Pyrazole amide compound and use

Abstract

Provided is an RIPK1 inhibitor, which is a compound as shown in formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof. Also provided are a method and a use of the RIPK1 inhibitor in treatment and / or prevention of diseases or symptoms related to abnormal RIPK1 activity, or mediated by RIPK1.

Description

Pyrazole amide compounds and uses Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a pyrazoleamide compound, and its use as a receptor interacting protein kinase 1 (RIPK1) inhibitor, as well as a method for treating and / or preventing diseases or symptoms associated with abnormal RIPK1 activity or mediated by RIPK1. Technical Background

[0002] Apoptosis and necroptosis are two different forms of cell death. Apoptosis is a strictly controlled mode of programmed cell death, characterized by obvious morphological changes and activation of specific Caspase and mitochondrial control pathways (Mifflin, L. et al., Nat Rev Drug Discov, 2020, 19 (8): 553-571). During apoptosis, the cell membrane can remain intact, thus preventing the release of intracellular cytokines and digestive enzymes to the extracellular space, thereby limiting the damage to adjacent tissues and the occurrence of inflammation (Zhuang, C. et al., J Med Chem, 2019, 63 (4): 1490-1510). During necroptosis, organelle swelling, cell membrane rupture, and decomposition of cytoplasm and nucleus can be observed. Therefore, necroptosis is often accompanied by excessive inflammatory response (He, S. et al., Nat Immunol, 2018, 19 (9): 912-922).

[0003] During apoptosis and necrosis, activation of RIPK1 mediated by TNFR1 signaling can promote excessive inflammatory responses (Degterev, A. et al., Proc Natl Acad Sci USA, 2019, 116(20):9714-9722). RIPK1 is a crucial regulator of cell death and inflammation and plays an important role in maintaining tissue homeostasis (Kondylis, V. et al., Trends Mol Med, 2018, 25(1):47-63). Due to the key role of RIPK1 in cell signaling, abnormal activation of its kinase is closely related to the occurrence and development of various diseases (Yuan, J. et al., Nat Rev Neurosci, 2019, 20(1):19-33). Activation of RIPK1 kinase has been demonstrated in pathological samples of autoimmune and neurodegenerative diseases, and inhibition of RIPK1 kinase activity has been shown to be effective in a variety of animal models of human diseases, demonstrating the effectiveness of its kinase activity as a drug target (Shi, K. et al., J Med Chem, 2022, 65:14971-14999; Li, W., Front Immunol, 2023, 14:1159743). Therefore, RIPK1 has gradually become one of the effective targets for the treatment of various diseases such as neurodegenerative diseases, autoimmune diseases, and inflammatory diseases. Summary of the Invention

[0004] An object of the present disclosure is to provide a RIPK1 inhibitor that can be used to treat and / or prevent diseases or symptoms associated with abnormal RIPK1 activity or mediated by RIPK1.

[0005] In one aspect of the present invention, a RIPK1 inhibitor is provided, which is a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0006] in,

[0007] Ring A is selected from a monocyclic or fused ring aryl or heteroaryl group;

[0008] R 1 is selected from C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, phenyl C1-3 alkyl, and unsubstituted or substituted by 1 to 3 independent R 7 substituted aryl, monocyclic heteroaryl containing 1 to 3 heteroatoms selected from N, O or S, or 5-membered or 6-membered heterocyclic group containing 1 heteroatom selected from N or O;

[0009] R 7Each is independently selected from halogen, cyano, oxo, carboxyl, sulfamoyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylaminoC1-3 alkyl, C1-6 alkylaminoacyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, C1-6 aminoalkyl, unsubstituted or substituted by 1 or 2 independently R 8 substituted 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N or O, and unsubstituted or replaced by 1 or 2 independently R 8 Substituted C1-6 alkyl (5-7 membered heterocyclic group), wherein the 5-7 membered heterocyclic group contains 1-2 heteroatoms selected from N or O, or two adjacent R 7 together to form an unsubstituted or substituted by 1 or 2 independently R 8 a substituted 5-membered or 6-membered heterocyclic group containing one heteroatom selected from N or O;

[0010] R 8 Each independently selected from amino, hydroxy, C1-3 alkyl, C1-4 alkylamino, and oxo;

[0011] R 2 H or -L-(CHR 4 ) n -R 5 , wherein L is selected from -O-, -NH-, -C(=O)-NR a -、-NR b -C(=O)-, and -NH-C(=O)-NH-, n is 0 or 1, R 4 is H or methyl, R 5 unsubstituted or substituted by 1 to 3 independent R 6 substituted aryl, a 5-membered or 6-membered heterocyclic group containing one heteroatom selected from N or O, and a 5-membered or 6-membered heteroaryl group containing one to two heteroatoms selected from N or O, R 6 Each is independently selected from halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterated alkoxy, C3-6 cycloalkyloxy, C3-6 cycloalkylC1-3 alkoxy, tetrahydropyranyloxy, or R in the L group a or R b The groups are connected to form a ring, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with 1 or 2 halogens;

[0012] m is 0, 1 or 2, R 3Each is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 haloalkoxy, or R in the L group a or R b The groups are linked to form a ring;

[0013] where R a and R b Each is H, or a substituent R of the A ring 3 C2-3 alkylene, C1-2 alkyleneoxy or C1-2 alkylenethio, or R 5 The substituent R 6 Connected to form a C2-3 alkylene.

[0014] In a specific embodiment, R 7 Each independently selected from halogen, cyano, oxo, carboxyl, sulfamoyl, C1-6 alkyl, C1-6 deuterated alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylaminoacyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, C1-6 aminoalkyl, and unsubstituted or substituted by 1 or 2 independently R 8 a substituted 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N or O, or two adjacent R 7 Together they form a 5- or 6-membered heterocyclic group containing one heteroatom selected from N or O.

[0015] In a preferred embodiment, R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, propenyl, benzyl, and unsubstituted or substituted by 1 to 3 independent R 7 Substituted phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, or pyrrolidinyl.

[0016] In a particularly preferred embodiment, R 7 are each independently selected from halogen, cyano, oxo, carboxyl, sulfamoyl, C1-3 alkyl, C1-3 haloalkyl, C1-3 deuterated alkyl, C3-5 cycloalkyl, C1-3 alkoxy, C1-4 alkylamino, C1-4 alkylaminoC1-2 alkyl, C1-3 alkylaminoacyl, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, C1-3 alkoxycarbonyl, C1-3 aminoalkyl, and unsubstituted or substituted by 1 or 2 independently R 8substituted piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, diazepanyl, tetrahydrofuranyl, or C1-3 alkyl (morpholinyl), or two adjacent R 7 together to form an unsubstituted or substituted by 1 or 2 independently R 8 substituted dioxolanyl, or piperidinyl.

[0017] In a further preferred embodiment, R 8 Each is independently selected from amino, hydroxy, methyl, ethyl, propyl, methylamino, dimethylamino, ethylamino, and oxo.

[0018] In addition, preferably, R 1 is selected from cyclopropyl, and unsubstituted or substituted by 1 or 2 independent R 7 substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, furanyl, or tetrahydropyridinyl; R 7 Each independently selected from halogen, oxo, sulfamoyl, C1-3 alkyl, C1-3 deuterated alkyl, C3-5 cycloalkyl, C1-3 alkoxy, C1-4 alkylamino, C1-3 alkylaminoacyl, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, C1-3 aminoalkyl, and unsubstituted or substituted by 1 or 2 independently R 8 substituted piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl, or two adjacent R 7 Together they form a dioxolane group; R 8 are each independently selected from amino, hydroxy, and methyl.

[0019] Particularly preferably, R 1 selected from cyclopropyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, thiazol-4-yl, oxazol-5-yl, furan-2-yl, 1 or 2 independently R 7 Substituted phenyl, substituted by 1 or 2 independently R 7 substituted pyridin-3-yl, substituted by 1 or 2 independently R 7 substituted pyridin-4-yl, substituted by 1 or 2 independently R 7 Substituted pyridazin-3-yl, substituted by 1 or 2 independently R 7 substituted pyrazol-3-yl, substituted by 1 or 2 independently R 7 substituted pyrazol-4-yl, substituted by 1 or 2 independently R 7 Substituted imidazol-4-yl, substituted by 1 or 2 independently R 7 Substituted pyrazin-2-yl, substituted by 1 or 2 independently R 7 substituted pyrimidin-5-yl, substituted by 1 or 2 independently R 7Substituted [1,3,4] oxadiazol-2-yl, substituted by 1 or 2 independently R 7 Substituted [1,2,3] triazol-4-yl, substituted by 1 or 2 independently R 7 substituted 1,2,3,6-tetrahydro-pyridin-4-yl, substituted by 1 or 2 independently R 7 substituted pyrrol-3-yl, and 1 or 2 independently R 7 Substituted thiazol-2-yl; R 7 R is each independently selected from fluoro, chloro, oxo, sulfamoyl, methyl, ethyl, isopropyl, fluoromethyl, deuterated methyl, cyclopropyl, methoxy, methylamino, dimethylamino, dimethylaminoethyl, methylaminoacyl, methylsulfinyl, methylsulfonyl, aminomethyl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, 4-amino-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, morpholin-1-yl, 3-amino-pyrrolidin-1-yl, piperidin-4-yl, pyrrolidin-3-yl, tetrahydrofuran-3-yl, and 2-morpholinoethyl, or two adjacent R 7 Together they form a dioxolanyl, a piperidinyl, or an N-methylpiperidinyl.

[0020] In another preferred embodiment, R 1 Selected from:

[0021] where X 1 and X 2 are each independently CH or N (preferably both are CH), R 7a is selected from H, fluoro, chloro, methoxy, methylamino, dimethylamino, methylaminoacyl, methylsulfinyl, methylsulfonyl, sulfamoyl, aminomethyl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, morpholin-1-yl, 4-amino-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, and 3-amino-pyrrolidin-1-yl;

[0022] Where Y is CH or N, R 7b is selected from H, methyl, ethyl, and deuterated methyl;

[0023] where R 7c Selected from H, methyl or methoxy;

[0024] where R 7d selected from H or methyl; and

[0025] where Z 1 、Z 2 and Z3 Two of them are CH, and the other one is N, R 7e is selected from methyl, isopropyl, and cyclopropyl.

[0026] In a further embodiment, Ring A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, benzothiazolyl, quinolinyl, isoquinolinyl, and indolyl.

[0027] Particularly preferably, ring A is selected from phenyl, naphth-2-yl, pyridin-3-yl, pyrimidin-5-yl, benzothiazol-5-yl, quinolin-3-yl, quinolin-7-yl, isoquinolin-7-yl, and indol-5-yl.

[0028] In another embodiment, the RIPK1 inhibitor of the present invention is a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0029] Among them, R 1 、R 2 , and R 3 As defined above, W is CH or N, preferably CH.

[0030] In a further embodiment, R 2 -L-(CHR 4 ) n -R 5 , wherein L is selected from -O-, -NH-, -C(=O)-NR a -、-NR b -C(=O)-, and -NH-C(=O)-NH-, n is 0 or 1, R 4 is H or methyl, R 5 unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, tetrahydrofuranyl, imidazolyl, pyridyl, and isoxazolyl, R 6 Each is independently selected from halogen, cyano, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuterated alkoxy, C3-5 cycloalkyloxy, C3-5 cycloalkylC1-2 alkoxy, tetrahydropyranyloxy, or R in the L group a or R b The groups are connected to form a ring, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with 1 or 2 halogens; R 3 is selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, C1-3 haloalkoxy, or R in the L group a or R bThe groups are connected to form a ring; wherein R a and R b Each is H, or a substituent R of the A ring 3 C2-3 alkylene, C1-2 alkyleneoxy or C1-2 alkylenethio, or R 5 The substituent R 6 Connected to form a C2-3 alkylene.

[0031] In a preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , wherein L is selected from -O- and -NH-, n is 0, R 5 is unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, R 6 are each independently selected from halogen, cyano, C1-3 alkoxy, and C1-3 haloalkyl; R 3 For H.

[0032] In another preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , wherein L is -C(=O)-NR a -, n is 1, R 4 is H or methyl, R 5 is unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, R 6 Each independently selected from halogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 deuterated alkoxy, C3-5 cycloalkyloxy, C3-5 cycloalkylC1-2 alkoxy, or R in the L group a The groups are connected to form a ring; R 3 R is selected from H, halogen, C1-3 alkyl, or L group a The groups are connected to form a ring; wherein R a is H, or is a substituent R on the A ring 3 C2-3 alkylene formed by connecting, or with R 5 The substituent R 6 Connected to form a C2-3 alkylene.

[0033] In this embodiment, the RIPK1 inhibitor of the present invention is preferably a compound represented by formula (IIa), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0034] Among them, R 1and R 4 As defined above; W is CH or N, preferably CH; R 3 is selected from H, fluorine, and methyl; R 4 is H or methyl; R 6a and R 6b Each is independently selected from fluoro, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0035] In another preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , wherein L is -NH-C(=O)-NH-, n is 0 or 1, R 4 H, R 5 unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, imidazol-3-yl, isoxazol-3-yl, and isoxazol-5-yl, R 6 R is independently selected from halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkoxy, and tetrahydropyranyloxy; 3 Selected from H, halogen, and C1-3 alkyl.

[0036] In this embodiment, preferably R 5 Selected from 1 to 3 independent R 6 Substituted phenyl, isoxazol-3-yl, and isoxazol-5-yl, R 6 R is independently selected from fluoro, isobutyl, isopropoxy, trifluoromethoxy, and tetrahydropyranyloxy; 3 Selected from H, fluoro, and methyl.

[0037] In another preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , where L is -NR b -C(=O)-.

[0038] In this embodiment, it is particularly preferred that the RIPK1 inhibitor of the present invention is a compound represented by formula (IIb), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0039] Among them, R 1 As defined above; U is selected from CH2, O and S; q is 1 or 2; p is 1, 2, or 3; R 6Each independently selected from halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuterated alkoxy, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with two fluorine groups.

[0040] More preferably, U is selected from CH2 and O; q is 1 or 2; p is 1, 2, or 3; R 6 Each is independently selected from fluoro, chloro, methyl, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0041] In addition, preferably, the RIPK1 inhibitor of the present invention is a compound represented by formula (IIc), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0042] Among them, R 1 As defined above; U is selected from CH2 and O; R 6a and R 6b Each is independently selected from fluoro, chloro, methyl, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0043] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0044] In other aspects, the present disclosure relates to the use of the aforementioned RIPK1 inhibitors in the preparation of a medicament for treating and / or preventing diseases or symptoms associated with abnormal RIPK1 activity or mediated by RIPK1, in particular one or more of hemophagocytic syndrome, inflammatory diseases, autoimmune diseases, ischemic diseases, destructive bone diseases, neurodegenerative diseases, proliferative diseases, angiogenesis disorders, infectious diseases, tumors and viral diseases associated with abnormal RIPK1 activity or mediated by RIPK1.

[0045] Preferably, the hemophagocytic syndrome is selected from one or more of primary hemophagocytic syndrome and secondary hemophagocytic syndrome.

[0046] The inflammatory disease is selected from one or more of Crohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, graft-versus-host disease, chronic obstructive pulmonary disease, and pulmonary fibrosis.

[0047] The autoimmune disease is selected from one or more of Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, and transplant rejection.

[0048] The ischemic disease is selected from one or more of liver or brain ischemic injury, myocardial ischemia-reperfusion injury, and ischemic injury during reperfusion or organ storage.

[0049] The destructive bone disease is selected from one or more of bone cysts, bone erosions, myeloma, and osteosarcoma.

[0050] The neurodegenerative disease is selected from one or more of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, and neurodegenerative diseases caused by traumatic injury.

[0051] The proliferative disease is selected from one or more of acute myeloid leukemia and chronic myeloid leukemia.

[0052] The angiogenic disorder is selected from one or more of solid tumors, ocular neovascularization, and infantile hemangioma.

[0053] The infectious disease is selected from one or more of sepsis, septic shock, and shigellosis.

[0054] The tumor is selected from one or more of non-small cell lung cancer, small cell lung cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, melanoma, glioblastoma, colorectal cancer, Kaposi's sarcoma, brain glioma, neuroglioma, and hematological malignancies.

[0055] The viral disease is selected from one or more of multiple myeloma, HIV infection, and CMV retinitis.

[0056] In another aspect, the present disclosure relates to a method or use for treating and / or preventing a disease or symptom associated with abnormal RIPK1 activity or mediated by RIPK1, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] FIG1 is a graph showing the effects of compound 249 and GSK2982772 on the body weight of mice after administration in a hemophagocytic syndrome mouse model.

[0058] FIG2 is a graph showing the effects of compound 249 and GSK2982772 on the number of leukocytes in mice after administration in a mouse model of hemophagocytic syndrome.

[0059] FIG3 is a graph showing the effects of compound 249 and GSK2982772 on the number of red blood cells in mice after administration in a hemophagocytic syndrome mouse model.

[0060] FIG4 is a graph showing the effects of compound 249 and GSK2982772 on hemoglobin in mice after administration in a hemophagocytic syndrome mouse model.

[0061] FIG5 is a graph showing the effects of compound 249 and GSK2982772 on platelets in mice after administration in a hemophagocytic syndrome mouse model.

[0062] FIG6 is a graph showing the effects of compound 249 and GSK2982772 on liver weight in a hemophagocytic syndrome mouse model.

[0063] FIG7 is a graph showing the effects of compound 249 and GSK2982772 on the spleen weight of mice after administration in a hemophagocytic syndrome mouse model.

[0064] FIG8 is a pathological section showing the internal structure of the spleen of mice after administration of Compound 249 and GSK2982772 in a mouse model of hemophagocytic syndrome. DETAILED DESCRIPTION

[0065] the term

[0066] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0067] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. Depending on the structure, the alkyl group can be a monovalent group or a divalent group (i.e., an alkylidene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "low alkyl group" having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that "alkyl" mentioned herein includes all possible configurations and conformations of the alkyl group, for example, "propyl" mentioned herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and penta-3-yl, etc.

[0068] The term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0069] The term "alkoxyalkyl" refers to an alkyl group, as defined herein, substituted by an alkoxy group, as defined herein.

[0070] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

[0071] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl group as defined herein substituted with a cycloalkyl group as defined herein. Non-limiting examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0072] The term "aromatic" refers to a planar ring having a delocalized π electron system and containing 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of five, six, seven, eight, nine, or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic" includes carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0073] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, an aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0074] The term "aryloxy" refers to an -O-aryl group, wherein aryl is as defined herein.

[0075] The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaryl" moiety refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (i.e., a heteroarylidene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridinyl.

[0076] The term "alkyl (aryl)" or "aralkyl" refers to an alkyl group as defined herein substituted with an aryl group as defined herein. Non-limiting examples of alkyl (aryl) groups include benzyl, phenethyl, and the like.

[0077] The term "alkyl(heteroaryl)" or "heteroarylalkyl" means an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.

[0078] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein where one or more of the backbone chain atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom(s) may be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.

[0079] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic ring in which one or more of the atoms forming the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be a monocyclic or polycyclic ring consisting of three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiinane, 1,4-oxathiinane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazolidine, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0080] The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0081] The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means an alkoxy group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0082] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0083] The terms "haloalkyl," "haloalkoxy," and "haloheteroalkyl" include structures of alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen atom is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from one another.

[0084] The term "hydroxy" refers to an -OH group.

[0085] The term "cyano" refers to a -CN group.

[0086] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).

[0087] The term "amino" refers to a -NH2 group.

[0088] The term "aminoacyl" refers to a -CO-NH2 group.

[0089] The term "alkylaminoacyl" means a -CO-NH-R group, wherein R is alkyl as defined herein.

[0090] The term "amido" or "amido" refers to a -NR-CO-R' group, wherein R and R' are each independently hydrogen or alkyl.

[0091] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups, and specifically refers to the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, with the proviso that -NRR' is not -NH2. "Alkylamino" includes groups of compounds in which the nitrogen of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes groups in which the nitrogen of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

[0092] The terms "arylamino" and "diarylamino" refer to amino substituents further substituted with one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, wherein N is attached to at least one or two aryl groups, respectively.

[0093] The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.

[0094] The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.

[0095] The term "aralkylamino" herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.

[0096] The term "heteroarylamino" refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.

[0097] The term "heterocycloalkylamino" refers to an amino group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0098] The term "alkylaminoalkyl" means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.

[0099] The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.

[0100] The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.

[0101] The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups.

[0102] The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.

[0103] The term "acyl" refers to a monovalent atomic group remaining after removing a hydroxyl group from an organic or inorganic oxygen-containing acid, and has the general formula RM(O)-, where M is usually C.

[0104] The term "carbonyl" refers to an organic functional group composed of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0105] The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.

[0106] The term "arylcarbonyl" means a carbonyl group, as defined herein, substituted with an aryl group, as defined herein.

[0107] The term "alkoxycarbonyl" refers to a carbonyl group further substituted with an alkoxy group.

[0108] The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted with a heterocycloalkyl group.

[0109] The terms "alkylaminocarbonyl," "cycloalkylaminocarbonyl," "arylaminocarbonyl," "aralkylaminocarbonyl," and "heteroarylaminocarbonyl" refer to a carbonyl group, as defined herein, substituted with an alkylamino group, a cycloalkylamino group, an arylamino group, an aralkylamino group, or a heteroarylamino group, as defined herein, respectively.

[0110] The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted with an alkylcarbonyl group.

[0111] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted with an alkylcarbonyl group.

[0112] The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.

[0113] The term "mercapto" refers to a -SH group. The term "alkylthio" refers to a mercapto group, as defined herein, substituted with an alkyl group, as defined herein.

[0114] The term "sulfone" or "sulfonyl" refers to the functional group of sulfonic acid after losing the hydroxyl group, specifically refers to the -S(=O)2- group.

[0115] The term "sulfoxide" or "sulfinyl" refers to -S(=O)-.

[0116] The term "aminosulfonyl" or "aminosulfonyl" refers to the -S(=O)2-NH2 group.

[0117] The term "alkylsulfoxide" or "alkylsulfinyl" refers to an alkyl-S(=O)- group.

[0118] The term "alkylsulfonyl" or "alkylsulfonyl" refers to -S(=O)2-R, where R is alkyl.

[0119] The term "alkylaminosulfonyl" refers to a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.

[0120] The term "alkylsulfonylamino(amine) group" or "alkylsulfonylamino(amine) group", and "cycloalkylsulfonylamino(amine) group" or "cycloalkylsulfonylamino(amine) group" means that an amino group as defined herein is substituted by an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e. -NH-S(=O)2-R, wherein R is an alkyl group and a cycloalkyl group, respectively.

[0121] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O)2-R, where R is cycloalkyl.

[0122] The term "quaternary ammonium group" refers to -N + RR'R", wherein R, R' and R" are each independently selected from an alkyl group having 1 to 8 carbon atoms.

[0123] The term "optionally" refers to one or more events described later that may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" refers to that the group mentioned can be substituted by one or more additional groups, each of which is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Among them, the amino protecting group is preferably selected from pivaloyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0124] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0125] The term "pharmaceutically acceptable salt" herein refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects, i.e., is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and is consistent with a reasonable benefit / risk ratio. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic acid salt, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, naphthalene-m,n-disulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0126] "Solvate" or "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the association of one or more water molecules with one molecule of the substance, where the water remains in its molecular form as HO.

[0127] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphoglucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from "The Pharmacological Basis of Therapeutics," 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art. In some embodiments, metabolites of the compound are formed by an oxidation process and correspond to the corresponding hydroxyl-containing compound. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

[0128] As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0129] The term "prodrug" or "prodrug" refers to a derivative that may not be pharmacologically active but, in certain circumstances, can be administered orally or parenterally and thereafter metabolized in vivo to form a pharmacologically active compound of the present invention. Non-limiting examples of prodrugs include esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketals, among others.

[0130] An "effective amount" refers to an amount of a drug or pharmaceutical formulation that will elicit the biological or medical response of a tissue, system, animal, or human being, for example, that is being studied by a researcher or physician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject that has not received that amount. Also included within the scope of the term is an amount effective to enhance normal physiological function.

[0131] As used herein, the term "treating" refers to alleviating at least one symptom of a disease, disorder, or condition. The term includes administering and / or applying one or more compounds described herein to a subject to provide management or treatment of a condition. "Treatment" for the purposes of this disclosure may, but does not necessarily, provide a cure; rather, it is meant that "treatment" can be a form of management of a condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes partial or complete destruction of the harmful proliferating cells with minimal damage to normal cells. The desired treatment mechanism for harmful rapidly proliferating cells (including cancer cells) at the cellular level is apoptosis.

[0132] As used herein, the term "prevention" includes both preventing or slowing the onset of clinically significant disease development or preventing or slowing the onset of a preclinically significant disease stage in an at-risk individual. This includes prophylactic treatment of individuals at risk of developing disease.

[0133] The term "subject" or "patient" includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or that can otherwise benefit from the administration of the compounds of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a disorder or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals, such as chickens, amphibians, reptiles, etc.

[0134] The GI used in this paper 50 It refers to the drug concentration required to inhibit 50% of cell growth, that is, the drug concentration when the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0135] IC used in this article 50 It refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal effect in the assay in which the effect is measured.

[0136] The EC used in this paper 50 It refers to the dose, concentration or amount of a test compound that elicits a dose-dependent response that elicits 50% of the maximal expression of a specific response induced, stimulated or potentiated by the particular test compound.

[0137] Unless otherwise indicated, the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of the art. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques associated with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those known to those skilled in the art. In general, the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific literature, which are cited and discussed in this specification.

[0138] Active compound

[0139] The present disclosure relates to a RIPK1 inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0140] Among them, A ring, R 1 、R 2 、R 3 and m are as defined above.

[0141] Specifically, ring A is selected from a monocyclic or condensed ring aromatic or heteroaromatic group; preferably, ring A is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, benzothiazolyl, quinolyl, isoquinolyl, and indolyl; more preferably, ring A is selected from phenyl, naphth-2-yl, pyridin-3-yl, pyrimidin-5-yl, benzothiazol-5-yl, quinol-3-yl, quinol-7-yl, isoquinol-7-yl, and indol-5-yl; further preferably, ring A is selected from phenyl and pyridin-3-yl.

[0142] In a specific embodiment, R 1 is selected from C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, phenyl C1-3 alkyl, and unsubstituted or substituted by 1 to 3 independent R 7 substituted aryl, monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O or S, or 5-membered or 6-membered heterocyclic group containing 1 heteroatom selected from N or O; wherein R 7 Each is independently selected from halogen, cyano, oxo, carboxyl, sulfamoyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylaminoC1-3 alkyl, C1-6 alkylaminoacyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, C1-6 aminoalkyl, unsubstituted or substituted by 1 or 2 independently R 8 substituted 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N or O, and unsubstituted or replaced by 1 or 2 independently R 8Substituted C1-6 alkyl (5-7 membered heterocyclic group), wherein the 5-7 membered heterocyclic group contains 1-2 heteroatoms selected from N or O, or two adjacent R 7 together to form an unsubstituted or substituted by 1 or 2 independently R 8 a substituted 5-membered or 6-membered heterocyclic group containing one heteroatom selected from N or O; wherein R 8 Each is independently selected from amino, hydroxy, C1-3 alkyl, C1-4 alkylamino, and oxo.

[0143] Preferably, R 1 is selected from C1-4 alkyl (e.g., methyl, ethyl, propyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C2-4 alkenyl (e.g., vinyl, propenyl), phenyl C1-2 alkyl (e.g., benzyl), and unsubstituted or substituted by 1 to 3 independent R 7 substituted phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, or pyrrolidinyl; wherein R 7 R is each independently selected from halogen (e.g., fluorine, chlorine), cyano, oxo, carboxyl, sulfamoyl, C1-3 alkyl (e.g., methyl, ethyl, propyl), C1-3 haloalkyl (e.g., trifluoromethyl, difluoromethyl), C1-3 deuterated alkyl (e.g., deuterated methyl), C3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), C1-3 alkoxy (e.g., methoxy, ethoxy, propoxy), C1-4 alkylamino (e.g., methylamino, dimethylamino, ethylamino, diethylamino), C1-4 alkylaminoC1-2 alkyl (e.g., dimethylaminoethyl), C1-3 alkylaminoacyl (e.g., methylaminoacyl), C1-3 alkylsulfinyl (e.g., methylsulfinyl), C1-3 alkylsulfonyl (e.g., methylsulfonyl), C1-3 alkoxycarbonyl (e.g., methoxycarbonyl), C1-3 aminoalkyl (e.g., aminomethyl, aminoethyl), and unsubstituted or substituted by 1 or 2 independently selected R 8 substituted piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, diazepanyl, tetrahydrofuranyl, or C1-3 alkyl (morpholinyl), or two adjacent R 7 together to form an unsubstituted or substituted by 1 or 2 independently R 8 substituted dioxolane or piperidinyl; wherein R 8 Each is independently selected from amino, hydroxy, C1-3 alkyl (eg, methyl, ethyl, propyl), C1-2 alkylamino (eg, methylamino, dimethylamino, ethylamino), and oxo.

[0144] More preferably, R 1is selected from cyclopropyl, and unsubstituted or substituted by 1 or 2 independent R 7 substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, furanyl, or tetrahydropyridinyl; wherein R 7 Each independently selected from halogen, oxo, sulfamoyl, C1-3 alkyl, C1-3 deuterated alkyl, C3-5 cycloalkyl, C1-3 alkoxy, C1-4 alkylamino, C1-3 alkylaminoacyl, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, C1-3 aminoalkyl, and unsubstituted or substituted by 1 or 2 independently R 8 substituted piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl, or two adjacent R 7 together to form a dioxolane group; wherein R 8 are each independently selected from amino, hydroxy, and methyl.

[0145] More preferably, R 1 selected from cyclopropyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, thiazol-4-yl, oxazol-5-yl, furan-2-yl, 1 or 2 independently R 7 Substituted phenyl, substituted by 1 or 2 independently R 7 substituted pyridin-3-yl, substituted by 1 or 2 independently R 7 substituted pyridin-4-yl, substituted by 1 or 2 independently R 7 Substituted pyridazin-3-yl, substituted by 1 or 2 independently R 7 substituted pyrazol-3-yl, substituted by 1 or 2 independently R 7 substituted pyrazol-4-yl, substituted by 1 or 2 independently R 7 Substituted imidazol-4-yl, substituted by 1 or 2 independently R 7 Substituted pyrazin-2-yl, substituted by 1 or 2 independently R 7 substituted pyrimidin-5-yl, substituted by 1 or 2 independently R 7 Substituted [1,3,4] oxadiazol-2-yl, substituted by 1 or 2 independently R 7 Substituted [1,2,3] triazol-4-yl, substituted by 1 or 2 independently R 7 substituted 1,2,3,6-tetrahydro-pyridin-4-yl, substituted by 1 or 2 independently R 7 substituted pyrrol-3-yl, and 1 or 2 independently R 7 Substituted thiazol-2-yl; wherein R 7R is each independently selected from fluoro, chloro, oxo, sulfamoyl, methyl, ethyl, isopropyl, fluoromethyl, deuterated methyl, cyclopropyl, methoxy, methylamino, dimethylamino, dimethylaminoethyl, methylaminoacyl, methylsulfinyl, methylsulfonyl, aminomethyl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, 4-amino-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, morpholin-1-yl, 3-amino-pyrrolidin-1-yl, piperidin-4-yl, pyrrolidin-3-yl, tetrahydrofuran-3-yl, and 2-morpholinoethyl, or two adjacent R 7 Together they form a dioxolanyl, a piperidinyl, or an N-methylpiperidinyl.

[0146] Particularly preferably, R 1 Selected from:

[0147] where X 1 and X 2 are each independently CH or N (preferably both are CH), R 7a is selected from H, fluoro, chloro, methoxy, methylamino, dimethylamino, methylaminoacyl, methylsulfinyl, methylsulfonyl, sulfamoyl, aminomethyl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, morpholin-1-yl, 4-amino-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, and 3-amino-pyrrolidin-1-yl;

[0148] Where Y is CH or N, R 7b is selected from H, methyl, ethyl, and deuterated methyl;

[0149] where R 7c Selected from H, methyl or methoxy;

[0150] where R 7d selected from H or methyl; and

[0151] where Z 1 、Z 2 and Z 3 Two of them are CH, and the other one is N, R 7e is selected from methyl, isopropyl, and cyclopropyl.

[0152] In a specific embodiment, R 2 H or -L-(CHR 4 ) n -R 5 , wherein L is selected from -O-, -NH-, -C(=O)-NRa -、-NR b -C(=O)-, and -NH-C(=O)-NH-, n is 0 or 1, R 4 is H or methyl, R 5 unsubstituted or substituted by 1 to 3 independent R 6 substituted aryl (e.g., phenyl), 5-membered or 6-membered heterocyclic group containing 1 heteroatom selected from N or O (e.g., tetrahydrofuranyl), and 5-membered or 6-membered heteroaryl group containing 1-2 heteroatoms selected from N or O (e.g., imidazolyl, pyridyl, and isoxazolyl), R 6 Each is independently selected from halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterated alkoxy, C3-6 cycloalkyloxy, C3-6 cycloalkylC1-3 alkoxy, tetrahydropyranyloxy, or R in the L group a or R b The groups are connected to form a ring, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with 1 or 2 halogens;

[0153] m is 0, 1 or 2, R 3 Each is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 haloalkoxy, or R in the L group a or R b The groups are linked to form a ring;

[0154] where R a and R b Each is H, or a substituent R of the A ring 3 C2-3 alkylene, C1-2 alkyleneoxy or C1-2 alkylenethio, or R 5 The substituent R 6 Connected to form a C2-3 alkylene.

[0155] In a preferred embodiment, the RIPK1 inhibitor of the present invention is a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0156] Among them, R 1 、R 2 and R 3 As defined above, W is CH or N, preferably CH.

[0157] More preferably, R 2 -L-(CHR 4 ) n -R5 , wherein L is selected from -O-, -NH-, -C(=O)-NR a -、-NR b -C(=O)-, and -NH-C(=O)-NH-, n is 0 or 1, R 4 is H or methyl, R 5 unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, tetrahydrofuranyl, imidazolyl, pyridyl, and isoxazolyl, R 6 Each is independently selected from halogen, cyano, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuterated alkoxy, C3-5 cycloalkyloxy, C3-5 cycloalkylC1-2 alkoxy, tetrahydropyranyloxy, or R in the L group a or R b The groups are connected to form a ring, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with 1 or 2 halogens; R 3 is selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, C1-3 haloalkoxy, or R in the L group a or R b The groups are connected to form a ring; wherein R a and R b Each is H, or a substituent R of the A ring 3 C2-3 alkylene, C1-2 alkyleneoxy or C1-2 alkylenethio, or R 5 The substituent R 6 Connected to form a C2-3 alkylene.

[0158] In a preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , wherein L is selected from -O- and -NH-, n is 0, R 5 is unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, R 6 are each independently selected from halogen, cyano, C1-3 alkoxy, and C1-3 haloalkyl; R 3 For H.

[0159] In another preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , wherein L is -C(=O)-NR a -, n is 1, R 4is H or methyl, R 5 is unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, R 6 Each independently selected from halogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 deuterated alkoxy, C3-5 cycloalkyloxy, C3-5 cycloalkylC1-2 alkoxy, or R in the L group a The groups are connected to form a ring; R 3 R is selected from H, halogen, C1-3 alkyl, or L group a The groups are connected to form a ring; wherein R a is H, or is a substituent R on the A ring 3 C2-3 alkylene formed by connecting, or with R 5 The substituent R 6 Connected to form a C2-3 alkylene.

[0160] In this embodiment, it is more preferred that the RIPK1 inhibitor of the present invention is a compound represented by formula (IIa), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0161] Among them, R 1 and R 4 As defined above; W is CH or N, preferably CH; R 3 is selected from H, fluorine, and methyl; R 4 is H or methyl; R 6a and R 6b Each is independently selected from fluoro, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0162] In another preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , wherein L is -NH-C(=O)-NH-, n is 0 or 1, R 4 H, R 5 unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, imidazol-3-yl, isoxazol-3-yl, and isoxazol-5-yl, R 6 R is independently selected from halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkoxy, and tetrahydropyranyloxy; 3 Selected from H, halogen, and C1-3 alkyl.

[0163] In this embodiment, preferably R 5 Selected from 1 to 3 independent R 6Substituted phenyl, isoxazol-3-yl, and isoxazol-5-yl, R 6 R is independently selected from fluoro, isobutyl, isopropoxy, trifluoromethoxy, and tetrahydropyranyloxy; 3 Selected from H, fluoro, and methyl.

[0164] In another preferred embodiment, R 2 -L-(CHR 4 ) n -R 5 , where L is -NR b -C(=O)-.

[0165] In this embodiment, it is particularly preferred that the RIPK1 inhibitor of the present invention is a compound represented by formula (IIb), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0166] Among them, R 1 As defined above; U is selected from CH2, O and S; q is 1 or 2; p is 1, 2, or 3; R 6 Each independently selected from halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuterated alkoxy, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with two fluorine groups.

[0167] More preferably, U is selected from CH2 and O; q is 1 or 2; p is 1, 2, or 3; R 6 Each is independently selected from fluoro, chloro, methyl, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0168] In addition, preferably, the RIPK1 inhibitor of the present invention is a compound represented by formula (IIc), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof,

[0169] Among them, R 1 As defined above; U is selected from CH2 and O; R 6a and R 6b Each is independently selected from fluoro, chloro, methyl, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0170] In a particularly preferred embodiment, the RIPK1 inhibitor of the present invention is selected from the following compounds, or pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, metabolites or prodrugs thereof:

[0171] For each variable, any combination of the above groups is also contemplated herein. It will be appreciated that substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0172] Also described herein are pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, metabolites, or prodrugs of this compound.

[0173] In particular, the compounds described herein can be made and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, or the like; or with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1- -formic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, etc.; (2) base addition salts, which are formed when the acidic protons in the parent compound are replaced by metal ions, such as alkali metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (such as magnesium or calcium) or aluminum ions; or coordinated with organic bases or inorganic bases, acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0174] The corresponding counter ion of the pharmaceutically acceptable salt can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

[0175] The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

[0176] Screening and characterizing pharmaceutically acceptable salts, polymorphs and / or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy, elemental analysis. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopic techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0177] All stereoisomers of the compounds of the present invention are contemplated, in mixtures or in pure or substantially pure form. Stereoisomers can include compounds that are optical isomers by having one or more chiral atoms, and compounds that are optical isomers (atropisomers) by means of limited rotation around one or more keys. All possible stereoisomers and mixtures thereof are encompassed by the definition of the compound of the present invention. It very specifically encompasses racemic forms and separated optical isomers with specified activity. The racemic form can be split by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Independent optical isomers can be obtained from racemates by conventional methods (e.g., forming salts with optically active acids, followed by crystallization).

[0178] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium and tritium. For example, an alkyl substituent is intended to encompass an alkyl group having hydrogen, deuterium, and / or some combination thereof. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent originally employed.

[0179] Also contemplated are prodrugs and solvates of the compounds of the present invention. The term "prodrug" refers to a compound that, after being administered to a subject, undergoes chemical conversion by metabolic or chemical processes to produce a compound of formula (I) and / or its salt and / or solvate. Any compound that will be converted in vivo to provide a bioactive agent is a prodrug within the scope and spirit of the present invention.

[0180] Drug uses

[0181] The compounds of the present invention modulate kinase activity, including modulation of RIPK1. Accordingly, the compounds of the present invention have utility in the treatment and / or prevention of conditions associated with modulation of kinase activity, and in particular, selective inhibition of RIPK1 activity.

[0182] Specifically, the present disclosure relates to the use of the aforementioned RIPK1 inhibitors as drugs for treating and / or preventing diseases or symptoms associated with abnormal RIPK1 activity or mediated by RIPK1, especially one or more of hemophagocytic syndrome, inflammatory diseases, autoimmune diseases, ischemic diseases, destructive bone diseases, neurodegenerative diseases, proliferative diseases, angiogenesis disorders, infectious diseases, tumors and viral diseases associated with abnormal RIPK1 activity or mediated by RIPK1.

[0183] Preferably, the hemophagocytic syndrome is selected from one or more of primary hemophagocytic syndrome and secondary hemophagocytic syndrome.

[0184] The inflammatory disease is selected from one or more of Crohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, graft-versus-host disease, chronic obstructive pulmonary disease, and pulmonary fibrosis.

[0185] The autoimmune disease is selected from one or more of Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, and transplant rejection.

[0186] The ischemic disease is selected from one or more of liver or brain ischemic injury, myocardial ischemia-reperfusion injury, and ischemic injury during reperfusion or organ storage.

[0187] The destructive bone disease is selected from one or more of bone cysts, bone erosions, myeloma, and osteosarcoma.

[0188] The neurodegenerative disease is selected from one or more of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, and neurodegenerative diseases caused by traumatic injury.

[0189] The proliferative disease is selected from one or more of acute myeloid leukemia and chronic myeloid leukemia.

[0190] The angiogenic disorder is selected from one or more of solid tumors, ocular neovascularization, and infantile hemangioma.

[0191] The infectious disease is selected from one or more of sepsis, septic shock, and shigellosis.

[0192] The tumor is selected from one or more of non-small cell lung cancer, small cell lung cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, melanoma, glioblastoma, colorectal cancer, Kaposi's sarcoma, brain glioma, neuroglioma, and hematological malignancies.

[0193] The viral disease is selected from one or more of multiple myeloma, HIV infection, and CMV retinitis.

[0194] The present invention provides a method for treating and / or preventing such disorders, comprising administering to a subject in need thereof a therapeutically and / or prophylactically effective amount of at least one RIPK1 inhibitor of the present invention. A "therapeutically and / or prophylactically effective amount" is intended to include an amount of a compound of the present invention that is effective in inhibiting RIPK1 when administered alone or in combination.

[0195] Methods for treating and / or preventing RIPK1 kinase-associated disorders may comprise administering the compounds of the present invention alone or in combination with one another and / or with other suitable therapeutic agents useful for treating such disorders. Thus, a "therapeutically and / or prophylactically effective amount" is also intended to include an amount of the combination of compounds claimed that is effective for inhibiting RIPK1 and / or treating and / or preventing a disease associated with RIPK1.

[0196] In an embodiment of the present invention, the medicine comprising the compounds of this invention can be administered to the patient by at least one of injection, oral administration, inhalation, rectal administration and transdermal administration. When the patient is treated according to the present invention, the amount of a given drug depends on many factors, such as specific dosage regimen, disease or disease type and severity thereof, the uniqueness (such as body weight) of the patient or host for treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, disease for treatment and the patient or host for treatment, the dosage can be conventionally determined by methods known in the art. Usually, for the dosage used in adult treatment, the dosage is typically 0.02-5000mg / days, such as the scope of about 1-1500mg / days. The desired dose can be conveniently expressed as a dose or simultaneously administered (or in a short time) or at appropriate intervals, such as two, three, four or more doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, specific effective amount can be appropriately adjusted according to the patient's situation and in conjunction with a physician's diagnosis.

[0197] In some embodiments of the methods or uses disclosed herein, a compound as described herein, any one of the compounds, is administered to a subject at a dosage (e.g., a therapeutically effective dose) of about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, or 0.1-50 mg. In some embodiments, the dosage (e.g., a therapeutically effective dose) is about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, 0.1-50 mg, 0.1-75 mg, 0.5-75 mg, 1-75 mg, 0.1-100 mg, 0.5-100 mg, or 1-100 mg. In some embodiments, the dosage is about 1-10 mg. In some embodiments, the dosage is about 1-50 mg. In some embodiments, the dosage is about 1-100 mg.

[0198] Preparation of compounds

[0199] Compounds of formula (I), (II), (IIa), (IIb), (IIc) can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions given herein can be varied according to those skilled in the art.

[0200] In certain embodiments, provided herein are methods for preparing the kinase inhibitor compounds described herein and methods for using the same. In certain embodiments, the compounds described herein can be synthesized using the following synthetic schemes. Compounds can be synthesized using methods similar to those described below using appropriate alternative starting materials.

[0201] The starting materials used to synthesize the compounds described herein can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and raw materials known to those skilled in the art. The reactions for preparing the compounds disclosed herein can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties into the molecules provided herein.

[0202] If desired, the reaction products can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. These products can be characterized using conventional methods, including physical constants and spectral data.

[0203] Silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. was used for column chromatography, silica gel plates produced by Qingdao Chemical were used for thin-layer chromatography, a Bruker nuclear magnetic resonance instrument was used for nuclear magnetic resonance chromatography, and an Agilent 1200 series liquid chromatography-mass spectrometer was used for liquid chromatography-mass spectrometry (LC-MS).

[0204] Abbreviations used herein are defined as follows: “°C” for degrees Celsius; “eq” for equivalent; “g” for gram; “mg” for milligram; “L” for liter; “mL” for milliliter; “μL” for microliter; “M” for mole; “mmol” for millimolar; “min” for minute; “h” for hour; “rt” for room temperature; “MW” for molecular weight; “MS” or “Mass Spec” for mass spectrometry; “ESI” for electrospray ionization mass spectrometry; “HRMS” for high resolution mass spectrometry; “LCMS” or “LC / MS” for liquid chromatography mass spectrometry; “HPLC” for high performance liquid chromatography; “TLC” or “tlc” for thin layer chromatography; “NMR” for nuclear magnetic resonance spectroscopy; “1H” for proton; “δ” for chemical shift; “s” for singlet; “d” for doublet; “t” for triplet; “q” for quartet; “m” for multiplet; “br” for broad; and “MHz” for megahertz.

[0205] The following abbreviations were used in the synthesis of the examples: DCM: dichloromethane; PE: petroleum ether; EA: ethyl acetate; THF: tetrahydrofuran; TEA: triethylamine; TFA: trifluoroacetic acid; DIEPA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMAP: 4-dimethylaminopyridine; K2CO3: potassium carbonate; Cs2CO3: cesium carbonate; KOAc: potassium acetate; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; MsCl: methanesulfonyl chloride; Ar: argon.

[0206] Example

[0207] The following specific non-limiting examples are to be interpreted as merely illustrative and not limiting of the present disclosure in any way. Although no further detailed description is required, it is believed that one skilled in the art can fully utilize the present disclosure based on the description herein.

[0208] Example 1: Preparation of N-(5-(Benzo[d]thiazol-5-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (1)

[0209] Step 1: To a 250 mL round-bottom flask, add 3-bromo-1H-pyrazol-5-amine (10.0 g, 61.7 mmol, 1 eq) and (Boc)2O (16.2 g, 74.0 mmol, 1.2 eq). Dissolve the mixture in anhydrous THF (100 mL). Add DMAP (1.50 g, 12.3 mmol, 0.2 eq) in portions and react at room temperature for 4 h. After completion of the reaction, monitor the reaction by TLC. Wash the mixture sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. Extract the mixture with EA, and concentrate the organic phase. Purify the mixture and filter the column to obtain 12.0 g of tert-butyl 3-amino-5-bromo-1H-pyrazole-1-carboxylate (IM-1) as a white solid in a yield of 74.1%. ESI-MS: 262.02 [M+H]. + .

[0210] Step 2: To a 500 mL round-bottom flask, add 4-(4-methylpiperazin-1-yl)benzoic acid (10.0 g, 45.4 mmol, 1 eq), HATU (19.0 g, 49.94 mmol, 1.1 eq), and KCO (18.8 g, 136.2 mmol, 3 eq). Dissolve the mixture in DMF (100 mL) and allow to react overnight at room temperature. After completion of the reaction as monitored by TLC, slowly add water (200 mL) dropwise to the system. Solid precipitates, which are filtered, washed with water, and dried. 14.0 g of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-4-(4-methylpiperazin-1-yl)benzoate (IM-2) is obtained as a yellow solid in a yield of 91.1%. ESI-MS: 339.16 [M+H] + .

[0211] Step 3: To a 25 mL round-bottom flask, tert-butyl 3-amino-5-bromo-1H-pyrazole-1-carboxylate (IM-1, 100 mg, 0.382 mmol, 1 eq), 5-benzothiazolylpinacol borate (149 mg, 0.572 mmol, 1.5 eq), Pd(dppf)Cl2 (28 mg, 0.0382 mmol, 0.1 eq) and K3PO4 (243 mg, 1.15 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 63 mg of tert-butyl 3-amino-5-(benzo[d]thiazol-5-yl)-1H-pyrazole-1-carboxylate as a yellow semisolid, in a 50.1% yield. ESI-MS: 317.11 [M+H] + .

[0212] Step 4: To a 25 mL round-bottom flask was added tert-butyl 3-amino-5-(benzo[d]thiazol-5-yl)-1H-pyrazole-1-carboxylate (50.0 mg, 0.158 mmol, 1 eq), dissolved in THF (2 mL), and NaH (60%) (19.0 mg, 0.474 mmol, 3 eq) was added under ice bath and stirring was continued for 15 minutes. 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-4-(4-methylpiperazin-1-yl)benzoate (IM-2, 80.0 mg, 0.237 mmol, 1.5 eq) was added, and the temperature was then raised to 60°C and reacted for 6 hours. After the reaction was complete, the mixture was quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and passed through a column to obtain 26 mg of a white solid of N-(5-(benzo[d]thiazol-5-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (1), in a yield of 40.9%. ESI-MS: 419.16 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ13.04(s,1H),10.58(s,1H),9.45(s,1H),8.48(s,1H),8.24(d,J=7.6Hz,1H),7.97(d,J= 8.8Hz,2H),7.90(s,1H),7.15(s,1H),7.04(d,J=8.0Hz,2H),3.42(s,3H),2.95-2.67(m,4H),2.50-2.35(m,4H).

[0213] Examples 2 to 7:

[0214] Examples 2 to 7 can be prepared by referring to the method of Example 1, except that different pinacol borate esters are used to replace 5-benzothiazole pinacol borate ester.

[0215] Example 8: Preparation of N-(5-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (8)

[0216] Step 1: To a 100 mL round-bottom flask, add 3,5-difluorophenylboronic acid (2.00 g, 12.7 mmol, 1 eq) and pyridine (1.00 g, 12.7 mmol, 1 eq), dissolve in anhydrous DCM (50 mL), and stir at room temperature for 6 h. To a 250 mL round-bottom flask, add 4-hydroxyphenylboronic acid pinacol ester (2.80 g, 12.7 mmol, 1 eq), copper acetate (3.00 g, 16.5 mmol, 1.3 eq), and triethylamine (2.57 g, 25.4 mmol, 2 eq), dissolve in anhydrous DCM (50 mL), and stir at room temperature for 6 h. The solution in the 100 mL round-bottom flask was then added to another reaction flask and allowed to react at room temperature for 15 h. After the reaction was complete as monitored by TLC, the mixture was filtered and washed with DCM. The filtrate was concentrated and filtered through a column to obtain 183 mg of 2-(4-(3,5-difluorophenoxy)phenyl)boronic acid pinacol ester as a yellow oil, with a yield of 4.3%. ESI-MS: 333.15 [M+H] + .

[0217] Step 2: To a 25 mL round-bottom flask, tert-butyl 3-amino-5-bromo-1H-pyrazole-1-carboxylate (IM-1, 100 mg, 0.382 mmol, 1 eq), 2-(4-(3,5-difluorophenoxy)phenyl)boronic acid pinacol ester (189 mg, 0.572 mmol, 1.5 eq), Pd(dppf)Cl2 (28.0 mg, 0.0382 mmol, 0.1 eq) and K3PO4 (243 mg, 1.15 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 110 mg of tert-butyl 3-amino-5-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazole-1-carboxylate as a white solid, in a yield of 74.3%. ESI-MS: 388.15 [M+H] + .

[0218] Step 3: To a 25 mL round-bottom flask was added tert-butyl 3-amino-5-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazole-1-carboxylate (60.0 mg, 0.155 mmol, 1 eq), dissolved in THF (2 mL), and NaH (60%) (19.0 mg, 0.465 mmol, 3 eq) was added under ice bath and stirring was continued for 15 minutes. 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-4-(4-methylpiperazin-1-yl)benzoate (IM-2, 79.0 mg, 0.232 mmol, 1.5 eq) was added, and the temperature was then raised to 60°C for 6 hours. After the reaction was complete, the mixture was quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column to obtain 13 mg of N-(5-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (8) as a white solid, with a yield of 17.1%. ESI-MS: 490.20 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.86(s,1H),10.50(s,1H),7.93(d,J=8.4Hz,2H),7.82(d,J=8.2Hz,2H),7.21(d,J=8.2Hz,2H) ,7.07-7.00(m,2H),7.00-6.92(m,2H),6.80(d,J=8.2Hz,2H),3.29(t,J=5.0Hz,4H),2.44(t,J=5.0Hz,4H),2.23(s,3H).

[0219] Examples 9 to 21:

[0220] Examples 9 to 21 can be prepared by referring to the method of Example 8, except that different phenylboronic acids are used instead of 3,5-difluorophenylboronic acid.

[0221] Example 22: Preparation of 4-(4-methyl-1,4-diazepin-1-yl)-N-(5-(4-phenoxyphenyl)-1H-pyrazol-3-yl)benzamide (22)

[0222] Step 1: 3-Bromo-1H-pyrazol-5-amine (10.0 g, 61.7 mmol, 1 eq) was added to a 500 mL round-bottom flask and dissolved in DMF (100 mL). The mixture was placed in an ice bath at -20°C. NaH (60%, 3.0 g 74.0 mmol, 1.2 eq) was added in six portions and stirred for 30 min. 4-Methoxybenzyl chloride (10.0 g, 61.7 mmol, 1 eq) was placed in a constant pressure dropping funnel and dissolved in DMF (100 mL). The mixture was added dropwise to the round-bottom flask in an ice bath at -20°C. Stirring was continued in the ice bath for 1 h after the mixture was added and the mixture was allowed to react at room temperature overnight. After the reaction was complete as monitored by TLC, the mixture was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase was concentrated and filtered through a column to yield 13.8 g of 5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-amine (IM-3) as a yellow solid, in a 66.0% yield. ESI-MS: 282.02 [M+H] + .

[0223] Step 2: To a 100 mL round-bottom flask, add 5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-amine (2.0 g, 7.09 mmol, 1 eq) and pyridine (1.68 g, 21.3 mmol, 3 eq). Dissolve the mixture in anhydrous DCM (40 mL) and stir at room temperature for 15 minutes. Transfer to an ice bath and add 4-fluorobenzoyl chloride (1.68 g, 10.6 mmol, 1.5 eq) dropwise. React at room temperature for 6 hours. After completion, wash the mixture with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase is concentrated and filtered through a column to yield 2.5 g of N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-fluorobenzamide (IM-4) as a yellow solid in an 87.1% yield. ESI-MS: 404.04 [M+H]. + .

[0224] Step 3: To a 100 mL sealed tube, add N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-fluorobenzamide (2.0 g, 4.95 mmol, 1 eq) and N-methylhomopiperazine (5.65 g, 49.5 mmol, 10 eq), dissolve in DMSO (50 mL), and react at 140°C for 12 h. After the reaction is complete, cool to room temperature and wash sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. Extract with EA, and concentrate the organic phase. Purify the column chromatography to obtain 1.2 g of N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methyl-1,4-azepin-1-yl)benzamide as a yellow solid in a yield of 48.6%. ESI-MS: 498.15 [M+H] + .

[0225] Step 4: To a 25 mL round-bottom flask, add N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methyl-1,4-azepine-1-yl)benzamide (100 mg, 0.200 mmol, 1 eq), phenoxybenzene-4-boronic acid pinacol ester (89 mg, 0.300 mmol, 1.5 eq), Pd(dppf)Cl2 (15 mg, 0.0200 mmol, 0.1 eq) and K3PO4 (127 mg, 0.600 mmol, 3 eq), dissolve in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protect with argon, and react at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 68 mg of N-(1-(4-methoxybenzyl)-5-(4-phenoxyphenyl)-1H-pyrazol-3-yl)-4-(4-methyl-1,4-azepin-1-yl)benzamide as a yellow solid, in a yield of 57.8%. ESI-MS: 588.30 [M+H] + .

[0226] Step 5: N-(1-(4-methoxybenzyl)-5-(4-phenoxyphenyl)-1H-pyrazol-3-yl)-4-(4-methyl-1,4-azepin-1-yl)benzamide (60 mg, 0.102 mmol, 1 eq) was added to a 25 mL round-bottom flask and dissolved in toluene (2 mL). TFA (2 mL) was then added and the mixture was reacted at 110°C for 2 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column to obtain 21 mg of a yellow solid of 4-(4-methyl-1,4-diazepin-1-yl)-N-(5-(4-phenoxyphenyl)-1H-pyrazol-3-yl)benzamide (22) in a yield of 44.0%. ESI-MS: 468.24 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.77(s,1H),10.36(s,1H),7.91(d,J=7.8Hz,2H),7.7 6(d,J=7.7Hz,2H),7.42(t,J=7.9Hz,2H),7.18(t,J=7.3Hz,1H),7.07(d,J=7.9H z, 4H), 6.97 (s, 1H), 6.75 (d, J = 6.7Hz, 2H), 3.61 (t, J = 5.0Hz, 2H), 3.51 (t, J = 6. 2Hz,2H),2.79-2.66(m,2H),2.61-2.53(m,2H),2.33(s,3H),1.99-1.90(m,2H).

[0227] Examples 23 to 24:

[0228] Examples 23 to 24 can be prepared by referring to the method of Example 22, except that different amines are used in place of N-methylhomopiperazine.

[0229] Example 25: Preparation of N-(5-(4-((3,5-difluorophenyl)amino)phenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (25)

[0230] Step 1: To a 100 mL round-bottom flask, add 4-(4-methylpiperazine)benzoic acid (4.4 g, 20.0 mmol, 1 eq), dissolve in SOCl2 (20 mL), add 1 drop of DMF as a catalyst, and react at 80°C for 4 h. After the reaction is complete, remove the SOCl2 by rotary evaporation and use directly in the next reaction.

[0231] Step 2: To a 100 mL round-bottom flask, 5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-amine (IM-3, 2.0 g, 7.09 mmol, 1 eq) and pyridine (1.68 g, 21.3 mmol, 3 eq) were added. The mixture was dissolved in anhydrous DCM (40 mL) and stirred at room temperature for 15 minutes. The mixture was then transferred to an ice bath and 4-(4-methylpiperazinyl)benzoyl chloride (2.53 g, 10.6 mmol, 1.5 eq) was added dropwise. The reaction was allowed to react at room temperature for 6 hours. After the reaction was complete, the mixture was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase was concentrated and filtered through a column chromatography column to obtain 3.1 g of N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5) as a yellow solid in a yield of 90.4%. ESI-MS:484.13[M+H] +.

[0232] Step 3: To a 25 mL round-bottom flask, add N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 200 mg, 0.413 mmol, 1 eq), 4-aminophenylboronic acid pinacol ester (136 mg, 0.619 mmol, 1.5 eq), Pd(dppf)Cl2 (30.2 mg, 0.0382 mmol, 0.1 eq) and K3PO4 (263 mg, 1.24 mmol, 3 eq), dissolve in a mixture of THF:H2O=10:1 (11 mL, V:V), protect with argon, and react at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 110 mg of N-(5-(4-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a white solid, in a 53.6% yield. ESI-MS: 497.27 [M+H] + .

[0233] Step 4: To a 25 mL round-bottom flask, N-(5-(4-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (100 mg, 0.201 mmol, 1 eq), 3,5-difluorobromobenzene (58.3 mg, 0.302 mmol, 1.5 eq), Pd2(dba)3 (27.6 mg, 0.0302 mmol, 0.15 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene Xantphos (34.9 mg, 0.0603 mmol, 0.3 eq) and Cs2CO3 (196 mg, 0.603 mmol, 3 eq) were added, dissolved with 1,4-dioxane (5 mL), protected by argon, and reacted at 120°C for 6 h. After the reaction was complete, the product was quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 63 mg of N-(5-(4-((3,5-difluorophenyl)amino)phenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a yield of 51.6%. ESI-MS: 609.28 [M+H] + .

[0234] Step 5: To a 25 mL round-bottom flask was added N-(5-(4-((3,5-difluorophenyl)amino)phenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (60 mg, 0.0986 mmol, 1 eq), dissolved in toluene (2 mL), and then added with TFA (2 mL). The reaction was allowed to proceed at 110°C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 23 mg of N-(5-(4-((3,5-difluorophenyl)amino)phenyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (25) as a yellow solid in a yield of 47.9%. ESI-MS: 489.22 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.71(s,1H),10.48(s,1H),8.81(s,1H),7.93(d,J=8.5Hz,2H),7.68(d,J=8.2Hz,2H),7.21(d,J=8. 3Hz,2H),7.13-6.83(m,3H),6.75-6.61(m,2H),6.64-6.52(m,1H),3.29(t,J=4.9Hz,4H),2.45(t,J=5.0Hz,4H),2.23(s,3H).

[0235] Example 26: Preparation of 4-(4-methylpiperazin-1-yl)-N-(5-(4-((3-(trifluoromethoxy)benzyl)oxy)quinolin-7-yl)-1H-pyrazol-3-yl)benzamide (26)

[0236] Step 1: To a 100 mL round-bottom flask, add 7-bromo-4-hydroxyquinoline (1.12 g, 5.0 mmol, 1 eq), 3-trifluoromethoxybenzyl bromide (1.40 g, 6.5 mmol, 1.1 eq), and K2CO3 (1.38 g, 10.0 mmol, 2 eq). Dissolve the mixture in DMF (10 mL) and stir at room temperature for 6 h. After completion of the reaction, as monitored by TLC, wash the mixture sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. Extract the mixture with EA, and concentrate the organic phase. Purify the mixture and filter the column to obtain 1.3 g of 7-bromo-4-((3-(trifluoromethoxy)benzyl)oxy)quinoline as a yellow solid in a 65% yield. ESI-MS: 398.00 [M+H] + .

[0237] Step 2: To a 100 mL round-bottom flask, 7-bromo-4-((3-(trifluoromethoxy)benzyl)oxy)quinoline (1.2 g, 3.01 mmol, 1 eq), pinacol diboron (1.53 g, 6.02 mmol, 2 eq), Pd(dppf)Cl2-DCM (246 mg, 0.301 mmol, 0.1 eq) and KOAc (886 mg, 9.03 mmol, 3 eq) were added, dissolved in 1,4-dioxane (20 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 1.2 g of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((3-(trifluoromethoxy)benzyl)oxy)quinoline as a reddish-brown oil, with a yield of 89.5%. ESI-MS: 446.18 [M+H] + .

[0238] Step 3: To a 25 mL round-bottom flask, tert-butyl 3-amino-5-bromo-1H-pyrazole-1-carboxylate (IM-1, 100 mg, 0.382 mmol, 1 eq), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((3-(trifluoromethoxy)benzyl)oxy)quinoline (255 mg, 0.572 mmol, 1.5 eq), Pd(dppf)Cl2 (28 mg, 0.0382 mmol, 0.1 eq) and K3PO4 (243 mg, 1.15 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 110 mg of tert-butyl 3-amino-5-(4-((3-(trifluoromethoxy)benzyl)oxy)quinolin-7-yl)-1H-pyrazole-1-carboxylate as a yellow solid, in a 57.6% yield. ESI-MS: 501.18 [M+H] + .

[0239] Step 4: To a 25 mL round-bottom flask was added tert-butyl 3-amino-5-(4-((3-(trifluoromethoxy)benzyl)oxy)quinolin-7-yl)-1H-pyrazole-1-carboxylate (100 mg, 0.200 mmol, 1 eq), dissolved in THF (2 mL), and NaH (60%) (24 mg, 0.600 mmol, 3 eq) was added under ice bath and stirring was continued for 15 minutes. 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-4-(4-methylpiperazin-1-yl)benzoate (IM-2, 102 mg, 0.300 mmol, 1.5 eq) was added, and the temperature was then raised to 60°C for 6 hours. After the reaction was complete, the reaction was quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and passed through a column to obtain 35 mg of 4-(4-methylpiperazin-1-yl)-N-(5-(4-((3-(trifluoromethoxy)benzyl)oxy)quinolin-7-yl)-1H-pyrazol-3-yl)benzamide (26) as a white solid, in a yield of 29.2%. ESI-MS: 603.23 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ13.07(s,1H),10.54(s,1H),8.22(t,J=8.3Hz,2H),8 .01-7.84(m,3H),7.76(s,1H),7.49(t,J=8.0Hz,1H),7.34(s,1H),7.28(d,J =8.3Hz,1H),7.24(d,J=7.8Hz,1H),7.18(s,1H),7.00(d,2H),6.17(d,J=7.7 Hz, 1H), 5.67 (s, 2H), 3.32-3.25 (m, 4H), 2.45 (t, J = 5.0Hz, 4H), 2.23 (s, 3H).

[0240] Examples 27 to 32

[0241] Examples 27 to 32 can be prepared by referring to the method of Example 26, except that phenol with different substituents is used to replace 7-bromo-4-hydroxyquinoline and benzyl bromide with different substituents is used to replace 3-trifluoromethoxybenzyl bromide.

[0242] Example 33: Preparation of 4-(4-methylpiperazin-1-yl)-N-(5-(6-((tetrahydrofuran-3-yl)oxy)naphthalen-2-yl)-1H-pyrazol-3-yl)benzamide (33)

[0243] Step 1: To a 100 mL round-bottom flask, add 3-hydroxytetrahydrofuran (2.64 g, 30.0 mmol, 1 eq) and DIPEA (7.75 g, 60.0 mmol, 2 eq). Dissolve the mixture in anhydrous THF (20 mL) and place in an ice bath. Add methanesulfonyl chloride (MsCl) (2.8 mL, 36.0 mmol, 1.2 eq) dropwise. Warm the mixture to room temperature and react for 6 h. After the reaction is complete, wash the mixture with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extract with EA, and concentrate the organic phase to obtain 3.2 g of tetrahydrofuran-3-yl methanesulfonate as a yellow oil (64.2% yield). This product was used directly in the next step.

[0244] Step 2: To a 100 mL round-bottom flask, add 6-bromo-2-naphthol (2.23 g, 10.0 mmol, 1 eq), tetrahydrofuran-3-yl methanesulfonate (1.99 g, 12.0 mmol, 1.2 eq), and KCO (4.14 g, 30.0 mmol, 3 eq). Dissolve the mixture in anhydrous DMF (40 mL) and react at 80°C for 6 h. After the reaction is complete, wash the mixture sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. Extract the mixture with EA, and concentrate the organic phase. Purify the mixture and filter it into a column chromatography column to obtain 2.1 g of 3-((6-bromonaphthalen-2-yl)oxy)tetrahydrofuran as a yellow semisolid, in a 71.7% yield. ESI-MS: 293.02 [M+H] + .

[0245] Step 3: To a 100 mL round-bottom flask, 3-((6-bromonaphthalen-2-yl)oxy)tetrahydrofuran (2.00 g, 6.82 mmol, 1 eq), bipyralidoborane (3.45 g, 13.6 mmol, 2 eq), Pd(dppf)Cl2-DCM (589 mg, 0.682 mmol, 0.1 eq) and KOAc (2.00 g, 20.5 mmol, 3 eq) were added, dissolved in 1,4-dioxane (40 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column to yield 1.7 g of a yellow semi-solid 4,4,5,5-tetramethyl-2-(6-((tetrahydrofuran-3-yl)oxy)naphthalen-2-yl)-1,3,2-dioxaborolane, in a yield of 73.9%. ESI-MS: 341.19 [M+H] + .

[0246] Step 4: To a 25 mL round-bottom flask, N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 200 mg, 0.413 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(6-((tetrahydrofuran-3-yl)oxy)naphthalen-2-yl)-1,3,2-dioxaborolane (210 mg, 0.619 mmol, 1.5 eq), Pd(dppf)Cl2 (30.2 mg, 0.0382 mmol, 0.1 eq) and K3PO4 (263 mg, 1.24 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (11 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 121 mg of N-(1-(4-methoxybenzyl)-5-(6-((tetrahydrofuran-3-yl)oxy)naphthalen-2-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a yield of 47.4%. ESI-MS: 618.31 [M+H] + .

[0247] Step 5: To a 25 mL round-bottom flask was added N-(1-(4-methoxybenzyl)-5-(6-((tetrahydrofuran-3-yl)oxy)naphthalen-2-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (100 mg, 0.162 mmol, 1 eq), dissolved in toluene (2 mL), and then added with TFA (2 mL). The reaction was allowed to proceed at 110°C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated sodium chloride, extracted with EA, and the organic phase was concentrated and filtered through a column to obtain 39 mg of 4-(4-methylpiperazin-1-yl)-N-(5-(6-((tetrahydrofuran-3-yl)oxy)naphthalen-2-yl)-1H-pyrazol-3-yl)benzamide (33) as a yellow solid in a yield of 48.4%. ESI-MS:498.25[M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),10.54(s,1H),8.23(s,1H),8.03-7.80(m,5H), 7.33(d,J=2.5Hz,1H),7.19(dd,J=8.9,2.5Hz,1H),7.00(d,J=8.5Hz,3H),5.18(dt,J= 6.3,3.2Hz,1H),3.98(dd,J=10.2,4.6Hz,1H),3.94-3.85(m,2H),3.80(td,J=8.3,4. 6Hz,1H),3.46-3.31(m,4H),2.62-2.51(m,4H),2.49-2.42(m,4H),2.08-2.03(m,1H).

[0248] Examples 34-35

[0249] Examples 34-35 can be prepared by referring to the method of Example 33, except that 2,2,2-trifluoroethyl methanesulfonate or 1-methyl-2-hydroxymethyl-1H-imidazole is used instead of tetrahydrofuran-3-yl methanesulfonate.

[0250] Example 36: Preparation of N-(5-(6-(methylamino)naphthalen-2-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (36)

[0251] Step 1: To a 100 mL round-bottom flask, add 6-bromo-2-aminonaphthalene (2.22 g, 10.0 mmol, 1 eq), iodomethane (1.56 g, 11.0 mmol, 1.1 eq), and K2CO3 (4.14 g, 30.0 mmol, 3 eq). Dissolve the mixture in DMF (40 mL) and react at 60°C for 6 h. After the reaction is complete, wash the mixture sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. Extract the mixture with EA, and concentrate the organic phase. Purify the mixture and filter the column to obtain 1.6 g of 6-bromo-N-methylnaphthalene-2-amine as a yellow solid in a 67.8% yield. ESI-MS: 236.01 [M+H] + .

[0252] Step 2: To a 100 mL round-bottom flask, 6-bromo-N-methylnaphthalen-2-amine (1.50 g, 6.35 mmol, 1 eq), bis(pinacolato)boron (3.22 g, 12.7 mmol, 2 eq), Pd(dppf)Cl2-DCM (548 mg, 0.635 mmol, 0.1 eq), and KOAc (1.87 g, 19.0 mmol, 3 eq) were added and dissolved in 1,4-dioxane (30 mL). Under argon, the mixture was reacted at 100°C for 8 h. After the reaction was complete, the mixture was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 1.3 g of N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-amine as a yellow solid in a yield of 72.2%. ESI-MS:284.18[M+H] + .

[0253] Step 3: To a 25 mL round-bottom flask, add N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 100 mg, 0.206 mmol, 1 eq), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-amine (87.5 mg, 0.309 mmol, 1.5 eq), Pd(dppf)Cl2 (15 mg, 0.0206 mmol, 0.1 eq) and K3PO4 (131 mg, 0.618 mmol, 3 eq), dissolve in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protect with argon, and react at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 59 mg of N-(1-(4-methoxybenzyl)-5-(6-(methylamino)naphthalen-2-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a yield of 51.1%. ESI-MS: 561.30 [M+H] + .

[0254] Step 4: To a 25 mL round-bottom flask was added N-(1-(4-methoxybenzyl)-5-(6-(methylamino)naphthalen-2-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (50 mg, 0.0892 mmol, 1 eq), dissolved in toluene (2 mL), and then added with TFA (2 mL). The reaction was allowed to proceed at 110°C for 6 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 19 mg of N-(5-(6-(methylamino)naphthalen-2-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (36) as a yellow solid in a yield of 48.7%. ESI-MS: 441.24 [M+H]. + . 1 H NMR (500MHz, DMSO-d6) δ12.77(s,1H),10.49(s,1H),8.03(s,1H),7.94(d,J=8.5Hz,2H),7.73-7.60(m,3H),7.13-6.89(m, 4H), 6.67 (d, J = 2.3Hz, 1H), 6.09 (s, 1H), 3.29 (t, J = 4.9Hz, 4H), 2.79 (d, J = 4.9Hz, 3H), 2.46 (t, J = 5.1Hz, 4H), 2.24 (s, 3H).

[0255] Example 37: Preparation of N-(4-(3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazol-5-yl)phenyl)nicotinamide (37)

[0256] Step 1: Nicotinic acid (1.00 g, 8.12 mmol, 1 eq) and HATU (3.09 g, 8.12 mmol, 1 eq) were added to a 100 mL round-bottom flask and dissolved in DCM (40 mL). The mixture was stirred at room temperature for 15 minutes. 4-Aminophenylboronic acid pinacol ester (1.78 g, 8.12 mmol, 1 eq) and DIPEA (3.15 g, 24.4 mmol, 3 eq) were then added sequentially. The reaction was continued at room temperature for 4 hours. After the reaction was complete, the mixture was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase was concentrated and filtered through a column to obtain 2.4 g of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)nicotinamide as a yellow solid in a yield of 91.2%. ESI-MS: 325.17 [M+H] + .

[0257] Step 2: To a 25 mL round-bottom flask were added N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 100 mg, 0.206 mmol, 1 eq), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)nicotinamide (100 mg, 0.309 mmol, 1.5 eq), Pd(dppf)Cl2 (15 mg, 0.0206 mmol, 0.1 eq) and K3PO4 (131 mg, 0.618 mmol, 3 eq), dissolved in a mixture of THF:H2O = 10:1 (5.5 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 63 mg of N-(4-(1-(4-methoxybenzyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazol-5-yl)phenyl)nicotinamide as a yellow solid, in a yield of 50.8%. ESI-MS: 602.29 [M+H] + .

[0258] Step 3: To a 25 mL round-bottom flask was added N-(4-(1-(4-methoxybenzyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazol-5-yl)phenyl)nicotinamide (60 mg, 0.0995 mmol, 1 eq), dissolved in toluene (2 mL), and then added with TFA (2 mL). The reaction was allowed to proceed at 110°C for 6 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 26 mg of N-(4-(3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazol-5-yl)phenyl)nicotinamide (37) as a yellow solid in a yield of 54.2%. ESI-MS: 482.23 [M+H]. + . 1H NMR(500MHz,DMSO-d6)δ12.79(s,1H),10.54(s,1H),10.50(s,1H),9.13(d,J=2.3 Hz,1H),8.78(dd,J=4.8,1.7Hz,1H),8.31(dt,J=8.0,2.0Hz,1H),7.94(d,J=8.4H z,2H),7.86(d,J=8.3Hz,2H),7.76(d,J=8.3Hz,2H),7.59(dd,J=7.9,4.8Hz,1H), 6.99 (d, J = 8.6 Hz, 3H), 3.29 (t, J = 5.5 Hz, 4H), 2.46 (t, J = 5.0 Hz, 4H), 2.24 (s, 3H).

[0259] Example 38: Preparation of N-(5-(4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (38)

[0260] Step 1: To a 100 mL round-bottom flask, add 4-bromobenzoic acid (2.0 g, 9.90 mmol, 1 eq) and HATU (3.76 g, 9.90 mmol, 1 eq). Dissolve the mixture in DCM (40 mL) and stir at room temperature for 15 minutes. Then, add 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.91 g, 9.90 mmol, 1 eq) and DIPEA (3.84 g, 29.7 mmol, 3 eq). Continue the reaction at room temperature for 4 hours. After the reaction is complete, wash with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase is concentrated and filtered through a column to yield 3.5 g of (4-bromophenyl)(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone as a yellow solid in a yield of 94.6%. ESI-MS: 376.05 [M+H]. + .

[0261] Step 2: To a 100 mL round-bottom flask, (4-bromophenyl)(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone (3.35 g, 8.90 mmol, 1 eq), bipyralidin (4.52 g, 17.8 mmol, 2 eq), Pd(dppf)Cl2-DCM (770 mg, 0.890 mmol, 0.1 eq) and KOAc (2.62 g, 26.7 mmol, 3 eq) were added, dissolved in 1,4-dioxane (50 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 3.2 g of (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone as a yellow solid, in an 84.8% yield. ESI-MS: 424.23 [M+H] + .

[0262] Step 3: To a 25 mL round-bottom flask, N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 100 mg, 0.206 mmol, 1 eq), (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (131 mg, 0.309 mmol, 1.5 eq), Pd(dppf)Cl2 (15 mg, 0.0206 mmol, 0.1 eq) and K3PO4 (131 mg, 0.618 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 71 mg of N-(5-(4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a yield of 49.3%. ESI-MS: 701.35 [M+H] + .

[0263] Step 4: To a 25 mL round-bottom flask was added N-(5-(4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (70 mg, 0.100 mmol, 1 eq), dissolved in toluene (2 mL), and then TFA (2 mL) was added and reacted at 110 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column to obtain 27 mg of a yellow solid of N-(5-(4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (38) in a yield of 46.6%. ESI-MS: 581.29 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.99(s,1H),10.55(s,1H),7.89(dd,J=48.1,8.1Hz,4H),7.52(d,J=7.8Hz,2H) ,7.16-6.93(m,3H),6.75(s,2H),4.75-4.49(m,2H),3.87-3.55(m,9H),2.84-2.73(m,2H),2.27(s,3H).

[0264] Example 39: Preparation of N-(5-(2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (39)

[0265] Step 1: To a 100 mL round-bottom flask, 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (1.13 g, 5.00 mmol, 1 eq), bis(pinacol)diboronate (2.54 g, 10.0 mmol, 2 eq), Pd(dppf)Cl2-DCM (432 mg, 0.500 mmol, 0.1 eq) and KOAc (2.94 g, 30.0 mmol, 3 eq) were added, dissolved in 1,4-dioxane (20 mL), and reacted at 100 °C under argon protection for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 900 mg of a yellow oily product, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one, in a 66.2% yield. ESI-MS: 274.16 [M+H] + .

[0266] Step 2: To a 25 mL round-bottom flask, N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 200 mg, 0.413 mmol, 1 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (169 mg, 0.619 mmol, 1.5 eq), Pd(dppf)Cl2 (30.2 mg, 0.0382 mmol, 0.1 eq) and K3PO4 (263 mg, 1.24 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (11 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 117 mg of N-(1-(4-methoxybenzyl)-5-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a 51.5% yield. ESI-MS: 551.28 [M+H] + .

[0267] Step 3: To a 25 mL round-bottom flask, add N-(1-(4-methoxybenzyl)-5-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (50 mg, 0.0908 mmol, 1 eq), benzyl bromide (23.3 mg, 0.136 mmol, 1.5 eq) and K2CO3 (37.6 mg, 0.272 mmol, 3 eq), dissolve in DMF (2 mL), and react at 80°C for 6 h. After the reaction was complete, the mixture was quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 31 mg of N-(5-(2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a yield of 53.4%. ESI-MS: 641.32 [M+H] + .

[0268] Step 4: To a 25 mL round-bottom flask was added N-(5-(2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (30 mg, 0.0468 mmol, 1 eq), dissolved in toluene (2 mL), and then TFA (2 mL) was added and reacted at 110 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column to obtain 11 mg of a yellow solid of N-(5-(2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (39) in a yield of 45.8%. ESI-MS: 521.27 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.99(s,1H),10.53(s,1H),7.95(dd,J=24.4,8.2Hz,3H),7.76(d,J=8.2Hz,1H),7.70(d,J=1.8Hz,1H),7.39-7.25( m,5H),7.21-6.91(m,3H),4.73(s,2H),3.52(t,J=6.6Hz,2H),3.30-3.26(m,4H),3.02(t,J=6.6Hz,2H),2.45(t,J=5.0Hz,4H),2.23(s,3H).

[0269] Example 40

[0270] Example 40 can be prepared by referring to the method of Example 39, except that 2-fluorobenzyl bromide is used instead of benzyl bromide.

[0271] Example 41: Preparation of 4-(3-(cyclopropanecarboxamide)-1H-pyrazol-5-yl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (41)

[0272] Step 1: To a 100 mL round-bottom flask, add 4-bromobenzoic acid (2.0 g, 9.90 mmol, 1 eq) and HATU (3.76 g, 9.90 mmol, 1 eq). Dissolve the mixture in DCM (40 mL) and stir at room temperature for 15 minutes. Then, add 2-fluoro-5-(trifluoromethoxy)benzylamine (2.07 g, 9.90 mmol, 1 eq) and DIPEA (3.84 g, 29.7 mmol, 3 eq). Continue the reaction at room temperature for 4 hours. After the reaction is complete, wash with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase is concentrated and filtered through a column to yield 3.6 g of 4-bromo-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide as a yellow solid in a 92.8% yield. ESI-MS: 391.99 [M+H] + .

[0273] Step 2: To a 100 mL round-bottom flask, 4-bromo-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (3.5 g, 8.90 mmol, 1 eq), pinacol diboronate (4.52 g, 17.8 mmol, 2 eq), Pd(dppf)Cl2-DCM (770 mg, 0.890 mmol, 0.1 eq) and KOAc (2.62 g, 26.7 mmol, 3 eq) were added, dissolved in 1,4-dioxane (50 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 3.1 g of N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide as a yellow solid, with a yield of 79.8%. ESI-MS: 440.16 [M+H] + .

[0274] Step 3: To a 250 mL round-bottom flask, tert-butyl 3-amino-5-bromo-1H-pyrazole-1-carboxylate (IM-1, 1.0 g, 3.82 mmol, 1 eq), N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (2.5 g, 5.73 mmol, 1.5 eq), Pd(dppf)Cl2 (280 mg, 0.382 mmol, 0.1 eq) and K3PO4 (2.4 g, 11.5 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (55 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and filtered through a column to yield 1.1 g of tert-butyl 3-amino-5-(4-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)phenyl)-1H-pyrazole-1-carboxylate as a yellow solid, in a 58.2% yield. ESI-MS: 495.16 [M+H] + .

[0275] Step 4: To a 25 mL round-bottom flask was added tert-butyl amino-5-(4-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)phenyl)-1H-pyrazole-1-carboxylate (60 mg, 0.121 mmol, 1 eq), dissolved in THF (2 mL), and NaH (60%) (15 mg, 0.364 mmol, 3 eq) was added under ice bath and stirring was continued for 15 minutes. Cyclopropyl chloride (19 mg, 0.182 mmol, 1.5 eq) was added, and the temperature was then raised to 50 ° C for 6 h. After the reaction was complete, the mixture was quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase concentrated and filtered through a column chromatography column to yield 42 mg of tert-butyl 3-(cyclopropanecarboxamide)-5-(4-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)phenyl)-1H-pyrazole-1-carboxylate as a yellow solid, in a 61.8% yield. ESI-MS: 563.19 [M+H] + .

[0276] Step 5: To a 25 mL round-bottom flask was added tert-butyl 3-(cyclopropanecarboxamide)-5-(4-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)phenyl)-1H-pyrazole-1-carboxylate (40 mg, 0.0711 mmol, 1 eq), dissolved in methanolic ammonia (2 mL, 7 mol / L), and reacted at room temperature for 2 h. After the reaction was complete, the solvent was removed by rotary evaporation and the mixture was purified by column chromatography to obtain 26 mg of a white solid of 4-(3-(cyclopropanecarboxamide)-1H-pyrazol-5-yl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (41), in a yield of 79.3%. ESI-MS: 463.14 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.92(s,1H),10.71(s,1H),9.11(s,1H),7.95(d,J=8.0Hz,2H),7.82(d,J= 7.7Hz, 2H), 7.68-7.31 (m, 3H), 6.97 (s, 1H), 4.54 (d, J = 5.6Hz, 2H), 1.86 (s, 1H), 0.93·0.65 (m, 4H).

[0277] Examples 42 to 59

[0278] Examples 42 to 59 can be prepared by referring to the method of Example 41, except that different acid chlorides are used in place of cyclopropylacyl chloride.

[0279] Example 60: Preparation of 4-(3-(cyclopropanecarboxamide)-1H-pyrazol-5-yl)-2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (60)

[0280] Step 1: To a 100 mL round-bottom flask, add 5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-amine (IM-3, 2.00 g, 7.09 mmol, 1 eq) and pyridine (1.68 g, 21.3 mmol, 3 eq). Dissolve the mixture in anhydrous DCM (40 mL) and stir at room temperature for 15 minutes. Transfer to an ice bath and add cyclopropanoyl chloride (1.11 g, 10.6 mmol, 1.5 eq) dropwise. React at room temperature for 6 hours. After completion, wash the mixture with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase is concentrated and filtered through a column to yield 2.1 g of N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)cyclopropanecarboxamide (IM-6) as a yellow solid in an 84.7% yield. ESI-MS: 350.05 [M+H].+ .

[0281] Step 2: To a 100 mL round-bottom flask, add 4-bromo-2-fluorobenzoic acid (2.20 g, 10.0 mmol, 1 eq) and HATU (3.80 g, 10.0 mmol, 1 eq). Dissolve the mixture in DCM (40 mL) and stir at room temperature for 15 minutes. Then, add 2-fluoro-5-(trifluoromethoxy)benzylamine (2.09 g, 10.0 mmol, 1 eq) and DIPEA (3.88 g, 30.0 mmol, 3 eq). Continue the reaction at room temperature for 4 hours. After the reaction is complete, wash with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase is concentrated and filtered through a column to yield 3.8 g of 4-bromo-2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide as a yellow solid in a 91.8% yield. ESI-MS: 409.98 [M+H] + .

[0282] Step 3: To a 100 mL round-bottom flask, 4-bromo-2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (3.50 g, 8.53 mmol, 1 eq), pinacol diboron (4.34 g, 17.1 mmol, 2 eq), Pd(dppf)Cl2-DCM (624 mg, 0.853 mmol, 0.1 eq) and KOAc (2.51 g, 25.6 mmol, 3 eq) were added, dissolved in 1,4-dioxane (50 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and filtered through a column to yield 3.2 g of 2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide as a yellow solid, with a yield of 82.0%. ESI-MS: 458.16 [M+H] + .

[0283] Step 4: To a 25 mL round-bottom flask, add N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)cyclopropanecarboxamide (IM-6, 100 mg, 0.286 mmol, 1 eq), 2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (196 mg, 0.429 mmol, 1.5 eq), Pd(dppf)Cl2 (21 mg, 0.0286 mmol, 0.1 eq) and K3PO4 (182 mg, 0.858 mmol, 3 eq), dissolve in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protect with argon, and react at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 92 mg of a yellow solid of 4-(3-(cyclopropanecarboxamide)-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide, in a yield of 53.4%. ESI-MS: 601.19 [M+H] + .

[0284] Step 5: 4-(3-(cyclopropanecarboxamide)-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (80 mg, 0.133 mmol, 1 eq) was added to a 25 mL round-bottom flask, dissolved in toluene (2 mL), and then TFA (2 mL) was added. The reaction was allowed to proceed at 110°C for 6 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 31 mg of 4-(3-(cyclopropanecarboxamide)-1H-pyrazol-5-yl)-2-fluoro-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (60) as a white solid in a yield of 48.4%. ESI-MS: 481.13 [M+H]. + . 1 H NMR(500MHz,DMSO-d6)δ12.99(s,1H),10.73(s,1H),8.96(s,1H),7.77·7.58(m,3H),7.4 3·7.31(m,3H),7.01(s,1H),4.53(d,J=6.0Hz,2H),1.90·1.79(m,1H),0.86-0.71(m,4H).

[0285] Examples 61 to 75

[0286] Examples 61 to 75 can be prepared by referring to the method of Example 60, except that different acyl chlorides are used to replace cyclopropaneyl chloride, and 4-bromo-2-fluorobenzoic acid with different substituents and benzylamine with different substituents are used to replace the corresponding acid and amine.

[0287] Example 76: Preparation of N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazol-5-yl)benzeneacetamide (76)

[0288] Step 1: To a 100 mL round-bottom flask, add 4-bromobenzoic acid (2.0 g, 9.90 mmol, 1 eq) and HATU (3.76 g, 9.90 mmol, 1 eq). Dissolve the mixture in DCM (40 mL) and stir at room temperature for 15 minutes. Then, add 2-fluoro-5-(trifluoromethoxy)benzylamine (2.07 g, 9.90 mmol, 1 eq) and DIPEA (3.84 g, 29.7 mmol, 3 eq). Continue the reaction at room temperature for 4 hours. After the reaction is complete, wash with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase is concentrated and filtered through a column to yield 3.6 g of 4-bromo-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide as a yellow solid in a 92.8% yield. ESI-MS: 391.99 [M+H] + .

[0289] Step 2: To a 100 mL round-bottom flask, 4-bromo-N-(2-fluoro-5-(trifluoromethoxy)benzyl)benzamide (3.5 g, 8.90 mmol, 1 eq), pinacol diboronate (4.52 g, 17.8 mmol, 2 eq), Pd(dppf)Cl2-DCM (770 mg, 0.890 mmol, 0.1 eq) and KOAc (2.62 g, 26.7 mmol, 3 eq) were added, dissolved in 1,4-dioxane (50 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 3.1 g of N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide as a yellow solid, with a yield of 79.8%. ESI-MS: 440.16 [M+H] + .

[0290] Step 3: To a 25 mL round-bottom flask, N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 100 mg, 0.206 mmol, 1 eq), N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (136 mg, 0.309 mmol, 1.5 eq), Pd(dppf)Cl2 (15 mg, 0.0206 mmol, 0.1 eq) and K3PO4 (131 mg, 0.618 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and filtered through a column chromatography column to yield 83 mg of N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(1-(4-methoxybenzyl)-3-(4-(4-methylpiperazin-1-yl)benzamide)-1H-pyrazol-5-yl)benzeneacetamide as a yellow solid, in a 56.2% yield. ESI-MS: 717.28 [M+H] + .

[0291] Step 4: To a 25 mL round-bottom flask was added N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(1-(4-methoxybenzyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazol-5-yl)benzeneacetamide (80 mg, 0.112 mmol, 1 eq), dissolved in toluene (2 mL), and then added with TFA (2 mL). The reaction was allowed to proceed at 110°C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 31 mg of N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-(3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazol-5-yl)benzeneacetamide (76) as a yellow solid in a yield of 46.4%. ESI-MS:597.22[M+H] + . 1H NMR (500MHz, DMSO-d6) δ13.04(s,1H),10.60(s,1H),9.16(t,J=5.8Hz,1H),7.97(t,J=6.8Hz,4H),7.88(d,J=8.1Hz,2H), 7.37(dd,J=8.1,5.0Hz,3H),7.19-6.97(m,3H),4.55(d,J=5.7Hz,2H),3.63·3.37(m,4H),3.00-2.67(m,4H),2.47(s,3H).

[0292] Examples 77 to 126

[0293] Examples 77 to 126 can be prepared by referring to the method of Example 76, except that different acids are used to replace 4-(4-methylpiperazine)benzoic acid, and 4-bromobenzoic acid with different substituents and benzylamine with different substituents are used to replace the corresponding acid and amine.

[0294] Example 127: N-(5-(4-(3-(2-fluoro-5-(trifluoromethoxy)benzyl)ureido)phenyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (127)

[0295] Step 1: To a 100 mL round-bottom flask, add 4-aminophenylboronic acid pinacol ester (2.19 g, 10.0 mmol, 1 eq) and pyridine (2.37 g, 30.0 mmol, 3 eq). Dissolve the mixture in anhydrous acetonitrile (40 mL) and stir at room temperature for 15 minutes. Place the reaction mixture in an ice bath, then add phenyl chloroformate (1.88 g, 12.0 mmol, 1.2 eq) dropwise. Allow to react at room temperature for 6 hours. After the reaction is complete, add water dropwise. A solid precipitates, which is filtered, washed with water, and dried. 2.7 g of phenyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate is obtained as a yellow solid in a yield of 79.6%. ESI-MS: 340.17 [M+H] + .

[0296] Step 2: To a 100 mL round-bottom flask, phenyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (2.50 g, 7.37 mmol, 1 eq), 2-fluoro-5-(trifluoromethoxy)benzylamine (2.31 g, 11.0 mmol, 1.5 eq), and DIPEA (2.86 g, 22.1 mmol, 3 eq) were added and dissolved in anhydrous THF (40 mL). The mixture was reacted at 70°C for 8 h. After the reaction was complete, the mixture was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 2.6 g of 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as a yellow solid in a yield of 77.6%. ESI-MS:455.18[M+H] + .

[0297] Step 3: To a 25 mL round-bottom flask, N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 100 mg, 0.206 mmol, 1 eq), 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (140 mg, 0.309 mmol, 1.5 eq), Pd(dppf)Cl2 (15 mg, 0.0206 mmol, 0.1 eq) and K3PO4 (131 mg, 0.618 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (5.5 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 86 mg of N-(5-(4-(3-(2-fluoro-5-(trifluoromethoxy)benzyl)ureido)phenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a yield of 57.1%. ESI-MS: 732.29 [M+H] + .

[0298] Step 4: To a 25 mL round-bottom flask was added N-(5-(4-(3-(2-fluoro-5-(trifluoromethoxy)benzyl)ureido)phenyl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (80 mg, 0.109 mmol, 1 eq), dissolved in toluene (2 mL), and then added with TFA (2 mL). The reaction was allowed to proceed at 110°C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column chromatography column to obtain 33 mg of N-(5-(4-(3-(2-fluoro-5-(trifluoromethoxy)benzyl)ureido)phenyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (127) as a white solid in a yield of 49.4%. ESI-MS:612.23[M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.67(s,1H),10.45(s,1H),8.89(s,1H),7.93(d,J=8.5Hz,2H),7.61(d,J=8.2Hz,2H),7.47(d,J=8.3Hz,2H),7.35(dd,J=7 .5,4.5Hz,3H),6.98(d,J=8.4Hz,2H),6.91(s,1H),6.84(t,J=6.1Hz,1H), 4.38(d,J=5.9Hz,2H),3.30-3.23(m,4H),2.48-2.40(m,4H),2.23(s,3H).

[0299] Examples 128 to 167

[0300] Examples 128 to 167 can be prepared by referring to the method of Example 127, except that different intermediates are used to replace N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5), different pinacol esters are used to replace 4-aminophenylboronic acid pinacol ester, or different amines are used to replace 2-fluoro-5-(trifluoromethoxy)benzylamine.

[0301] Example 168: 4-(4-methylpiperazin-1-yl)-N-(5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)benzamide (168)

[0302] Step 1: To a 100 mL round-bottom flask, 3-trifluoromethoxyphenylacetic acid (2.20 g, 10.0 mmol, 1 eq) and HATU (3.80 g, 10.0 mmol, 1 eq) were added and dissolved in DCM (40 mL). The mixture was stirred at room temperature for 15 minutes. 7-Bromo-3,4-dihydro-2H-1,4-benzoxazine (2.14 g, 10.0 mmol, 1 eq) and DIPEA (3.88 g, 30.0 mmol, 3 eq) were then added sequentially. The reaction was continued at room temperature for 4 hours. After the reaction was complete, the mixture was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase was concentrated and filtered through a column chromatography column to obtain 3.8 g of 1-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one as a yellow solid in a yield of 91.3%. ESI-MS:416.01[M+H] + .

[0303] Step 2: To a 100 mL round-bottom flask, 1-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one (3.5 g, 8.41 mmol, 1 eq), bipyralidin (4.27 g, 16.8 mmol, 2 eq), Pd(dppf)Cl2-DCM (726 mg, 0.841 mmol, 0.1 eq) and KOAc (2.48 g, 25.2 mmol, 3 eq) were added, dissolved in 1,4-dioxane (50 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 3.1 g of 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one as a yellow solid, in a yield of 79.5%. ESI-MS: 464.19 [M+H] + .

[0304] Step 3: To a 25 mL round bottom flask was added N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5, 100 mg, 0.206 mmol, 1 eq), 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)- 2-(3-(Trifluoromethoxy)phenyl)ethan-1-one (143 mg, 0.309 mmol, 1.5 eq), Pd(dppf)Cl2 (15 mg, 0.0206 mmol, 0.1 eq) and K3PO4 (131 mg, 0.618 mmol, 3 eq) were dissolved in a mixture of THF:H2O=10:1 (5.5 mL, V:V) under argon protection and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to obtain 89 mg of N-(1-(4-methoxybenzyl)-5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide as a yellow solid, in a yield of 58.2%. ESI-MS: 741.30 [M+H]. + .

[0305] Step 4: To a 25 mL round-bottom flask was added N-(1-(4-methoxybenzyl)-5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (80 mg, 0.108 mmol, 1 eq), dissolved in toluene (2 mL), and then TFA (2 mL) was added and the reaction was carried out at 110 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column to obtain 31 mg of 4-(4-methylpiperazin-1-yl)-N-(5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)benzamide (168) as a white solid in a yield of 46.3%. ESI-MS: 621.24 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.80(s,1H),10.50(s,1H),7.93(d,J=8.5Hz,2H),7.46(t,J=8.0Hz,1H),7.34-7.20(m,5H),7 .00(d,J=8.5Hz,3H),4.31(t,J=4.5Hz,2H),4.09(s,2H),3.95(t,J=4.5Hz,2H),3.34(s,4H),2.59(s,4H),2.33(s,3H).

[0306] Examples 169 to 310

[0307] Examples 169 to 310 can be prepared according to the method of Example 168, except that different intermediates are used to replace N-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide (IM-5), different amines are used to replace 7-bromo-3,4-dihydro-2H-1,4-benzoxazine, or different phenylacetic acids are used to replace 3-trifluoromethoxyphenylacetic acid.

[0308] Example 311: 5-Methoxy-N-(5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)pyrazine-2-carboxamide (311)

[0309] Step 1: To a 100 mL round-bottom flask, 3-trifluoromethoxyphenylacetic acid (2.20 g, 10.0 mmol, 1 eq) and HATU (3.80 g, 10.0 mmol, 1 eq) were added and dissolved in DCM (40 mL). The mixture was stirred at room temperature for 15 minutes. 7-Bromo-3,4-dihydro-2H-1,4-benzoxazine (2.14 g, 10.0 mmol, 1 eq) and DIPEA (3.88 g, 30.0 mmol, 3 eq) were then added sequentially. The reaction was continued at room temperature for 4 hours. After the reaction was complete, the mixture was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. After extraction, the organic phase was concentrated and filtered through a column chromatography column to obtain 3.8 g of 1-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one as a yellow solid in a yield of 91.3%. ESI-MS:416.01[M+H] + .

[0310] Step 2: To a 100 mL round-bottom flask, 1-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one (3.5 g, 8.41 mmol, 1 eq), bipyralidin (4.27 g, 16.8 mmol, 2 eq), Pd(dppf)Cl2-DCM (726 mg, 0.841 mmol, 0.1 eq) and KOAc (2.48 g, 25.2 mmol, 3 eq) were added, dissolved in 1,4-dioxane (50 mL), protected by argon, and reacted at 100 °C for 8 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 3.1 g of 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one as a yellow solid, in a yield of 79.5%. ESI-MS: 464.19 [M+H] + .

[0311] Step 3: To a 25 mL round-bottom flask, 5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-amine (IM-3, 100 mg, 0.354 mmol, 1 eq), 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one (246 mg, 0.532 mmol, 1.5 eq), Pd(dppf)Cl2 (26 mg, 0.0354 mmol, 0.1 eq) and K3PO4 (225 mg, 1.06 mmol, 3 eq) were added and dissolved in a mixture of THF:H2O=10:1 (11 mL, V:V), protected by argon, and reacted at 90°C for 4 h. After the reaction was complete, the product was washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, extracted with EA, and the organic phase concentrated and passed through a column chromatography column to yield 103 mg of 1-(7-(3-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one as a yellow semi-solid, in a yield of 53.9%. ESI-MS: 539.19 [M+H] + .

[0312] Step 4: To a 25 mL round-bottom flask, add 1-(7-(3-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-1-one (100 mg, 0.186 mmol, 1 eq) and pyridine (44 mg, 0.558 mmol, 3 eq). Dissolve the mixture in anhydrous DCM and stir at room temperature for 15 min. Place the mixture in an ice bath, add 5-methoxypyrazine-2-carbonyl chloride (48 mg, 0.279 mmol, 1.5 eq), and warm to room temperature for 4 h. After the reaction was complete, the mixture was washed sequentially with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. After extraction, the organic phase was concentrated and filtered through a column to obtain 93 mg of 5-methoxy-N-(1-(4-methoxybenzyl)-5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)pyrazine-2-carboxamide as a yellow solid, with a yield of 74.4%. ESI-MS: 675.22 [M+H] + .

[0313] Step 5: To a 25 mL round-bottom flask was added 5-methoxy-N-(1-(4-methoxybenzyl)-5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)pyrazine-2-carboxamide (90 mg, 0.133 mmol, 1 eq), dissolved in toluene (2 mL), and then TFA (2 mL) was added and the reaction was carried out at 110 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was washed sequentially with water and saturated aqueous sodium chloride solution, extracted with EA, and the organic phase was concentrated and filtered through a column to obtain 33 mg of 5-methoxy-N-(5-(4-(2-(3-(trifluoromethoxy)phenyl)acetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazol-3-yl)pyrazine-2-carboxamide (311) as a white solid in a yield of 44.8%. ESI-MS: 555.16 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.96(s,1H),10.27(s,1H),8.90(s,1H),8.41(s,1H),7.92(s,1H),7.46(t,J=7.9Hz ,1H),7.37-7.20(m,5H),6.99(s,1H),4.31(t,J=4.4Hz,2H),4.10(s,2H),4.02(s,3H),3.95(t,J=4.5Hz,2H).

[0314] Examples 312 to 334

[0315] Examples 312 to 334 can be prepared according to the method of Example 311, except that different amines are used instead of 7-bromo-3,4-dihydro-2H-1,4-benzoxazine, different phenylacetic acids are used instead of 3-trifluoromethoxyphenylacetic acid, or different acid chlorides are used instead of 5-methoxypyrazine-2-carbonyl chloride.

[0316] Example 335 Cell necrosis assay

[0317] method:

[0318] HT-29 cells (purchased from ATCC) were cultured in McCoy's 5A medium (Invitrogen). On the first day, HT-29 cells were plated in a 96-well assay plate at a density of 2500-3500 cells per well. On the second day, necrosis was induced by the addition of TSZ necrosis factor (TNF-α) (purchased from Sino-Bio, catalog number: GMP-10602-HNAE), 100 nM Smac mimetic (S) (purchased from Shanghai MCE, CAS: 957135-43-2), and 20 mM Z-VAD-FMK (Z) (purchased from Shanghai MCE, CAS: 161401-82-7). Simultaneously, the compounds obtained according to the method of the present invention were added to the 96-well plate according to a concentration gradient (maximum concentration 10 μM, 3-fold dilution, a total of 10 gradients). After 24 hours of treatment, cell viability was determined by measuring ATP levels using the CellTiter-Glo Luminescent Cell Viability Assay Kit (purchased from Promega). The CellTiter-Glo assay (Promega) was performed according to the manufacturer's instructions, and chemiluminescence data was read using a microplate reader (PerkinElmer Enspire, USA). GSK2982772 (purchased from Shanghai Medchem Express) was used as a positive control for screening necrosis inhibitors. Data are expressed as the mean ± standard deviation of replicates.

[0319] Dose-dependent inhibition of necrosis by compounds in HT-29 cells was determined by measuring ATP levels as described above.

[0320] The activity data of the compounds inducing necrosis in HT-29 cells are shown in Table 1.

[0321] Where "+" indicates EC 50 The value is 50-100nM; "++" indicates EC 50 The value is 20-50nM; "+++" indicates EC 50 Value <20nM.

[0322] Table 1.

[0323] Example 336 Hemophagocytic Syndrome Animal Model Experiment

[0324] In this example, the efficacy of compound 249 and the reported RIPK1 inhibitor GSK2982772 were tested in a mouse model of hemophagocytic syndrome.

[0325] The experimental steps are as follows:

[0326] (1) Twenty 8-week-old C57BL / 6J female mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. All mice were housed in an SPF-grade laboratory. The drinking water and bedding were sterilized by high-pressure sterilization. All operations related to mice were performed under sterile conditions.

[0327] (2) Fifteen mice in the treatment group were intraperitoneally injected with 200 μL of 250 μg / mL CpG-ODN1826 (purchased from MCE, China) on days 0, 2, 4, 6, and 8. Starting on the fourth day after induction, the mice were divided into three groups of five mice each: the vehicle group, the compound 249 group, and the GSK2982772 group. The remaining five mice served as the normal group.

[0328] (3) After grouping, drug administration began. The normal group and the vehicle group were given the vehicle (5% DMSO + 10% HS-15 + water), the compound 249 group was given 30 mg / kg of compound 249, and the GSK2982772 group was given 30 mg / kg of GSK2982772 (purchased from MCE, China). All drugs were administered intraperitoneally once a day for 9 consecutive days.

[0329] (4) The mice were weighed at regular intervals every day, and the results are shown in Figure 1. Their mental state was also observed. On the 9th day after administration, peripheral blood was collected from the mice using the orbital blood sampling method, and blood routine was measured. The data are shown in Figures 2-5. After the mice were euthanized, the liver and spleen were weighed, and the organ index was calculated. The liver and spleen indexes were represented by the ratio of organ weight to body weight. The liver and spleen index data of each group of mice are shown in Figures 6 and 7, respectively. The spleen was subjected to pathological examination, and the pathological section images were observed using a pathological section fluorescence scanner, see Figure 8.

[0330] The results showed that the body weight of each group of mice was not significantly affected after administration, as shown in Figure 1. The blood routine indicators and liver and spleen indexes of the model group were significantly different from those of the normal group, and the compound 249 of the present invention was compared with the RIPK1 inhibitor GSK2982772 that has entered the clinic. It can restore the white blood cell count (Figure 2), red blood cell count (Figure 3), hemoglobin amount (Figure 4) and platelet amount (Figure 5) in the blood routine to a certain extent. In addition, the compound 249 of the present invention can significantly inhibit the swelling of the liver and spleen, as shown in Figures 6 and 7. Compared with the positive drug group, the organ weight is quite large. From the pathological data, the internal structure of the spleen in the vehicle group is relatively chaotic, while the compound 249 of the present invention can significantly improve the internal structure of the spleen (Figure 8), which is also improved to a certain extent compared with GSK2982772.

[0331] Industrial Applicability

[0332] The present invention provides a pyrazole amide compound that can be used to reduce or inhibit RIPK1 protein activity in cells or subjects, and / or treat diseases or symptoms associated with or mediated by aberrant RIPK1 activity in subjects, such as inflammatory diseases, autoimmune diseases, ischemic diseases, destructive bone diseases, neurodegenerative diseases, proliferative diseases, angiogenic disorders, infectious diseases, tumors, or viral diseases. Thus, the compound can be formulated into a corresponding pharmaceutical suitable for industrial application.

[0333] Although the present invention is described in detail herein, the present invention is not limited thereto. Those skilled in the art may make modifications based on the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood to fall within the scope of protection of the present invention.

Claims

1. A RIPK1 inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, in, Ring A is selected from a monocyclic or fused ring aryl or heteroaryl group; R 1 is selected from C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, phenyl C1-3 alkyl, and unsubstituted or substituted by 1 to 3 independent R 7 substituted aryl, monocyclic heteroaryl containing 1 to 3 heteroatoms selected from N, O or S, or 5-membered or 6-membered heterocyclic group containing 1 heteroatom selected from N or O; R 7 Each is independently selected from halogen, cyano, oxo, carboxyl, sulfamoyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylaminoC1-3 alkyl, C1-6 alkylaminoacyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, C1-6 aminoalkyl, unsubstituted or substituted by 1 or 2 independently R 8 substituted 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N or O, and unsubstituted or replaced by 1 or 2 independently R 8 Substituted C1-6 alkyl (5-7 membered heterocyclic group), wherein the 5-7 membered heterocyclic group contains 1-2 heteroatoms selected from N or O, or two adjacent R 7 together to form an unsubstituted or substituted by 1 or 2 independently R 8 a substituted 5-membered or 6-membered heterocyclic group containing one heteroatom selected from N or O; R 8 Each independently selected from amino, hydroxy, C1-3 alkyl, C1-4 alkylamino, and oxo; R 2 H or -L-(CHR 4 ) n -R 5 , wherein L is selected from -O-, -NH-, -C(=O)-NR a -、-NR b -C(=O)-, and -NH-C(=O)-NH-, n is 0 or 1, R 4 is H or methyl, R 5 unsubstituted or substituted by 1 to 3 independent R 6 substituted aryl, a 5-membered or 6-membered heterocyclic group containing one heteroatom selected from N or O, and a 5-membered or 6-membered heteroaryl group containing one to two heteroatoms selected from N or O, R 6 Each is independently selected from halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 deuterated alkoxy, C3-6 cycloalkyloxy, C3-6 cycloalkylC1-3 alkoxy, tetrahydropyranyloxy, or R in the L group a or R b The groups are connected to form a ring, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with 1 or 2 halogens; m is 0, 1 or 2, R 3 Each is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 haloalkoxy, or R in the L group a or R b The groups are linked to form a ring; where R a and R b Each is H, or a substituent R of the A ring 3 C2-3 alkylene, C1-2 alkyleneoxy or C1-2 alkylenethio, or R 5 The substituent R 6 Connected to form a C2-3 alkylene.

2. The RIPK1 inhibitor according to claim 1, wherein R 7 Each independently selected from halogen, cyano, oxo, carboxyl, sulfamoyl, C1-6 alkyl, C1-6 deuterated alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylaminoacyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, C1-6 aminoalkyl, and unsubstituted or substituted by 1 or 2 independently R 8 a substituted 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N or O, or two adjacent R 7 Together they form a 5- or 6-membered heterocyclic group containing one heteroatom selected from N or O.

3. The RIPK1 inhibitor according to claim 1, wherein R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, propenyl, benzyl, and unsubstituted or substituted by 1 to 3 independent R 7 substituted phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, or pyrrolidinyl; R 7 are each independently selected from halogen, cyano, oxo, carboxyl, sulfamoyl, C1-3 alkyl, C1-3 haloalkyl, C1-3 deuterated alkyl, C3-5 cycloalkyl, C1-3 alkoxy, C1-4 alkylamino, C1-4 alkylaminoC1-2 alkyl, C1-3 alkylaminoacyl, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, C1-3 alkoxycarbonyl, C1-3 aminoalkyl, and unsubstituted or substituted by 1 or 2 independently R 8 substituted piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, diazepanyl, tetrahydrofuranyl, or C1-3 alkyl (morpholinyl), or two adjacent R 7 together to form an unsubstituted or substituted by 1 or 2 independently R 8 substituted dioxolanyl or piperidinyl; R 8 Each is independently selected from amino, hydroxy, methyl, ethyl, propyl, methylamino, dimethylamino, ethylamino, and oxo.

4. The RIPK1 inhibitor according to claim 2, wherein R 1 is selected from cyclopropyl, and unsubstituted or substituted by 1 or 2 independent R 7 substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, furanyl, or tetrahydropyridinyl; R 7 Each independently selected from halogen, oxo, sulfamoyl, C1-3 alkyl, C1-3 deuterated alkyl, C3-5 cycloalkyl, C1-3 alkoxy, C1-4 alkylamino, C1-3 alkylaminoacyl, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, C1-3 aminoalkyl, and unsubstituted or substituted by 1 or 2 independently R 8 substituted piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl, or two adjacent R 7 Together they form a dioxolane group; R 8 are each independently selected from amino, hydroxy, and methyl.

5. The RIPK1 inhibitor according to claim 1, wherein R 1 selected from cyclopropyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, thiazol-4-yl, oxazol-5-yl, furan-2-yl, 1 or 2 independently R 7 Substituted phenyl, substituted by 1 or 2 independently R 7 substituted pyridin-3-yl, substituted by 1 or 2 independently R 7 substituted pyridin-4-yl, substituted by 1 or 2 independently R 7 Substituted pyridazin-3-yl, substituted by 1 or 2 independently R 7 substituted pyrazol-3-yl, substituted by 1 or 2 independently R 7 substituted pyrazol-4-yl, substituted by 1 or 2 independently R 7 Substituted imidazol-4-yl, substituted by 1 or 2 independently R 7 Substituted pyrazin-2-yl, substituted by 1 or 2 independently R 7 substituted pyrimidin-5-yl, substituted by 1 or 2 independently R 7 Substituted [1,3,4] oxadiazol-2-yl, substituted by 1 or 2 independently R 7 Substituted [1,2,3] triazol-4-yl, substituted by 1 or 2 independently R 7 substituted 1,2,3,6-tetrahydro-pyridin-4-yl, substituted by 1 or 2 independently R 7 substituted pyrrol-3-yl, and 1 or 2 independently R 7 substituted thiazol-2-yl; R 7 R is each independently selected from fluoro, chloro, oxo, sulfamoyl, methyl, ethyl, isopropyl, fluoromethyl, deuterated methyl, cyclopropyl, methoxy, methylamino, dimethylamino, dimethylaminoethyl, methylaminoacyl, methylsulfinyl, methylsulfonyl, aminomethyl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, 4-amino-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, morpholin-1-yl, 3-amino-pyrrolidin-1-yl, piperidin-4-yl, pyrrolidin-3-yl, tetrahydrofuran-3-yl, and 2-morpholinoethyl, or two adjacent R 7 Together they form a dioxolanyl, a piperidinyl, or an N-methylpiperidinyl.

6. The RIPK1 inhibitor according to claim 2, wherein R 1 Selected from: where X 1 and X 2 are each independently CH or N (preferably both are CH), R 7a is selected from H, fluoro, chloro, methoxy, methylamino, dimethylamino, methylaminoacyl, methylsulfinyl, methylsulfonyl, sulfamoyl, aminomethyl, 4-methyl-piperazin-1-yl, 3,5-dimethyl-piperazin-1-yl, morpholin-1-yl, 4-amino-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, and 3-amino-pyrrolidin-1-yl; Where Y is CH or N, R 7b is selected from H, methyl, ethyl, and deuterated methyl; where R 7c Selected from H, methyl or methoxy; where R 7d selected from H or methyl; and where Z 1 , Z 2 and Z 3 Two of them are CH, and the other one is N, R 7e is selected from methyl, isopropyl, and cyclopropyl.

7. The RIPK1 inhibitor of any one of claims 1 to 6, wherein ring A is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, benzothiazolyl, quinolyl, isoquinolyl, and indolyl.

8. The RIPK1 inhibitor of claim 7, wherein ring A is selected from phenyl, naphth-2-yl, pyridin-3-yl, pyrimidin-5-yl, benzothiazol-5-yl, quinolin-3-yl, quinolin-7-yl, isoquinolin-7-yl, and indol-5-yl.

9. The RIPK1 inhibitor according to any one of claims 1 to 6, which is a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, in, W is CH or N, preferably CH.

10. The RIPK1 inhibitor according to claim 9, wherein R 2 -L-(CHR 4 ) n -R 5 , wherein L is selected from -O-, -NH-, -C(=O)-NR a -、-NR b -C(=O)-, and -NH-C(=O)-NH-, n is 0 or 1, R 4 is H or methyl, R 5 unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, tetrahydrofuranyl, imidazolyl, pyridyl, and isoxazolyl, R 6 Each is independently selected from halogen, cyano, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuterated alkoxy, C3-5 cycloalkyloxy, C3-5 cycloalkylC1-2 alkoxy, tetrahydropyranyloxy, or R in the L group a or R b The groups are connected to form a ring, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with 1 or 2 halogens; R 3 is selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, C1-3 haloalkoxy, or R in the L group a or R b The groups are linked to form a ring; where R a and R b Each is H, or a substituent R of the A ring 3 C2-3 alkylene, C1-2 alkyleneoxy or C1-2 alkylenethio, or R 5 The substituent R 6 Connected to form a C2-3 alkylene.

11. The RIPK1 inhibitor according to claim 9, wherein R 2 -L-(CHR 4 ) n -R 5 , wherein L is selected from -O- and -NH-, n is 0, R 5 is unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, R 6 Each is independently selected from halogen, cyano, C1-3 alkoxy, and C1-3 haloalkyl; R 3 For H.

12. The RIPK1 inhibitor according to claim 9, wherein R 2 -L-(CHR 4 ) n -R 5 , wherein L is -C(=O)-NR a -, n is 1, R 4 is H or methyl, R 5 is unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, R 6 Each independently selected from halogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 deuterated alkoxy, C3-5 cycloalkyloxy, C3-5 cycloalkylC1-2 alkoxy, or R in the L group a The groups are linked to form a ring; R 3 R is selected from H, halogen, C1-3 alkyl, or L group a The groups are linked to form a ring; where R a is H, or is a substituent R on the A ring 3 C2-3 alkylene formed by connecting, or with R 5 The substituent R 6 Connected to form a C2-3 alkylene.

13. The RIPK1 inhibitor according to claim 9, which is a compound of formula (IIa), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, in, W is CH or N, preferably CH; R 3 is selected from H, fluoro, and methyl; R 4 is H or methyl; R 6a and R 6b Each is independently selected from fluoro, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

14. The RIPK1 inhibitor according to claim 9, wherein R 2 -L-(CHR 4 ) n -R 5 , wherein L is -NH-C(=O)-NH-, n is 0 or 1, R 4 H, R 5 unsubstituted or substituted by 1 to 3 independent R 6 Substituted phenyl, imidazol-3-yl, isoxazol-3-yl, and isoxazol-5-yl, R 6 Each is independently selected from halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkoxy, and tetrahydropyranyloxy; R 3 Selected from H, halogen, and C1-3 alkyl.

15. The RIPK1 inhibitor according to claim 14, wherein R 5 Selected from 1 to 3 independent R 6 Substituted phenyl, isoxazol-3-yl, and isoxazol-5-yl, R 6 each independently selected from fluoro, isobutyl, isopropoxy, trifluoromethoxy, and tetrahydropyranyloxy; R 3 Selected from H, fluoro, and methyl.

16. The RIPK1 inhibitor according to claim 9, which is a compound of formula (IIb), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, in, U is selected from CH2, O and S; q is 1 or 2; p is 1, 2, or 3; R 6 Each independently selected from halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuterated alkoxy, or two adjacent R 6 Together they form a dioxolanyl group which is unsubstituted or substituted with two fluorine groups.

17. The RIPK1 inhibitor according to claim 16, wherein U is selected from CH2 and O; q is 1 or 2; p is 1, 2, or 3; R 6 Each is independently selected from fluoro, chloro, methyl, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

18. The RIPK1 inhibitor according to claim 16, which is a compound of formula (IIc), or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, in, U is selected from CH2 and O; R 6a and R 6b Each is independently selected from fluoro, chloro, methyl, methoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

19. A RIPK1 inhibitor, which is a compound as listed below, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, metabolite or prodrug thereof, 20. A pharmaceutical composition comprising the RIPK1 inhibitor according to any one of claims 1 to 19, and a pharmaceutically acceptable carrier or excipient.

21. The RIPK1 inhibitor according to any one of claims 1 to 19, for use in treating and / or preventing diseases or symptoms associated with abnormal RIPK1 activity or mediated by RIPK1.

22. The use of a RIPK1 inhibitor according to claim 21, wherein the disease or condition is selected from inflammatory diseases, autoimmune diseases, ischemic diseases, destructive bone diseases, neurodegenerative diseases, proliferative diseases, angiogenic disorders, infectious diseases, tumors and viral diseases.

23. The use of a RIPK1 inhibitor according to claim 22, wherein The inflammatory disease is selected from one or more of Crohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, graft-versus-host disease, chronic obstructive pulmonary disease, and pulmonary fibrosis; The autoimmune disease is selected from one or more of Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, and transplant rejection; The ischemic disease is selected from one or more of liver or brain ischemic injury, myocardial ischemia-reperfusion injury, and ischemic injury during reperfusion or organ storage; Destructive bone disease selected from one or more of bone cysts, bone erosions, myeloma, and osteosarcoma; The neurodegenerative disease is selected from one or more of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, and neurodegenerative diseases caused by traumatic injury; The proliferative disease is selected from one or more of acute myeloid leukemia and chronic myeloid leukemia; The angiogenesis disorder is selected from one or more of solid tumors, ocular neovascularization, and infantile hemangioma; The infectious disease is selected from one or more of sepsis, septic shock, and shigellosis; The tumor is selected from one or more of non-small cell lung cancer, small cell lung cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, melanoma, glioblastoma, colorectal cancer, Kaposi's sarcoma, brain glioma, neuroglioma, and hematological malignancies; The viral disease is selected from one or more of multiple myeloma, HIV infection, and CMV retinitis.

24. The use of the RIPK1 inhibitor according to claim 21, wherein the disease or symptom is hemophagocytic syndrome, more preferably the disease or symptom is selected from one or more of primary hemophagocytic syndrome and secondary hemophagocytic syndrome.

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