Decernotinib或其他激酶抑制剂治疗有抗药性的自身免疫疾病、癌症等。
本发明的给药方法包括对需要本发明化合物的受试者确定治疗有效量。“治疗有效剂量”依疾病的阶段、进展或严重程度而不同。本发明的化合物和组合物的每日剂量将取决于患者的多种因素，包括所治疗的病症、该病症的严重程度、所采用的具体化合物的药效、特定组合物、年龄、体重、一般健康状况、性别和饮食、给药的途径和时间表、代谢和/或所述化合物的排泄速率、治疗的持续时间等。此外，本发明的化合物所需剂量与药学上可接受的载体制成药剂后，可施用于人和其他动物。给药模式包括口服、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如通过透皮贴剂、粉剂、软膏、或滴剂)、舌下、经颊、或鼻喷雾等。本发明的化合物的有效剂量通常以每公斤患者体重所施药量来计量，优选于0.1～125毫克/千克体重，一般为0.01～500毫克/千克体重。给药可以是一次或多次、每天、每周、每隔一日或每隔多日、或一个间歇时间表。例如，所述化合物可以每天给药、每周给药(例如，每周一)、无限期给药或延续数周给药(例如4-10周)。本发明的化合物的有效剂量将根据所使用的化合物，给药模式、疾病的严重性、所治疗条件以及相关的患者的各种物理因素而变化。在多数情况下，当本发明的优选化合物的每日剂量约为0.01～500毫克/公斤时，可以达到令人满意的治疗效果。优选剂量为0.1～125毫克/千克，更优选的剂量为1～25毫克/千克。肠胃外给药剂量通常是在大约10％-20％的口服剂量水平。当本发明的化合物被用作组合治疗方案的一部分时，每一个组合物的组分将在一个所需的治疗期间被施用。无论是作为单独的剂量单元或者作为单一剂型包含两种组分，组合物中的组分可以在治疗期中同时施用，也可以在治疗期中的不同时间施用，或者某个可以作为另一个的预处理施用。
本发明还提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述实施例中所涉及的方法，本发明的化合物或者其药学上可接受的盐，异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明，除非特别说明，所有的温度为℃。本申请中最终化合物的命名通过Chemdraw中的命名程序产生并翻译成中文而得。
部分中间体的合成
中间体1. 2-甲氧基-6-甲基-4-(吡啶-3-基氧基)苯胺的制备
Figure PCTCN2020080203-appb-000016
步骤1)4-溴-2-甲氧基-6-甲基苯胺的制备
将2-甲氧基-6-甲基苯胺20克(0.145mol)，N-溴代琥珀酰亚胺31克(0.175mol)置于反应瓶中，加入100毫升N,N-二甲基甲酰胺，搅拌至反应完毕，加入500毫升水，抽滤，所得固体柱层析纯化得产品24 克，产率76％。MS:216[M+H] +。
步骤2)：将步骤1)所得产品(4-溴-2-甲氧基-6-甲基苯胺)216毫克(1mmol)、吡啶-3-醇95毫克(1mmol)、溴化亚铜14.3毫克(0.1mmol)、碳酸铯326毫克(1mmol)置于反应瓶中，加入5毫升N,N-二甲基甲酰胺，氮气保护，加热搅拌至反应完毕。蒸去溶剂，柱层析纯化得产品108毫克，产率47％。MS:231[M+H]+。
中间体2. 4-氨基-3-甲氧基-5-甲基苯甲酰胺的制备
Figure PCTCN2020080203-appb-000017
步骤1)4-氨基-3-甲氧基-5-甲基苯甲腈的制备
将4-溴-2-甲氧基-6-甲基苯胺7.5克(34.7mmol)、亚铁氰化钾16.1克(38.2mmol)、醋酸钯786毫克(3.5mmol)、碳酸钠5.5克(52mmol)置于反应瓶中，加入50毫升N,N-二甲基乙酰胺，氮气保护，加热搅拌至反应完毕。加入300毫升水稀释后，抽滤，所得固体柱层析纯化得产品5克，产率88％。MS:163[M+H] +。
步骤2)：将步骤1)所得的产品230毫克(1.4mmol)、碳酸钾196毫克(1.4mmol)置于反应瓶中，加入3毫升二甲基亚砜，30％双氧水793毫克(7mmol)，不超过20℃搅拌至反应完毕。加水15毫升稀释，乙酸乙酯萃取，有机相旋干，柱层析纯化得到产品150毫克，产率60％。MS:181[M+H] +。
中间体3. 1-(4-(4-氨基-3-甲氧基-5-甲基苯基)哌嗪-1-基)乙-1-酮的制备
Figure PCTCN2020080203-appb-000018
将4-溴-2-甲氧基-6-甲基苯胺1.1克(5mmol)、1-(哌嗪-1-基)乙-1-酮653毫克(5mmol)、三(二亚苄基丙酮)二钯458毫克(0.5mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯197毫克(0.5mmol)、磷酸钾2.1克(10mmol)置于反应瓶中，加入20毫升二氧六环，氮气保护，加热搅拌至反应完毕。蒸干溶剂，柱层析纯化得产品800毫克，产率60％。MS:264[M+H] +。
中间体4. 3-甲氧基-5-甲基-[1,1'-联苯基]-4-胺的制备
Figure PCTCN2020080203-appb-000019
将(4-溴-2-甲氧基-6-甲基苯胺)2.16克(10mmol)、苯硼酸1.22克(10mmol)、醋酸钯449毫克(2mmol)、三环己基膦561毫克(2mmol)、磷酸钾3.18克(15mmol)置于反应瓶中，加入50毫升甲苯/水(10：1，v/v)，氮气保护，加热搅拌至反应完毕。蒸干溶剂，所得固体柱层析纯化得产品1.6克，产率75％。MS:214[M+H] +。
中间体5. 2-甲氧基-6-甲基-4-(吡啶-3-基)苯胺的制备
Figure PCTCN2020080203-appb-000020
将(4-溴-2-甲氧基-6-甲基苯胺)2.16克(10mmol)、吡啶-3-硼酸1.23克(10mmol)、1,1'-双(二苯基膦基)二茂铁二氯化钯1463毫克(2mmol)、磷酸钾3.18克(15mmol)置于反应瓶中，加入50毫升甲苯/水(10：1，v/v)，氮气保护，加热搅拌至反应完毕。蒸干溶剂，所得固体柱层析纯化得产品1.6克，产率75％。MS:215[M+H] +。
中间体6/7. 2-甲氧基-6-甲基-4-(甲基磺酰基)苯胺、2-甲氧基-6-甲基-4-(乙基磺酰基)苯胺的制备
Figure PCTCN2020080203-appb-000021
将(4-溴-2-甲氧基-6-甲基苯胺)1.1克(5mmol)、甲基亚磺酸钠520毫克(5mmol)、碘化亚铜95毫克(0.5mmol)、L-脯氨酸钠69毫克(0.5mmol)置于反应瓶中，加入5毫升二甲基亚砜，氮气保护，加热搅拌至反应完毕。加入25毫升水稀释后，乙酸乙酯萃取，有机相旋干，所得固体柱层析纯化得产品700毫克，产率63％。MS:216[M+H] +。
2-甲氧基-6-甲基-4-(乙基磺酰基)苯胺的制备采用相同的方法，不同之处在于用等当量的乙基亚磺酸钠替代甲基亚磺酸钠进行反应。
中间体8. 3-(4-(4-氨基-3-甲氧基-5-甲基苯基)哌嗪-1-基)-3-氧代丙腈的制备
Figure PCTCN2020080203-appb-000022
步骤1)：N,N-二苄基-4-溴-2-甲氧基-6-甲基苯胺的制备
将4-溴-2-甲氧基-6-甲基苯胺4.32克(20mmol)、苄基氯2.53克(20mmol)、碳酸钾5.52克(40mmol)置于反应瓶中，加入20毫升N,N-二甲基甲酰胺，加热搅拌至反应完毕。加入100毫升水稀释后，乙酸乙酯萃取，有机相旋干，所得固体柱层析纯化得产品5.9克，产率75％。MS:396[M+H] +。
步骤2)叔-丁基4-(4-(二苄基氨基)-3-甲氧基-5-甲基苯基)哌嗪-1-甲酸酯的制备
将步骤1)的产品(N,N-二苄基-4-溴-2-甲氧基-6-甲基苯胺)3.96克(10mmol)、叔-丁基-哌嗪-1-甲酸酯1.86克(10mmol)、三(二亚苄基丙酮)二钯916毫克(1mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯394毫克(1mmol)、磷酸钾3.18克(15mmol)置于反应瓶中，加入50毫升二氧六环，氮气保护，加热搅拌至反应完毕。蒸干溶剂，柱层析纯化得产品3.0克，产率60％。MS:502[M+H] +。
步骤3)N,N-二苄基-2-甲氧基-6-甲基-4-(哌嗪-1-基)苯胺的制备
将步骤2)所得产品(叔-丁基4-(4-(二苄基氨基)-3-甲氧基-5-甲基苯基)哌嗪-1-甲酸酯)3.0克(6mmol)置 于反应瓶中，加入12毫升二氯甲烷，3毫升三氟乙酸，搅拌至反应完毕，蒸去溶剂，得到产品2.4克，产率100％。MS:402[M+H] +。
步骤4)3-(4-(4-(二苄基氨基)-3-甲氧基-5-甲基苯基)哌嗪-1-基)-3-氧代丙腈的制备
将2-氰基乙酸425毫克(5mmol)置于反应瓶中，加入15毫升N,N-二甲基甲酰胺，随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯2281毫克(6mmol)、N,N-二异丙基乙基胺774毫克(6mmol)，搅拌0.5小时后加入步骤4)所得的产品(N,N-二苄基-2-甲氧基-6-甲基-4-(哌嗪-1-基)苯胺)2.0克(5mmol)，搅拌至反应完毕。加入75毫升水稀释后，乙酸乙酯萃取，有机相减压旋干，所得固体柱层析纯化得产品1.4克，产率60％。MS:469[M+H] +。
步骤5)：将步骤4)所得产品(3-(4-(4-(二苄基氨基)-3-甲氧基-5-甲基苯基)哌嗪-1-基)-3-氧代丙腈)1.4克(3mmol)、含水钯碳0.2克置于反应瓶中，加入10毫升甲醇，催化氢化至反应完毕。过滤，滤液蒸干得产品800毫克，产率92％。MS:289[M+H] +。
中间体9. 2-环丙基-6-甲氧基苯胺的制备
Figure PCTCN2020080203-appb-000023
将2-溴-6-甲氧基苯胺2.02克(10mmol)、环丙基硼酸0.86克(10mmol)、醋酸钯224毫克(1mmol)、三环己基膦280毫克(1mmol)、磷酸钾3.18克(15mmol)置于反应瓶中，加入20毫升甲苯/水(1：1，v/v)，氮气保护，加热搅拌至反应完毕。蒸干溶剂，所得固体柱层析纯化得产品1.3克，产率80％。MS:164[M+H] +。
中间体10. 4-乙基-6-甲基嘧啶-5-胺的制备
Figure PCTCN2020080203-appb-000024
步骤1)4-氯-6-乙烯基嘧啶-5-胺的制备
将4,6-二氯嘧啶-5-胺4.0克(24.4mmol)、乙烯基硼酸频哪醇酯4.2克(24.4mmol)、三(二亚苄基丙酮)二钯2.2克(2.4mmol)、三环己基膦684毫克(2.4mmol)、磷酸钾7.7克(36.6mmol)置于反应瓶中，加入100毫升二氧六环/水(1：1，v/v)，氮气保护，加热搅拌至反应完毕。减压浓缩，乙酸乙酯萃取，有机相旋干，柱层析纯化得产品900毫克，产率23％。MS:156[M+H] +。
步骤2)4-甲基-6-乙烯基嘧啶-5-胺的制备
将步骤1)所得产品(4-氯-6-乙烯基嘧啶-5-胺)450毫克(2.9mmol)、甲基硼酸174毫克(2.9mmol)、醋酸钯67毫克(0.3mmol)、三环己基膦84毫克(0.3mmol)、磷酸钾955毫克(4.5mmol)置于反应瓶中，加入10毫升甲苯/水(1：1，v/v)，氮气保护，加热搅拌至反应完毕。蒸干溶剂，所得固体柱层析纯化得产品270毫克，产率69％。MS:136[M+H] +。
步骤3)：将步骤2)所得产品(4-甲基-6-乙烯基嘧啶-5-胺)270毫克(2mmol)、含水钯碳27毫克置于反应瓶中，加入5毫升甲醇，催化氢化至反应完毕。过滤，滤液蒸干得产品185毫克，产率67％。MS:138[M+H] +。
中间体11. 4-环丙基-6-乙基嘧啶-5-胺的制备
Figure PCTCN2020080203-appb-000025
中间体11的制备参考中间体10的制备方法，其中步骤2)中以等摩尔当量的环丙基硼酸替代甲基硼酸。
中间体12. 5-甲氧基-N 1,N 1,3-三甲基苯-1,2-二胺的制备
Figure PCTCN2020080203-appb-000026
步骤1)1-氟-5-甲氧基-3-甲基-2-硝基苯的制备
将1-氟-3-甲氧基-5-甲基苯3.5克(25mmol)置于反应瓶中，加入15毫升乙酸，滴加70％硝酸3.2克(35mmol)，搅拌至反应完毕，加入100毫升水，乙酸乙酯萃取，有机相旋干，柱层析纯化得产品2.5克，产率54％。MS:186[M+H] +。
步骤2)5-甲氧基-N,N,3-三甲基-2-硝基苯胺的制备
将步骤1)所得产品(1-氟-5-甲氧基-3-甲基-2-硝基苯)500毫克(2.7mmol)、二甲胺的四氢呋喃溶液(2M)2毫升(4mmol)、碳酸钾559毫克(4mmol)置于反应瓶中，加入2毫升N,N-二甲基甲酰胺，加热搅拌至反应完毕。蒸干溶剂，所得固体柱层析纯化得产品284毫克，产率50％。MS:211[M+H] +。
步骤3)：将步骤2)所得产品(5-甲氧基-N,N,3-三甲基-2-硝基苯胺)280毫克(1.3mmol)、雷尼镍280毫克置于反应瓶中，加入5毫升甲醇，催化氢化至反应完毕。过滤，滤液蒸干得产品220毫克，产率91％。MS:181[M+H] +。
中间体13. 4-甲氧基-2-甲基-6-苯氧基苯胺
Figure PCTCN2020080203-appb-000027
中间体13的制备参考中间体12的制备方法，其中步骤2)中以等摩尔当量的苯酚替代二甲胺的四氢呋喃溶液。
中间体14. 4-环丙基-6-甲氧基嘧啶-5-胺的制备
Figure PCTCN2020080203-appb-000028
将4-氯-6-甲氧基嘧啶-5-胺1.1克(6.9mmol)、环丙基硼酸592毫克(6.9mmol)、1,1'-双(二苯基膦基)二茂铁二氯化钯512毫克(0.7mmol)、磷酸钾2.2克(10.3mmol)置于反应瓶中，加入20毫升甲苯/水 (10：1，v/v)，氮气保护，加热搅拌至反应完毕。蒸干溶剂，所得固体柱层析纯化得产品170毫克，产率35％。MS:166[M+H] +。
中间体15. 4-氨基-3-甲氧基-N,5-二甲基苯磺酰胺的合成
Figure PCTCN2020080203-appb-000029
步骤1)叔-丁基(4-溴-2-甲氧基-6-甲基苯基)氨基甲酸酯的制备
将4-溴-2-甲氧基-6-甲基苯胺2.16克(10mmol)、二碳酸二叔丁酯2.18克(10mmol)置于反应瓶中，加入20毫升叔丁醇，加热搅拌至反应完毕，蒸干溶剂，柱层析纯化得产品2.53克，产率80％。MS:316[M+H] +。
步骤2)叔-丁基(2-甲氧基-4-((4-甲氧基苄基)硫基)-6-甲基苯基)氨基甲酸酯的制备
将步骤1)所得产品(叔-丁基(4-溴-2-甲氧基-6-甲基苯基)氨基甲酸酯)632毫克(2mmol)、4-甲氧基苄基硫醇308毫克(2mmol)、三(二亚苄基丙酮)二钯183毫克(0.2mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽116毫克(0.2mmol)、二异丙基乙基胺516毫克(4mmol)置于反应瓶中，加入10毫升二氧六环，氮气保护，加热搅拌至反应完毕。减压浓缩，乙酸乙酯萃取，有机相旋干，柱层析纯化得产品584毫克，产率75％。MS:390[M+H] +。
步骤3)叔-丁基(4-(氯磺酰基)-2-甲氧基-6-甲基苯基)氨基甲酸酯的制备
将步骤2)所得的产品(叔-丁基(2-甲氧基-4-((4-甲氧基苄基)硫)-6-甲基苯基)氨基甲酸酯)390毫克(1mmol)、二氯二甲基海因197毫克(1mmol)置于反应瓶中，加入5毫升乙腈，搅拌至反应完毕，蒸干溶剂，柱层析纯化得产品202毫克，产率60％。MS:336[M+H] +。
步骤4)叔-丁基(2-甲氧基-6-甲基-4-(N-甲基磺酰基)苯基)氨基甲酸酯的制备
将步骤3)所得的产品(叔-丁基(4-(氯磺酰基)-2-甲氧基-6-甲基苯基)氨基甲酸酯)336毫克(1mmol)、甲胺盐酸盐68毫克(1mmol)、氢氧化钾112毫克(2mmol)置于反应瓶中，加入5毫升二氯甲烷，搅拌至反应完毕，蒸干溶剂，柱层析纯化得产品231毫克，产率70％。MS:331[M+H] +。
步骤5)：将步骤4)所得产品(叔-丁基(2-甲氧基-6-甲基-4-(N-甲基磺酰基)苯基)氨基甲酸酯)231毫克(0.7mmol)置于反应瓶中，加入4毫升二氯甲烷，1毫升三氟乙酸，搅拌至反应完毕，蒸去溶剂，得到产品160毫克，产率100％。MS:231[M+H] +。
中间体16. 4-氨基-N-(2-羟基乙基)-3-甲氧基-5-甲基苯磺酰胺的制备
Figure PCTCN2020080203-appb-000030
中间体16的制备参照中间体15的制备，其中步骤4)中以等摩尔当量的2-氨基乙-1-醇替代甲胺盐酸 盐。
实施例
实施例1.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环丙基氨基)嘧啶-5-甲酰胺
Figure PCTCN2020080203-appb-000031
步骤1)2-氯-4-(环丙基氨基)嘧啶-5-甲酰胺的制备
将环丙胺570毫克(10mmol)、2,4-二氯嘧啶-5-甲酰胺1910毫克(10mmol)、置于反应瓶中，加入10毫升四氢呋喃，二异丙基乙基胺2580毫克(20mmol)，搅拌至反应完毕，加入200毫升水、抽滤得产品1484毫克，产率70％。MS:213[M+H] +。
步骤2)叔-丁基(R)-3-(4-((5-氨基甲酰-4-(环丙基氨基)嘧啶-2-基)氨基)-1H-吡唑-1-基)哌啶-1-羧酸酯的制备
将步骤1)所得产品(2-氯-4-(环丙基氨基)嘧啶-5-甲酰胺)212毫克(1mmol)、叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯(制备方法参考WO 2014139465)266毫克(1mmol)置于反应瓶中，加入2毫升仲丁醇，随后滴入0.05毫升三氟乙酸，加热搅拌至反应完毕。加入5毫升水稀释后，加入饱和碳酸氢钠水溶液调节反应体系至中性，抽滤，所得固体柱层析纯化得产品221毫克，产率50％。MS:443[M+H] +。
步骤3)(R)-4-(环丙基氨基)-2-((1-(哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备
将步骤2)所得产品(叔-丁基(R)-3-(4-((5-氨基甲酰-4-(环丙基氨基)嘧啶-2-基)氨基)-1H-吡唑-1-基)哌啶-1-羧酸酯)221毫克(0.5mmol)置于反应瓶中，加入4毫升二氯甲烷，1毫升三氟乙酸，搅拌至反应完毕，蒸去溶剂，得到产品171毫克，产率100％。MS:343[M+H] +。
步骤4)(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环丙基氨基)嘧啶-5-甲酰胺的制备
将步骤3)所得产品((R)-4-(环丙基氨基)-2-((1-(哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺)171毫克(0.5mmol)置于反应瓶中，加入4毫升四氢呋喃，滴入丙烯酰氯45毫克(0.5mmol)，搅拌至反应完毕，乙酸乙酯与碳酸钠水溶液萃取，有机相浓缩、柱层析得产品99毫克，产率50％。 1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.31(s,1H),8.46(s,1H),8.12(s,1H),8.01-7.74(m,1H),7.68(s,1H),7.33-7.02(m,1H),6.94-6.69(m,1H),6.19-5.98(m,1H),5.81-5.58(m,1H),4.67-4.23(m,1H),4.23-3.95(m,2H),3.17-2.98(m,1H),2.98-2.80(m,2H),2.20-1.91(m,2H),1.90-1.75(m,1H),1.62-1.38(m,1H),0.95-0.69(m,2H),0.61-0.42(m,2H).MS:397[M+H] +。
实施例2.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环丙基氨基)嘧啶-5-甲酰胺
Figure PCTCN2020080203-appb-000032
步骤1)2-氯-4-(环丙基氨基)嘧啶-5-甲酰胺的制备
将环丙胺570毫克(10mmol)、2,4-二氯嘧啶-5-甲酰胺1910毫克(10mmol)、置于反应瓶中，加入10毫升四氢呋喃，二异丙基乙基胺2580毫克(20mmol)，搅拌至反应完毕，加入200毫升水、抽滤得产品1484毫克，产率70％。MS:213[M+H] +。
步骤2)叔-丁基(S)-3-(4-((5-氨基甲酰-4-(环丙基氨基)嘧啶-2-基)氨基)-1H-吡唑-1-基)哌啶-1-羧酸酯的制备
将步骤1)所得产品(2-氯-4-(环丙基氨基)嘧啶-5-甲酰胺)212毫克(1mmol)、叔-丁基(S)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯(制备方法参考WO 2014139465)266毫克(1mmol)置于反应瓶中，加入2毫升仲丁醇，随后滴入0.05毫升三氟乙酸，加热搅拌至反应完毕。加入5毫升水稀释后，加入饱和碳酸氢钠水溶液调节反应体系至中性，抽滤，所得固体柱层析纯化得产品221毫克，产率50％。MS:443[M+H] +。
步骤3)(S)-4-(环丙基氨基)-2-((1-(哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备
将步骤2)所得产品(叔-丁基(S)-3-(4-((5-氨基甲酰-4-(环丙基氨基)嘧啶-2-基)氨基)-1H-吡唑-1-基)哌啶-1-羧酸酯)221毫克(0.5mmol)置于反应瓶中，加入4毫升二氯甲烷，1毫升三氟乙酸，搅拌至反应完毕，蒸去溶剂，得到产品171毫克，产率100％。MS:343[M+H] +。
步骤4)(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环丙基氨基)嘧啶-5-甲酰胺的制备
将步骤3)所得产品((S)-4-(环丙基氨基)-2-((1-(哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺)171毫克(0.5mmol)置于反应瓶中，加入4毫升四氢呋喃，滴入丙烯酰氯45毫克(0.5mmol)，搅拌至反应完毕，乙酸乙酯与碳酸钠水溶液萃取，有机相浓缩、柱层析得产品99毫克，产率50％。 1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.19(s,1H),8.46(s,1H),8.12(s,1H),7.74-7.66(m,2H),7.21-6.94(m,1H),6.93-6.71(m,1H),6.21-6.00(m,1H),5.74-5.60(m,1H),4.66-4.22(m,1H),4.21-3.98(m,2H),3.57-3.39(m,1H),3.16-2.93(m,1H),2.93-2.82(m,1H),2.12(s,1H),2.02(s,1H),1.86-1.76(m,1H),1.59-1.35(m,1H),0.95-0.76(m,2H),0.58-0.48(m,2H).MS:397[M+H] +。
实施例3.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(邻-甲苯基氨基)嘧啶-5-甲酰胺
实施例3的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的邻甲苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.42-11.06(m,1H),9.67-9.43(m,1H),8.78-8.61(m,1H),8.46-8.12(m,1H),8.11-7.83(m,1H),7.73-7.54(m,1H),7.51-7.41(m,1H),7.39-7.30(m,2H),7.30-7.08(m,2H),7.06-6.69(m,1H),6.21-6.05(m,1H),5.76-5.63(m,1H),4.61-4.20(m,1H),4.19-3.77(m,2H),3.11-2.70(m,1H),2.36-2.10(m,4H),2.09-1.68(m,3H),1.57-1.42(m,1H).MS:447[M+H] +。
Figure PCTCN2020080203-appb-000033
实施例4.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(邻-甲苯基氨基)嘧啶-5-甲酰胺
实施例4的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的邻甲苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.40-11.00(m,1H),9.65-9.45(m,1H),8.78-8.65(m,1H),8.48-7.74(m,2H),7.74-7.53(m,1H),7.53-7.41(m,1H),7.41-7.18(m,3H),7.18-6.94(m,1H),6.92-6.69(m,1H),6.24-6.00(m,1H),5.76-5.60(m,1H),4.60-4.25(m,1H),4.17-3.75(m,2H),3.29-2.96(m,1H),2.92-2.62(m,1H),2.46-2.14(m,3H),2.14-1.69(m,3H),1.60-1.36(m,1H).MS:447[M+H] +。
实施例5.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氟苯基)氨基)嘧啶-5-甲酰胺
实施例5的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.79-11.43(m,1H),9.64(s,1H),8.75(s,1H),8.67(s,1H),8.12-7.91(m,2H),7.59(s,1H),7.40(s,1H),7.38-7.15(m,3H),6.91-6.71(m,1H),6.20-6.03(m,1H),5.74-5.62(m,1H),4.61-3.86(m,3H),3.19-2.98(m,1H),2.96-2.77(m,1H),2.19-1.72(m,3H),1.58-1.41(m,1H).MS:451[M+H] +。
Figure PCTCN2020080203-appb-000034
实施例6.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氟苯基)氨基)嘧啶-5-甲酰胺
实施例6的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.79-11.43(m,1H),9.66(s,1H),8.76(s,1H),8.70-7.75(m,3H),7.60(s,1H),7.45-7.03(m,4H),6.91-6.69(m,1H),6.22-6.02(m,1H),5.76-5.61(m,1H),4.57-3.85(m,3H),3.21-2.96(m,1H),2.96-2.75(m,1H),2.22-1.70(m,3H),1.58-1.39(m,1H).MS:451[M+H] +。
实施例7.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环己基氨基)嘧啶-5-甲酰胺
实施例7的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环己基胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.24(s,1H),8.45(s,1H),7.87(s,1H),7.79-7.47(m,2H),7.04(s,1H),6.89-6.74(m,1H),6.10(t,J＝17.5Hz,1H),5.78-5.59(m,1H),4.69-4.22(m,1H),4.19-3.85(m,3H),3.00-2.82(m,1H),2.20-2.10(m,1H),2.09-1.90(m,3H),1.86-1.76(m,1H),1.75-1.65(m,2H),1.62-1.48(m,2H),1.48-1.36(m,2H),1.36-1.13(m,4H).MS:439[M+H] +。
Figure PCTCN2020080203-appb-000035
实施例8.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环己基氨基)嘧啶-5-甲酰胺
实施例8的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环己基胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.25(s,1H),8.46(s,1H),7.88(s,1H),7.82-7.45(m,2H),7.04(s,1H),6.90-6.72(m,1H),6.11(t,J＝17.5Hz,1H),5.78-5.59(m,1H),4.70-3.88(m,4H),3.58-3.06(m,1H),3.04-2.83(m,1H),2.24-1.87(m,4H),1.87-1.55(m,4H),1.55-1.07(m,6H).MS:439[M+H] +。
实施例9.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(苯基氨基)嘧啶-5-甲酰胺
实施例9的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.54-11.41(m,1H),9.59(s,1H),8.75-8.65(m,1H),8.14-7.64(m,3H),7.64-7.28(m,5H),7.19-7.01(m,1H),6.91-6.70(m,1H),6.18-6.05(m,1H),5.76-5.61(m,1H),4.63-3.89(m,3H),3.24-2.75(m,2H),2.16-1.70(m,3H),1.58-1.39(m,1H).MS:433[M+H] +。
Figure PCTCN2020080203-appb-000036
实施例10.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(苯基氨基)嘧啶-5-甲酰胺
实施例10的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.64-11.38(m,1H),9.74-9.55(m,1H),8.78-8.56(m,1H),8.16-7.65(m,3H),7.62-7.32(m,5H),7.23-7.03(m,1H),6.99-6.70(m,1H),6.20-6.04(m,1H),5.77-5.58(m,1H),4.65-4.22(m,1H),4.22-3.92(m,2H),3.41-2.78(m,2H),2.17-1.72(m,3H),1.59-1.40(m,1H).MS:433[M+H] +。
实施例11.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-氟苯基)氨基)嘧啶-5-甲酰胺
实施例11的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.84-11.58(m,1H),9.80-9.52(m,1H),8.81-8.61(m,1H),8.22-7.92(m,2H),7.86-7.29(m,4H),7.30-7.18(m,1H),6.99-6.68(m,2H),6.21-6.01(m,1H),5.79-5.58(m,1H),4.67-3.90(m,3H),3.23-2.98(m,1H),2.98-2.74(m,1H),2.17-1.73(m,3H),1.59-1.39(m,1H).MS:451[M+H] +。
Figure PCTCN2020080203-appb-000037
实施例12.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-氟苯基)氨基)嘧啶-5-甲酰胺
实施例12的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.81-11.62(m,1H),9.77-9.58(m,1H),8.80-8.62(m,1H),8.24-7.87(m,2H),7.86-7.48(m,2H),7.48-7.19(m,3H),6.98-6.69(m,2H),6.20-6.02(m,1H),5.76-5.60(m,1H),4.60-3.98(m,3H),3.21-2.98(m,1H),2.97-2.71(m,1H),2.14-1.76(m,3H),1.59-1.39(m,1H).MS:451[M+H] +。
实施例13.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氟苯基)氨基)嘧啶-5-甲酰胺
实施例13的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.59-11.20(m,1H),9.68-9.50(m,1H),8.77-8.60(m,1H),7.98(s,1H),7.80(s,1H),7.71-7.31(m,4H),7.30-7.12(m,2H),6.92-6.71(m,1H),6.19-6.02(m,1H),5.74-5.60(m,1H),4.63-3.82(m,3H),3.22-2.95(m,1H),2.96-2.73(m,1H),2.17-1.68(m,3H),1.58-1.40(m,1H).MS:451[M+H] +。
Figure PCTCN2020080203-appb-000038
实施例14.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氟苯基)氨基)嘧啶-5-甲酰胺
实施例14的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.56-11.20(m,1H),9.66-9.55(m,1H),8.74-8.57(m,1H),8.02-7.77(m,2H),7.65-7.47(m,3H),7.45-7.37(m,1H),7.30-7.13(m,2H),6.92-6.70(m,1H),6.21-6.01(m,1H),5.78-5.59(m,1H),4.74-3.83(m,3H),3.21-2.96(m,1H),2.89-2.76(m,1H),2.08-1.97(m,1H),1.86-1.69(m,2H),1.54-1.42(m,1H).MS:451[M+H] +。
实施例15.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氯苯基)氨基)嘧啶-5-甲酰胺
实施例15的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氯苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.71-11.35(m,1H),9.74-9.57(m,1H),8.78-8.62(m,1H),8.14-7.78(m,2H),7.72-7.29(m,6H),6.96-6.71(m,1H),6.27-6.00(m,1H),5.78-5.58(m,1H),4.68-3.86(m,3H),3.24-2.97(m,1H),2.96-2.75(m,1H),2.18-1.71(m,3H),1.59-1.41(m,1H).MS:467[M+H] +。
Figure PCTCN2020080203-appb-000039
实施例16.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氯苯基)氨基)嘧啶-5-甲酰胺
实施例16的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氯苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.69-11.38(m,1H),9.79-9.56(m,1H),8.77-8.61(m,1H),8.10-7.81(m,2H),7.69-7.47(m,3H),7.47-7.36(m,3H),6.91-6.72(m,1H),6.23-6.02(m,1H),5.77-5.61(m,1H),4.57-4.01(m,3H),3.17-3.00(m,1H),2.95-2.77(m,1H),2.14-1.76(m,3H),1.60-1.40(m,1H).MS:467[M+H] +。
实施例17.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-氯苯基)氨基)嘧啶-5-甲酰胺
实施例17的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-氯苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.77-11.55(m,1H),9.67(s,1H),8.79-8.63(m,1H),8.35-7.83(m,2H),7.81-7.67(m,1H),7.65-7.52(m,1H),7.51-7.44(m,1H),7.43-7.30(m,2H),7.22-7.06(m,1H),6.91-6.66(m,1H),6.18-6.02(m,1H),5.76-5.59(m,1H),4.64-3.93(m,3H),3.27-2.97(m,1H),2.96-2.73(m,1H),2.16-1.74(m,3H),1.59-1.38(m,1H).MS:467[M+H] +。
Figure PCTCN2020080203-appb-000040
实施例18.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-氯苯基)氨基)嘧啶-5-甲酰胺
实施例18的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-氯苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.76-11.56(m,1H),9.67(s,1H),8.79-8.62(m,1H),8.02(s,2H),7.82-7.70(m,1H),7.69-7.56(m,1H),7.53-7.31(m,3H),7.20-7.07(m,1H),6.90-6.68(m,1H),6.20-6.03(m,1H),5.76-5.58(m,1H),4.65-3.96(m,3H),3.22-2.95(m,1H),2.95-2.75(m,1H),2.21-1.71(m,3H),1.60-1.38(m,1H).MS:467[M+H] +。
实施例19.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,4-二氟苯基)氨基)嘧啶-5-甲酰胺实施例19的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,4- 二氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.78-11.10(m,1H),9.78-9.61(m,1H),8.75-8.66(m,1H),8.19-7.79(m,2H),7.79-7.43(m,2H),7.43-7.24(m,2H),7.23-7.03(m,1H),6.93-6.70(m,1H),6.24-6.01(m,1H),5.76-5.60(m,1H),4.58-3.84(m,3H),3.23-2.97(m,1H),2.96-2.72(m,1H),2.14-1.71(m,3H),1.57-1.40(m,1H).MS:469[M+H] +。
Figure PCTCN2020080203-appb-000041
实施例20.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,4-二氟苯基)氨基)嘧啶-5-甲酰胺实施例20的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,4-二氟苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.72-11.10(m,1H),9.73-9.62(m,1H),8.75-8.65(m,1H),8.10-7.78(m,2H),7.62-7.42(m,2H),7.42-7.22(m,2H),7.21-7.03(m,1H),6.91-6.71(m,1H),6.21-6.03(m,1H),5.75-5.62(m,1H),4.60-3.83(m,3H),3.23-2.97(m,1H),2.96-2.69(m,1H),2.15-1.76(m,3H),1.56-1.37(m,1H).MS:469[M+H] +。
实施例21.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环戊基氨基)嘧啶-5-甲酰胺
实施例21的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环戊胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.28-9.03(m,1H),8.45(s,1H),7.95(s,1H),7.88-7.62(m,1H),7.59(s,1H),7.29-6.92(m,1H),6.91-6.71(m,1H),6.23-6.00(m,1H),5.79-5.58(m,1H),4.69-4.21(m,2H),4.21-3.96(m,2H),3.55-3.34(m,1H),3.11-2.87(m,1H),2.27-2.10(m,1H),2.09-1.91(m,3H),1.88-1.76(m,1H),1.75-1.66(m,2H),1.65-1.55(m,2H),1.54-1.31(m,3H).MS:425[M+H] +。
Figure PCTCN2020080203-appb-000042
实施例22.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环戊基氨基)嘧啶-5-甲酰胺
实施例22的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环戊胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.30-9.02(m,1H),8.45(s,1H),7.95(s,1H),7.87-7.52(m,2H),7.23-6.93(m,1H),6.90-6.74(m,1H),6.17-6.01(m,1H),5.75-5.62(m,1H),4.69-4.21(m,2H),4.21-3.99(m,2H),3.53-3.34(m,1H),3.12-2.89(m,1H),2.22-2.04(m,2H),2.03-1.91(m,2H),1.87-1.75(m,1H),1.75-1.67(m,2H),1.66-1.57(m,2H),1.55-1.41(m,3H).MS:425[M+H] +。
实施例23.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环庚基氨基)嘧啶-5-甲酰胺
实施例23的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环 庚胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.34-9.06(m,1H),8.44(s,1H),7.98-7.86(m,1H),7.85-7.48(m,2H),7.44-6.93(m,1H),6.89-6.75(m,1H),6.10(t,J＝18.1Hz,1H),5.77-5.61(m,1H),4.65-4.22(m,1H),4.17-4.01(m,2H),3.54-3.34(m,1H),3.32-2.99(m,1H),2.99-2.79(m,1H),2.21-2.09(m,1H),2.09-2.00(m,1H),1.99-1.86(m,2H),1.86-1.78(m,1H),1.64-1.46(m,11H).MS:453[M+H] +。
Figure PCTCN2020080203-appb-000043
实施例24.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环庚基氨基)嘧啶-5-甲酰胺
实施例24的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环庚胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.35-9.04(m,1H),8.54-8.40(m,1H),7.90(s,1H),7.83-7.62(m,1H),7.61-7.49(m,1H),7.20-6.93(m,1H),6.90-6.74(m,1H),6.17-6.02(m,1H),5.72-5.61(m,1H),4.68-4.22(m,1H),4.16-3.93(m,2H),3.55-3.34(m,1H),3.12-2.86(m,1H),2.20-2.09(m,1H),2.09-1.99(m,1H),1.98-1.86(m,2H),1.86-1.75(m,1H),1.70-1.41(m,12H).MS:453[M+H] +。
实施例25.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基苯基)氨基)嘧啶-5-甲酰胺实施例25的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.73-11.32(m,1H),9.56(s,1H),8.79-8.62(m,1H),8.12-7.96(m,1H),7.95-7.76(m,1H),7.75-7.54(m,1H),7.44(s,1H),7.30-7.13(m,1H),7.12-7.00(m,2H),7.00-6.91(m,1H),6.91-6.70(m,1H),6.18-6.04(m,1H),5.76-5.61(m,1H),4.61-3.95(m,3H),3.84(s,3H),3.31-2.97(m,1H),2.96-2.76(m,1H),2.14-1.74(m,3H),1.59-1.38(m,1H).MS:463[M+H] +。
Figure PCTCN2020080203-appb-000044
实施例26.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基苯基)氨基)嘧啶-5-甲酰胺实施例26的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.76-11.31(m,1H),9.56(s,1H),8.82-8.62(m,1H),8.10-7.96(m,1H),7.96-7.77(m,1H),7.76-7.54(m,1H),7.54-7.31(m,1H),7.31-7.10(m,1H),7.10-6.91(m,3H),6.90-6.71(m,1H),6.24-6.03(m,1H),5.78-5.60(m,1H),4.64-3.94(m,3H),3.84(s,3H),3.19-2.96(m,1H),2.96-2.75(m,1H),2.17-1.71(m,3H),1.58-1.37(m,1H).MS:463[M+H] +。
实施例27.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-5-甲酰胺
实施例27的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,3-二氢苯并[b][1,4]二噁英-6-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.40-11.11(m,1H),9.67-9.44(m,1H),8.74-8.54(m,1H),8.07-7.89(m,1H),7.80-7.58(m,1H),7.57-7.26(m,2H),7.13(s,1H),7.00-6.69(m,3H),6.21-6.02(m,1H),5.75-5.59(m,1H),4.61-4.20(m,4H),4.17-3.86(m,2H),3.55-3.34(m,1H),3.32-2.99(m,1H),2.98-2.78(m,1H),2.18-1.74(m,3H),1.64-1.38(m,1H).MS:491[M+H] +。
Figure PCTCN2020080203-appb-000045
实施例28.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-5-甲酰胺
实施例28的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,3-二氢苯并[b][1,4]二噁英-6-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.43-11.10(m,1H),9.66-9.47(m,1H),8.72-8.55(m,1H),8.03-7.84(m,1H),7.80-7.09(m,4H),7.00-6.69(m,3H),6.18-6.03(m,1H),5.77-5.53(m,1H),4.61-4.16(m,6H),4.05-3.89(m,1H),3.18-2.94(m,1H),2.94-2.79(m,1H),2.12-1.75(m,3H),1.59-1.38(m,1H).MS:491[M+H] +。
实施例29.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-甲氧基丙基)氨基)嘧啶-5-甲酰胺
实施例29的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-甲氧基丙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.56-9.27(m,1H),9.26-8.97(m,1H),8.55-8.39(m,1H),8.01-7.78(m,1H),7.77-7.31(m,2H),7.26-6.92(m,1H),6.90-6.73(m,1H),6.19-6.01(m,1H),5.75-5.59(m,1H),4.67-3.96(m,3H),3.63-3.44(m,2H),3.40(t,J＝6.1Hz,2H),3.22(s,3H),3.20-3.00(m,1H),2.99-2.84(m,1H),2.22-1.93(m,2H),1.93-1.71(m,3H),1.57-1.43(m,1H).MS:429[M+H] +。
Figure PCTCN2020080203-appb-000046
实施例30.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-甲氧基丙基)氨基)嘧啶-5-甲酰胺
实施例30的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-甲氧基丙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.27-8.99(m,1H),8.45(s,1H),8.01-7.89(m,1H),7.87-7.61(m,1H),7.57(s,1H),7.25-6.93(m,1H),6.91-6.75(m,1H),6.17-6.03(m,1H),5.75-5.60(m,1H),4.67-3.98(m,3H),3.61-3.45(m,2H),3.45-3.41(m,1H),3.40-3.38(m,1H),3.22(s,3H),3.16-2.99(m,1H),2.99-2.83(m,1H),2.21-1.95(m,2H),1.87-1.73(m,3H),1.60-1.45(m,1H).MS:429[M+H] +。
实施例31.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙基苯基)氨基)嘧啶-5-甲酰胺
实施例31的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.45-11.09(m,1H),9.71-9.41(m,1H),8.77-8.56(m,1H),8.35-7.59(m,2H),7.59-7.20(m,5H),7.20-6.99(m,1H),6.93-6.66(m,1H),6.23-6.04(m,1H),5.79-5.61(m,1H),4.60-3.75(m,3H),3.31-2.96(m,1H),2.95-2.65(m,1H),2.65-2.54(m,2H),2.17-1.66(m,3H),1.58-1.38(m,1H),1.20-1.07(m,3H).MS:461[M+H] +。
Figure PCTCN2020080203-appb-000047
实施例32.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙基苯基)氨基)嘧啶-5-甲酰胺
实施例32的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.44-11.13(m,1H),9.61-9345(m,1H),8.75-8.62(m,1H),7.97(s,1H),7.68-7.55(m,1H),7.46-7.39(m,1H),7.38-7.19(m,4H),7.17(t,J＝7.4Hz,1H),6.91-6.69(m,1H),6.20-6.06(m,1H),5.74-5.64(m,1H),4.57-4.03(m,2H),3.90-3.80(m,1H),3.16-2.95(m,1H),2.87-2.69(m,1H),2.68-2.55(m,2H),1.91(s,1H),1.86-1.70(m,2H),1.55-1.43(m,1H),1.13(t,J＝7.5Hz,3H).MS:461[M+H] +。
实施例33.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)嘧啶-5-甲酰胺
实施例33的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,3-二氢苯并[b][1,4]二噁英-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.72-11.18(m,1H),9.56(s,1H),8.79-8.56(m,1H),8.48-7.97(m,1H),7.97-7.81(m,1H),7.79-7.57(m,1H),7.56-7.42(m,1H),7.25(s,1H),6.93-6.70(m,2H),6.68-6.51(m,1H),6.27-6.00(m,1H),5.78-5.58(m,1H),4.65-4.27(m,3H),4.27-4.08(m,3H),4.08-3.90(m,1H),3.21-2.92(m,1H),2.91-2.74(m,1H),2.18-1.69(m,3H),1.57-1.41(m,1H).MS:491[M+H] +。
Figure PCTCN2020080203-appb-000048
实施例34.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)嘧啶-5-甲酰胺
实施例34的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,3- 二氢苯并[b][1,4]二噁英-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.56-11.28(m,1H),9.56(s,1H),8.72-8.62(m,1H),8.10-7.91(m,1H),7.74(s,1H),7.64-7.51(m,1H),7.45(s,1H),7.25(s,1H),6.90-6.72(m,2H),6.67-6.55(m,1H),6.18-6.05(m,1H),5.74-5.63(m,1H),4.39-4.11(m,6H),4.09-3.96(m,1H),3.20-3.00(m,1H),2.96-2.78(m,1H),2.16-1.99(m,2H),1.94-1.75(m,2H).MS:491[M+H] +。
实施例35.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((环己基甲基)氨基)嘧啶-5-甲酰胺
实施例35的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环己基甲胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.40-9.05(m,1H),8.45(s,1H),7.99-7.89(m,1H),7.86-7.65(m,1H),7.57(s,1H),7.27-6.92(m,1H),6.91-6.74(m,1H),6.18-6.01(m,1H),5.75-5.59(m,1H),4.65-3.99(m,3H),3.58-3.35(m,1H),3.28-3.05(m,1H),3.03-2.82(m,1H),2.21-2.11(m,1H),2.09-1.94(m,1H),1.90-1.74(m,2H),1.74-1.69(m,2H),1.69-1.60(m,3H),1.59-1.34(m,2H),1.26-1.11(m,3H),1.04-0.93(m,2H).MS:453[M+H] +。
Figure PCTCN2020080203-appb-000049
实施例36.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((环己基甲基)氨基)嘧啶-5-甲酰胺
实施例36的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环己基甲胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.35-9.06(m,1H),8.54-8.41(m,1H),8.00-7.89(m,1H),7.87-7.50(m,2H),7.26-6.75(m,2H),6.20-6.02(m,1H),5.77-5.54(m,1H),4.68-3.98(m,3H),3.55-3.36(m,1H),3.29-3.03(m,1H),3.02-2.80(m,1H),2.20-1.89(m,2H),1.88-1.78(m,1H),1.78-1.74(m,1H),1.74-1.69(m,2H),1.69-1.66(m,1H),1.66-1.59(m,2H),1.59-1.41(m,2H),1.28-1.07(m,3H),1.05-0.90(m,2H).MS:453[M+H] +。
实施例37.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环丁基氨基)嘧啶-5-甲酰胺
实施例37的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环丁基胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.44(s,1H),8.46(s,1H),7.99(s,1H),7.91-7.70(m,1H),7.60(s,1H),7.25-7.08(m,1H),6.87-6.77(m,1H),6.16-6.05(m,1H),5.72-5.64(m,1H),4.57-4.50(m,1H),4.22-4.16(m,1H),4.08-4.00(m,1H),3.55-3.48(m,1H),3.18-3.07(m,1H),3.04-2.87(m,1H),2.39-2.33(m,2H),2.23-2.16(m,1H),2.09-2.01(m,1H),1.96-1.90(m,2H),1.83-1.74(m,3H),1.58-1.50(m,1H).MS:411[M+H] +。
Figure PCTCN2020080203-appb-000050
实施例38.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(环丁基氨基)嘧啶-5-甲酰胺
实施例38的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环丁基胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.38-9.15(m,1H),8.53-8.42(m,1H),7.98(s,1H),7.74(s,1H),7.58(s,1H),7.08(s,1H),6.89-6.77(m,1H),6.17-6.03(m,1H),5.75-5.63(m,1H),4.73-4.50(m,2H),4.28-4.02(m,3H),3.02-2.87(m,1H),2.45-2.29(m,3H),2.24-2.02(m,2H),1.94-1.71(m,5H).MS:411[M+H] +。
实施例39.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙炔基苯基)氨基)嘧啶-5-甲酰胺
实施例39的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙炔基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.93-11.76(m,1H),9.67-9.62(m,1H),8.88-8.74(m,1H),8.69(s,1H),8.12(d,J＝6.6Hz,1H),8.03-7.96(m,1H),7.74-7.59(m,1H),7.55-7.51(m,1H),7.46(s,1H),7.44-7.38(m,1H),7.14-7.04(m,1H),6.91-6.78(m,1H),6.18-6.05(m,1H),5.73-5.64(m,1H),4.62-4.48(m,2H),4.24-4.13(m,1H),4.07-4.00(m,1H),3.08-2.82(m,1H),2.18-1.98(m,2H),1.90-1.75(m,2H),1.50(s,1H).MS:457[M+H] +。
Figure PCTCN2020080203-appb-000051
实施例40.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙炔基苯基)氨基)嘧啶-5-甲酰胺
实施例40的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙炔基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.91-11.77(m,1H),9.63(s,1H),8.75(s,1H),8.69(s,1H),8.13(d,J＝8.1Hz,1H),7.99(s,1H),7.72(s,1H),7.64-7.52(m,1H),7.50-7.37(m,2H),7.15-6.99(m,1H),6.92-6.74(m,1H),6.18-6.05(m,1H),5.73-5.63(m,1H),4.64-4.45(m,2H),4.28-4.15(m,1H),4.09-3.95(m,1H),3.07(s,1H),2.87(s,1H),2.18-2.01(m,2H),1.84-1.78(m,2H).MS:457[M+H] +。
实施例41.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氰基苯基)氨基)嘧啶-5-甲酰胺
实施例41的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氨基苯甲腈替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ12.18-11.85(m,2H),9.76-9.73(m,1H),8.73(s,1H),8.04-8.02(m,1H),7.90-7.87(m,1H),7.78-7.72(m,1H),7.54-7.51(m,1H),7.39(s,1H),7.34-7.31(m, 1H),6.90-6.82(m,1H),6.58(s,1H),6.15-6.10(m,1H),5.73-5.67(m,1H),4.63-4.49(m,1H),4.24-4.10(m,2H),2.15-2.10(m,2H),1.98-1.96(m,1H),1.82-1.80(m,2H),1.50-1.46(m,1H).MS:458[M+H] +。
Figure PCTCN2020080203-appb-000052
实施例42.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氰基苯基)氨基)嘧啶-5-甲酰胺
实施例42的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氨基苯甲腈替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ12.17-11.86(m,1H),9.75-9.69(m,1H),8.80-8.77(m,1H),8.15-7.96(m,2H),7.93-7.68(m,2H),7.64-7.42(m,2H),7.42-7.19(m,2H),6.90-6.73(m,1H),6.20-6.05(m,1H),5.75-5.64(m,1H),4.30-3.87(m,3H),3.20-2.99(m,1H),2.82(s,1H),2.13-1.97(m,1H),1.91-1.74(m,2H),1.55-1.42(m,1H).MS:458[M+H] +。
实施例43.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-三氟甲基)苯基)氨基)嘧啶-5-甲酰胺
实施例43的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-(三氟甲基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.90-11.83(m,1H),9.72(s,1H),8.79-8.70(m,1H),8.09-7.99(m,2H),7.85-7.74(m,2H),7.74-7.56(m,3H),7.52-7.46(m,1H),6.90-6.68(m,1H),6.19-6.02(m,1H),5.75-5.59(m,1H),4.61-3.98(m,3H),3.52-3.38(m,1H),3.14-2.84(m,1H),2.15-2.04(m,1H),1.99-1.63(m,2H),1.55-1.38(m,1H).MS:501[M+H] +。
Figure PCTCN2020080203-appb-000053
实施例44.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-三氟甲基)苯基)氨基)嘧啶-5-甲酰胺
实施例44的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-(三氟甲基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.89-11.84(m,1H),9.72(s,1H),8.80-8.69(m,1H),8.18-8.07(m,1H),8.06-7.94(m,2H),7.87-7.76(m,2H),7.70-7.67(m,2H),7.48(s,1H),6.85-6.81(m,1H),6.18-6.05(m,1H),5.78-5.61(m,1H),4.33-3.98(m,3H),3.55-3.48(m,1H),3.18-2.94(m,1H),2.23-2.02(m,2H),1.86-1.73(m,1H),1.55-1.43(m,1H).MS:501[M+H] +。
实施例45.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基乙基)氨基)嘧啶-5-甲酰胺
实施例45的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基乙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.25(s,1H),8.46(s,1H),7.94-7.91(m,1H),7.81-7.61(m,1H),7.56(s,1H),7.06(s,1H),6.88-6.76(m,1H),6.15-6.04(m,1H),5.72-5.64(m,1H),4.63-4.50(m,1H),4.22-4.12(m,2H),4.12-3.99(m,1H),3.65-3.62(m,1H),3.55-3.53(m,1H),3.51-3.45(m,1H),3.29(s,3H),3.16-2.86(m,2H),2.17-2.12(m,1H),2.06-1.98(m,1H),1.86-1.79(m,1H),1.57-1.48(m,1H).MS:415[M+H] +。
Figure PCTCN2020080203-appb-000054
实施例46.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基乙基)氨基)嘧啶-5-甲酰胺
实施例46的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基乙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.25(s,1H),8.46(s,1H),7.93-7.92(m,1H),7.71(s,1H),7.56(s,1H),7.06(s,1H),6.90-6.75(m,1H),6.17-6.04(m,1H),5.73-5.62(m,1H),4.60-4.01(m,3H),3.66-3.49(m,4H),3.29(s,3H),3.19-2.83(m,2H),2.18-1.98(m,2H),1.88-1.77(m,1H),1.58-1.46(m,1H).MS:415[M+H] +。
实施例47.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((环丙基甲基)氨基)嘧啶-5-甲酰胺
实施例47的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环丙基甲胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.25(s,1H),8.46(s,1H),7.97(s,1H),7.82-7.63(m,1H),7.58-7.56(m,1H),7.16-6.97(m,1H),6.86-6.78(m,1H),6.15-6.05(m,1H),5.72-5.65(m,1H),4.63(s,1H),4.21-4.13(m,2H),4.07-4.00(m,1H),3.18-3.05(m,1H),3.01-2.92(m,1H),2.18-2.13(m,1H),2.05-2.00(m,1H),1.87-1.81(m,1H),1.56-1.50(m,1H),1.24-1.18(m,1H),1.17-1.10(m,1H),0.49-0.47(d,J＝7.8Hz,2H),0.27-0.26(s,2H).MS:411[M+H] +。
Figure PCTCN2020080203-appb-000055
实施例48.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((环丙基甲基)氨基)嘧啶-5-甲酰胺
实施例48的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的环丙基甲胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.25(s,1H),8.46(s,1H),7.98(s,1H),7.71(s,1H),7.57(s,1H),7.07(s,1H),6.90-6.75(m,1H),6.15-6.03(m,1H),5.75-5.63(m,1H),4.61-4.02(m,3H),3.56-3.37(m,2H),3.21-3.00(m,1H),3.03-2.85(m,1H),2.22-1.98(m,2H),1.82(s,1H),1.52(s,1H),1.21-1.08(m,1H),0.49-0.47(t,J＝7.9Hz,2H),0.27-0.26(m,2H).MS:411[M+H] +。
实施例49.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(异戊基氨基)嘧啶-5-甲酰胺
实施例49的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的异戊胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.19(s,1H),8.45(s,1H),7.93(d,J＝7.4Hz,1H),7.80-7.65(m,1H),7.62-7.59(m,1H),7.22-6.97(m,1H),6.88-6.78(m,1H),6.15-6.05(m,1H),5.72-5.64(m,1H),4.65-4.55(m,1H),4.20-4.15(m,1H),4.10-3.99(m,1H),3.52-3.45(m,3H),3.14-2.86(m,2H),2.16-2.11(m,1H),2.05-1.99(m,1H),1.85-1.79(m,1H),1.68-1.62(m,1H),1.51-1.48(m,2H),0.93(s,3H),0.91(s,3H).MS:427[M+H] +。
Figure PCTCN2020080203-appb-000056
实施例50.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(异戊基氨基)嘧啶-5-甲酰胺
实施例50的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的异戊胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.19(s,1H),8.45(s,1H),7.93(d,J＝7.1Hz,1H),7.81-7.64(m,1H),7.60(s,1H),7.15-6.96(m,1H),6.89-6.75(m,1H),6.17-6.04(m,1H),5.73-5.63(m,1H),4.28-3.97(m,3H),3.53-3.46(m,2H),3.17-2.99(m,1H),2.99-2.82(m,1H),2.17-2.09(m,1H),2.07-1.98(m,1H),1.86-1.77(m,1H),1.73-1.60(m,1H),1.56-1.44(m,3H),0.92(d,J＝6.6Hz,6H).MS:427[M+H] +。
实施例51.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(异丙基氨基)嘧啶-5-甲酰胺
实施例51的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的异丙胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.13-9.09(m,1H),8.45(s,1H),7.91(s,1H),7.77-7.64(m,1H),7.61-7.58(m,1H),7.13-6.97(m,1H),6.87-6.79(m,1H),6.15-6.05(m,1H),5.71-5.64(m,1H),4.67-4.56(m,1H),4.17-4.11(m,2H),4.06-3.99(m,1H),3.12(t,J＝12.8,12.8Hz,1H),3.00-2.92(m,1H),2.16-2.13(m,1H),2.04-1.99(m,1H),1.85-1.80(m,1H),1.55-1.51(m,1H),1.25(s,6H).MS:399[M+H] +。
Figure PCTCN2020080203-appb-000057
实施例52.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(异丙基氨基)嘧啶-5-甲酰胺
实施例52的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的异丙胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.11(s,1H),8.45(s,1H),7.91(s,1H),7.70(s,1H),7.59(s,1H),7.06(s,1H),6.91-6.74(m,1H),6.17-6.04(m,1H),5.73-5.63(m,1H),4.61(s,1H),4.27-4.10(m,3H),4.03(d,J＝13.9Hz,1H),3.17-3.06(m,1H),3.03-2.87(m,1H),2.18-1.99(m,1H),1.87-1.79(m, 1H),1.59-1.47(m,1H),1.25(s,6H).MS:399[M+H] +。
实施例53.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-羟基-2-甲基丙基)氨基)嘧啶-5-甲酰胺
实施例53的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的1-氨基-2-甲基丙-2-醇替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.47-9.13(m,2H),8.46(s,1H),7.97(s,1H),7.83-7.53(m,2H),7.31-6.70(m,2H),6.16-6.04(m,1H),5.73-5.63(m,1H),4.64(s,1H),4.26-4.12(m,2H),4.12-3.98(m,1H),3.52-3.37(m,3H),3.13-2.88(m,1H),2.18-2.00(m,2H),1.86-1.76(m,1H),1.58-1.45(m,1H),1.15(s,6H).MS:429[M+H] +。
Figure PCTCN2020080203-appb-000058
实施例54.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-羟基-2-甲基丙基)氨基)嘧啶-5-甲酰胺
实施例54的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的1-氨基-2-甲基丙-2-醇替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.40-9.16(m,1H),8.46(s,1H),7.97(s,1H),7.69(s,1H),7.56(s,1H),7.19-6.91(m,1H),6.88-6.76(m,1H),6.17-6.04(m,1H),5.73-5.63(m,1H),4.64(s,1H),4.25-4.10(m,2H),4.09-4.00(m,1H),3.48-3.39(m,2H),3.16-3.01(m,1H),3.00-2.86(m,1H),2.21-2.00(m,2H),1.86-1.76(m,1H),1.57-1.46(m,1H),1.16(s,6H).MS:429[M+H] +。
实施例55.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)嘧啶-5-甲酰胺
实施例55的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的(四氢-2H-吡喃-4-基)甲胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.34(s,1H),8.52-8.44(m,1H),7.93(d,J＝4.5Hz,1H),7.73(s,1H),7.59(s,1H),7.23-6.97(m,1H),6.89-6.76(m,1H),6.16-6.04(m,1H),5.73-5.63(m,1H),4.59-4.01(m,3H),3.89-3.83(m,2H),3.45-3.36(m,2H),3.28(t,J＝11.6Hz,2H),3.16-3.03(m,1H),3.03-2.87(m,1H),2.20-1.99(m,2H),1.90-1.75(m,2H),1.64-1.47(m,3H),1.32-1.21(m,2H).MS:455[M+H] +。
Figure PCTCN2020080203-appb-000059
实施例56.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)嘧啶-5-甲酰胺
实施例56的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的(四氢-2H-吡喃-4-基)甲胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.34(s,1H),8.46(s,1H),7.96-7.90(m,1H),7.80-7.71(m,1H),7.59(s,1H),7.06(s,1H),6.89-6.75(m,1H),6.16-6.04(m,1H),5.73-5.63(m,1H),4.59-4.02(m,3H),3.89-3.84(m,2H),3.44-3.36(m,2H),3.31-3.26(m,2H),3.17-3.04(m,1H),3.03-2.86(m,1H),2.16-1.99(m,2H),1.82(s,2H),1.64-1.56(m,2H),1.52(s,1H),1.31-1.22(m,2H).MS:455[M+H] +。
实施例57.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)嘧啶-5-甲酰胺
实施例57的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-(四氢-2H-吡喃-4-基)乙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.20(s,1H),8.45(s,1H),7.93(s,1H),7.71(s,1H),7.57(s,1H),7.07(s,1H),6.89-6.77(m,1H),6.16-6.04(m,1H),5.73-5.63(m,1H),4.60-4.01(m,3H),3.86-3.78(m,2H),3.49(s,2H),3.25(t,J＝11.6Hz,2H),3.18-2.86(m,2H),2.19-1.97(m,2H),1.87-1.76(m,1H),1.64-1.50(m,6H),1.27-1.14(m,2H).MS:469[M+H] +。
Figure PCTCN2020080203-appb-000060
实施例58.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)嘧啶-5-甲酰胺
实施例58的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-(四氢-2H-吡喃-4-基)乙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.20(s,1H),8.45(s,1H),7.93(s,1H),7.71(s,1H),7.57(s,1H),7.06(s,1H),6.89-6.76(m,1H),6.17-6.04(m,1H),5.74-5.63(m,1H),4.60-4.02(m,3H),3.86-3.79(m,2H),3.49(s,2H),3.29-3.20(m,2H),3.17-3.04(m,1H),3.01-2.84(m,1H),2.18-1.97(m,2H),1.82(s,1H),1.62-1.48(m,6H),1.25-1.16(m,2H).MS:469[M+H] +。
实施例59.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙氧基苯基)氨基)嘧啶-5-甲酰胺
实施例59的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.79-11.58(m,1H),9.55(s,1H),8.90-8.69(m,1H),8.64(s,1H),8.15-8.00(m,1H),7.95-7.76(m,1H),7.62-7.45(m,1H),7.45-7.19(m,1H),7.10-6.92(m,3H),6.91-6.71(m,1H),6.18-6.05(m,1H),5.74-5.62(m,1H),4.32-3.97(m,5H),3.20-3.00(m,1H),2.97-2.81(m,1H),2.19-2.05(m,1H),2.01-1.89(m,1H),1.88-1.76(m,1H),1.58-1.37(m,4H).MS:477[M+H] +。
Figure PCTCN2020080203-appb-000061
实施例60.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙氧基苯基)氨基)嘧啶-5-甲酰胺
实施例60的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.79-11.58(m,1H),9.55(s,1H),8.85-8.69(m,1H),8.67-8.62(m,1H),8.20-7.98(m,1H),7.97-7.76(m,1H),7.66-7.47(m,1H),7.49-7.29(m,1H),7.12-6.93(m,3H),6.91-6.77(m,1H),6.18-6.05(m,1H),5.75-5.63(m,1H),4.28-4.04(m,5H),3.18-3.02(m,1H),3.00-2.82(m,1H),2.08-2.06(s,1H),2.00-1.89(m,1H),1.86-1.78(m,1H),1.61-1.40(m,4H).MS:477[M+H] +。
实施例61.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((5-氟-2-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例61的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的5-氟-2-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.90-11.80(m,1H),9.73-9.55(m,1H),8.86-8.64(m,2H),8.18-7.87(m,2H),7.67-7.26(m,2H),7.03(s,1H),6.90-6.75(m,2H),6.18-6.04(m,1H),5.75-5.62(m,1H),4.33-4.12(m,2H),4.08-3.99(m,1H),3.85(s,3H),3.33-3.30(m,1H),3.18-2.90(m,1H),2.20-1.96(m,2H),1.87-1.77(m,1H),1.57-1.44(m,1H).MS:481[M+H] +。
Figure PCTCN2020080203-appb-000062
实施例62.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((5-氟-2-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例62的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的5-氟-2-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.90-11.80(m,1H),9.74-9.55(m,1H),8.81-8.65(m,2H),8.15-7.89(m,2H),7.65-7.49(m,1H),7.33(s,1H),7.09-7.01(m,1H),6.94-6.73(m,2H),6.18-6.03(m,1H),5.78-5.62(m,1H),4.33-4.00(m,3H),3.85(s,3H),3.76-3.51(m,1H),3.18-2.90(m,1H),2.18-2.03(m,2H),1.87-1.76(m,1H),1.57-1.44(m,1H).MS:481[M+H] +。
实施例63.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例63的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2- 甲氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.58(s,1H),8.58(s,1H),7.88(s,1H),7.32-7.14(m,3H),7.08-7.03(m,1H),7.03-6.80(m,3H),6.20-6.08(m,1H),5.77-5.65(m,1H),4.55-4.22(m,1H),4.14-3.97(m,1H),3.76-3.71(m,4H),3.27-3.04(m,1H),2.86-2.61(m,1H),2.13(s,3H),1.92-1.80(m,2H),1.79-1.70(m,1H),1.54-1.44(m,1H).MS:477[M+H] +。
Figure PCTCN2020080203-appb-000063
实施例64.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例64的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.41(d,J＝3.5Hz,1H),9.58(s,1H),8.58(s,1H),7.89(s,1H),7.32-7.14(m,3H),7.10-7.03(m,1H),7.02-6.89(m,2H),6.90-6.72(m,1H),6.21-6.09(m,1H),5.77-5.65(m,1H),4.59-4.26(m,1H),4.14-3.96(m,1H),3.76-3.71(m,4H),3.34-3.31(m,1H),3.28-3.03(m,1H),2.13(s,3H),1.91-1.71(m,3H),1.56-1.42(m,1H).MS:477[M+H] +。
实施例65.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丙氧基苯基)氨基)嘧啶-5-甲酰胺
实施例65的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丙氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.77-11.63(m,1H),9.57-9.51(m,1H),8.87-8.69(m,1H),8.63(s,1H),8.20-8.01(m,1H),7.94-7.81(m,1H),7.60-7.49(m,1H),7.38-7.30(m,1H),7.08(s,1H),7.04-6.77(m,3H),6.17-6.05(m,1H),5.74-5.63(m,1H),4.66-4.59(m,1H),4.29-3.98(m,3H),3.21-2.79(m,2H),2.18-1.90(m,2H),1.87-1.75(m,1H),1.57-1.45(m,1H),1.31(s,6H).MS:491[M+H] +。
Figure PCTCN2020080203-appb-000064
实施例66.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丙氧基苯基)氨基)嘧啶-5-甲酰胺
实施例66的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丙氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.77-11.63(m,1H),9.61-9.48(m,1H),8.92-8.68(m,1H),8.68-8.60(m,1H),8.25-7.97(m,1H),7.94-7.80(m,1H),7.60-7.49(m,1H),7.45-7.23(m,1H),7.08(s,1H),7.05-6.90(m,2H),6.91-6.74(m,1H),6.18-6.05(m,1H),5.74-5.63(m,1H),4.67-4.59(m,1H),4.34-3.99(m,3H),3.20-2.97(m,1H),2.96-2.78(m,1H),2.15-1.93(m,2H),1.89-1.76(m,1H),1.58-1.45(m,1H),1.31(s,6H).MS:491[M+H] +。
实施例67.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氟-2-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例67的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氟-2-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.64-11.13(m,1H),9.58(s,1H),8.78-8.61(m,2H),8.03-7.81(m,2H),7.63-7.59(m,1H),7.28(s,1H),7.07-6.95(m,1H),6.93-6.70(m,2H),6.18-6.05(m,1H),5.74-5.63(m,1H),4.58-4.03(m,3H),3.88-3.83(m,3H),3.16-3.00(m,1H),2.95-2.77(m,1H),2.09-1.99(m,1H),1.93-1.73(m,2H),1.55-1.44(m,1H).MS:481[M+H] +。
Figure PCTCN2020080203-appb-000065
实施例68.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氟-2-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例68的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氟-2-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.64-11.13(m,1H),9.58(s,1H),8.81-8.68(m,1H),8.68-8.59(m,1H),8.05-7.83(m,2H),7.64-7.59(m,1H),7.41-7.28(m,1H),7.08-6.98(m,1H),6.92-6.74(m,2H),6.19-6.05(m,1H),5.74-5.63(m,1H),4.62-4.01(m,3H),3.88-3.83(m,3H),3.23-3.00(m,1H),2.94-2.78(m,1H),2.16-2.04(m,1H),1.94-1.71(m,2H),1.57-1.43(m,1H).MS:481[M+H] +。
实施例69.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-环丙基乙基)氨基)嘧啶-5-甲酰胺
实施例69的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-环丙基乙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.33-9.19(m,1H),8.52-8.43(m,1H),7.98-7.92(m,1H),7.72(s,1H),7.67-7.53(m,1H),7.07(s,1H),6.90-6.75(m,1H),6.16-6.03(m,1H),5.73-5.62(m,1H),4.64-4.00(m,3H),3.56-3.45(m,2H),3.18-2.83(m,2H),2.19-1.98(m,2H),1.87-1.76(m,1H),1.56-1.46(m,3H),0.78-0.68(m,1H),0.44-0.38(m,2H),0.14-0.07(m,2H).MS:425[M+H] +。
Figure PCTCN2020080203-appb-000066
实施例70.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-环丙基乙基)氨基)嘧啶-5-甲酰胺
实施例70的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-环丙基乙-1-胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.28(s,1H),8.45(s,1H),7.96-7.90(m,1H),7.82-7.66(m,1H),7.61(s,1H),7.07(s,1H),6.89-6.76(m,1H),6.15-6.04(m,1H),5.73-5.62(m,1H),4.64-3.99(m,3H),3.52-3.46(m,2H),3.18-3.02(m,1H),3.03-2.86(m,1H),2.19-1.98(m,2H),1.87-1.76 (m,1H),1.52-1.51(m,3H),0.78-0.68(m,1H),0.45-0.39(m,2H),0.13-0.08(m,2H).MS:425[M+H] +。
实施例71.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-羟基-3-甲基丁基)氨基)嘧啶-5-甲酰胺
实施例71的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-2-甲基丁-2-醇替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.18(s,1H),8.44(s,1H),8.07-7.92(m,1H),7.71(s,1H),7.56(d,J＝4.4Hz,1H),7.06(s,1H),6.89-6.77(m,1H),6.17-6.04(m,1H),5.72-5.62(m,1H),4.65-4.51(m,1H),4.41(s,1H),4.27-4.19(m,1H),4.18-4.11(m,1H),4.11-3.99(m,1H),3.58-3.54(m,1H),3.51-3.43(m,1H),3.15-2.93(m,1H),2.14-2.01(m,2H),1.85-1.77(m,1H),1.71-1.66(m,2H),1.54-1.45(m,1H),1.15(s,6H).MS:443[M+H] +。
Figure PCTCN2020080203-appb-000067
实施例72.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-羟基-3-甲基丁基)氨基)嘧啶-5-甲酰胺
实施例72的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-2-甲基丁-2-醇替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.18(s,1H),8.44(s,1H),8.06-8.00(m,1H),7.70(s,1H),7.57-7.54(m,1H),7.05(s,1H),6.89-6.77(m,1H),6.17-6.04(m,1H),5.73-5.63(m,1H),4.63-4.54(m,1H),4.41(s,1H),4.27-4.18(m,1H),4.17-4.02(m,2H),3.60-3.53(m,2H),3.47(t,J＝11.4Hz,1H),3.14-2.94(m,1H),2.13-2.00(m,2H),1.84-1.77(m,1H),1.71-1.68(m,1H),1.54-1.46(m,1H),1.15(s,6H).MS:443[M+H] +。
实施例73.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氟-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例73的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氟-6-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.46-10.42(m,1H),9.65(s,1H),8.60(s,1H),7.93(s,1H),7.35-7.28(m,2H),7.24(s,1H),7.19(d,J＝11.0Hz,1H),7.06-6.99(m,2H),6.92-6.78(m,1H),6.20-6.09(m,1H),5.74-5.67(m,1H),4.52-4.25(m,1H),4.10-4.01(m,1H),3.79(s,3H),3.78-3.67(m,1H),3.29-3.03(m,1H),2.83-2.68(m,1H),1.91-1.76(m,3H),1.49-1.48(m,1H).MS:481[M+H] +。
Figure PCTCN2020080203-appb-000068
实施例74.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氟-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例74的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氟-6-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.44-10.43(m,1H),9.65(s,1H),8.61(s,1H),7.93(s,1H),7.35-7.27(m,2H),7.24(s,1H),7.21-7.16(m,1H),7.06-7.00(m,2H),6.91-6.77(m,1H),6.20-6.08(m,1H),5.75-5.67(m,1H),4.52-4.25(m,1H),4.11-4.00(m,1H),3.79(s,3H),3.78-3.69(m,1H),3.29-3.02(m,1H),2.86-2.67(m,1H),1.90-1.76(m,3H),1.51-1.44(m,1H).MS:481[M+H] +。
实施例75.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氯-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例75的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氯-6-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.63(s,1H),8.60(s,1H),7.93(s,1H),7.40-7.27(m,3H),7.24-7.20(m,2H),7.12-7.05(m,1H),6.93-6.72(m,1H),6.22-6.07(m,1H),5.76-5.67(m,1H),4.50-4.25(m,1H),4.10-4.04(m,1H),3.75(s,3H),3.74-3.73(m,1H),3.32(s,2H),1.88-1.77(m,3H),1.52-1.46(m,1H).MS:497[M+H] +。
Figure PCTCN2020080203-appb-000069
实施例76.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氯-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例76的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氯-6-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.63(s,1H),8.60(s,1H),7.93(s,1H),7.38-7.28(m,3H),7.25-7.22(m,1H),7.21-7.20(m,1H),7.12-7.06(m,1H),6.93-6.73(m,1H),6.21-6.08(m,1H),5.75-5.67(m,1H),4.51-4.24(m,1H),4.10-4.01(m,1H),3.75(s,3H),3.74(s,1H),3.33-3.03(m,1H),2.86-2.69(m,1H),1.88-1.77(m,3H),1.51-1.45(m,1H).MS:497[M+H] +。
实施例77.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丁氧基苯基)氨基)嘧啶-5-甲酰胺
实施例77的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丁氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),11.52(s,1H),9.58-9.54(m,1H),8.86-8.63(m,2H),8.12-7.99(m,1H),7.90-7.78(m,1H),7.60-7.47(m,1H),7.37(s,1H),7.05-7.03(m,1H),6.96-6.92(m,1H),6.89-6.81(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.62-4.19(m,2H),4.17-4.01(m,2H),3.82-3.79(m,2H),3.16-3.00(m,1H),2.92-2.79(m,1H),2.06-1.83(m,3H),1.50(s,1H),1.07(d,J＝6.8Hz,3H),1.01(d,J＝6.6Hz,3H).MS:505[M+H] +。
Figure PCTCN2020080203-appb-000070
实施例78.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丁氧基苯基)氨基)嘧啶-5-甲酰胺
实施例78的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丁氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),11.52(s,1H),9.57-9.54(m,1H),8.87-8.63(m,2H),8.13-7.99(m,1H),7.90-7.77(m,1H),7.61-7.47(m,1H),7.39(s,1H),7.05-7.03(m,1H),6.96-6.92(m,1H),6.89-6.81(m,1H),6.17-6.06(m,1H),5.72-5.64(m,1H),4.61-4.20(m,1H),4.18-3.97(m,2H),3.82-3.79(m,2H),3.21-2.98(m,1H),2.96-2.77(m,1H),2.12-2.03(m,2H),1.92-1.75(m,2H),1.49(s,1H),1.09-1.05(m,3H),1.03-1.00(m,3H).MS:505[M+H] +。
实施例79.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(2-甲氧基乙氧基)苯基)氨基)嘧啶-5-甲酰胺
实施例79的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-(2-甲氧基乙氧基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),11.55(s,1H),9.64(s,1H),8.83-8.66(m,1H),8.63(s,1H),8.07-7.93(m,2H),7.79-7.59(m,1H),7.48-7.36(m,1H),7.10-7.06(m,1H),6.99-6.96(m,1H),6.90-6.82(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.62-4.22(m,2H),4.16(s,2H),4.07-4.01(m,1H),3.78-3.70(m,2H),3.30(s,3H),3.18-3.04(m,1H),2.93-2.77(m,1H),2.12-1.81(m,3H),1.55-1.46(m,1H).MS:507[M+H] +。
Figure PCTCN2020080203-appb-000071
实施例80.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(2-甲氧基乙氧基)苯基)氨基)嘧啶-5-甲酰胺
实施例80的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-(2-甲氧基乙氧基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),11.48(s,1H),9.58-9.53(m,1H),8.83-8.63(m,2H),8.09-7.99(m,1H),7.90-7.76(m,1H),7.60-7.46(m,1H),7.35(s,1H),7.08-7.05(m,1H),6.99-6.95(m,1H),6.90-6.82(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.62-4.20(m,2H),4.18-4.15(m,2H),4.08-4.02(m,1H),3.79-3.70(m,2H),3.35(s,3H),3.17-3.02(m,1H),2.92-2.81(m,1H),2.10-1.90(m,2H),1.91-1.79(m,1H),1.50(s,1H).MS:507[M+H] +。
实施例81.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丁氧基-6-甲基苯基)氨基)嘧啶- 5-甲酰胺
实施例81的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丁氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.53(s,1H),8.58(s,1H),7.86(s,1H),7.21(s,2H),7.18-7.07(m,2H),7.02-6.82(m,3H),6.21-6.07(m,1H),5.76-5.65(m,1H),4.54-4.22(m,1H),4.10-3.99(m,1H),3.71-3.63(m,3H),3.33-3.18(m,2H),2.17(s,3H),1.94-1.66(m,5H),0.79(d,J＝7.6Hz,6H).MS:519[M+H] +。
Figure PCTCN2020080203-appb-000072
实施例82.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丁氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例82的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丁氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.53(s,1H),8.58(s,1H),7.86(s,1H),7.31-7.17(m,2H),7.17-7.06(m,2H),7.05-6.82(m,3H),6.21-6.06(m,1H),5.75-5.64(m,1H),4.51-4.26(m,1H),4.13-3.99(m,1H),3.80-3.59(m,3H),3.28-3.02(m,1H),2.86-2.64(m,1H),2.17(s,3H),1.92-1.70(m,4H),1.55-1.42(m,1H),0.79(d,J＝7.1Hz,6H).MS:519[M+H] +。
实施例83.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(2-甲氧基乙氧基)-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例83的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-(2-甲氧基乙氧基)-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.55(s,1H),8.58(s,1H),7.86(s,1H),7.20-7.17(m,3H),7.09(s,1H),7.05-6.94(m,2H),6.92-6.83(m,1H),6.20-6.07(m,1H),5.76-5.66(m,1H),4.54-4.21(m,1H),4.06-4.04(m,3H),3.81-3.64(m,1H),3.50(s,2H),3.33-3.31(d,J＝6.3Hz,1H),3.23-3.20(m,1H),3.15(s,3H),2.15(s,3H),1.90-1.70(m,3H),1.50-1.48(s,1H).MS:521[M+H] +。
Figure PCTCN2020080203-appb-000073
实施例84.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(2-甲氧基乙氧基)-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例84的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2- (2-甲氧基乙氧基)-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.55(s,1H),8.58(s,1H),7.86(s,1H),7.20(s,2H),7.16-7.15(m,1H),7.09-7.08(m,1H),7.05-6.95(m,2H),6.93-6.84(m,1H),6.21-6.07(m,1H),5.81-5.66(m,1H),4.50-4.28(m,1H),4.15-3.96(m,4H),3.75-3.71(m,1H),3.51-3.49(m,3H),3.15(s,3H),2.15(s,3H),1.91-1.70(m,3H),1.57-1.42(m,1H).MS:521[M+H] +。
实施例85.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,6-二甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例85的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.50(s,1H),8.55(s,1H),7.86(s,1H),7.28-7.23(m,1H),7.22(s,1H),7.15-7.12(m,1H),6.93-6.73(m,4H),6.21-6.09(m,1H),5.76-5.68(m,1H),4.52-4.27(m,1H),4.12-3.99(m,1H),3.83-3.74(m,1H),3.72-3.69(m,6H),3.28-3.04(m,1H),2.85-2.67(m,1H),1.91-1.82(m,2H),1.81-1.74(m,1H),1.54-1.45(m,1H).MS:493[M+H] +。
Figure PCTCN2020080203-appb-000074
实施例86.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,6-二甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例86的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二甲氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.50(s,1H),8.55(s,1H),7.86(s,1H),7.28-7.23(m,1H),7.22(s,1H),7.15-7.11(m,1H),6.91-6.73(m,4H),6.21-6.09(m,1H),5.75-5.67(m,1H),4.52-4.27(m,1H),4.11-3.99(m,1H),3.81-3.73(m,1H),3.72-3.69(m,6H),3.26-3.04(m,1H),2.84-2.67(m,1H),1.90-1.82(m,2H),1.81-1.75(m,1H),1.53-1.45(m,1H).MS:493[M+H] +。
实施例87.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例87的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.57(s,1H),8.59(s,1H),7.88(s,1H),7.21-7.14(m,3H),7.12-7.07(m,1H),7.03-6.81(m,3H),6.20-6.06(m,1H),5.75-5.66(m,1H),4.53-4.25(m,1H),4.13-3.92(m,3H),3.78-3.71(m,1H),3.27-3.04(m,1H),2.84-2.61(m,1H),2.15(s,3H),1.89-1.68(m,3H),1.54-1.42(m,1H),1.16(t,J＝6.9Hz,3H).MS:491[M+H] +。
Figure PCTCN2020080203-appb-000075
Figure PCTCN2020080203-appb-000076
实施例88.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例88的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.55(s,1H),8.58(s,1H),7.88(s,1H),7.29-7.07(m,4H),7.04-6.82(m,3H),6.21-6.07(m,1H),5.76-5.66(m,1H),4.53-4.24(m,1H),4.10-3.99(m,3H),3.76-3.71(m,1H),3.29-3.03(m,1H),2.86-2.67(m,1H),2.15(s,3H),1.89-1.68(m,3H),1.48(s,1H),1.16(t,J＝7.0Hz,3H).MS:491[M+H] +。
实施例89.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丙氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例89的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丙氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.59(s,1H),8.59(s,1H),7.90(s,1H),7.35-7.07(m,4H),7.06-6.71(m,3H),6.21-6.06(m,1H),5.76-5.64(m,1H),4.54-4.23(m,2H),4.14-3.96(m,1H),3.85-3.68(m,1H),3.25-3.02(m,1H),2.86-2.63(m,1H),2.14(s,3H),1.91-1.65(m,3H),1.56-1.41(m,1H),1.16-1.07(m,6H).MS:505[M+H] +。
Figure PCTCN2020080203-appb-000077
实施例90.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-异丙氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例90的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丙氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),9.71(s,1H),8.58(s,1H),7.93(s,1H),7.23(s,2H),7.17-7.06(m,2H),7.05-6.70(m,3H),6.21-6.06(m,1H),5.77-5.63(m,1H),4.53-4.26(m,2H),4.15-3.93(m,2H),3.24-3.03(m,1H),2.90-2.64(m,1H),2.15(s,3H),1.89-1.69(m,3H),1.48(s,1H),1.17-1.08(m,6H).MS:505[M+H] +。
实施例91.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,6-二甲基苯基)氨基)嘧啶-5-甲酰胺
实施例91的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.58(s,1H),9.59(s,1H),8.60(s,1H),7.90(s,1H),7.32-7.09(m,5H),6.98(s,1H),6.94-6.71(m,1H),6.21-6.07(m,1H),5.76-5.67(m,1H),4.51-4.23(m,1H),4.04(dd,J＝31.5,13.6Hz,1H),3.70(d,J＝16.0Hz,1H),3.27-3.02(m,1H),2.85-2.61(m,1H),2.15(d,J＝6.2Hz,6H),1.90-1.66(m,3H),1.48(s,1H).MS:461[M+H] +.
Figure PCTCN2020080203-appb-000078
实施例92.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,6-二甲基苯基)氨基)嘧啶-5-甲酰胺
实施例92的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.58(s,1H),9.59(s,1H),8.60(s,1H),7.90(s,1H),7.33-7.10(m,5H),6.98(s,1H),6.91-6.72(m,1H),6.20-6.08(m,1H),5.75-5.66(m,1H),4.38(dd,J＝75.6,12.7Hz,1H),4.13-3.97(m,1H),3.69(s,1H),3.14(d,J＝61.1Hz,1H),2.70-2.63(m,1H),2.15(d,J＝6.2Hz,6H),1.89-1.65(m,3H),1.54-1.41(m,1H).MS:461[M+H] +.
实施例93. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2,6-二甲基苯基)氨基)嘧啶-5-甲酰胺
实施例93的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二甲基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯(制备方法参考WO 2014139465)代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.59(s,1H),9.58(s,1H),8.60(s,1H),7.89(s,1H),7.15(d,J＝9.7Hz,5H),7.01-6.92(m,2H),6.21(dd,J＝16.6,2.5Hz,1H),5.76(dd,J＝10.4,2.4Hz,1H),4.56(d,J＝13.2Hz,1H),4.19(d,J＝13.8Hz,1H),4.08-3.99(m,1H),3.19(t,J＝13.0Hz,1H),2.76(t,J＝12.7Hz,1H),2.13(s,6H),1.83-1.74(m,2H),1.52-1.34(m,2H).MS:461[M+H] +.
Figure PCTCN2020080203-appb-000079
实施例94. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-氯-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例94的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氯-6-甲基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.76(s,1H),9.65(s,1H),8.63(s,1H),7.93(s,1H),7.42(d,J＝7.2Hz,2H),7.33-7.27(m,2H),7.15(s,1H),7.01-6.91(m,2H),6.21(dd,J＝16.6,2.5Hz,1H),5.76(dd,J＝10.4,2.4Hz,1H),4.55(d,J＝13.4Hz,1H),4.23-4.02(m,2H),3.21(t,J＝12.9Hz,1H),2.78(t,J＝12.8Hz,1H),2.20(s,3H),1.85-1.75(m,2H),1.52-1.34(m,2H).MS:481[M+H] +.
实施例95.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氯-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例95的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2- 氯-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.76(s,1H),9.66(s,1H),8.63(s,1H),7.93(s,1H),7.54-7.25(m,4H),7.18(s,1H),7.01(d,J＝12.6Hz,1H),6.93-6.71(m,1H),6.21-6.07(m,1H),5.73(d,J＝12.2Hz,1H),4.37(d,J＝94.5Hz,1H),4.07(d,J＝16.1Hz,1H),3.74(d,J＝34.6Hz,1H),3.27-3.01(m,1H),2.87-2.65(m,1H),2.21(d,J＝4.9Hz,3H),1.91-1.66(m,3H),1.49(s,1H).MS:481[M+H] +.
Figure PCTCN2020080203-appb-000080
实施例96.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-氯-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例96的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氯-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.76(s,1H),9.66(s,1H),8.63(s,1H),7.93(s,1H),7.55-7.29(m,3H),7.29-7.17(m,2H),7.06-6.98(m,1H),6.91-6.71(m,1H),6.14(dd,J＝26.9,16.4Hz,1H),5.73(d,J＝12.2Hz,1H),4.37(dd,J＝88.0,13.1Hz,1H),4.07(d,J＝16.1Hz,1H),3.74(d,J＝34.3Hz,1H),3.28-3.01(m,1H),2.87-2.63(m,1H),2.21(d,J＝4.9Hz,3H),1.91-1.67(m,3H),1.49(s,1H).MS:481[M+H] +.
实施例97. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例97的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),9.56(s,1H),8.57(s,1H),7.87(s,1H),7.32-7.19(m,2H),7.16(s,1H),7.03(s,1H),6.99-6.89(m,3H),6.22(dd,J＝16.6,2.5Hz,1H),5.76(dd,J＝10.4,2.5Hz,1H),4.56(d,J＝13.2Hz,1H),4.20(d,J＝13.7Hz,1H),4.10-4.01(m,1H),3.70(s,3H),3.25-3.15(m,1H),2.83-2.72(m,1H),2.12(s,3H),1.78(d,J＝14.0Hz,2H),1.55-1.33(m,2H).MS:477[M+H] +.
Figure PCTCN2020080203-appb-000081
实施例98. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2,6-二甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例98的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二甲氧基苯胺苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),9.49(s,1H),8.54(s,1H),7.85(s,1H),7.33-7.20(m,2H),7.17(s,1H),7.10(s,1H),7.00-6.91(m,1H),6.75(d, J＝8.4Hz,2H),6.21(dd,J＝16.7,2.5Hz,1H),5.76(dd,J＝10.4,2.5Hz,1H),4.56(d,J＝13.2Hz,1H),4.19(d,J＝13.8Hz,1H),4.12-4.02(m,1H),3.69(s,6H),3.27-3.16(m,1H),2.83-2.74(m,1H),1.80(s,2H),1.56-1.39(m,2H).MS:493[M+H] +.
实施例99.(R,E)-2-((1-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例99的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基苯胺替代环丙胺，步骤4)中以等当量的(E)-4-(二甲基氨基)丁-2-烯酰氯盐酸盐代替丙烯酰氯。 1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),9.55(s,1H),8.58(s,1H),7.99–7.74(m,1H),7.29–7.11(m,3H),7.08–6.93(m,3H),6.67–6.52(m,2H),4.51–4.19(m,1H),4.10–3.93(m,1H),3.71(s,3H),3.12–2.94(m,3H),2.24–2.04(m,11H),1.89–1.69(m,3H),1.53–1.42(m,1H).MS:534[M+H] +.
Figure PCTCN2020080203-appb-000082
实施例100.(S,E)-2-((1-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例100的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基苯胺替代环丙胺，步骤4)中以等当量的(E)-4-(二甲基氨基)丁-2-烯酰氯盐酸盐代替丙烯酰氯。 1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),9.55(s,1H),8.58(s,1H),7.96-7.75(m,1H),7.30-7.13(m,3H),7.08-7.04(m,1H),7.01-6.92(m,2H),6.67-6.63(m,1H),6.59–6.49(m,1H),4.56-4.17(m,1H),4.09-3.95(m,1H),3.71(s,3H),3.09-2.94(m,3H),2.18-2.08(m,11H),1.90-1.81(m,2H),1.78-1.70(m,1H),1.52-1.44(m,1H).MS:534[M+H] +.
实施例101.(R,E)-4-((2-氯-6-甲氧基苯基)氨基)-2-((1-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺
实施例101的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氯-6-甲氧基苯胺替代环丙胺，步骤4)中以等当量的(E)-4-(二甲基氨基)丁-2-烯酰氯盐酸盐代替丙烯酰氯。 1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.60(s,1H),8.60(s,1H),8.02-7.80(m,1H),7.59-7.28(m,2H),7.28-7.20(m,2H),7.19-7.03(m,2H),6.72-6.48(m,2H),4.54-4.17(m,1H),4.11-3.97(m,1H),3.84-3.66(m,4H),3.27-2.96(m,3H),2.84–2.63(m,1H),2.21-2.09(m,6H),2.02-1.66(m,3H),1.55-1.38(m,1H).MS:554[M+H] +.
Figure PCTCN2020080203-appb-000083
实施例102.(S,E)-4-((2-氯-6-甲氧基苯基)氨基)-2-((1-(1-(4-(二甲基氨基)丁-2-烯酰基)哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺
实施例102的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氯-6-甲氧基苯胺替代环丙胺，步骤4)中以等当量的(E)-4-(二甲基氨基)丁-2-烯酰氯盐酸盐代替丙烯酰氯。 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),9.60(s,1H),8.60(s,1H),8.03–7.79(m,1H),7.39–7.26(m,2H),7.26–7.19(m,2H),7.19–7.03(m,2H),6.72–6.44(m,2H),4.56–4.14(m,1H),4.12–3.95(m,1H),3.88–3.61(m,4H),3.27–2.92(m,3H),2.91–2.65(m,1H),2.21–2.09(m,6H),1.92–1.67(m,3H),1.56–1.43(m,1H).MS:554[M+H] +.
实施例103.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氯-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例103的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氯-2-甲氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.48-10.22(m,1H),9.63(s,1H),8.59(s,1H),7.90(s,1H),7.54-6.96(m,5H),6.86(m,1H),6.24-5.99(m,1H),5.83-5.55(m,1H),4.60-4.26(m,1H),4.19-4.01(m,1H),3.79-3.62(m,4H),3.17-2.61(m,2H),2.12(s,3H),2.00-1.69(m,3H),1.63-1.39(m,1H).MS:511[M+H] +.
Figure PCTCN2020080203-appb-000084
实施例104.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氯-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例104的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氯-2-甲氧基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.51-10.27(m,1H),9.63(s,1H),8.59(s,1H),7.90(s,1H),7.49-6.94(m,5H),6.94-6.71(m,1H),6.31-5.99(m,1H),5.71(t,J＝12.6Hz,1H),4.64-4.23(m,1H),4.18-3.94(m,1H),3.75(s,3H),3.65(s,1H),3.30-2.59(m,2H),2.12(s,3H),2.03-1.68(m,3H),1.66-1.45(m,1H).MS:511[M+H] +.
实施例105. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-氯-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例105的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氯-2-甲氧基-6-甲基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),9.59(s,1H),8.58(s,1H),8.01-7.77(m,1H),7.40-7.22(m,1H),7.20(s,1H),7.10(s,2H),7.05(s,1H),6.94-6.79(m,1H),6.19-6.06(m,1H),5.73-5.64(m,1H),4.53(d,J＝13.2Hz,1H),4.18(d,J＝13.8Hz,1H),4.04-3.85(m,1H),3.74(s,3H),3.23(t,J＝12.9Hz,1H),2.83(t,J＝12.7Hz,1H),2.12(s,3H),1.95-1.79(m,2H),1.79-1.49(m,2H).MS:511[M+H] +.
Figure PCTCN2020080203-appb-000085
实施例106. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2,6-二氯苯基)氨基)嘧啶-5-甲酰胺
实施例106的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二氯苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.92(s,1H),9.70(s,1H),8.65(s,1H),7.97(s,1H),7.66-7.60(m,2H),7.47-7.33(m,2H),7.16(s,1H),7.05-6.90(m,2H),6.21(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.3,2.4Hz,1H),4.58-4.50(m,1H),4.13(d,J＝37.2Hz,2H),3.22(t,J＝13.2Hz,1H),2.80(t,J＝12.8Hz,1H),1.87-1.78(m,2H),1.53-1.37(m,2H).MS:501[M+H] +.
实施例107.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,6-二氯苯基)氨基)嘧啶-5-甲酰胺
实施例107的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二氯苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),9.71(s,1H),8.66(s,1H),7.97(s,1H),7.77-7.63(m,2H),7.39(d,J＝7.9Hz,2H),7.19(s,1H),7.07(d,J＝22.0Hz,1H),6.92-6.71(m,1H),6.22-6.05(m,1H),5.76-5.65(m,1H),4.54-4.19(m,1H),4.06(s,1H),3.77(d,J＝43.5Hz,1H),3.20-3.02(m,1H),2.88-2.66(m,1H),1.92-1.70(m,3H),1.55-1.42(m,1H).MS:501[M+H] +.
Figure PCTCN2020080203-appb-000086
实施例108.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2,6-二氯苯基)氨基)嘧啶-5-甲酰胺
实施例108的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2,6-二氯苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),9.71(s,1H),8.66(s,1H),7.97(s,1H),7.69(dt,J＝20.6,10.2Hz,2H),7.39(s,2H),7.21-6.99(m,2H),6.93-6.71(m,1H),6.21-6.06(m,1H), 5.76-5.65(m,1H),4.53-4.18(m,1H),4.07(d,J＝14.6Hz,1H),3.77(d,J＝43.1Hz,1H),3.14-2.96(m,1H),2.86-2.66(m,1H),1.93-1.70(m,3H),1.55-1.42(m,1H).MS:501[M+H] +.
实施例109.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氰基-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例109的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲腈替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.81-10.47(m,1H),9.69(s,1H),8.62(s,1H),7.94(s,1H),7.65-7.45(m,2H),7.44-7.15(m,2H),7.13-6.94(m,1H),6.91-6.65(m,1H),6.24-5.96(m,1H),5.84-5.55(m,1H),4.62-4.17(m,1H),4.17-4.02(m,1H),3.80(s,4H),3.27-2.59(m,2H),2.18(s,3H),2.05-1.43(m,4H).MS:502[M+H] +.
Figure PCTCN2020080203-appb-000087
实施例110.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氰基-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例110的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲腈替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.85-10.46(m,1H),9.68(s,1H),8.62(s,1H),7.93(s,1H),7.63-7.15(m,4H),7.14-6.95(m,1H),6.93-6.64(m,1H),6.32-5.99(m,1H),5.84-5.51(m,1H),4.58-4.18(m,1H),4.15-3.95(m,1H),3.93-3.42(m,4H),3.30-2.66(m,2H),2.18(s,3H),1.99-1.40(m,4H).MS:502[M+H] +.
实施例111. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-氰基-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例111的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲腈替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.63(s,1H),9.63(s,1H),8.61(s,1H),8.09-7.83(m,1H),7.62-7.24(m,3H),7.18(s,1H),7.00(s,1H),6.92-6.80(m,1H),6.13(dd,J＝16.7,2.4Hz,1H),5.70(dd,J＝10.4,2.4Hz,1H),4.63-4.04(m,2H),4.02-3.85(m,1H),3.78(s,3H),3.25(t,J＝13.2Hz,1H),2.86(t,J＝12.7Hz,1H),2.17(s,3H),1.94-1.48(m,4H).MS:502[M+H] +.
Figure PCTCN2020080203-appb-000088
实施例112. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡啶-3-基氧基)苯基)氨基)嘧啶-5-甲酰胺
实施例112的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(吡啶-3-基氧基)苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),9.54(s,1H),8.57(s,1H),8.46-8.44(m,1H),8.35-8.31(m,1H),7.92-7.71(m,1H),7.52-7.49(m,1H),7.43-7.40(m,1H),7.21(d,J＝10.5Hz,3H),6.87-6.80(m,2H),6.73(s,1H),6.13-6.09(m,1H),5.69-5.65(m,1H),4.53-4.47(m,1H),4.17-4.08(m,2H),3.68(s,3H),3.18-3.11(m,1H),2.79-2.71(m,1H),2.12(s,3H),1.94-1.88(m,2H),1.72-1.63(m,2H).MS:570[M+H] +.
实施例113.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡啶-3-基氧基)苯基)氨基)嘧啶-5-甲酰胺
实施例113的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(吡啶-3-基氧基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),9.58(s,1H),8.58(s,1H),8.40-8.33(m,2H),7.99-7.76(m,1H),7.44-7.40(m,2H),7.28-7.18(m,3H),6.84-6.71(m,3H),6.09-6.03(m,1H),5.67-5.62(m,1H),4.63-4.19(m,1H),4.12-4.05(m,1H),3.92-3.75(m,1H),3.69(s,3H),3.11-2.73(m,1H),2.11(s,3H),1.97-1.82(m,3H),1.50-1.31(m,2H).MS:570[M+H] +.
Figure PCTCN2020080203-appb-000089
实施例114.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡啶-3-基氧基)苯基)氨基)嘧啶-5-甲酰胺
实施例114的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(吡啶-3-基氧基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),9.59(s,1H),8.58(s,1H),8.42-8.32(m,2H),7.99-7.73(m,1H),7.46-7.40(m,2H),7.35-7.16(m,3H),6.84-6.64(m,3H),6.11-6.03(m,1H),5.68-5.62(m,1H),4.58-4.30(m,1H),4.12-4.03(m,1H),3.91-3.75(m,1H),3.69(s,3H),3.28-3.00(m,1H),2.83-2.70(m,1H),2.11(s,3H),2.00-1.95(m,1H),1.88-1.77(m,2H),1.49-1.38(m,1H).MS:570[M+H] +.
实施例115. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-苯氧基苯基)氨基)嘧啶-5-甲酰胺
实施例115的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-苯氧基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),9.53(s,1H),8.72-8.27(m,2H),7.93-7.74(m,1H),7.42-7.37(m,2H),7.23-7.20(m,2H),7.11-7.07(m,3H),6.86-6.79(m,1H),6.76-6.72(m,1H),6.69-6.64(m,1H),6.14-6.08(m,1H),5.69-5.64(m,1H),4.52-4.46(m,1H),4.15-4.05(m,2H),3.67(s,3H),3.17-3.08(m,1H),2.78-2.71(m,1H),2.11(s,3H),1.93-1.86(m,2H),1.72-1.61(m,2H).MS:569[M+H] +.
Figure PCTCN2020080203-appb-000090
实施例116.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-苯氧基苯基)氨基)嘧啶-5-甲酰胺
实施例116的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-苯氧基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),9.58(s,1H),8.71-8.29(m,2H),7.94-7.82(m,1H),7.39-7.37(m,2H),7.25-7.24(m,1H),7.21-7.19(m,1H),7.12-7.09(m,1H),7.04-7.00(m,2H),6.79-6.63(m,3H),6.11-6.06(m,1H),5.68-5.64(m,1H),4.53-4.30(m,1H),4.10-4.05(m,1H),3.90-3.80(m,1H),3.67(s,3H),3.14-3.00(m,1H),2.83-2.75(m,1H),2.10(s,3H),2.02-1.93(m,2H),1.83-1.78(m,2H).MS:569[M+H] +.
实施例117. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-乙基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例117的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基-6-甲基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),9.44(s,1H),8.44(s,1H),7.76(s,1H),7.09-6.97(m,5H),6.85-6.78(m,1H),6.77(s,1H),6.09-6.03(m,1H),5.63-5.59(m,1H),4.44-4.37(m,1H),4.07-4.00(m,1H),3.91-3.83(m,1H),3.10-2.95(m,1H),2.65-2.56(m,1H),2.38-2.36(m,1H),2.33-2.30(m,1H),1.95(s,3H),1.64-1.56(m,2H),1.30-1.16(m,2H),0.89(t,J＝7.6,7.6Hz,3H).MS:475[M+H] +.
Figure PCTCN2020080203-appb-000091
实施例118. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-氯-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例118的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-氯-6-甲氧基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),7.92(s,1H),7.41-7.26(m,2H),7.18-7.07(m,4H),7.01-6.92(m,1H),6.22(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝10.3,2.4Hz,1H),4.56(d,J＝13.3Hz,1H),4.14(d,J＝44.4Hz,2H),3.74(s,3H),3.28-3.18(m,1H),2.85-2.75(m,1H),1.88-1.77(m,2H),1.56-1.35(m,2H).MS:497[M+H] +.
实施例119.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例119的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.64-10.59(m,1H),9.59(s,1H),8.61(s,1H),7.90(s,1H),7.28-7.16(m,5H),6.97-6.70(m,2H),6.20-6.09(m,1H),5.75-5.67(m,1H),4.49-4.25(m,1H),4.12-3.95(m,1H),3.76-3.63(m,1H),3.24-3.01(m,1H),2.84-2.59(m,1H),2.55-2.52(m,1H),2.49(s,1H),2.14-2.11(m,3H),1.87-1.78(m,2H),1.73-1.60(m,1H),1.54-1.42(m,1H),1.09-1.03(m,3H).MS:475[M+H] +.
Figure PCTCN2020080203-appb-000092
实施例120.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例120的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基-6-甲基苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.63-10.60(m,1H),9.59(s,1H),8.61(s,1H),7.90(s,1H),7.28-7.16(m,5H),6.98-6.92(m,1H),6.92-6.72(m,1H),6.20-6.08(m,1H),5.75-5.66(m,1H),4.50-4.24(m,1H),4.10-3.96(m,1H),3.75-3.61(m,1H),3.28-3.00(m,2H),2.86-2.54(m,2H),2.14-2.11(m,3H),1.87-1.79(m,2H),1.69-1.44(m,2H),1.09-1.05(m,3H).MS:475[M+H] +.
实施例121.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙基-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例121的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基-6-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.36-7.20(m,2H),7.20–6.90(m,3H),6.90-6.68(m,1H),6.34-6.16(m,1H),5.88-5.69(m,1H),4.63-4.38(m,1H),4.23-4.02(m,1H),3.75(s,3H),3.21-2.69(m,2H),2.67–2.54(m,2H),2.32-1.85(m,3H),1.84-1.62(m,1H),1.61-1.21(m,1H),1.21-1.04(m,3H).MS:491[M+H] +.
Figure PCTCN2020080203-appb-000093
实施例122.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-乙基-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例122的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基-6-甲氧基苯胺替代环丙胺。1H NMR(400MHz,Methanol-d4)δ8.50(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] +.
实施例123.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-环丙基-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例123的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-环丙基-6-甲氧基苯胺替代环丙胺。 1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.31(s,1H),7.28-7.13(m,2H),7.08-6.92(m,1H),6.89-6.74(m,1H),6.74-6.64(m,1H),6.33-6.20(m,1H),5.85-5.73(m,1H),4.64-4.40(m,1H),4.20-4.04(m,1H),3.86–3.71(m,4H),3.27-3.04(m,1H),2.96-2.77(m,1H),2.02-1.84(m,4H),1.66–1.56(m,1H),0.92-0.84(m,1H),0.83-0.75(m,1H),0.70-0.53(m,2H).MS:503[M+H] +.
Figure PCTCN2020080203-appb-000094
实施例124.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-环丙基-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例124的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-环丙基-6-甲氧基苯胺替代环丙胺。1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.31(s,1H),7.27-7.11(m,2H),7.10-6.91(m,1H),6.90-6.74(m,1H),6.74-6.61(m,1H),6.33-6.20(m,1H),5.85-5.74(m,1H),4.68-4.39(m,1H),4.23-4.02(m,1H),3.90-3.63(m,4H),3.18-3.11(m,1H),2.93-2.78(m,1H),2.04-1.82(m,4H),1.67-1.56(m,1H),0.92-0.85(m,1H),0.83-0.72(m,1H),0.71-0.51(m,2H).MS:503[M+H] +.
实施例125. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-环丙基-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例125的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-环丙基-6-甲氧基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.52(s,1H),8.57(s,1H),7.87(s,1H),7.31-7.20(m,2H),7.16(s,1H),7.06(s,1H),6.99-6.89(m,2H),6.56(d,J＝7.9Hz,1H),6.25-6.18(m,1H),5.76(dd,J＝10.4,2.5Hz,1H),4.56(d,J＝13.2Hz,1H),4.19(d,J＝13.8Hz,1H),4.04(s,1H),3.68(s,3H),3.24-3.15(m,1H),2.82-2.72(m,1H),1.86(q,J＝4.9,3.1Hz,1H),1.76(s,2H),1.49-1.34(m,2H),0.88-0.73(m,2H),0.66-0.47(m,2H).MS:503[M+H] +.
Figure PCTCN2020080203-appb-000095
实施例126. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-乙氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例126的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙氧基-6-甲基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),9.54(s,1H),8.57(s,1H),8.01-7.67(m,1H),7.32-7.10(m,3H),7.06(s,1H),6.99-6.87(m,3H),6.26-6.16(m,1H),5.79-5.73(m,1H),4.59-4.50(m,1H),4.23-4.14(m,1H),4.09-3.91(m,3H),3.19(t,J＝13.0Hz,1H),2.76(t,J＝12.7Hz,1H),2.13(s,3H),1.85-1.74(m,2H),1.56-1.32(m,2H),1.15(t,J＝6.9Hz,3H).MS:491[M+H] +.
实施例127. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-异丙氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例127的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-异丙氧基-6-甲基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),9.53(s,1H),8.57(s,1H),7.99-7.74(m,1H),7.30-7.14(m,3H),7.07(s,1H),6.98-6.87(m,3H),6.26-6.17(m,1H),5.79-5.72(m,1H),4.60-4.51(m,1H),4.45-4.39(m,1H),4.22-4.13(m,1H),4.12-4.01(m,1H),3.19(t,J＝13.0Hz,1H),2.76(t,J＝12.8Hz,1H),2.12(s,3H),1.84-1.74(m,2H),1.52-1.32(m,2H),1.17-1.02(m,6H).MS:505[M+H] +.
Figure PCTCN2020080203-appb-000096
实施例128. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-甲氧基-6-甲基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例128的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-甲氧基-6-甲基-5-嘧啶胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.58(s,1H),9.68(s,1H),8.61(d,J＝9.7Hz,2H),8.00-7.86(m,1H),7.45-7.29(m,1H),7.17(s,1H),7.01(s,1H),6.96-6.88(m,1H),6.22-6.15(m,1H),5.73(dd,J＝10.4,2.4Hz,1H),4.55(d,J＝13.3Hz,1H),4.24-4.09(m,2H),3.88(s,3H),3.26-3.19(m,1H),2.84-2.75(m,1H),2.27(s,3H),1.88(s,2H),1.68-1.45(m,2H).MS:479[M+H] +.
实施例129.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-甲氧基-6-甲基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例129的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-甲氧基-6-甲基-5-嘧啶胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.59(s,1H),9.70(s,1H),8.64(d,J＝10.9Hz,2H),7.94(s,1H),7.35(m,1H),7.19(s,1H),7.11(s,1H),6.92-6.76(m,1H),6.19-6.04(m,1H),5.75-5.63(m,1H),4.57-4.17(m,1H),4.10-4.07(m,1H),3.89(s,4H),3.30-3.05(m,1H),2.87-2.79(m,1H),2.29(s,3H),1.96(s,1H),1.72(s,2H),1.50(s,1H).MS:479[M+H] +.
Figure PCTCN2020080203-appb-000097
实施例130.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-甲氧基-6-甲基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例130的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-甲氧基-6-甲基-5-嘧啶胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.59(s,1H),9.70(s,1H),8.64(d,J＝8.7Hz,2H),7.93(s,1H),7.35(s,1H),7.19(s,1H),7.11(s,1H),6.91-6.76(m,1H),6.18-6.05(m,1H),5.75-5.64(m,1H),4.57-4.21(m,1H),4.13-4.04(m,1H),3.90(d,J＝4.5Hz,4H),3.32-3.06(m,1H),2.92-2.74(m,1H),2.29(s,3H),2.03-1.63(m,3H),1.51(s,1H).MS:479[M+H] +.
实施例131. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-乙基-6-甲氧基苯基)氨基)嘧啶-5-甲酰胺
实施例131的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-乙基-6-甲氧基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),9.53(s,1H),8.56(s,1H),8.00-7.67(m,1H),7.32-7.26(m,1H),7.26-7.15(m,1H),7.14(s,1H),7.00-6.91(m, 4H),6.27-6.17(m,1H),5.79-5.74(m,1H),4.61-4.52(m,1H),4.24-4.15(m,1H),4.09-3.98(m,1H),3.67(s,3H),3.19(t,J＝12.9Hz,1H),2.77(t,J＝12.8Hz,1H),2.46-2.41(m,1H),1.81-1.72(m,2H),1.49-1.34(m,2H),1.27-1.19(m,1H),1.04(t,J＝7.5Hz,3H).MS:491[M+H] +.
Figure PCTCN2020080203-appb-000098
实施例132. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-乙基-6-甲基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例132的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-乙基-6-甲基嘧啶-5-胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.77(s,1H),9.70(s,1H),8.89(s,1H),8.65(s,1H),8.03-7.86(m,1H),7.48-7.31(m,1H),7.13(s,1H),6.96-6.89(m,1H),6.84(s,1H),6.22-6.15(m,1H),5.76-5.72(m,1H),4.59-4.52(m,1H),4.22-4.15(m,1H),4.13-4.04(m,1H),3.26-3.18(m,1H),2.83-2.77(m,1H),2.68-2.64(m,2H),2.31(s,3H),1.88-1.82(m,2H),1.58-1.41(m,2H),1.10(t,J＝7.5,7.5Hz,3H).MS:477[M+H] +.
实施例133.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-乙基-6-甲基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例133的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-乙基-6-甲基嘧啶-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.79(s,1H),9.82-9.25(m,1H),8.95-8.83(m,1H),8.73-8.64(m,1H),8.09-7.86(m,1H),7.52-7.29(m,1H),7.14(s,1H),6.97(s,1H),6.89-6.76(m,1H),6.17-6.06(m,1H),5.73-5.64(m,1H),4.54-4.21(m,1H),4.11-4.01(m,1H),3.92-3.79(m,1H),3.25-3.09(m,1H),2.92-2.78(m,1H),2.70-2.65(m,2H),2.33(s,3H),1.94-1.79(m,2H),1.60-1.51(m,2H),1.15-1.09(m,3H).MS:477[M+H] +.
Figure PCTCN2020080203-appb-000099
实施例134.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-乙基-6-甲基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例134的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-乙基-6-甲基嘧啶-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.81-10.72(m,1H),9.72(s,1H),8.96-8.92(m,1H),8.71-8.65(m,1H),8.02-7.89(m,1H),7.46-7.30(m,1H),7.14(s,1H),6.96(s,1H),6.89- 6.76(m,1H),6.17-6.06(m,1H),5.74-5.64(m,1H),4.54-4.21(m,1H),4.12-4.04(m,1H),3.92-3.79(m,1H),3.27-3.08(m,1H),2.89-2.72(m,1H),2.69-2.65(m,2H),2.33(s,3H),1.94-1.89(m,1H),1.86-1.77(m,1H),1.73-1.58(m,1H),1.55-1.47(m,1H),1.14-1.10(m,3H).MS:477[M+H] +.
实施例135.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氨基甲酰基-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例135的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酰胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.60-10.55(m,1H),9.61(s,1H),8.60(s,1H),8.03-7.87(m,2H),7.57-7.48(m,2H),7.45-7.28(m,2H),7.22(s,1H),7.08(s,1H),6.87-6.61(m,1H),6.14-6.00(m,1H),5.71-5.60(m,1H),4.48-4.12(m,1H),4.01-3.92(m,1H),3.78(s,3H),3.09-2.78(m,1H),2.18(s,3H),1.85-1.72(m,2H),1.63-1.44(m,2H),1.31-1.21(m,2H).MS:520[M+H] +.
Figure PCTCN2020080203-appb-000100
实施例136.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-氨基甲酰基-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例136的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酰胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.60-10.54(m,1H),9.61(s,1H),8.60(s,1H),8.03-7.90(m,2H),7.56-7.47(m,2H),7.42-7.28(m,2H),7.22(s,1H),7.08(s,1H),6.84-6.63(m,1H),6.14-6.00(m,1H),5.71-5.60(m,1H),4.48-4.12(m,1H),4.01-3.93(m,1H),3.78(s,3H),3.44-3.36(m,1H),3.31-3.18(m,1H),3.07-2.82(m,1H),2.18(s,3H),1.85-1.74(m,2H),1.63-1.48(m,2H).MS:520[M+H] +.
实施例137. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-氨基甲酰基-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
Figure PCTCN2020080203-appb-000101
实施例137的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酰胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.58(s,1H),8.59(s,1H),8.14(s,1H),7.89(s,1H),7.58(s,2H),7.52(s,1H),7.43-7.24(m,1H),7.19(s,1H),6.90(s,1H),6.88-6.82(m,1H),6.12(dd,J＝16.6,2.4Hz,1H),5.70(dd,J＝10.4,2.4Hz,1H), 4.49-4.38(m,2H),4.16-4.08(m,1H),3.77(s,3H),3.43-3.35(m,1H),3.31-3.16(m,2H),2.82(s,1H),2.17(s,3H),1.68(s,2H).MS:520[M+H] +.
实施例138. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(甲基氨基甲酰基)苯基)氨基)嘧啶-5-甲酰胺
Figure PCTCN2020080203-appb-000102
一).4-((2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸的制备
制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酸替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯；
二).2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(甲基氨基甲酰基)苯基)氨基)嘧啶-5-甲酰胺的制备
将(4-((2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸)104毫克(0.2mmol)置于反应瓶中，加入1毫升N,N-二甲基甲酰胺，随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯114毫克(0.3mmol)、N,N-二异丙基乙基胺52毫克(0.4mmol)，搅拌0.5小时后加入甲胺盐酸盐14毫克(0.2mmol)，搅拌至反应完毕。加入5毫升水稀释后，乙酸乙酯萃取，有机相减压旋干，所得固体柱层析纯化得产品53毫克，产率50％。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.58(s,1H),8.62-8.58(m,2H),7.89(s,1H),7.53-7.46(m,2H),7.35-7.23(m,1H),7.19(s,1H),6.96(s,1H),6.89-6.82(m,1H),6.15-6.10(m,1H),5.72-5.68(m,1H),4.49-4.41(m,1H),4.15-4.07(m,1H),3.78(s,3H),3.26-3.06(m,2H),2.82(d,J＝4.4Hz,3H),2.77-2.66(m,1H),2.17(s,3H),1.76-1.59(m,4H).MS:534[M+H] +.
实施例139.(R)-4-((2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸
实施例139的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酸替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.59(s,1H),9.60(s,1H),8.60(s,1H),8.00–7.83(m,1H),7.57(s,1H),7.47(s,1H),7.22(s,2H),7.11(s,1H),6.85–6.61(m,1H),6.14–6.02(m, 1H),5.69–5.59(m,1H),4.11–3.96(m,1H),3.77(s,3H),3.41–3.19(m,4H),2.17(s,3H),1.78–1.48(m,4H).MS:521[M+H] +.
Figure PCTCN2020080203-appb-000103
实施例140.(S)-4-((2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸
实施例140的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酸替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.58(s,1H),8.59(s,1H),7.94–7.87(m,1H),7.55(s,1H),7.46(s,1H),7.21(s,2H),7.11(s,1H),6.88–6.59(m,1H),6.11–6.03(m,1H),5.68–5.61(m,1H),3.96–3.93(m,1H),3.75(s,3H),3.17–2.83(m,4H),2.15(s,3H),1.73–1.52(m,4H).MS:521[M+H] +.
实施例141.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(甲基氨基甲酰基)苯基)氨基)嘧啶-5-甲酰胺
将((R)-4-((2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸)104毫克(0.2mmol)置于反应瓶中，加入1毫升N,N-二甲基甲酰胺，随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯114毫克(0.3mmol)、N,N-二异丙基乙基胺52毫克(0.4mmol)，搅拌0.5小时后加入甲胺盐酸盐14毫克(0.2mmol)，搅拌至反应完毕。加入5毫升水稀释后，乙酸乙酯萃取，有机相减压旋干，所得固体柱层析纯化得产品。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.61(s,1H),8.60(s,1H),8.48-8.43(m,1H),7.90(s,1H),7.51-7.43(m,2H),7.35-7.20(m,2H),7.02(s,1H),6.88-6.64(m,1H),6.17-6.02(m,1H),5.73-5.61(m,1H),4.48-4.20(m,1H),4.06-3.93(m,1H),3.78(s,3H),3.73-3.61(m,1H),3.33-3.31(m,1H),3.21-2.93(m,1H),2.78-2.75(m,3H),2.17(s,3H),1.84-1.69(m,2H),1.65-1.47(m,2H).MS:534[M+H] +.
Figure PCTCN2020080203-appb-000104
实施例142.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(甲基氨基甲酰基)苯基)氨基)嘧啶-5-甲酰胺
将((S)-4-((2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸)104毫克(0.2mmol)置于反应瓶中，加入1毫升N,N-二甲基甲酰胺，随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯114毫克(0.3mmol)、N,N-二异丙基乙基胺52毫克(0.4mmol)，搅拌0.5小时后加入甲胺盐酸盐14毫克(0.2mmol)，搅拌至反应完毕。加入5毫升水稀释后，乙酸乙酯萃取，有机相减压旋干，所得固体柱层析纯化得产品。 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.60(s,1H),8.59(s,1H),8.47(s,1H),7.91(s,1H),7.50-7.42(m,2H),7.36-7.21(m,2H),7.02(s,1H),6.87-6.62(m,1H),6.17-6.01(m,1H),5.73-5.61(m,1H),4.51-4.39(m,1H),4.26-4.13(m,1H),4.06-3.99(m,1H),3.98-3.90(m,1H),3.78(s,3H),3.04-2.93(m,1H),2.78-2.74(m,3H),2.17(s,3H),1.84-1.68(m,2H),1.65-1.47(m,2H).MS:534[M+H] +.
实施例143.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(二甲基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例143的制备方法参考实施例141的制备方法，其中以等摩尔当量的二甲胺的四氢呋喃溶液(2M)替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.59(s,1H),8.59(s,1H),7.96-7.88(m,1H),7.23-7.21(m,2H),7.12-7.08(m,2H),6.98-6.95(m,1H),6.86-6.73(m,1H),6.24-5.97(m,1H),5.76-5.71(m,1H),3.75(s,3H),3.30-3.30(m,2H),3.02-2.97(m,7H),2.95-2.92(m,6H),2.16(s,3H).MS:548[M+H] +.
Figure PCTCN2020080203-appb-000105
实施例144.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(二甲基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例144的制备方法参考实施例142的制备方法，其中以等摩尔当量的二甲胺的四氢呋喃溶液(2M)替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),9.64(s,1H),8.59(s,1H),7.91(s,1H),7.33-7.21(m,2H),7.16-7.07(m,2H),6.97(s,1H),6.91-6.82(m,1H),6.20-6.05(m,1H),5.75-5.64(m,1H),4.48-4.22(m,1H),4.11-4.03(m,1H),4.01-3.87(m,1H),3.78-3.74(m,3H),3.34-3.26(m,1H),3.08-3.00(m,1H),2.98(s,3H),2.95(s,3H),2.82-2.66(m,1H),2.17(s,3H),1.94-1.89(m,1H),1.82-1.73(m,1H),1.64-1.50(m,1H).MS:548[M+H] +.
实施例145.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(乙基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例145的制备方法参考实施例141的制备方法，其中以等摩尔当量的乙胺的四氢呋喃溶液(2M)替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.58(s,1H),9.65(s,1H),8.63(s,1H),8.50(s,1H),7.94(s,1H),7.54(s,1H),7.49(s,1H),7.30-7.20(m,2H),7.10(s,1H),6.89-6.68(m,1H),6.20-6.04(m,1H),5.76- 5.65(m,1H),4.55-4.19(m,1H),4.08-3.99(m,1H),3.81(s,3H),3.31-3.24(m,3H),3.21-3.00(m,1H),2.78-2.63(m,1H),2.15(s,3H),1.86-1.70(m,2H),1.65-1.45(m,2H),1.18-1.10(m,3H).MS:548[M+H] +.
Figure PCTCN2020080203-appb-000106
实施例146.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(乙基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例146的制备方法参考实施例142的制备方法，其中以等摩尔当量的乙胺的四氢呋喃溶液(2M)替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.47(s,1H),7.91(s,1H),7.51(s,1H),7.45(s,1H),7.31-7.22(m,2H),7.06(s,1H),6.87-6.65(m,1H),6.16-6.00(m,1H),5.72-5.60(m,1H),4.50-4.17(m,1H),4.04-3.94(m,1H),3.79(s,3H),3.31-3.24(m,3H),3.21-2.99(m,1H),2.78-2.66(m,1H),2.18(s,3H),1.83-1.71(m,2H),1.61-1.47(m,2H),1.15-1.12(m,3H).MS:548[M+H] +.
实施例147.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(异丙基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例147的制备方法参考实施例141的制备方法，其中以等摩尔当量的异丙胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.60(s,1H),8.60(s,1H),8.44-8.39(m,3H),8.20(d,J＝7.8Hz,1H),7.52(s,1H),7.44(s,1H),7.22(s,1H),7.09(s,1H),6.13-6.02(m,1H),5.70-5.62(m,1H),4.09-3.95(m,3H),3.79(s,3H),2.18(s,3H),1.75-1.49(m,4H),1.24-1.23(m,3H),1.18-1.16(m,6H).MS:562[M+H] +.
Figure PCTCN2020080203-appb-000107
实施例148.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(异丙基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例148的制备方法参考实施例142的制备方法，其中以等摩尔当量的异丙胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.21(d,J＝7.6Hz,1H),7.91(s,1H),7.52(s,1H),7.44(s,1H),7.33-7.21(m,2H),7.10(s,1H),6.86-6.65(m,1H),6.14-5.99(m,1H),5.71-5.60(m,1H),4.51-4.15(m,1H),4.14-4.06(m,2H),4.03-3.92(m,1H),3.79(s,3H),3.23-3.00(m,1H),2.84-2.66(m,1H),2.18(s,3H),1.85-1.72(m,2H),1.62-1.49(m,2H),1.19-1.16(m,6H).MS:562[M+H] +.
实施例149.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(环丁基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例149的制备方法参考实施例141的制备方法，其中以等摩尔当量的环丁胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.59(s,1H),8.62-8.27(m,3H),7.98-7.79(m,1H),7.53-7.51(m,1H),7.45-7.42(m,1H),7.23-7.21(m,1H),7.06(s,1H),6.85-6.63(m,1H),6.14-6.01(m,1H),5.71-5.61(m,1H),4.49-4.38(m,2H),4.17-3.93(m,2H),3.79(s,3H),2.28-2.20(m,3H),2.18(s,3H),2.11-2.02(m,3H),1.77-1.66(m,4H),1.55-1.44(m,2H).MS:574[M+H] +.
Figure PCTCN2020080203-appb-000108
实施例150.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(环丁基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例150的制备方法参考实施例142的制备方法，其中以等摩尔当量的环丁胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.61(s,1H),8.63-8.59(m,2H),7.91(s,1H),7.52(s,1H),7.44(s,1H),7.31-7.21(m,2H),7.06(s,1H),6.87-6.67(m,1H),6.15-6.00(m,1H),5.72-5.60(m,1H),4.49-4.39(m,2H),4.22-4.08(m,1H),4.01-3.94(m,1H),3.79(s,3H),3.19-2.97(m,1H),2.77-2.67(m,1H),2.24-2.21(m,2H),2.18(s,3H),2.10-2.04(m,2H),1.82-1.77(m,1H),1.72-1.66(m,3H),1.59-1.48(m,2H).MS:574[M+H] +.
实施例151.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(环戊基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例151的制备方法参考实施例141的制备方法，其中以等摩尔当量的环戊胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.59(s,1H),8.60(s,1H),8.46(s,1H),8.27(d,J＝7.3Hz,1H),7.96-7.79(m,1H),7.53-7.51(m,1H),7.43(s,1H),7.23-7.21(m,1H),7.09-7.06(m,1H),6.86-6.63(m,1H),6.14-6.04(m,1H),5.71-5.62(m,1H),4.26-4.14(m,2H),4.13-3.88(m,2H),3.79(s,3H),2.18(s,3H),1.94-1.86(m,3H),1.79-1.67(m,5H),1.57-1.51(m,6H).MS:588[M+H] +.
Figure PCTCN2020080203-appb-000109
Figure PCTCN2020080203-appb-000110
实施例152.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(环戊基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例152的制备方法参考实施例142的制备方法，其中以等摩尔当量的环戊胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.29-8.26(m,1H),7.91(s,1H),7.53(s,1H),7.43(s,1H),7.31-7.22(m,2H),7.08(s,1H),6.86-6.65(m,1H),6.15-6.01(m,1H),5.71-5.61(m,1H),4.53-4.42(m,1H),4.25-4.14(m,2H),4.03-3.95(m,1H),3.79(s,3H),3.21-3.00(m,1H),2.80-2.68(m,1H),2.18(s,3H),1.93-1.88(m,2H),1.82-1.78(m,1H),1.73-1.68(m,3H),1.57-1.52(m,6H).MS:588[M+H] +.
实施例153.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(环己基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例153的制备方法参考实施例141的制备方法，其中以等摩尔当量的环己胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.59(s,1H),8.60(s,1H),8.28-8.17(m,1H),7.98-7.79(m,1H),7.54-7.50(m,1H),7.44-7.40(m,1H),7.37-7.21(m,2H),7.12-7.08(m,1H),6.84-6.63(m,1H),6.14-6.01(m,1H),5.70-5.58(m,1H),4.49-3.95(m,2H),3.78(s,3H),2.18(s,3H),1.85-1.71(m,8H),1.62-1.44(m,4H),1.35-1.26(m,6H).MS:602[M+H] +.
Figure PCTCN2020080203-appb-000111
实施例154.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(环己基氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例154的制备方法参考实施例142的制备方法，其中以等摩尔当量的环己胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.22-8.16(m,1H),7.90(s,1H),7.52(s,1H),7.43(s,1H),7.31-7.21(m,2H),7.10(s,1H),6.86-6.65(m,1H),6.14-6.00(m,1H),5.71-5.59(m,1H),4.50-4.11(m,1H),4.04-3.94(m,1H),3.79(s,3H),3.25-2.99(m,1H),2.84-2.63(m,1H),2.18(s,3H),1.86-1.79(m,4H),1.78-1.70(m,4H),1.64-1.56(m,2H),1.34-1.27(m,5H),1.17-1.09(m,1H).MS:602[M+H] +.
实施例155.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(氮杂环丁烷-1-羰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例155的制备方法参考实施例141的制备方法，其中以等摩尔当量的氮杂环丁烷替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.60(s,1H),8.59(s,1H),7.98-7.83(m,1H),7.27-7.16(m,4H),7.06-7.00(m,1H),6.96-6.74(m,1H),6.29-6.06(m,1H),5.76-5.66(m,1H),4.45-4.27(m,3H),4.08-4.00 (m,3H),3.77(s,3H),3.31-3.29(m,2H),2.27-2.21(m,3H),2.17(s,3H),1.85-1.73(m,3H),1.55-1.49(m,1H).MS:560[M+H] +.
Figure PCTCN2020080203-appb-000112
实施例156.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(氮杂环丁烷-1-羰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例156的制备方法参考实施例142的制备方法，其中以等摩尔当量的氮杂环丁烷替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55-10.48(m,1H),9.60(s,1H),8.60(s,1H),7.90(s,1H),7.25-7.14(m,4H),7.07-7.00(m,1H),6.98-6.86(m,1H),6.27-6.08(m,1H),5.78-5.66(m,1H),4.47-4.28(m,3H),4.12-4.07(m,1H),4.05-4.01(m,2H),3.77(s,3H),3.72-3.60(m,1H),3.24-3.00(m,1H),2.74-2.65(m,1H),2.27-2.22(m,2H),2.18(s,3H),1.90-1.84(m,1H),1.81-1.72(m,2H),1.58-1.46(m,1H).MS:560[M+H] +.
实施例157.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡咯烷-1-羰基)苯基)氨基)嘧啶-5-甲酰胺
实施例157的制备方法参考实施例141的制备方法，其中以等摩尔当量的四氢吡咯替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.50-10.46(m,1H),9.58(s,1H),8.59(s,1H),8.02-7.75(m,1H),7.20(s,2H),7.13-7.01(m,3H),6.91-6.74(m,1H),6.19-6.06(m,1H),5.73-5.66(m,1H),3.76(s,3H),3.51-3.42(m,6H),3.31-3.30(m,1H),2.86-2.86(m,3H),2.16(s,3H),1.90-1.81(m,7H).MS:574[M+H] +.
Figure PCTCN2020080203-appb-000113
实施例158.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡咯烷-1-羰基)苯基)氨基)嘧啶-5-甲酰胺
实施例158的制备方法参考实施例142的制备方法，其中以等摩尔当量的四氢吡咯替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.50-10.45(m,1H),9.59(s,1H),8.59(s,1H),7.89(s,1H),7.30-7.21(m,1H),7.20(s,1H),7.12-6.98(m,3H),6.91-6.80(m,1H),6.19-6.04(m,1H),5.76-5.65(m,1H),4.50-4.22(m,1H),4.09-3.85(m,2H),3.78-3.74(m,3H),3.50-3.43(m,4H),3.22-2.98(m,1H),2.75-2.64(m,1H),2.17(s,3H),1.90-1.79(m,7H),1.66-1.51(m,1H).MS:574[M+H] +.
实施例159.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(哌啶-1-羰基)苯基)氨基)嘧啶-5-甲酰胺
实施例159的制备方法参考实施例141的制备方法，其中以等摩尔当量的哌啶替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),9.58(s,1H),8.59(s,1H),7.98-7.80(m,1H),7.32-7.19(m,2H),7.10(s,1H),6.99-6.70(m,3H),6.19-6.06(m,1H),5.75-5.65(m,1H),4.33-3.81(m,3H),3.75(s,3H),3.61-3.41(m,3H),3.31-3.30(m,1H),2.16(s,3H),1.94-1.90(m,1H),1.80-1.75(m,1H),1.63-1.47(m,8H),1.27-1.18(m,2H).MS:588[M+H] +.
Figure PCTCN2020080203-appb-000114
实施例160.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(哌啶-1-羰基)苯基)氨基)嘧啶-5-甲酰胺
实施例160的制备方法参考实施例142的制备方法，其中以等摩尔当量的哌啶替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),9.59(s,1H),8.59(s,1H),7.90(s,1H),7.29-7.20(m,2H),7.12-7.09(m,1H),6.95-6.90(m,1H),6.89-6.65(m,2H),6.19-6.05(m,1H),5.75-5.64(m,1H),4.50-4.22(m,1H),4.09-4.00(m,1H),3.99-3.79(m,2H),3.75(s,3H),3.62-3.43(m,3H),3.18-2.98(m,1H),2.82-2.66(m,1H),2.17(s,3H),1.99-1.88(m,2H),1.84-1.71(m,2H),1.64-1.60(m,2H),1.55-1.48(m,4H).MS:588[M+H] +.
实施例161.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吗啉-4-羰基)苯基)氨基)嘧啶-5-甲酰胺
实施例161的制备方法参考实施例141的制备方法，其中以等摩尔当量的吗啉替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),9.60(s,1H),8.60(s,1H),8.00-7.78(m,1H),7.25-7.16(m,2H),7.15(s,1H),7.05-6.95(m,2H),6.93-6.82(m,1H),6.20–6.05(m,1H),5.75-5.66(m,1H),4.48-4.25(m,1H),4.10-4.00(m,1H),4.00-3.84(m,2H),3.80-3.74(m,4H),3.65(s,3H),3.50-3.40(m,3H),3.08-3.00(m,1H),2.78-2.71(m,1H),2.15(s,3H),2.00-1.90(m,2H),1.80-1.75(m,1H),1.68-1.56(m,1H).MS:590[M+H] +.
Figure PCTCN2020080203-appb-000115
实施例162.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吗啉-4-羰基)苯基)氨基)嘧啶-5-甲酰胺
实施例162的制备方法参考实施例142的制备方法，其中以等摩尔当量的吗啉替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),9.59(s,1H),8.59(s,1H),7.98-7.79(m,1H),7.25-7.18(m,2H),7.13(s,1H),7.03-6.93(m,2H),6.90-6.81(m,1H),6.18-6.05(m,1H),5.74-5.66(m,1H),4.49-4.24(m,1H),4.08-4.01(m,1H),3.99-3.84(m,2H),3.78-3.74(m,4H),3.62(s,3H),3.50-3.42(m,3H),3.08-2.99(m,1H),2.78-2.70(m,1H),2.17(s,3H),1.97-1.90(m,2H),1.81-1.76(m,1H),1.66-1.54(m,1H).MS:590[M+H] +.
实施例163.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-4-((2-甲氧基乙基)氨基甲酰基)-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例163的制备方法参考实施例141的制备方法，其中以等摩尔当量的2-甲氧基乙-1-胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.62(s,1H),9.65(s,1H),8.61(s,1H),8.56(s,1H),7.90(s,1H),7.52(s,1H),7.47(s,1H),7.40-7.29(m,1H),7.23(s,1H),7.05(s,1H),6.89-6.76(m,1H),6.15-6.00(m,1H),5.70-5.60(m,1H),4.50-4.13(m,1H),4.04-3.91(m,1H),3.79(s,3H),3.48-3.45(m,4H),3.43-3.42(m,1H),3.28(s,3H),3.18-3.00(m,1H),2.84-2.67(m,1H),2.19(s,3H),1.85-1.76(m,2H),1.62-1.50(m,2H)..MS:578[M+H] +.
Figure PCTCN2020080203-appb-000116
实施例164.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-4-((2-甲氧基乙基)氨基甲酰基)-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例164的制备方法参考实施例142的制备方法，其中以等摩尔当量的2-甲氧基乙-1-胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.60(s,1H),9.65(s,1H),8.60(s,1H),8.56(s,1H),7.92(s,1H),7.53(s,1H),7.47(s,1H),7.41-7.28(m,1H),7.23(s,1H),7.07(s,1H),6.88-6.77(m,1H),6.16-6.01(m,1H),5.72-5.60(m,1H),4.49-4.13(m,1H),4.04-3.91(m,1H),3.79(s,3H),3.48-3.45(m,4H),3.43-3.42(m,1H),3.28(s,3H),3.18-2.98(m,1H),2.83-2.67(m,1H),2.18(s,3H),1.84-1.74(m,2H),1.61-1.48(m,2H).MS:578[M+H] +.
实施例165.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-羟基乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例165的制备方法参考实施例141的制备方法，其中以等摩尔当量的2-氨基乙-1-醇替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.60(s,1H),8.60(s,1H),8.49-8.46(m,1H),7.94-7.86(m,1H),7.54-7.52(m,1H),7.47-7.46(m,1H),7.37-7.26(m,1H),7.22(s,1H),7.06(s,1H),6.87-6.58(m,1H), 6.13-6.01(m,1H),5.71-5.64(m,1H),4.75-4.73(m,1H),4.21-3.99(m,2H),3.79(s,3H),3.74-3.65(m,1H),3.53-3.50(m,3H),3.31-3.30(m,3H),2.18(s,3H),1.76-1.46(m,4H).MS:564[M+H] +.
Figure PCTCN2020080203-appb-000117
实施例166.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-羟基乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例166的制备方法参考实施例142的制备方法，其中以等摩尔当量的2-氨基乙-1-醇替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.50-8.46(m,1H),7.91(s,1H),7.53(s,1H),7.47(s,1H),7.31-7.22(m,2H),7.07(s,1H),6.86-6.64(m,1H),6.16-6.01(m,1H),5.72-5.61(m,1H),4.76-4.73(m,1H),4.49-4.13(m,1H),4.04-3.95(m,1H),3.79(s,3H),3.77-3.67(m,1H),3.53-3.50(m,2H),3.22-2.98(m,1H),2.80-2.65(m,1H),2.18(s,3H),1.84-1.67(m,3H),1.63-1.41(m,3H).MS:564[M+H] +.
实施例167.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-((四氢-2H-吡喃-4-基)氨基甲酰基)苯基)氨基)嘧啶-5-甲酰胺
实施例167的制备方法参考实施例141的制备方法，其中以等摩尔当量的四氢-2H-吡喃-4-胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.31-8.29(m,1H),7.92-7.87(m,1H),7.52(s,1H),7.44(s,1H),7.33-7.27(m,1H),7.22(s,1H),7.08(s,1H),6.90-6.76(m,1H),6.11-6.05(m,1H),5.69-5.63(m,1H),4.50-4.14(m,1H),4.01-3.98(m,2H),3.91-3.87(m,2H),3.79(s,3H),3.39-3.38(m,2H),3.30-3.30(m,1H),3.24-2.96(m,1H),2.83-2.69(m,1H),2.18(s,3H),1.79-1.74(m,4H),1.59-1.54(m,4H).MS:604[M+H] +.
Figure PCTCN2020080203-appb-000118
实施例168.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-((四氢-2H-吡喃-4-基)氨基甲酰基)苯基)氨基)嘧啶-5-甲酰胺
实施例168的制备方法参考实施例142的制备方法，其中以等摩尔当量的四氢-2H-吡喃-4-胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.61(s,1H),8.61(s,1H),8.32-8.29(m,1H),7.91(s, 1H),7.53(s,1H),7.44(s,1H),7.32-7.21(m,2H),7.09(s,1H),6.87-6.67(m,1H),6.15-6.01(m,1H),5.72-5.61(m,1H),4.50-4.14(m,1H),4.05-3.98(m,2H),3.91-3.87(m,2H),3.79(s,3H),3.43-3.36(m,3H),3.24-2.96(m,1H),2.83-2.69(m,1H),2.19(s,3H),1.81-1.74(m,4H),1.61-1.53(m,4H).MS:604[M+H] +.
实施例169.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((氰基甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例169的制备方法参考实施例141的制备方法，其中以等摩尔当量的氨基乙腈替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),9.63(s,1H),9.24(s,1H),8.61(s,1H),7.99-7.87(m,1H),7.56-7.46(m,3H),7.43-7.25(m,1H),7.22(s,1H),7.10-7.06(m,1H),6.24-5.97(m,1H),5.73-5.63(m,1H),4.39-4.28(m,3H),4.15-3.96(m,2H),3.80(s,3H),3.75-3.68(m,1H),2.19(s,3H),1.81-1.43(m,5H).MS:559[M+H] +.
Figure PCTCN2020080203-appb-000119
实施例170.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((氰基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例170的制备方法参考实施例142的制备方法，其中以等摩尔当量的氨基乙腈替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),9.63(s,1H),9.24(s,1H),8.61(s,1H),7.91(s,1H),7.56-7.47(m,2H),7.36-7.24(m,1H),7.22(s,1H),7.11-7.06(m,1H),6.85-6.58(m,1H),6.16-6.01(m,1H),5.74-5.59(m,1H),4.47-4.35(m,1H),4.34-4.29(m,2H),4.02-3.91(m,1H),3.80(s,3H),3.79-3.74(m,1H),3.22-2.95(m,1H),2.83-2.61(m,1H),2.19(s,3H),1.86-1.71(m,2H),1.61-1.45(m,2H).MS:559[M+H] +.
实施例171. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-((氰甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
Figure PCTCN2020080203-appb-000120
实施例171的制备方法参考实施例138的制备方法，其中最后一步中以等摩尔当量的氨基乙腈替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.59(s,1H),9.33(t,J＝5.4,5.4Hz,1H),8.60(s,1H),7.90(s,1H),7.57-7.49(m,2H),7.37-7.23(m,1H),7.19(s,1H),7.01(s,1H),6.87-6.79(m,1H),6.11(dd,J＝16.6,2.4Hz,1H),5.69(dd,J＝10.4,2.4Hz,1H),4.47-4.41(m,1H),4.39-4.37(m,2H),4.12-4.05(m,1H), 3.84-3.81(m,1H),3.80(s,3H),3.22-3.12(m,1H),2.84-2.73(m,1H),2.19(s,3H),1.78-1.70(m,2H),1.66-1.57(m,2H).MS:559[M+H] +.
实施例172.(R)-4-((4-(4-乙酰基哌嗪-1-基)-2-甲氧基-6-甲基苯基)氨基)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺
实施例172的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的1-(4-(4-氨基-3-甲氧基-5-甲基苯基)哌嗪-1-基)乙-1-酮替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.21(s,1H),9.54(s,1H),8.55(s,1H),7.95-7.46(m,1H),7.29-7.08(m,3H),6.99-6.76(m,1H),6.61-6.45(m,2H),6.26-6.08(m,1H),5.79-5.69(m,1H),4.53-3.76(m,2H),3.73-3.63(m,4H),3.59-3.49(m,4H),3.31(s,1H),3.16-3.00(m,5H),2.09-2.01(m,6H),1.96-1.73(m,4H).MS:603[M+H] +.
Figure PCTCN2020080203-appb-000121
实施例173.(S)-4-((4-(4-乙酰基哌嗪-1-基)-2-甲氧基-6-甲基苯基)氨基)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺
实施例173的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的1-(4-(4-氨基-3-甲氧基-5-甲基苯基)哌啶-1-基)乙-1-酮替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.24-10.19(m,1H),9.54(s,1H),8.55(s,1H),7.85(s,1H),7.24(s,1H),7.21-7.16(m,1H),6.96-6.77(m,1H),6.65-6.40(m,3H),6.28-6.09(m,1H),5.80-5.66(m,1H),4.57-4.28(m,1H),4.17-3.97(m,1H),3.77-3.73(m,1H),3.70(s,3H),3.58-3.50(m,4H),3.15-3.06(m,4H),2.17-2.10(m,2H),2.07(s,3H),2.04(s,3H),1.93-1.80(m,3H),1.49-1.41(m,1H).MS:603[M+H] +.
实施例174.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-甲氧基-5-甲基-[1,1'-联苯基]-4-基)氨基)嘧啶-5-甲酰胺
实施例174的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-甲氧基-5-甲基-[1,1'-联苯基]-4-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.59(s,1H),8.59(s,1H),7.83-7.64(m,3H),7.44-7.34(m,4H),7.32-7.27(m,1H),7.25-7.21(m,2H),7.13-7.07(m,1H),6.76-6.64(m,1H),6.23-6.08(m,1H),5.77-5.66(m,1H),4.49-4.30(m,1H),4.00-3.90(m,1H),3.82(s,3H),3.60-3.49(m,1H),3.28-3.21(m,1H),2.36-2.26(m,1H),2.21(s,3H),2.10-0.93(m,4H).MS:553[M+H] +.
Figure PCTCN2020080203-appb-000122
实施例175.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((3-甲氧基-5-甲基-[1,1'-联苯基]-4-基)氨基)嘧啶-5-甲酰胺
实施例175的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-甲氧基-5-甲基-[1,1'-联苯基]-4-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.59(s,1H),8.59(s,1H),7.76-7.66(m,3H),7.47-7.34(m,5H),7.25-7.21(m,2H),7.13-7.05(m,1H),6.81-6.66(m,1H),6.24-6.07(m,1H),5.78-5.68(m,1H),4.54-4.19(m,1H),3.82(s,3H),3.76-3.61(m,1H),3.58-3.49(m,1H),3.31-3.31(m,1H),2.31-2.25(m,1H),2.20(s,3H),1.88-1.01(m,4H).MS:553[M+H] +.
实施例176. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((3-甲氧基-5-甲基-[1,1'-联苯基]-4-基)氨基)嘧啶-5-甲酰胺
实施例176的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-甲氧基-5-甲基-[1,1'-联苯基]-4-胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),9.54(s,1H),8.59(s,1H),7.94-7.82(m,3H),7.51(t,2H),7.40-7.36(m,2H),7.34-7.21(m,2H),7.17(s,1H),7.04(s,1H),6.68-6.57(m,1H),6.08-6.01(m,1H),5.66-5.62(m,1H),4.22-4.08(m,1H),3.82(s,3H),3.80-3.63(m,1H),3.61-3.53(m,1H),3.31(m,1H),2.20(s,3H),2.01-1.87(m,1H),1.65-1.47(m,4H).MS:553[M+H] +.
Figure PCTCN2020080203-appb-000123
实施例177. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡啶-3-基)苯基)氨基)嘧啶-5-甲酰胺
实施例177的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(吡啶-3-基)苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),9.56(s,1H),9.12(s,1H),8.60-8.58(m,2H),8.31-8.25(m,1H),8.10-7.73(m,1H),7.55-7.52(m,1H),7.45(s,1H),7.38(s,1H),7.32-7.21(m,1H),7.18(s,1H),7.06(s,1H),6.73-6.58(m,1H),6.09-6.02(m, 1H),5.67-5.63(m,1H),4.22-4.12(m,1H),3.83(s,3H),3.61(s,1H),2.21(s,3H),2.04-1.88(m,1H),1.67-1.47(m,4H),1.29-1.20(m,2H).MS:554[M+H] +.
实施例178.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡啶-3-基)苯基)氨基)嘧啶-5-甲酰胺
实施例178的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(吡啶-3-基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.52-10.44(m,1H),9.60(s,1H),9.02-8.95(m,1H),8.61-8.54(m,2H),8.13-8.05(m,1H),8.01-7.77(m,1H),7.53-7.28(m,4H),7.24-7.21(m,1H),7.15-7.06(m,1H),6.75-6.57(m,1H),6.17-5.92(m,1H),5.73-5.59(m,1H),4.54-4.14(m,1H),3.94-3.81(m,4H),3.79-3.58(m,1H),3.54-3.36(m,1H),2.76-2.63(m,1H),2.63-2.53(m,1H),2.28-2.17(m,3H),1.84-1.59(m,2H),1.56-1.32(m,1H).MS:554[M+H] +.
Figure PCTCN2020080203-appb-000124
实施例179.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(吡啶-3-基)苯基)氨基)嘧啶-5-甲酰胺
实施例179的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(吡啶-3-基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.51-10.41(m,1H),9.60(s,1H),9.02-8.94(m,1H),8.62-8.54(m,2H),8.13-8.05(m,1H),7.98-7.75(m,1H),7.49-7.26(m,4H),7.24-7.21(m,1H),7.15-7.04(m,1H),6.76-6.57(m,1H),6.19-6.02(m,1H),5.74-5.62(m,1H),4.46-4.08(m,1H),3.94-3.79(m,4H),3.76-3.52(m,1H),3.51-3.36(m,1H),2.80-2.64(m,1H),2.64-2.54(m,1H),2.29-2.17(m,3H),1.84-1.58(m,2H),1.44-1.24(m,1H).MS:554[M+H] +.
实施例180.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(二甲基氨基)-4-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例180的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的5-甲氧基-N 1,N 1,3-三甲基苯-1,2-二胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.50-10.21(m,1H),9.58(s,1H),8.58(s,1H),7.87(s,1H),7.54-6.98(m,3H),6.94-6.65(m,1H),6.65-6.29(m,2H),6.25-5.91(m,1H),5.80-5.52(m,1H),4.62-4.17(m,1H),4.15-3.95(m,1H),3.81-3.62(m,4H),3.21-2.93(m,1H),2.86-2.65(m,1H),2.62-2.53(m,6H),2.15-1.98(m,3H),1.95-1.56(m,3H),1.55-1.32(m,1H).MS:520[M+H] +.
Figure PCTCN2020080203-appb-000125
实施例181.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-(二甲基氨基)-4-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例181的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的5-甲氧基-N 1,N 1,3-三甲基苯-1,2-二胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.43-10.14(m,1H),9.58(s,1H),8.58(s,1H),7.87(s,1H),7.28-7.12(m,3H),6.97-6.64(m,1H),6.65-6.35(m,2H),6.18-6.07(m,1H),5.80-5.59(m,1H),4.61-4.16(m,1H),4.16-3.91(m,1H),3.79-3.58(m,4H),3.23-2.93(m,1H),2.89-2.62(m,1H),2.62-2.53(m,6H),2.15-1.98(m,3H),1.94-1.57(m,3H),1.54-1.35(m,1H).MS:520[M+H] +.
实施例182. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((2-(二甲基氨基)-4-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例182的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的5-甲氧基-N 1,N 1,3-三甲基苯-1,2-二胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),9.54(s,1H),8.57(s,1H),7.85(s,1H),7.40-6.98(m,3H),6.93-6.73(m,1H),6.60-6.32(m,2H),6.13(dd,J＝16.6,2.4Hz,1H),5.71(d,J＝10.4Hz,1H),4.55-4.34(m,1H),4.13(d,J＝13.6Hz,1H),3.92(t,J＝11.7Hz,1H),3.79(s,3H),3.21-3.11(m,1H),2.82-2.70(m,1H),2.57(s,6H),2.03(s,3H),1.91-1.71(m,2H),1.67-1.37(m,2H).MS:520[M+H] +.
Figure PCTCN2020080203-appb-000126
实施例183. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-甲氧基-2-甲基-6-苯氧基苯基)氨基)嘧啶-5-甲酰胺
实施例183的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-甲氧基-2-甲基-6-苯氧基苯胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),9.52(s,1H),8.49(s,1H),7.87-7.65(m,1H),7.24(s,1H),7.22-7.11(m,4H),7.00-6.97(m,1H),6.87-6.80(m,4H),6.49-6.40(m,1H),6.13-6.08(m,1H),5.70-5.67(m,1H),4.53-4.44(m,1H),4.16-4.09(m, 1H),3.96-3.89(m,1H),3.76(s,3H),3.19-3.07(m,1H),2.79-2.71(m,1H),2.17(s,3H),1.91-1.83(m,1H),1.81-1.58(m,3H).MS:569[M+H] +.
实施例184.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-环丙基-6-甲氧基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例184的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-环丙基-6-甲氧基嘧啶-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.60(s,1H),9.68(s,1H),8.70-8.51(m,2H),7.94(s,1H),7.36(s,1H),7.22(s,1H),7.15(s,1H),6.91-6.72(m,1H),6.18-6.05(m,1H),5.74-5.63(m,1H),4.57-4.20(m,1H),4.11-3.99(m,1H),3.86(s,4H),3.28-3.02(m,1H),2.88-2.65(m,1H),2.09-1.72(m,4H),1.57-1.43(m,1H),0.97(s,4H).MS:505[M+H] +.
Figure PCTCN2020080203-appb-000127
实施例185.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-环丙基-6-甲氧基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例185的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-环丙基-6-甲氧基嘧啶-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.60(s,1H),9.68(s,1H),8.70-8.51(m,2H),7.94(s,1H),7.35(s,1H),7.22(s,1H),7.15(s,1H),6.90-6.74(m,1H),6.18-6.05(m,1H),5.74-5.63(m,1H),4.53-4.26(m,1H),4.07(d,J＝14.1Hz,1H),3.86(s,4H),3.29-3.02(m,1H),2.91-2.68(m,1H),2.07(d,J＝5.7Hz,1H),1.98-1.65(m,3H),1.55-1.43(m,1H),0.97(s,4H).MS:505[M+H] +.
实施例186. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-环丙基-6-甲氧基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例186的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-环丙基-6-甲氧基嘧啶-5-胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.58(s,1H),9.66(s,1H),8.62(s,1H),8.56(s,1H),7.94(s,1H),7.34(s,1H),7.18(s,1H),7.05(s,1H),6.95-6.86(m,1H),6.17(dd,J＝16.7,2.5Hz,1H),5.73(dd,J＝10.5,2.4Hz,1H),4.53(d,J＝13.2Hz,1H),4.24-4.04(m,2H),3.85(s,3H),3.25-3.17(m,1H),2.84-2.75(m,1H),2.10-2.03(m,1H),1.86(d,J＝12.4Hz,2H),1.62-1.40(m,2H),1.02-0.88(m,4H).MS:505[M+H] +.
Figure PCTCN2020080203-appb-000128
Figure PCTCN2020080203-appb-000129
实施例187. 2-((1-(1-丙烯酰基哌啶-4-基)-1H-吡唑-4-基)氨基)-4-((4-环丙基-6-乙基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例187的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-环丙基-6-乙基嘧啶-5-胺替代环丙胺，步骤2)中以等当量的叔-丁基4-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯代替叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.84-10.78(m,1H),9.71(s,1H),8.83-8.65(m,1H),8.02-7.85(m,1H),7.49-7.30(m,1H),7.23-7.14(m,1H),7.13-7.08(m,1H),6.98-6.93(m,1H),6.91-6.87(m,1H),6.21-6.14(m,1H),5.75-5.71(m,1H),4.58-4.48(m,1H),4.21-4.14(m,1H),4.10-4.02(m,1H),3.44-3.34(m,2H),3.30-3.17(m,2H),2.83-2.75(m,1H),2.64-2.59(m,2H),2.10-2.05(m,1H),1.84-1.81(m,1H),1.50-1.40(m,1H),1.09(t,J＝7.4,7.4Hz,3H),1.00-0.96(m,2H),0.88-0.77(m,1H).MS:503[M+H] +.
实施例188.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-环丙基-6-乙基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例188的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-环丙基-6-乙基嘧啶-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.86-10.79(m,1H),9.71(s,1H),9.01-8.83(m,1H),8.65(s,1H),8.02-7.89(m,1H),7.53-7.33(m,1H),7.18-7.12(m,1H),7.02-6.92(m,1H),6.88-6.76(m,1H),6.17-6.06(m,1H),5.74-5.64(m,1H),4.55-4.21(m,1H),4.11-4.02(m,1H),3.89-3.76(m,1H),3.25-3.06(m,1H),2.86-2.67(m,1H),2.65-2.61(m,2H),2.12-2.04(m,1H),1.92-1.79(m,2H),1.65-1.60(m,1H),1.54-1.45(m,1H),1.14-1.09(m,3H),1.03-0.96(m,2H),0.85-0.77(m,2H).MS:503[M+H] +.
Figure PCTCN2020080203-appb-000130
实施例189.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-环丙基-6-乙基嘧啶-5-基)氨基)嘧啶-5-甲酰胺
实施例189的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-环丙基-6-乙基嘧啶-5-胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.85-10.79(m,1H),9.71(s,1H),9.01-8.85(m,1H),8.71-8.64(m,1H),8.01-7.90(m,1H),7.53-7.35(m,1H),7.18-7.12(m,1H),7.01-6.92(m,1H),6.89-6.77(m,1H),6.17-6.05(m,1H),5.73-5.64(m,1H),4.54-4.27(m,1H),4.11-4.02(m,1H),3.84(s,1H),3.15-3.01(m,1H),2.90-2.77(m,1H),2.66-2.63(m,2H),2.13-2.07(m,1H),1.89-1.79(m,2H),1.65-1.60(m,1H),1.51(s,1H),1.17-1.13(m,2H),1.12-1.09(m,3H),1.01-0.97(m,1H),0.82-0.79(m,1H).MS:503[M+H] +.
实施例190.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(甲基磺酰基)苯基)氨基)嘧啶-5-甲酰胺
实施例190的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(甲基磺酰基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.72(s,1H),9.65(s,1H),8.62(s,1H),7.99-7.88(m,1H),7.54-7.44(m,2H),7.39-7.27(m,1H),7.20-7.12(m,2H),6.93-6.59(m,1H),6.16-6.03(m,1H),5.72-5.63(m,1H),4.13-3.94(m,2H),3.89-3.85(m,3H),3.83-3.76(m,1H),3.32-3.30(m,2H),3.26-3.22(m,3H),3.05-2.76(m,1H),2.24(s,3H),1.95-1.91(m,1H),1.81-1.76(m,1H),1.62-1.47(m,1H).MS:555[M+H] +.
Figure PCTCN2020080203-appb-000131
实施例191.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(甲基磺酰基)苯基)氨基)嘧啶-5-甲酰胺
实施例191的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(甲基磺酰基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.75-10.66(m,1H),9.68-9.63(m,1H),8.69-8.61(m,1H),7.99-7.89(m,1H),7.54-7.44(m,2H),7.36-7.18(m,2H),7.16-7.13(m,1H),6.87-6.65(m,1H),6.16-6.01(m,1H),5.72-5.60(m,1H),4.56-4.42(m,1H),4.24-4.07(m,1H),4.06-3.99(m,1H),3.86(s,3H),3.84-3.81(m,1H),3.27-3.23(m,3H),3.14-3.03(m,1H),2.95-2.72(m,1H),2.27-2.23(m,3H),1.94-1.90(m,1H),1.82-1.76(m,1H),1.62-1.51(m,1H).MS:555[M+H] +.
实施例192.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(乙基磺酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例192的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(乙基磺酰基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.74(s,1H),9.65(s,1H),8.62(s,1H),7.99-7.89(m,1H),7.58-7.47(m,1H),7.46-7.22(m,3H),7.19-7.16(m,1H),6.89-6.56(m,1H),6.17-6.04(m,1H),5.73-5.63(m,1H),4.51-3.91(m,3H),3.85-3.81(m,4H),3.31-3.26(m,2H),3.05-2.75(m,1H),2.30-2.21(m,4H),1.94-1.90(m,1H),1.81-1.76(m,1H),1.62-1.49(m,1H),1.17-1.14(m,3H).MS:569[M+H] +.
Figure PCTCN2020080203-appb-000132
实施例193.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(乙基磺酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例193的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的2-甲氧基-6-甲基-4-(乙基磺酰基)苯胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.75(s,1H),9.67–9.63(m,1H),8.68–8.62(m,1H),7.94(s,1H),7.51–7.44(m,1H),7.41–7.29(m,2H),7.20–7.15(m,2H),6.87–6.66(m,1H),6.17–6.01(m,1H),5.72–5.61(m,1H),4.56–4.43(m,1H),4.21–4.07(m,1H),4.06–3.98(m,1H),3.85(s,3H),3.83–3.82(m,1H),3.38–3.35(m,1H),3.32–3.28(m,1H),3.14–3.01(m,1H),2.91–2.72(m,1H),2.28–2.24(m,3H),1.95–1.90(m,1H),1.82–1.76(m,1H),1.62–1.47(m,1H),1.17–1.14(m,3H).MS:569[M+H] +.
实施例194.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(4-(2-氰基乙酰基)哌嗪-1-基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例194的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-(4-(4-氨基-3-甲氧基-5-甲基苯基)哌嗪-1-基)-3-氧代丙腈替代环丙胺。 1H NMR(600MHz,DMSO-d 6)δ10.22(s,1H),9.54(s,1H),8.55(s,1H),7.93-7.75(m,1H),7.28-7.18(m,3H),6.93-6.77(m,1H),6.60-6.44(m,2H),6.27-6.07(m,1H),5.78-5.70(m,1H),4.55-4.31(m,1H),4.15-4.09(m,3H),4.08-3.97(m,1H),3.78-3.73(m,1H),3.70(s,3H),3.59-3.50(m,2H),3.46-3.45(m,1H),3.30-3.30(m,1H),3.20-3.07(m,5H),2.14-2.07(m,3H),1.93-1.82(m,3H),1.47-1.43(m,1H).MS:628[M+H] +.
Figure PCTCN2020080203-appb-000133
实施例195.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(4-(2-氰基乙酰基)哌嗪-1-基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例195的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的3-(4-(4-氨基-3-甲氧基-5-甲基苯基)哌嗪-1-基)-3-氧代丙腈替代环丙胺。 1H NMR(600MHz,DMSO-d 6)δ10.21(s,1H),9.53(s,1H),8.55(s,1H),7.93-7.69(m,1H),7.25-7.14(m,3H),6.91-6.72(m,1H),6.59-6.47(m,2H),6.26-6.13(m,1H),5.76-5.68(m,1H),4.56-4.43(m,1H),4.16-4.09(m,3H),4.07-3.96(m,1H),3.77-3.73(m,1H),3.70(s,3H),3.59-3.50(m,2H),3.46-3.44(m,1H),3.30-3.29(m,1H),3.18-3.07(m,4H),2.82-2.67(m,1H),2.12-2.04(m,3H),1.96-1.82(m,3H),1.48-1.42(m,1H).MS:628[M+H] +.
实施例196.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((3-羟基丙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例196的制备方法参考实施例141的制备方法，其中以等摩尔当量的3-氨基丙-1-醇替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.62(s,1H),8.60(s,1H),8.48(s,1H),7.91(s,1H),7.51(s,1H),7.45(s,1H),7.37–7.25(m,1H),7.22(s,1H),7.07(s,1H),6.88–6.63(m,1H),6.15–6.01(m,1H),5.71–5.61(m,1H),4.51–4.45(m,1H),4.21–4.07(m,1H),4.02–3.93(m,1H),3.79(s,3H),3.71–3.61(m,1H),3.48–3.46(m,2H),3.31–3.22(m,2H)，2.18(s,3H),1.84–1.78(m,1H),1.76–1.62(m,4H),1.62–1.21(m,3H).MS:578[M+H] +.
Figure PCTCN2020080203-appb-000134
实施例197.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((3-羟基丙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例197的制备方法参考实施例142的制备方法，其中以等摩尔当量的3-氨基丙-1-醇替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.47(s,1H),7.91(s,1H),7.51(s,1H),7.44(s,1H),7.36–7.24(m,1H),7.22(s,1H),7.06(s,1H),6.86–6.64(m,1H),6.16–6.02(m,1H),5.71–5.61(m,1H),4.52–4.47(m,1H),4.19–3.92(m,2H),3.78(s,3H),3.75–3.64(m,1H),3.49–3.45(m,2H),3.30–3.23(m,2H),2.17(s,3H),1.87–1.45(m,8H).MS:578[M+H] +.
实施例198.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-(二甲基氨基)乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例198的制备方法参考实施例141的制备方法，其中以等摩尔当量的N 1,N 1-二甲基乙-1,2-二胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.56(s,1H),9.61(s,1H),8.60(s,1H),8.42(s,1H),8.08–7.78(m,1H),7.51(s,1H),7.44(s,1H),7.36–7.26(m,1H),7.22(s,1H),7.06(s,1H),6.99–6.42(m,-1H),6.16–6.05(m,1H),5.77–5.63(m,1H),4.51–4.14(m,1H),4.12–3.84(m,2H),3.78(s,3H),3.31–3.30(m,4H),3.24–2.75(m,2H),2.42–2.37(m,4H),2.18(s,9H).MS:591[M+H] +.
Figure PCTCN2020080203-appb-000135
实施例199.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-(二甲基氨基)乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例199的制备方法参考实施例142的制备方法，其中以等摩尔当量的N 1,N 1-二甲基乙-1,2-二胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.42(s,1H),8.26(s, 1H),7.96–7.85(m,1H),7.50(s,1H),7.44(s,1H),7.22(s,1H),7.06(s,1H),6.86–6.62(m,1H),6.15–6.01(m,1H),5.71–5.61(m,1H),4.57–4.13(m,1H),4.13–3.81(m,2H),3.78(s,3H),3.30–3.15(m,4H),3.13–2.61(m,2H),2.43–2.35(m,4H),2.19(s,9H).MS:591[M+H] +.
实施例200.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((氰基甲基)(甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例200的制备方法参考实施例141的制备方法，其中以等摩尔当量的2-(甲基氨基)乙腈替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.61(s,1H),8.60(s,1H),7.96–7.82(m,1H),7.38–6.93(m,6H),6.88–6.72(m,1H),6.17–6.04(m,1H),5.76–5.67(m,1H),4.53–4.44(m,2H),4.21–4.02(m,2H),3.80–3.74(m,4H),3.31–3.31(m,1H),3.11–3.04(m,4H),2.79–2.73(m,1H),2.18(s,3H),1.92–1.78(m,2H).MS:573[M+H] +.
Figure PCTCN2020080203-appb-000136
实施例201.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((氰基甲基)(甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例201的制备方法参考实施例142的制备方法，其中以等摩尔当量的2-(甲基氨基)乙腈替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),9.61(s,1H),8.60(s,1H),7.90(s,1H),7.39–6.96(m,6H),6.89–6.70(m,1H),6.18–6.06(m,1H),5.73–5.65(m,1H),4.55–4.45(m,2H),4.24–3.95(m,2H),3.81–3.75(m,4H),3.32–3.28(m,1H),3.11–3.03(m,4H),2.81–2.70(m,1H),2.18(s,3H),1.91–1.77(m,2H).MS:573[M+H] +.
实施例202.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-氰基乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例202的制备方法参考实施例141的制备方法，其中以等摩尔当量的3-氨基丙腈替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.58(s,1H),9.62(s,1H),8.88(s,1H),8.60(s,1H),7.94–7.69(m,1H),7.58–7.41(m,3H),7.36–7.20(m,2H),7.11–6.70(m,1H),6.17–6.02(m,1H),5.75–5.61(m,1H),4.17–3.89(m,2H),3.79(s,3H),3.75–3.66(m,1H),3.51–3.46(m,2H),3.31–3.30(m,2H),2.80–2.77(m,2H),2.19(s,3H),1.81–1.50(m,4H).MS:573[M+H] +.
Figure PCTCN2020080203-appb-000137
实施例203.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-氰基乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例203的制备方法参考实施例142的制备方法，其中以等摩尔当量的3-氨基丙腈替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.58(s,1H),9.62(s,1H),8.89(s,1H),8.60(s,1H),7.91(s,1H),7.53–7.45(m,2H),7.36–7.20(m,2H),7.06(s,1H),6.89–6.61(m,1H),6.15–6.01(m,1H),5.71–5.60(m,1H),4.19–3.94(m,2H),3.79(s,3H),3.74–3.67(m,1H),3.51–3.46(m,2H),3.35–3.31(m,2H),2.80–2.77(m,2H),2.18(s,3H),1.82–1.49(m,4H).MS:573[M+H] +.
实施例204.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-羟基乙基)(甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例204的制备方法参考实施例141的制备方法，其中以等摩尔当量的2-(甲基氨基)乙-1-醇替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.60(s,1H),8.59(s,1H),7.96–7.83(m,1H),7.45–7.22(m,2H),7.22–7.11(m,2H),7.11–6.93(m,2H),6.93–6.72(m,1H),6.18–6.04(m,1H),5.76–5.65(m,1H),4.90–4.78(m,1H),4.48–4.22(m,1H),4.04–3.85(m,2H),3.75(s,3H),3.63–3.52(m,3H),3.31–3.31(m,1H),3.01–2.92(m,4H),2.89–2.69(m,1H),2.16(s,3H),1.93–1.89(m,1H),1.84–1.68(m,2H).MS:578[M+H] +.
Figure PCTCN2020080203-appb-000138
实施例205.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-羟基乙基)(甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例205的制备方法参考实施例142的制备方法，其中以等摩尔当量的2-(甲基氨基)乙-1-醇替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),9.60(s,1H),8.59(s,1H),7.90(s,1H),7.56–7.21(m,2H),7.21–7.08(m,2H),7.08–6.89(m,2H),6.87–6.64(m,1H),6.18–6.03(m,1H),5.75–5.64(m,1H),4.99–4.73(m,1H),4.59–4.16(m,1H),4.10–3.83(m,2H),3.75(s,3H),3.66–3.51(m,3H),3.32–3.28(m,1H),3.03–2.92(m,4H),2.91–2.68(m,1H),2.16(s,3H),1.93–1.89(m,1H),1.85–1.67(m,2H).MS:578[M+H] +.
实施例206.(R)-4-((2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸
实施例206的制备方法参考实施例1的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酸替代环丙胺，步骤2)中以等摩尔当量的叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)吡咯烷-1-羧酸酯替代叔-丁基(R)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),9.56(s,1H),8.59(s,1H),8.52–8.38(m,1H),8.03–7.78(m,1H),7.56–7.47(m,1H),7.33–7.22(m,1H),7.19(d,J＝2.8Hz,1H),6.97(s,1H),6.70–6.40(m,1H),6.24–6.00(m,1H),5.66(s,1H),4.55–4.44(m,1H),3.74(s,3H),3.68–3.38(m,4H),2.14(s,3H),2.05–1.82(m,1H),1.58–1.26(m,1H).MS:507[M+H] +.
Figure PCTCN2020080203-appb-000139
实施例207.(S)-4-((2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸
实施例207的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-5-甲基苯甲酸替代环丙胺，步骤2)中以等摩尔当量的叔-丁基(S)-3-(4-氨基-1H-吡唑-1-基)吡咯烷-1-羧酸酯替代叔-丁基(S)-3-(4-氨基-1H-吡唑-1-基)哌啶-1-羧酸酯。 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),9.56(s,1H),8.59(s,1H),8.49–8.42(m,1H),7.90(s,1H),7.62–7.51(m,1H),7.36–7.22(m,1H),7.19(s,1H),6.98(s,1H),6.70–6.42(m,1H),6.22–6.02(m,1H),5.83–5.57(m,1H),4.49(s,1H),3.74(s,3H),3.71–3.29(m,4H),2.13(s,3H),2.07–1.82(m,1H),1.54–1.28(m,1H).MS:507[M+H] +.
实施例208.(R)-2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-4-((4-((氰基甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
将((R)-4-((2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸)101毫克(0.2mmol)置于反应瓶中，加入1毫升N,N-二甲基甲酰胺，随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯114毫克(0.3mmol)、N,N-二异丙基乙基胺52毫克(0.4mmol)，搅拌0.5小时后加入氨基乙腈11毫克(0.2mmol)，搅拌至反应完毕。加入5毫升水稀释后，乙酸乙酯萃取，有机相减压旋干，所得固体柱层析纯化得产品。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.76–9.52(m,1H),9.31(s,1H),8.61(s,1H),7.91(s,1H),7.67–7.47(m,2H),7.42–7.25(m,1H),7.20(s,1H),6.98(d,J＝5.4Hz,1H),6.64–6.38(m,1H),6.24–6.06(m,1H),5.76–5.57(m,1H),4.50–4.37(m,1H),4.34(t,J＝4.8Hz,2H),3.80(s,3H),3.70–3.39(m,4H),2.19(s,3H),2.12–1.85(m,1H),1.58–1.32(m,1H).MS:545[M+H] +.
Figure PCTCN2020080203-appb-000140
实施例209.(S)-2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-4-((4-((氰基甲基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
将((S)-4-((2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-5-氨基甲酰基嘧啶-4-基)氨基)-3-甲氧基-5-甲基苯甲酸)101毫克(0.2mmol)置于反应瓶中，加入1毫升N,N-二甲基甲酰胺，随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯114毫克(0.3mmol)、N,N-二异丙基乙基胺52毫克(0.4mmol)，搅拌0.5小时后加入氨基乙腈11毫克(0.2mmol)，搅拌至反应完毕。加入5毫升水稀释后，乙酸乙酯萃取，有机相减压旋干，所得固体柱层析纯化得产品。 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.61(s,1H),9.32(s,1H),8.61(s,1H),7.91(s,1H),7.67–7.45(m,2H),7.44–7.21(m,1H),7.25–7.16(m,1H),6.98(d,J＝5.3Hz,1H),6.67–6.43(m,1H),6.21–6.07(m,1H),5.72–5.58(m,1H),4.53–4.37(m,1H),4.34(t,J＝4.8Hz,2H),3.80(s,3H),3.69–3.39(m,4H),2.19(s,3H),2.11–1.85(m,1H),1.68–1.38(m,1H).MS:545[M+H] +.
实施例210.(R)-2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-羟基乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例210的制备方法参考实施例208的制备方法，其中以等摩尔当量的2-氨基乙-1-醇替代氨基乙腈。 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),9.60(s,1H),8.78–8.51(m,2H),8.08–7.79(m,1H),7.63–7.45(m,2H),7.38–7.23(m,1H),7.20(d,J＝3.9Hz,1H),6.96(d,J＝6.6Hz,1H),6.66–6.35(m,1H),6.25–6.03(m,1H),5.77–5.55(m,1H),4.82–4.71(m,1H),4.43(d,J＝31.4Hz,1H),3.79(s,3H),3.69–3.58(m,2H),3.56–3.48(m,3H),3.48–3.36(m,2H),2.17(s,3H),2.11–1.83(m,2H),1.52–1.30(m,1H).MS:550[M+H] +.
Figure PCTCN2020080203-appb-000141
实施例211.(S)-2-((1-(1-丙烯酰基吡咯烷-3-基)-1H-吡唑-4-基)氨基)-4-((4-((2-羟基乙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例211的制备方法参考实施例209的制备方法，其中以等摩尔当量的2-氨基乙-1-醇替代氨基乙腈。 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),9.60(s,1H),8.60(s,1H),8.58–8.53(m,1H),7.90(s,1H), 7.64–7.42(m,2H),7.35–7.23(m,1H),7.20(d,J＝3.9Hz,1H),6.96(d,J＝6.7Hz,1H),6.68–6.44(m,1H),6.22–6.02(m,1H),5.73–5.50(m,1H),4.82–4.68(m,1H),4.43(d,J＝31.3Hz,1H),3.78(s,3H),3.71–3.60(m,2H),3.60–3.49(m,3H),3.48–3.37(m,2H),2.17(s,3H),2.16–1.84(m,2H),1.55–1.32(m,1H).MS:550[M+H] +.
实施例212.(R)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-((3-(二甲基氨基)丙基)氨基甲酰基)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
Figure PCTCN2020080203-appb-000142
实施例212的制备方法参考实施例141的制备方法，其中以等摩尔当量的N 1,N 1-二甲基丙-1,3-二胺替代甲胺盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.61(s,1H),8.60(s,1H),8.55–8.52(m,1H),7.94–7.84(m,1H),7.50(s,1H),7.43(s,1H),7.38–7.27(m,1H),7.22(s,1H),7.06(s,1H),6.88–6.59(m,1H),6.15–6.01(m,1H),5.71–5.60(m,1H),4.47–3.93(m,2H),3.78(s,3H),3.27–3.23(m,2H),2.29–2.24(m,3H),2.17(s,3H),2.14(s,6H),1.74–1.49(m,8H).MS:605[M+H] +.
实施例213.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((2-甲氧基-6-甲基-4-(N-甲基氨磺酰)苯基)氨基)嘧啶-5-甲酰胺
实施例213的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-3-甲氧基-N,5-二甲基苯磺酰胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.67(s,1H),9.63(s,1H),8.61(s,1H),7.93–7.89(m,1H),7.40–7.37(m,2H),7.33–7.31(m,2H),7.21–7.16(m,2H),6.94–6.54(m,1H),6.11–6.05(m,1H),5.70–5.67(m,1H),4.05–3.99(m,2H),3.81(s,3H),3.30–3.30(m,2H),3.02–2.81(m,3H),2.44(s,3H),2.22(s,3H),1.89–1.81(m,2H).MS:570[M+H] +.
Figure PCTCN2020080203-appb-000143
实施例214.(S)-2-((1-(1-丙烯酰基哌啶-3-基)-1H-吡唑-4-基)氨基)-4-((4-(N-(2-羟基乙基)氨磺酰)-2-甲氧基-6-甲基苯基)氨基)嘧啶-5-甲酰胺
实施例214的制备方法参考实施例2的制备方法步骤1)至步骤4)，其中步骤1)中以等摩尔当量的4-氨基-N-(2-羟基乙基)-3-甲氧基-5-甲基苯磺酰胺替代环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.67(s, 1H),9.63(s,1H),8.61(s,1H),7.92(s,1H),7.63–7.47(m,2H),7.39–7.32(m,2H),7.22–7.13(m,2H),6.91–6.62(m,1H),6.15–6.04(m,1H),5.72–5.63(m,1H),4.73(s,1H),4.60–4.20(m,1H),4.19–3.89(m,3H),3.81(s,3H),3.43–3.38(m,3H),3.30–3.30(m,2H),3.16–3.00(m,1H),2.87–2.81(m,3H),2.22(s,3H).MS:600[M+H] +.
试验例1.本发明化合物抑制JAK1、JAK2、JAK3、TYK2激酶活性的测试
在体外组装的酶促反应中，加入不同浓度的化合物检测化合物对特异性酶促反应的抑制作用，具体测试方法如下：
表1.测试用仪器、材料和试剂
Figure PCTCN2020080203-appb-000144
二.测试方法
下述将以JAK3为例，JAK1、JAK2、JAK3、TYK2具体的实验条件见附录。
1.试剂配制：
EDTA(0.5M pH8.0)溶液配制:准确称量14.612g EDTA粉末，加入超纯水后定容到100mL(若有不溶 则加热到37℃，用1N NaOH溶液调pH至8.0)
1×Kinase Assay Buffer：于试剂瓶中分别加入25mL HEPES溶液(1M)、190.175mg EGTA、5mL MgCl 2溶液(1M)、1mL DTT、50μL Tween-20，加超纯水定容到500mL(调pH至7.5)。
1×Detection Buffer:取1mL 10×Detection Buffer加入9mL水混匀。
4×终止液：将0.8mL上述EDTA(0.5M，pH8.0)溶液、1mL 10×Detection Buffer及8.2mL超纯水混匀。
4×JAK3激酶溶液:用1×Kinase Assay Buffer稀释激酶原液到浓度为0.36nM，混匀，冰上保存。
4×底物溶液：用1×Kinase Assay Buffer稀释底物ULight TM-labeled JAK-1(Tyr1023)Peptide原液到200nM，混匀。
4×ATP溶液：用1×Kinase Assay Buffer稀释ATP原液到浓度为40μM，混匀。
4×检测液：用1×Detection Buffer稀释检测抗体Europium-anti-phospho-tyrosine antibody(PT66)到浓度为8nM，混匀。
2×底物/ATP混合液：4×底物溶液和600μl 4×ATP溶液等量混匀(使用前配制)。
2、实验步骤
1)化合物的稀释，
在96孔板中，将化合物用DMSO溶液按3倍比例稀释，形成11个梯度，另一纯DMSO溶液作为阳性对照；取一块新的96孔板，将上述溶液用超纯水稀释25倍(DMSO浓度为4％)
2)将化合物转盘到384孔板
将上述96孔板中用超纯水稀释过的化合物溶液按照2复孔的标准转盘到384孔板相应的孔中。
3)加4×激酶溶液：用排枪取2.5μl上述4×激酶溶液加入到384孔板相应的反应孔中，混匀室温预反应5分钟。
4)加2×底物/ATP混合液:用排枪取5μl上述2×底物/ATP混合液到384孔板相应的反应孔中。
5)阴性对照：在384孔板中设置阴性对照孔，该孔加入2.5μl/孔4×底物、2.5μl 4×酶溶液、2.5μl 1×Kinase Assay Buffer和2.5μl含4％DMSO的超纯水。
6)离心混匀，避光室温反应60min。
7)终止酶促反应：
吸取5μl上述4×终止液到384孔板相应孔中，离心混匀，室温反应5分钟。
8)显色反应：
吸取5μl上述4×检测液加入到384孔板中孔中，离心混匀，室温反应60min。
9)将384孔板放入读板仪，调取相应的程序检测信号。
10)抑制率和IC 50计算：
孔读值＝10000*EU665值/EU615值
抑制率＝[1-(实验孔读值-阴性对照孔读值)/(阳性对照孔读值-阴性对照孔读值)]*100％
将药物浓度和相应抑制率输入GraphPad Prism5处理计算出相应的IC 50值。
三.测试条件：
JAK1激酶活性测试：
JAK1(终浓度10nM)；ATP(终浓度10μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度100nM)；酶促反应时间为2小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
JAK2激酶活性测试：
JAK2(终浓度0.25nM)；ATP(终浓度5μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度50nM)；酶促反应时间为1小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
JAK3激酶活性测试：
JAK3(终浓度0.36nM)；ATP(终浓度10μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度50nM)；酶促反应时间为1小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
TYK2激酶活性测试：
TYK2(终浓度8nM)；ATP(终浓度20μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度100nM)；酶促反应时间为2小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
表2列出了本发明中部分化合物对酪氨酸激酶JAK1，JAK2，JAK3，TYK2抑制活性的测定结果，其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM，NT表示没有测试相对应的激酶。
由下表的测试结果可知，本申请化合物对酪氨酸激酶JAK1，JAK2，JAK3，TYK2表现出一定的抑制活性，尤其是对JAK3激酶的活性具有强力的抑制作用，同时本申请部分化合物(以165和166为例)，相对于JAK1，JAK2和TYK2，对JAK3表现出高选择性，可以成为安全有效的JAK3抑制剂。
表2、本发明部分化合物对JAK1、JAK2、JAK3和TYK2酪氨酸激酶抑制活性测定结果
Figure PCTCN2020080203-appb-000145
Figure PCTCN2020080203-appb-000146
Figure PCTCN2020080203-appb-000147
Figure PCTCN2020080203-appb-000148
Figure PCTCN2020080203-appb-000149
Figure PCTCN2020080203-appb-000150
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原则的前提下，本发明的实施方式还可以作出若干改进和修饰，这些改进和修饰也应视为本发明的保护范围。

Claims (15)

  1. 一种式(I)表示的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，
    Figure PCTCN2020080203-appb-100001
    其中，n1为1至3的整数，n2为1至2的整数；
    R 1为由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8环烷基，
    或由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的4-7元杂环烷基，
    或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 8环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 10烷基，
    或由1至3个选自C 1-C 10烷基、卤素、卤代C 1-C 10烷基、氰基、羟基取代C 1-C 10烷基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5 ’、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 6烷氧基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基C 1-C 6烷基、(C 3-C 8环烷基)-O-(C 1-C 6烷基)、任选被一个或多个A取代或非取代的4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、任选被一个或多个B取代的芳基或杂芳基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
    A为C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 1-C 3酰基、氰基取代C 1-C 3酰基、-(CH 2)t-NR aR b，
    B为氢、C 1-C 6烷基，
    R 5为氢、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、芳基或杂芳基、-(CH 2)t-NR aR b、4-7元杂环烷基取代C 1-C 6烷基，
    -(CH 2)t-NR aR b中t为0至6的整数，
    R 5 ’为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、-NR aR b、4-7元杂环烷基取代C 1-C 6烷基，
    所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基，
    R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、氰基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-7元杂环烷基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
    R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至8的整数，
    R 4为氢、羟基、C 1-C 3烷基、C 3-C 7环烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、-NR cR d，或者被1至3 个选自C 1-C 3烷基、醛基、C 1-C 4烷基酰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、羟基、卤素、氧代(＝O)、羟基C 1-C 3烷基、氨基、单或双C 1-C 3烷基取代氨基、卤代C 1-C 3烷基中的取代基所取代或者未取代的4-7元杂环烷基，
    R c和R d分别独立的为氢、C 1-C 6烷基、C 3-C 6环烷基、羟基取代C 1-C 6烷基或C 1-C 3烷氧基取代C 1-C 6烷基，
    所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
  2. 根据权利要求1所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 1为C 3-C 8环烷基，4-7元杂环烷基，
    或由1至3个选自C 1-C 3烷氧基、C 1-C 3烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 6环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
    或由1至3个选自C 1-C 6烷基、卤素、卤代C 1-C 6烷基、氰基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5’、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、羟基取代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 6烷基、C 3-C 6环烷基、C 3-C 6环烷基C 1-C 6烷基、(C 3-C 6环烷基)-O-(C 1-C 6烷基)、任选被一个或多个A取代或非取代的4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、任选被一个或多个B取代的芳基或杂芳基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
    A为C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 1-C 3酰基、氰基取代C 1-C 3酰基、-(CH 2)t-NR aR b，
    B为氢、C 1-C 3烷基，
    R 5为氢、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 3-C 6环烷基、4-7元杂环烷基、芳基或杂芳基、-(CH 2)t-NR aR b、4-7元杂环烷基取代C 1-C 3烷基，
    -(CH 2)t-NR aR b中t为0至3的整数，
    R 5’为氢、羟基、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 3-C 6环烷基、4-7元杂环烷基、-NR aR b、4-7元杂环烷基取代C 1-C 3烷基，
    R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、4-7元杂环烷基、C 1-C 3烷氧基取代C 1-C 3烷基、羟基取代C 1-C 3烷基、氰基取代C 1-C 3烷基、C 3-C 6环烷基C 1-C 3烷基、4-7元杂环烷基取代C 1-C 3烷基、C 1-C 3烷硫基取代C 1-C 3烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 3烷基，
    所述芳基为苯基、萘基、
    Figure PCTCN2020080203-appb-100002
    所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、异噻唑基、吲唑基、吲哚基、异吲哚基、二氢吲哚基、异二氢吲哚基、异喹啉基、吲嗪基、异噁唑基、1,5-萘啶基、1,6-萘啶酮基、噁二唑基、噁唑基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡喃基、吡唑基、吡唑并[3,4-d]嘧啶基、吡啶并[3,2-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、
    Figure PCTCN2020080203-appb-100003
    所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
  3. 根据权利要求2所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 1为 C 3-C 7环烷基，4-6元杂环烷基，
    或由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、三氟甲基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、氰基、-CONH 2、环丙基、环丁基、环戊基、环己基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
    或由1至3个选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、-SO 2-R 5、-SO-R 5、-CO-R 5’、-O-R 5、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、4-甲基哌嗪-1-基、4-羟乙基哌嗪-1-基、4-乙基哌嗪-1-基、4-乙酰基哌嗪-1-基、4-(2-氰基乙酰基)哌嗪-1-基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、二甲氨基、二乙氨基、二丙氨基、甲氨基、乙氨基、丙氨基、甲基乙基氨基、甲基丙基氨基、或者乙基丙基氨基中的取代基所取代或者非取代的芳基或者杂芳基，
    R 5为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、苯基、吡啶2-基、吡啶-3-基、吡啶-4-基、吡咯基、呋喃基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、或者-(CH 2)t-NR aR b，
    -(CH 2)t-NR aR b中t为0至3的整数，
    R 5’为氢、羟基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、或-NR aR b，
    R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃-4-基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基，
    所述芳基为苯基，所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、
    Figure PCTCN2020080203-appb-100004
    所述4-6元杂环烷基为含有1-2个选自 N、O、S中的原子作为环原子的4-6元杂环烷基。
  4. 根据权利要求3所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 1为环丙基、环丁基、环戊基、环己基、环庚基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环戊基甲基、环戊基乙基、环己基甲基、环己基乙基、四氢吡喃-4-基甲基、四氢吡喃-4-基乙基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、或者为
    Figure PCTCN2020080203-appb-100005
    Figure PCTCN2020080203-appb-100006
    R 6、R 7、R 8各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、-SO 2-R 5、-SO-R 5、-CO-R 5’、-O-R 5、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、4-甲基哌嗪-1-基、4-羟乙基哌嗪-1-基、4-乙基哌嗪-1-基、4-乙酰基哌嗪-1-基、4-(2-氰基乙酰基)哌嗪-1-基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、二甲氨基、二乙氨基、二丙氨基、甲氨基、乙氨基、丙氨基、甲基乙基氨基、甲基丙基氨基、或者乙基丙基氨基，
    R 5为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、苯基、吡啶2-基、吡啶-3-基、吡啶-4-基、吡咯基、呋喃基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、或者-(CH 2)t-NR aR b，
    -(CH 2)t-NR aR b中t为0至3的整数，
    R 5’为氢、羟基、吡咯烷基、哌啶-1-基、哌嗪基、吗啉基、硫代吗啉基、氮杂环丁烷基、或者-NR aR b，
    R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、四氢吡喃-4-基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环 丁烷基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基。
  5. 根据权利要求1至4中任一项所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至6的整数，
    R 4为氢、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、环庚基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、-NR cR d，或者被1至3个选自甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、丁酰基、异丁酰基、氨基酰基、甲氨基酰基、二甲氨基酰基、甲砜基、乙砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、羟基、氟、氯、羟甲基、羟乙基、羟丙基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、甲基乙基氨基、甲基丙基氨基、甲基异丙基氨基、氧代(＝O)、三氟甲基中的取代基所取代或者未取代的4-6元杂环烷基；
    R c和R d分别独立地为氢、甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、仲丁基、叔丁基、1-乙基丙基、新戊基、环丙基、环丁基、环戊基、环己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、丙氧基乙基、丙氧基丙基、丙氧基丁基、丙氧基戊基、丙氧基己基、异丙氧基乙基、异丙氧基丙基、异丙氧基丁基、异丙氧基戊基或异丙氧基己基，
    所述4-6元杂环烷基为吡咯烷基、四氢呋喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡喃基、氧杂环丁烷基、氮杂环丁烷基。
  6. 根据权利要求1所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，所述化合物具有式(Ia)：
    Figure PCTCN2020080203-appb-100007
    其中，R 1为由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8环烷基，
    或由1至3个选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的4-7元杂环烷基，
    或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 8环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 10烷基，
    或由1至3个选自C 1-C 10烷基、卤素、卤代C 1-C 10烷基、氰基、羟基取代C 1-C 10烷基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5、-CONH-R 5、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 6烷氧基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基C 1-C 6烷基、(C 3-C 8环烷基)-O-(C 1-C 6烷基)、4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
    R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基，
    所述芳基为含有6至12个碳环原子且具有至少一个芳香环的单环或双环基团，杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子且含有5至10个环原子的单环或双环基团，所述4-7元杂环烷 基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基，
    R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-7元杂环烷基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
    R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至8的整数，
    R 4为氢、羟基、C 1-C 3烷基、C 3-C 7环烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、-NR cR d，或者被1至3个选自C 1-C 3烷基、醛基、C 1-C 4烷基酰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基、羟基、卤素、氧代(＝O)、羟基C 1-C 3烷基、氨基、单或双C 1-C 3烷基取代氨基、卤代C 1-C 3烷基中的取代基所取代或者未取代的4-7元杂环烷基，
    R c和R d分别独立的为氢、C 1-C 6烷基、C 3-C 6环烷基、羟基取代C 1-C 6烷基或C 1-C 3烷氧基取代C 1-C 6烷基，
    所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
  7. 根据权利要求6所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 1为C 3-C 8环烷基，4-7元杂环烷基，
    或由1至3个选自C 1-C 3烷氧基、C 1-C 3烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、4-7元杂环烷基、氰基、-CONH 2、C 3-C 6环烷基、或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
    或由1至3个选自C 1-C 6烷基、卤素、卤代C 1-C 6烷基、氰基、C 1-C 6烷硫基、-SO 2-R 5、-SO-R 5、-CO-R 5、-CONH-R 5、-O-R 5、C 2-C 6炔基、C 2-C 6烯基、羟基取代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 6烷基、C 3-C 6环烷基、C 3-C 6环烷基C 1-C 6烷基、(C 3-C 6环烷基)-O-(C 1-C 6烷基)、4-7元杂环烷基、4-7元杂环烷基取代C 1-C 6烷基、-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
    R 5为氢、羟基、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、C 3-C 6环烷基、4-7元杂环烷基、4-7元杂环烷基取代C 1-C 3烷基，
    R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、4-7元杂环烷基、C 1-C 3烷氧基取代C 1-C 3烷基、羟基取代C 1-C 3烷基、C 3-C 6环烷基C 1-C 3烷基、4-7元杂环烷基取代C 1-C 3烷基、C 1-C 3烷硫基取代C 1-C 3烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 3烷基，
    所述芳基为苯基、萘基、
    Figure PCTCN2020080203-appb-100008
    所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、异噻唑基、吲唑基、吲哚基、异吲哚基、二氢吲哚基、异二氢吲哚基、异喹啉基、吲嗪基、异噁唑基、1,5-萘啶基、1,6-萘啶酮基、噁二唑基、噁唑基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡喃基、吡唑基、吡唑并[3,4-d]嘧啶基、吡啶并[3,2-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、
    Figure PCTCN2020080203-appb-100009
    所述4-7元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂环烷基。
  8. 根据权利要求7所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 1为C 3-C 7环烷基，4-6元杂环烷基，
    或由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、三氟甲基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗 啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、氰基、-CONH 2、环丙基、环丁基、环戊基、环己基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
    或由1至3个选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、-SO 2-CH 3、-SO 2-CH 2CH 3、-SO-CH 3、-SO-CH 2CH 3、-COOH、-COCH 3、-COCH 2CH 3、醛基、-CONH 2、-CONH-CH 3、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、哌嗪基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、-O-R 5、或者-NR aR b中的取代基所取代或者非取代的芳基或者杂芳基，
    R 5为氢、C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、羟基取代C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环烷基、4-6元杂环烷基取代C 1-C 3烷基，
    R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基，
    所述芳基为苯基，所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、噁二唑基、噁唑基、异噁唑基、吡喃基、吡唑基、吡嗪基、嘧啶基、哒嗪基、
    Figure PCTCN2020080203-appb-100010
    所述4-6元杂环烷基为含有1-2个选自N、O、S中的原子作为环原子的4-6元杂环烷基。
  9. 根据权利要求8所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 1为环丙基、环丁基、环戊基、环己基、环庚基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基，
    或者为由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、三氟甲基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、氰基、-CONH 2、环丙基、环丁基、环戊基、环己基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，
    或者为
    Figure PCTCN2020080203-appb-100011
    Figure PCTCN2020080203-appb-100012
    R 6、R 7、R 8各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、氟、氯、三氟甲基、氰基、甲硫基、乙硫基、丙硫基、异丙硫基、 -SO 2-CH 3、-SO 2-CH 2CH 3、-SO-CH 3、-SO-CH 2CH 3、-COOH、-COCH 3、-COCH 2CH 3、醛基、-CONH 2、-CONH-CH 3、乙炔基、乙烯基、羟甲基、羟乙基、羟丙基、羟基丁基、羟基戊基、羟基己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、四氢吡喃基甲基、四氢呋喃基甲基、吡咯烷基甲基、哌啶基甲基、哌嗪基甲基、吗啉基甲基、硫代吗啉基甲基、氧杂环丁烷基甲基、氮杂环丁烷基甲基、-O-R 5、或者-NR aR b，
    R 5为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基，
    R a和R b各自独立地为氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、羟甲基、羟乙基、羟丙基、四氢吡喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基。
  10. 根据权利要求6至9中任一项所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，R 2或者R 3各自独立地为-(CH 2)n-R 4，n为0至6的整数，
    R 4为氢、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、环庚基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、-NR cR d，或者被1至3个选自甲基、乙基、丙基、异丙基、醛基、乙酰基、丙酰基、丁酰基、异丁酰基、氨基酰基、甲氨基酰基、二甲氨基酰基、甲砜基、乙砜基、丙基砜基、异丙基砜基、甲基亚砜基、乙基亚砜基、丙基亚砜基、异丙基亚砜基、羟基、氟、氯、羟甲基、羟乙基、羟丙基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、甲基乙基氨基、甲基丙基氨基、甲基异丙基氨基、氧代(＝O)、三氟甲基中的取代基所取代或者未取代的4-6元杂环烷基；
    R c和R d分别独立地为氢、甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、仲丁基、叔丁基、1-乙基丙基、新戊基、环丙基、环丁基、环戊基、环己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、丙氧基乙基、丙氧基丙基、丙氧基丁基、丙氧基戊基、丙氧基己基、异丙氧基乙基、异丙氧基丙基、异丙氧基丁基、异丙氧基戊基或异丙氧基己基，
    所述4-6元杂环烷基为吡咯烷基、四氢呋喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡喃基、氧杂环丁烷基、氮杂环丁烷基。
  11. 根据权利要求1所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，其中，所述化合物选自：
    Figure PCTCN2020080203-appb-100013
    Figure PCTCN2020080203-appb-100014
    Figure PCTCN2020080203-appb-100015
    Figure PCTCN2020080203-appb-100016
    Figure PCTCN2020080203-appb-100017
    Figure PCTCN2020080203-appb-100018
    Figure PCTCN2020080203-appb-100019
    Figure PCTCN2020080203-appb-100020
  12. 一种药物组合物，包括权利要求1至11中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。
  13. 如权利要求12所述的药物组合物，其中，所述药物组合物还包括一种或多种其他治疗剂。
  14. 根据权利要求1-11中任一项所述的化合物或其异构体、溶剂化物、药学上可接受的盐或前药，在制备治疗与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症的药物中的应用。
  15. 根据权利要求14所述的应用，其中，所述与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症包括：眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
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