Six-membered-ring and five-membered n-heterocycle fused amide compounds and use thereof

Abstract

Disclosed in the present invention are six-membered-ring and five-membered N-heterocycle fused amide compounds and the use thereof, belonging to the technical fields of chemical and medicine. The six-membered-ring and five-membered N-heterocycle fused amide compounds shown as formula (I) provided by the present invention can target the RIPK1 enzyme, have the advantages of high activity and high selectivity, and also have excellent pharmacokinetic properties.

Description

Hexa-pentaazaheterocyclic amide compounds and uses thereof Technical Field

[0001] The present invention belongs to the field of chemical medicine, and specifically relates to a class of hexa-pentazaheterocyclic amide compounds and uses thereof. Background Art

[0002] Receptor-interacting protein kinases (RIPKs) are a group of threonine / serine protein kinases that play an important role in the regulation of innate immune signaling. They have a relatively conserved kinase domain but distinct non-kinase regions. The RIPK family consists of seven members with distinct functional domains, but all share a homologous serine-threonine kinase domain with a catalytic site. In addition, RIPK2 possesses additional tyrosine kinase activity. Currently, RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL) proteins are widely considered to be key therapeutic targets of the necroptotic machinery. Among the RIPK kinases, RIPK1 has emerged as a pleiotropic regulator of the inflammatory response, acting by directly regulating intracellular inflammatory signaling pathways or inducing cell apoptosis or necrosis. RIPK1 was the first member of this family to be discovered and is one of the most intensively studied members of the same family. RIPK1 is a key mediator of several signaling pathways that lead to activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-B (NF-κB), as well as cell death. RIPK1 consists of a carboxy-terminal region containing a death domain (DD), an amino-terminal region with a kinase domain, and a bridging intermediate domain (ID), which contains a RIP homotypic interaction motif (RHIM). The DD domain of RIPK1 mediates direct binding to death receptors of the TNF receptor superfamily (including TNFR1, Fas, and TRAIL), as well as to adaptor proteins such as FADD or TRADD. Upon binding, an oligomeric protein complex is formed that can regulate survival or cell death.

[0003] In TNF-stimulated cells, the RIPK1 kinase executes pro-cell death and pro-inflammatory activities by activating RIPK1-dependent apoptosis and necrosis, thereby influencing the mechanisms of TNF-induced intestinal epithelial cell death. For example, TNF is one of many genes implicated in the pathogenesis of NF-κB-stimulated inflammatory bowel disease (IBD). It encodes the prototypical inflammatory cytokine tumor necrosis factor (TNF), a major pathogenic factor and therapeutic target in IBD. Furthermore, NF-κB signaling responds to a wide range of inflammatory and pro-lethal stimuli in human disease, and its K63 ubiquitination process inhibits cell death during embryonic development and inflammation by regulating the kinase activity of RIPK1. RIPK1 is a master regulator of NF-κB signaling and the cellular determinants of the death response. Mutations in the gene encoding RIPK1 and in multiple proteins that regulate RIPK1 signaling can lead to immune and autoinflammatory diseases. These clinically identified mutations highlight the important role of RIPK1 in regulating the innate immune response and provide mechanistic insights into its functional role in disease. Furthermore, in addition to its role downstream of TNF receptor 1, RIPK1 has been shown to be a key driver of inflammation downstream of various other pathways (FasL, TRAIL, TLR3, and TLR4).

[0004] Therefore, inhibiting RIP1 activation may have broad therapeutic potential for a variety of inflammatory diseases and is a small molecule drug that can replace anti-tumor necrosis factor antibodies and is suitable for the treatment of tumor necrosis factor-driven autoimmune diseases. Summary of the Invention

[0005] The purpose of the present invention is to provide a class of hexapentaazaheterocyclic amide compounds, which can be used as RIPK1 targeting compounds to achieve highly selective and efficient prevention or treatment of diseases related to RIPK1 function.

[0006] In a first aspect, the present invention provides a compound represented by Formula I or a pharmaceutically acceptable form thereof, wherein the structure of Formula I is as follows:

[0007] in:

[0008] represents a single bond or a double bond, and the structural unit It is a conjugated structure;

[0009] X1 selected from CR 7a Or N, X2 is selected from CR 7b Or N, X3 selected from CR 7c Or N, X4 selected from CR 7d Or N, X5 selected from CR 7eor N, and at most 3 of X1, X2, X3, X4 and X5 are selected from N;

[0010] Y and Z are independently selected from C or N, and when one of them is N, the other is C;

[0011] Ring A is selected from a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; in Ring A, the 5- to 10-membered heteroaryl group contains 1 to 6 heteroatoms selected from N, S, and O;

[0012] L is selected from -CONH-, -NHCO-, -NHCONH-, -O(O)CNH-, -SO2NH-, -NHSO2-, -O- or -NH- (the left end is connected to R1 and the right end is connected to ring A);

[0013] R1 is selected from hydrogen, deuterium or the following substituted or unsubstituted groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered spirocycloalkyl, 5-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, 6-10 membered aryl or 5-6 membered heteroaryl; in R1, the substituents of the following groups are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy or C 1-4 Fluorinated alkoxy; in R1, the 3- to 6-membered heterocycloalkyl, 5- to 10-membered heterospirocycloalkyl, 6- to 10-membered heterobridged cycloalkyl, or 5- to 6-membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0014] R2 is selected from H, deuterium, halogen, NH2, OH, CN, oxo or substituted or unsubstituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R2, the substituent of the following substituted groups is selected from: deuterium, halogen, -OH, -NH2, -CN or 3-6 membered cycloalkyl; in R2, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S and O;

[0015] R3 is selected from hydrogen or substituted or unsubstituted groups: C 1-4alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R3, the substituent of the following substituted groups is selected from: deuterium, halogen, OH, NH2 or CN; in R3, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S and O;

[0016] R4 is selected from hydrogen, deuterium or the following substituted or unsubstituted groups: C 1-6 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R5 is selected from hydrogen, deuterium or the following substituted or unsubstituted groups: C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; in R4 and R5, the substituent of the following substituted groups is selected from: deuterium, halogen, -OH, -NH2, -CN or 3-6 membered cycloalkyl; in R4 and R5, the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1-3 heteroatoms selected from at least one of N, S and O;

[0017] Alternatively, R4 and R5, together with the atoms to which they are attached, form a substituted or unsubstituted 3- to 6-membered alkyl ring or a 4- to 6-membered alkyl heterocycle; when R4 and R5, together with the atoms to which they are attached, form a ring, the substituent is selected from: deuterium, halogen, OH, or NH2; when R4 and R5, together with the atoms to which they are attached, form a ring, the 4- to 6-membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0018] or R3 and R4 or R3 and R5 and the atoms to which they are attached form a substituted or unsubstituted 5- to 6-membered alkyl heterocyclic ring; when R3 and R4 or R3 and R5 and the atoms to which they are attached form a ring, the substituent is selected from: deuterium, halogen, OH or NH2; when R3 and R4 or R3 and R5 and the atoms to which they are attached form a ring, the 5- to 6-membered alkyl heterocyclic ring contains, in addition to N as shown in Formula I, 0 to 2 heteroatoms selected from at least one of N, S and O;

[0019] Ring B is selected from a 3-10 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, a 6-10 membered aryl group, a 5-10 membered spirocycloalkyl group, a 6-10 membered heterospirocycloalkyl group, a 6-10 membered bridged cycloalkyl group, a 6-10 membered heterobridged cycloalkyl group, or a 5-10 membered heteroaryl group; in Ring B, the 6-10 membered heterospirocycloalkyl group, the 6-10 membered heterobridged cycloalkyl group, the 5-10 membered heteroaryl group, or the 5-10 membered heterocycloalkyl group contains 1-3 heteroatoms selected from N, S, and O;

[0020] R6 is selected from H, deuterium, halogen, NH2, OH, CN, oxo or substituted or unsubstituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, 3-4 membered cycloalkyl or In R6, the substituent of the following substituted groups is selected from deuterium or halogen;

[0021] R 7a is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7b is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7c is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7d is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7e is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy;

[0022] n1 is selected from 0, 1, 2, 3, 4, 5 or 6; n2 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0023] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites or prodrugs.

[0024] In some embodiments of the present invention, in the compound of formula I, at most two of X1, X2, X3, X4 and X5 are selected from N.

[0025] In some preferred embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures (the left end is connected to ring A, and the right end is connected to the acyl group):

[0026] In some more preferred embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures (the left end is connected to ring A, and the right end is connected to the acyl group):

[0027] In some embodiments of the present invention, in the compound of formula I, ring A is selected from a 9- to 10-membered heteroaryl group; in ring A, the 9- to 10-membered heteroaryl group contains 1 to 4 heteroatoms selected from N, S, and O, and at least one heteroatom is N.

[0028] In some preferred embodiments of the present invention, in the compound of formula I, ring A is selected from (the left end is connected to L, and the right end is connected to a hexaazacyclic ring):

[0029] In some embodiments of the present invention, in the compound of formula I, R2 is selected from H, deuterium, halogen, NH2, CN, oxo, methyl, fluoromethyl, methoxy, fluoromethoxy or cyclopropyl.

[0030] In some preferred embodiments of the present invention, in the compound of formula I above, R2 is selected from H, fluorine, chlorine, NH2, CN, methyl, fluoromethyl, methoxy or fluoromethoxy.

[0031] In some more preferred embodiments of the present invention, in the compound of formula I above, R2 is selected from H, fluorine, chlorine or CN.

[0032] In some embodiments of the present invention, in the compound of formula I, L is selected from -CONH, -NHCONH-, -O(O)CNH- or -NH- (the left end is connected to R1 and the right end is connected to ring A).

[0033] In some embodiments of the present invention, in the compound of formula I, R1 is selected from H, deuterium, or the following substituted or unsubstituted groups: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered spirocycloalkyl, phenyl or 5-6 membered heteroaryl; in R1, the substituent of the following substituted groups is selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy or C 1-4 Fluoroalkoxy; in R1, the 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S, and O.

[0034] In some preferred embodiments of the present invention, in the compound of formula I, R1 is selected from H, deuterium or substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered spirocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 membered heteroaryl; in R1, the substituted C 1-4 The substituent of the alkyl group is selected from deuterium, fluorine, -OH, -NH2, -CN, methoxy or fluoromethoxy; in R1, the substituent of the substituted 3-6 membered cycloalkyl, substituted 4-6 membered heterocycloalkyl, substituted 5-10 membered spirocycloalkyl, substituted phenyl, substituted 5-6 membered heteroaryl is selected from deuterium, fluorine, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy or fluoromethoxy; in R1, the 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 2 heteroatoms selected from at least one of N, S and O.

[0035] In some more preferred embodiments of the present invention, in the compound of formula I, R1 is selected from H, deuterium, methyl, fluoromethyl, deuterated methyl, ethyl, fluoroethyl, propyl, fluoropropyl, substituted or unsubstituted 3-4 membered cycloalkyl, substituted or unsubstituted In R1, the substituted 3-4 membered cycloalkyl, substituted The substituents are selected from deuterium, halogen, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy or fluoromethoxy.

[0036] In some of the most preferred embodiments of the present invention, in the above compounds of formula I, R1 is selected from H, deuterium, methyl, fluoromethyl, deuterated methyl, ethyl, n-propyl, isopropyl, cyclopropyl, Cyclobutyl, or

[0037] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures: amino,

[0038] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0039] In some embodiments of the present invention, in the compound of formula I, R3 is selected from hydrogen, methyl, fluoromethyl or cyclopropyl.

[0040] In some preferred embodiments of the present invention, in the compound of formula I above, R3 is selected from hydrogen.

[0041] In some embodiments of the present invention, in the above compounds of formula I, when R3 does not form a ring with R4 or R5, R4 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-4 Alkyl or 3-4 membered cycloalkyl; R5 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-4 Alkyl or 3-4 membered cycloalkyl; in R4 and R5, the substituted C 1-4 The substituent of the alkyl group is selected from: deuterium, fluorine, -OH, -NH2 or -CN; or R4 and R5 and the atoms to which they are attached form a 3-6 membered alkyl ring.

[0042] In some preferred embodiments of the present invention, in the above compounds of formula I, when R3 does not form a ring with R4 or R5, R4 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4Deuterated alkyl or 3-4 membered cycloalkyl; R5 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 deuterated alkyl or 3-4 membered cycloalkyl; or R4 and R5 and the atoms to which they are attached form a 3-4 membered alkyl ring.

[0043] In some more preferred embodiments of the present invention, in the above-mentioned compound of formula I, when R3 does not form a ring with R4 or R5, R4 is selected from H, deuterium, methyl, fluoromethyl, deuterated methyl; R5 is selected from H, deuterium, methyl, fluoromethyl, deuterated methyl; or R4 and R5 form a 3-membered alkyl ring with the atoms to which they are attached.

[0044] In some embodiments of the present invention, in the compound of formula I above, when R3 and R4 or R5 form a ring, R3 and R4 or R3 and R5 and the atoms to which they are attached form the following substituted or unsubstituted groups: or (the N-terminus is connected to the acyl group, and the other end is connected to ring B); n3 is selected from 1 or 2; when R3 and R4 or R3 and R5 form a ring with the atoms to which they are connected, the substituent is selected from: deuterium, fluorine, -OH, -NH2, and -CN.

[0045] In some preferred embodiments of the present invention, in the above-mentioned compound of formula I, when R3 and R4 or R5 form a ring, R3 and R4 or R3 and R5 and the atoms to which they are attached form the following substituted or unsubstituted groups: or (The N-terminus is connected to the acyl group and the other end is connected to ring B).

[0046] In some embodiments of the present invention, in the compound of formula I, ring B is selected from a 5-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a 6-10 membered aryl or a 5-10 membered heteroaryl; in ring B, the 5-6 membered heterocycloalkyl or 5-10 membered heteroaryl contains 1-2 heteroatoms, and the heteroatoms are selected from N, S, and O.

[0047] In some preferred embodiments of the present invention, in the compound of formula I, ring B is selected from 5-6 membered cycloalkyl, hexahydropyridinyl, phenyl or pyridinyl.

[0048] In some more preferred embodiments of the present invention, in the above compounds of formula I, ring B is selected from Phenyl, or

[0049] In some embodiments of the present invention, in the compound of formula I, R6 is selected from H, deuterium, fluorine, chlorine, NH2, OH, CN, oxo, substituted or unsubstituted groups: C 1-4 Alkyl, C1-4 Alkoxy, 3-4 membered cycloalkyl or In R6, the substituent of the substituted following group is selected from deuterium or F.

[0050] In some preferred embodiments of the present invention, in the compound of formula I, R6 is selected from H, fluorine, chlorine, cyano, methyl, fluoromethyl, methoxy, fluoromethoxy, cyclopropyl, or

[0051] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures (the N-terminus is connected to the acyl group, and the other end is connected to the ring B):

[0052] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0053] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0054] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures (the N-terminus is connected to the acyl group, and the other end is connected to the ring B):

[0055] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0056] The present invention also provides some specific compounds, including the following structures:

[0057] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures (the left end is connected to ring A, and the right end is connected to the acyl group):

[0058] In some embodiments of the present invention, in the compound of formula I, ring A is selected from (the left end is connected to L, and the right end is connected to a hexa-pentaaza ring):

[0059] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures: methyl, fluoromethyl, amino,

[0060] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0061] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures (the N-terminus is connected to the acyl group, and the other end is connected to the ring B):

[0062] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0063] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0064] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures (the N-terminus is connected to the acyl group, and the other end is connected to the ring B):

[0065] In some embodiments of the present invention, in the compound of formula I, the structural unit Selected from the following structures:

[0066] The present invention also provides some specific compounds, including the following structures:

[0067] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula I or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites or prodrugs as an active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0068] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining any compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0069] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0070] In a third aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of drugs for preventing and / or treating RIPK1 kinase-related diseases.

[0071] The present invention provides a method for preventing or treating RIPK1 kinase-related diseases, comprising administering a compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention to an individual in need thereof.

[0072] The present invention provides a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, for use in preventing or treating RIPK1 kinase-related diseases.

[0073] The present invention provides a method for preventing or treating RIPK1 kinase-related diseases in combination with a compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, wherein the additional treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0074] In some embodiments, in the above use, the RIPK1 kinase-related disease is a disease that is sensitive or responsive to RIPK1 enzyme inhibition.

[0075] In some embodiments, in the above use, the RIPK1 kinase-related disease is an inflammatory disease, an immune disease, a nervous system disease or a tumor.

[0076] In some preferred embodiments, in the above use, the RIPK1 kinase-related disease is amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, Parkinson's disease, spinal muscular atrophy, stroke, human immunodeficiency virus-associated dementia, autism, schizophrenia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic juvenile idiopathic arthritis, psoriasis, dermatitis, systemic lupus erythematosus, systemic inflammatory response syndrome, pancreatitis, encephalitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, ulcerative colitis, Crohn's disease, retinal degenerative disease, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, Sjögren's syndrome, systemic scleroderma, solid organ ischemia-reperfusion injury, cerebral ischemia, ischemic heart disease, acute kidney injury, ischemic brain injury, sepsis, diabetes mellitus, or atherosclerosis.

[0077] In some preferred embodiments, in the above use, the RIPK1 kinase-related disease is leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, neurilemoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor or myeloma.

[0078] In a fourth aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of RIPK1 inhibitors.

[0079] Beneficial effects of the present invention:

[0080] The present invention provides a class of hexapentaazaheterocyclic amide compounds, which can be used as highly active and highly selective RIPK1 kinase inhibitors, and can achieve at least one of the following technical effects: (1) significant inhibitory effect on RIPK1 kinase; (2) selective inhibition of RIPK1 kinase; (3) excellent inhibitory effect on necrosis of both human HT29 cells and mouse L929 cells; (4) excellent pharmacokinetic properties (such as good bioavailability, suitable half-life and duration of action); (5) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0081] Definition of terms:

[0082] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. It should be understood by those skilled in the art that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0083] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0084] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form "about a to b," or equivalently, "approximately a to b," or equivalently, "about a b") should be understood to represent each value and range encompassed within the broader range.

[0085] For example, the statement "C 1-4 " should be understood to include any sub-ranges and each point value therein, such as C 2-4 、C 3-4 、C 1-2 、C 1-3 、C 1-4 etc., as well as C1, C2, C3, C4, etc. For another example, the expression "6-10 yuan" should be understood to cover any sub-range therein and each point value, such as 6-7 yuan, 6-8 yuan, 6-7 yuan, etc., as well as 6, 7, 8, 9, 10 yuan, etc.

[0086] In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.

[0087] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-4 C in "alkyl" 1-4 It refers to a group containing 1, 2, 3 or 4 carbon atoms in a straight or branched chain.

[0088] In the present invention, unless otherwise specified, "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalinyl, etc. For example, "C 3-12 cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12).

[0089] In the present invention, unless otherwise specified, "heterocycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example, fused, bridged, or spirocyclic) non-aromatic group, whose ring atoms consist of carbon atoms and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur. If the valence requirements are met, the heterocycloalkyl group can be attached to the rest of the molecule through any one of the ring atoms. For example, "3-8 membered heterocycloalkyl" refers to a heterocycloalkyl group having 3 to 8 ring atoms. Common heterocycloalkyl groups include (but are not limited to) oxiranyl, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolane, and the like.

[0090] In the present invention, unless otherwise specified, "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) aromatic group or aromatic ring having a conjugated π electron system. As used herein, the term "C6-10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms. Examples include, but are not limited to, phenyl and naphthyl.

[0091] In the present invention, unless otherwise specified, "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring having a conjugated π-electron system, wherein one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, and the remaining ring atoms are C. A heteroaryl or heteroaromatic ring can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, in particular 5, 6, 9, or 10 ring atoms. Examples of heteroaryl groups are, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like; the term also encompasses heteroaryl or heteroaromatic rings that are optionally further fused to an aryl or heteroaryl ring to form a fused ring.

[0092] In the present invention, unless otherwise specified, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), hydroxyl, amino, C 1-8 Alkyl, C 3-7 Cycloalkyl, -OR', -SR', =O, =S, -C(O)R', -C(S)R', =NR', -C(O)OR', -C(S)OR', -NR'R", -C(O)NR'R", cyano, nitro, -S(O)2R', -OS(O)2OR', -OS(O)2R', -OP(O)(OR')(OR"); wherein R' and R" are independently selected from -H, C 1-8 Alkyl, C 1-8 Halogenated alkyl.

[0093] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of iodine (e.g. 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 34S).

[0094] In the present invention, "polymorph" refers to different solid crystalline phases of certain compounds of the present invention due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof. Generally, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including single hydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms.

[0095] As used herein, "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers may occur. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0096] In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences," Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects.

[0097] In the present invention, unless otherwise indicated, "ester" refers to an ester derived from a compound described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compound of the present invention in the form of a free acid or alcohol). The compound of the present invention itself may also be an ester.

[0098] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0099] Those skilled in the art will appreciate that, since nitrogen requires an available lone pair of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.

[0100] As used herein, "metabolite" refers to a substance formed in vivo upon administration of a compound of the present invention. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0101] In the present invention, "prodrug" refers to certain derivatives of the compounds of the present invention that can be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compound in vivo.

[0102] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0103] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved or accepted by relevant governmental regulatory authorities for use in humans or livestock.

[0104] As used herein, the terms "drug combination," "drug combination," "combination therapy," "administration of an additional therapy," "administration of an additional therapeutic agent," and the like refer to a drug therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as separate entities, either in combination or sequentially at variable intervals. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0105] As used herein, unless otherwise indicated, "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0106] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] FIG1 is a diagram showing the pharmacodynamic evaluation of compound F20 of the present invention on SIRS mouse model - body temperature changes.

[0108] FIG2 is a diagram showing the effect of compound F20 of the present invention on the phosphorylation of RIPK1 and its downstream kinase proteins.

[0109] FIG3 is a graph showing the results of the inhibition of the inflammatory factor IL-6 by compounds F20 and F21 of the present invention in a TNFα-induced SIRS model in mice. DETAILED DESCRIPTION

[0110] The scheme of the present invention will be explained below with reference to the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or the product specifications shall be followed.

[0111] The reagents and raw materials used in the examples of the present invention are all commercially available.

[0112] Table 1 Abbreviations and their meanings in the present invention

[0113] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were measured at 10 -6 The units are given in ppm.

[0114] MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0115] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150×4.5 mm, 5 μm column).

[0116] The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm silica gel plate.

[0117] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0118] Unless otherwise specified, all reactions in the following examples were conducted under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask being connected to an approximately 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction flask being connected to an approximately 1 L hydrogen balloon. The hydrogenation reaction was typically performed by evacuating the flask and then filling it with hydrogen, repeating this process three times.

[0119] Route 1

[0120] Example 1

[0121] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(3-fluorobenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F1)

[0122] Step 1: Sodium nitrite (252 mg, 3.65 mmol) was added to Intermediate 1 (500 mg, 2.44 mmol) in aqueous hydrogen bromide (10 mL, 48% w / w) under ice-cooling conditions and stirred for 5 minutes. Subsequently, cuprous bromide (699 mg, 4.87 mmol) was added under the same conditions and stirred for 10 minutes. The resulting reaction solution was slowly warmed to 50°C and allowed to react for 20 minutes. After completion of the reaction, the mixture was monitored by TLC and extracted with ethyl acetate and saturated sodium bicarbonate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The residue was purified by column chromatography to afford Intermediate 2 as a pale yellow solid in 80% yield.

[0123] Step 2: Intermediate 2 (500 mg, 1.86 mmol) was dissolved in a mixture of tetrahydrofuran and water (5:1 by volume). Solid NaOH (373 mg, 9.34 mmol) was added and stirred at 50°C for 6 h. After completion of the reaction, the pH was adjusted to neutral with hydrochloric acid and extracted with ethyl acetate and water. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to remove the solvent, and the residue was purified by column chromatography to afford Intermediate 3 as a white solid in 85% yield.

[0124] Step 3: Intermediate 3 (293 mg, 1 mmol), 1-hydroxybenzotriazole (HOBt) (203 mg, 1.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol) were dissolved in 5 mL of DMF. N,N-diisopropylethylamine (DIEA) (258 mg, 2 mmol) was added. After stirring at room temperature for 0.5 h, 3-fluorobenzylamine (138 mg, 1.1 mmol) was added and the reaction was heated to 50°C for 12 h. After completion of the reaction, the mixture was monitored by TLC and extracted with ethyl acetate and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The residue was purified by column chromatography to afford Intermediate 4 as a white solid in 90% yield.

[0125] Step 4: 2-Amino-6-bromobenzothiazole (Intermediate 5) (229 mg, 1 mmol), cyclopropanoic acid (86 mg, 1 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) (570 mg, 1.5 mmol), and DIEA (261 μL, 1.5 mmol) were dissolved in DMF and heated at 70°C for 8 hours. After completion of the reaction, the mixture was monitored by TLC and extracted with ethyl acetate and water. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to remove the solvent, and the residue was purified by column chromatography to afford Intermediate 6 as a white solid in a 33% yield.

[0126] Step 5: Dissolve Intermediate 6 (296 mg, 1 mmol), PdCl(dppf) (73 mg, 0.1 mmol), potassium acetate (196 mg, 2 mmol), and pinacol diboron (508 mg, 2 mmol) in 10 mL of 1,4-dioxane. Heat at 90°C under nitrogen for 12 hours. Monitor the reaction by TLC. Extract with ethyl acetate and water. The combined organic phases are dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to remove the solvent, and the residue is purified by column chromatography to afford Intermediate 7 as a white solid in 70% yield.

[0127] Step 6: Dissolve Intermediate 4 (347 mg, 1 mmol), Intermediate 7 (344 mg, 1 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), and potassium carbonate (276 mg, 1.5 mmol) in 10 mL of a mixture of 1,4-dioxane and water. Heat at 90°C under nitrogen for 8 hours. After completion of the reaction, monitor the reaction by TLC and extract with ethyl acetate and water. The combined organic phases are dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to remove the solvent, and the residue is purified by column chromatography to afford Compound F1 as a white solid in a 67% yield. (400MHz, DMSO-d6) δ12.75(s,1H),8.90–8.81(m,2H),8.62(s,1H),8.54–8.50(m,1H),8.48(s,1H),7.88–7.84(m,2H),7.49(dd,J=7.3,2. 0Hz,1H),7.44–7.34(m,1H),7.24–7.13(m,2H),7.08(td,J=8.6,2.3Hz,1H),4.53(d,J=5.9Hz,2H),2.06–1.97(m,1H),1.04–0.91(m,4H). MS(ESI),m / z:486.1[M+H] + .

[0128] Example 2

[0129] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(3-(trifluoromethoxy)benzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F2)

[0130] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(3-(trifluoromethoxy)benzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F2) Referring to Example 1. 1H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.88(d,J=7.3Hz,1H),8.83(t,J=6.4Hz,1H),8.65(d,J=1.7Hz,1H),8.50(d,J=13.5Hz,2H),7.86 (s,2H),7.51(td,J=6.0,5.4,3.3Hz,2H),7.40(qt,J=5.7,3.9,3.3Hz,3H),4.59(d,J=5.8Hz,2H),2.07–1.97(m,1H),1.02–0.95(m,4H). MS(ESI),m / z:552.1[M+H] + .

[0131] Example 3

[0132] Preparation of N-(3-cyanobenzyl)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F3)

[0133] The preparation of N-(3-cyanobenzyl)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F3) was performed with reference to Example 1. 1 H NMR(400MHz,DMSO-d6)δ12.75(s,1H),8.88(s,1H),8.87(s,1H),8.62(s,1H),8.53–8.49(m,1H),8.48(s,1H),7.88–7.84(m,2H),7.80(s,1 H),7.72(t,J=8.7Hz,2H),7.57(t,J=7.8Hz,1H),7.49(dd,J=7.3,1.9Hz,1H),4.56(d,J=5.9Hz,2H),2.06–1.97(m,1H),1.01–0.95(m,4H). MS(ESI),m / z:493.2[M+H] + .

[0134] Example 4

[0135] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(2,5-difluorobenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F4)

[0136] The preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(2,5-difluorobenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F4) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.87(d,J=7.3Hz,1H),8.82(t,J=5.8Hz,1H),8.64(s,1H),8.52–8.49(m,1H),8.48(s,1H) ,7.91–7.81(m,2H),7.49(dd,J=7.3,1.9Hz,1H),7.32–7.11(m,3H),4.53(d,J=5.8Hz,2H),2.06–1.97(m,1H),1.01–0.94(m,4H). MS(ESI),m / z:504.1[M+H] + .

[0137] Example 5

[0138] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(3,4-difluorobenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F5)

[0139] The preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(3,4-difluorobenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F5) was performed with reference to Example 1. 1 H NMR(400MHz, DMSO-d6)δ12.75(s,1H),8.85(dd,J=15.0,6.8Hz,2H),8.61(s,1H),8.53–8.49(m,1H),8.47(s,1H),7.88–7.84(m,2H),7. 49(dd,J=7.2,1.9Hz,1H),7.46–7.34(m,2H),7.25–7.17(m,1H),4.49(d,J=5.8Hz,2H),2.02(dt,J=12.9,6.5Hz,1H),1.01–0.94(m,4H). MS(ESI),m / z:504.1[M+H] + .

[0140] Example 6

[0141] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(2,3-difluorobenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F6)

[0142] The preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(2,3-difluorobenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F6) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.90–8.81(m,2H),8.63(s,1H),8.52–8.49(m,1H),8.47(s,1H),7.88–7.81(m,2H),7.49(dd,J=7. 3,2.1Hz,1H),7.38–7.27(m,1H),7.27–7.23(m,1H),7.23–7.14(m,1H),4.58(d,J=5.6Hz,2H),2.02(p,J=6.8Hz,1H),1.04–0.91(m,4H). MS(ESI),m / z:504.1[M+H] + .

[0143] Example 7

[0144] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F7)

[0145] The preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F7) was performed with reference to Example 1. 1 H NMR(400MHz, DMSO-d6)δ12.71(s,1H),8.97(t,J=5.9Hz,1H),8.88(d,J=7.2Hz,1H),8.64(s,1H),8.52–8.47(m,1H), 8.43(s,1H),7.88–7.77(m,2H),7.62–7.47(m,4H),4.61(d,J=5.9Hz,2H),2.03–1.95(m,1H),0.95(d,J=5.1Hz,4H). MS(ESI),m / z:554.2[M+H] + .

[0146] Example 8

[0147] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-((1-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F8)

[0148] The preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-((1-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F8) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),8.85(d,J=7.3Hz,1H),8.58(s,1H),8.52–8.49(m,2H),8.46(s,1H),8.30(t,J=6.0Hz,1H),7.88–7.84(m ,2H),7.47(dd,J=7.4,1.9Hz,1H),3.25–3.10(m,4H),2.52(s,3H),2.07 –1.99(m,1H),1.87–1.62(m,4H),1.46–1.25(m,3H),1.02–0.94(m,4H). MS(ESI),m / z:489.2[M+H] + .

[0149] Example 9

[0150] Preparation of 5-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(pyridin-4-ylmethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F9)

[0151] The preparation of 5-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(pyridin-4-ylmethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F9) was performed with reference to Example 1. 1 H NMR(400MHz,DMSO-d6)δ12.75(s,1H),8.89(dd,J=9.7,6.7Hz,2H),8.64(s,1H),8.54–8.45(m,4H),7.86(s,2H),7 .50(dd,J=7.3,2.1Hz,1H),7.35(d,J=5.8Hz,2H),4.53(d,J=5.9Hz,2H),2.02(t,J=5.4Hz,1H),1.02–0.89(m,4H). MS(ESI),m / z:469.1[M+H] + .

[0152] Example 10

[0153] Preparation of 5-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(pyridin-3-ylmethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F10)

[0154] The preparation of 5-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(pyridin-3-ylmethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F10) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.90–8.82(m,2H),8.65–8.57(m,2H),8.53–8.41(m,3H),7.91–7.81(m,2H),7.76(d,J=7. 9Hz, 1H), 7.49 (dd, J=7.3, 2.0Hz, 1H), 7.37 (dd, J=7.7, 4.8Hz, 1H), 4.53 (d, J=5.9Hz, 2H), 2.06–2.00 (m, 1H), 1.03–0.92 (m, 4H). MS(ESI),m / z:469.1[M+H] + .

[0155] Example 11

[0156] Preparation of N-(Benzo[d][1,3]dihydroxy-5-ylmethyl)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F11)

[0157] The preparation of N-(benzo[d][1,3]dihydroxy-5-ylmethyl)-5-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F11) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.86(d,J=7.3Hz,1H),8.73(t,J=6.0Hz,1H),8.60(s,1H),8.53–8.51(m,1H),8.48(s,1H),7.89–7.82(m,2H ),7.48(dd,J=7.3,2.1Hz,1H),6.92(d,J=1.1Hz,1H),6.90–6.80(m,2H), 5.98(s,2H),4.41(d,J=5.9Hz,2H),2.06–1.96(m,1H),1.01–0.95(m,4H). MS(ESI),m / z:512.2[M+H] + .

[0158] Example 12

[0159] Preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)cyclopropyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F12)

[0160] The preparation of 5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)cyclopropyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F12) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),9.00(s,1H),8.87(d,J=7.3Hz,1H),8.67(s,1H),8.51–8.44(m,2H),7.89–7.80(m,2H),7.49(dd, J=7.3,2.1Hz,1H),7.37–7.27(m,1H),7.08(d,J=8.2Hz,1H),7.05–6.93(m,2H),2.02(p,J=6.6Hz,1H),1.33(s,4H),1.02–0.93(m,4H). MS(ESI),m / z:512.1[M+H] + .

[0161] Example 13

[0162] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F13)

[0163] The preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F13) was performed with reference to Example 1. 1H NMR (400MHz, DMSO-d6) δ12.75 (s, 1H), 8.85 (dd, J = 7.2, 0.9Hz, 1H), 8.72 (s, 1H), 8.59 (d,J=7.9Hz,1H),8.49–8.43(m,2H),7.84(s,1H),7.84(s,1H),7.47(dd,J=7.4,2.2H z,1H),7.38(td,J=8.1,6.3Hz,1H),7.27–7.20(m,2H),7.05(td,J=8.5,2.4Hz,1H),5 .21(p,J=7.2Hz,1H),2.02(p,J=7.0Hz,1H),1.50(d,J=7.1Hz,3H),1.02–0.89(m,4H). MS(ESI),m / z:500.2[M+H] + .

[0164] Example 14

[0165] Preparation of (R)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F14)

[0166] The preparation of (R)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F14) was performed with reference to Example 1. 1 H NMR(400MHz,DMSO-d6)δ12.75(s,1H),8.86(d,J=7.3Hz,1H),8.72(s,1H),8 .59(d,J=7.9Hz,1H),8.49–8.43(m,2H),7.86–7.82(m,2H),7.47(dd,J=7.3, 2.1Hz,1H),7.43–7.33(m,1H),7.28–7.19(m,2H),7.10–7.01(m,1H),5.21(p ,J=7.1Hz,1H),2.06–1.97(m,1H),1.50(d,J=7.1Hz,3H),1.03–0.92(m,4H). MS (ESI), m / z: 500.2 [M+H] + .

[0167] Example 15

[0168] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(m-tolyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F15)

[0169] The preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(m-tolyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F15) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75 (s, 1H), 8.86 (d, J = 7.3Hz, 1H), 8.77 (t, J = 5.9Hz, 1H),8.62(s,1H),8.53(d,J=1.5Hz,1H),8.47(s,1H),7.91–7.82(m,2H),7.48(d d,J=7.3,2.1Hz,1H),7.22(t,J=7.5Hz,1H),7.19–7.12(m,2H),7.06(d,J=7.4Hz ,1H),4.48(d,J=5.9Hz,2H),2.29(s,3H),2.07–2.00(m,1H),1.04–0.92(m,4H). MS (ESI), m / z: 496.1 [M+H] + .

[0170] Example 16

[0171] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F16)

[0172] The preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F16) was performed with reference to Example 1. 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.86(d,J=7.2Hz,1H),8.72(s,1H),8.67(d,J=7.6Hz,1H),8.47–8.43(m,2H),7.86–7.81(m,2H),7.78– 7.70(m,2H),7.62–7.54(m,2H),7.48(dd,J=7.3,2.1Hz,1H),5.32–5.24(m,1H),2.06–1.96(m,1H),1.53(d,J=7.1Hz,3H),1.01–0.91(m,4H). MS(ESI),m / z:550.2[M+H] + .

[0173] Example 17

[0174] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F17)

[0175] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F17) Reference Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.85(d,J=7.3Hz,1H),8.72(s,1H),8.54( d,J=8.1Hz,1H),8.50–8.43(m,2H),7.87–7.82(m,2H),7.47(dd,J=7.3,2.1Hz,1 H),7.25(t,J=8.0Hz,1H),7.02–6.95(m,2H),6.83–6.76(m,1H),5.18(p,J=7.1H z,1H),3.74(s,3H),2.06–1.98(m,1H),1.49(d,J=7.1Hz,3H),1.02–0.93(m,4H). MS (ESI), m / z: 566.1 [M+H] + .

[0176] Example 18

[0177] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3,5-difluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F18)

[0178] The preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3,5-difluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F18) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.86(d,J=7.2Hz,1H),8.71(s,1H),8.60(d,J=7.7Hz,1H),8.48–8.43(m,2H),7.86–7.78(m,2H),7. 48(dd,J=7.3,2.1Hz,1H),7.16–7.03(m,3H),5.20(p,J=7.4Hz,1H),2.03(q,J=6.2,5.5Hz,1H),1.49(d,J=7.1Hz,3H),1.01–0.94(m,4H). MS(ESI),m / z:518.1[M+H] + .

[0179] Example 19

[0180] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F19)

[0181] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F19) Referring to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.85(d,J=7.3Hz,1H),8.72(s,1H),8.61(d,J=7.7Hz,1H),8.49–8.43(m,2H),7.86–7.82(m,2H),7.53(d,J= 8.6Hz,2H),7.47(dd,J=7.3,2.0Hz,1H),7.34(d,J=8.2Hz,2H),5.23(q,J =7.3Hz,1H),2.06–1.97(m,1H),1.51(d,J=7.1Hz,3H),1.03–0.92(m,4H). MS(ESI),m / z:566.1[M+H] + .

[0182] Example 20

[0183] Preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F20)

[0184] The preparation of (S)-5-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F20) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.85(d,J=7.3Hz,1H),8.70(s,1H),8.56(d,J=7.9Hz,1H),8.49–8.43(m,2H),7.90–7.82( m,2H),7.50–7.40(m,3H),7.16(t,J=8.9Hz,2H),5.24–5.17(m,1H),2.06–1.99(m,1H),1.50(d,J=7.1Hz,3H),1.03–0.94(m,4H). MS(ESI),m / z:500.1[M+H] + .

[0185] Example 21

[0186] Preparation of (S)-3-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrrolo[1,2-a]pyrimidine-6-carboxamide (F21)

[0187] Preparation of (S)-3-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrrolo[1,2-a]pyrimidine-6-carboxamide (F21) Reference Example 1. 1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),10.07(dd,J=2.4,0.7Hz,1H),8.76–8.69(m,2H),8 .36(d,J=1.9Hz,1H),8.00(d,J=4.6Hz,1H),7.84(d,J=8.4Hz,1H),7.75(dd,J=8.4,1.9Hz ,1H),7.38(td,J=8.1,6.1Hz,1H),7.29–7.19(m,2H),7.10–7.01(m,1H),6.71(d,J=4.5Hz ,1H),5.23(p,J=7.1Hz,1H),2.06–1.99(m,1H),1.51(d,J=7.1Hz,3H),1.01–0.94(m,4H). MS(ESI),m / z:500.1[M+H] + .

[0188] Example 22

[0189] Preparation of (S)-7-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,5-a]pyridine-1-carboxamide (F22)

[0190] The preparation of (S)-7-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,5-a]pyridine-1-carboxamide (F22) was carried out with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.57(d,J=7.4Hz,1H),8.52–8.46(m,2H),8.41(t,J=1.2Hz,1H),8.35(d,J=1.7Hz,1H),7.84–7.79(m,2H),7. 41–7.30(m,2H),7.30–7.24(m,2H),7.04(td,J=8.5,2.5Hz,1H),5.20(p,J =7.2Hz,1H),2.07–1.96(m,1H),1.52(d,J=7.0Hz,3H),1.03–0.92(m,4H). MS(ESI),m / z:500.1[M+H] + .

[0191] Example 23

[0192] Preparation of (S)-6-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (F23)

[0193] Preparation of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (F23) Reference Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.71 (s, 1H), 9.77–9.72 (m, 1H), 8.88 (d, J = 7.9Hz, 1H), 8.53(s,1H),8.31(d,J=1.9Hz,1H),7.90–7.78(m,3H),7.72(dd,J=8.4,2.0Hz,1H ),7.39(td,J=8.1,6.1Hz,1H),7.30–7.21(m,2H),7.10–7.03(m,1H),5.24(p,J= 7.3Hz, 1H), 2.05–1.98 (m, 1H), 1.52 (d, J = 7.1Hz, 3H), 0.96 (q, J = 2.8, 2.0Hz, 4H). MS (ESI), m / z: 500.1 [M+H] + .

[0194] Example 24

[0195] Preparation of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,2-b]pyridazine-3-carboxamide (F24)

[0196] Preparation of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,2-b]pyridazine-3-carboxamide (F24) Reference Example 1. 1H NMR (400MHz, DMSO-d6) δ12.85(s,1H),9.06(d,J=7.3Hz,1H),8.71(d,J=1.6Hz,1H),8.44(d,J=9.6Hz,1H),8.31(s,1H),8.13–8.04(m,2H),7. 87(d,J=8.5Hz,1H),7.46–7.32(m,3H),7.16–7.07(m,1H),5.25(q,J=6 .8Hz,1H),2.07–2.00(m,1H),1.62(d,J=6.9Hz,3H),1.03–0.92(m,4H). MS(ESI),m / z:501.1[M+H] + .

[0197] Example 25

[0198] Preparation of (S)-6-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (F25)

[0199] Preparation of (S)-6-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (F25) Reference Example 1. 1 H NMR (400MHz, DMSO-d6) δ9.73(d,J=8.3Hz,1H),9.41(d,J=1.5Hz,1H),8.32(d,J=1. 9Hz,1H),8.07(d,J=9.5Hz,1H),7.98(dd,J=9.6,1.8Hz,1H),7.80(d,J=8.4Hz,1H) ,7.72(dd,J=8.4,1.9Hz,1H),7.43–7.28(m,3H),7.06(td,J=8.5,2.6Hz,1H),5.27 (p,J=7.2Hz,1H),1.97(p,J=6.2Hz,1H),1.56(d,J=7.1Hz,3H),1.00–0.86(m,4H). MS (ESI), m / z: 501.1 [M+H] + .

[0200] Example 26

[0201] Preparation of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,5-a]pyridine-3-carboxamide (F26)

[0202] The preparation of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)imidazo[1,5-a]pyridine-3-carboxamide (F26) was performed with reference to Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),9.67(s,1H),9.06(d,J=8.5Hz,1H),8.33(d,J=1. 9Hz,1H),7.91(dd,J=9.4,1.1Hz,1H),7.84(d,J=8.4Hz,1H),7.73(dd,J=8.5,1.9Hz,1H ),7.66(d,J=0.8Hz,1H),7.50(dd,J=9.4,1.6Hz,1H),7.40–7.26(m,3H),7.10–7.01(m, 1H), 5.23 (q, J=7.3Hz, 1H), 2.05–1.99 (m, 1H), 1.54 (d, J=7.0Hz, 3H), 1.01–0.92 (m, 4H). MS(ESI),m / z:500.1[M+H] + .

[0203] Route 2

[0204] Example 27

[0205] Preparation of (S)-5-(2-(1-cyanocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F27)

[0206] Step 1: Dissolve Intermediate 15 (361 mg, 1 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), potassium acetate (196 mg, 2 mmol), and pinacol diboron (508 mg, 2 mmol) in 10 mL of 1,4-dioxane. Heat at 90°C under nitrogen for 12 hours. Monitor the reaction by TLC. Extract with ethyl acetate and water. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is purified by column chromatography to afford Intermediate 16 as a white solid in 70% yield.

[0207] Step 2: Dissolve Intermediate 16 (409 mg, 1 mmol), 2-amino-6-bromobenzothiazole (229 mg, 1 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), and potassium carbonate (276 mg, 1.5 mmol) in 10 mL of a mixture of 1,4-dioxane and water. Heat at 90°C under nitrogen for 8 hours. After completion of the reaction, monitor the reaction by TLC and extract with ethyl acetate and water. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is purified by column chromatography to afford Intermediate 17 as a white solid in 67% yield.

[0208] Step 3: Intermediate 17 (100 mg, 0.23 mmol), 1-cyano-1-cyclopropanecarboxylic acid (26 mg, 0.23 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) (131 mg, 0.35 mmol), and DIEA (61 μL, 0.35 mmol) were dissolved in DMF and heated at 70°C for 8 hours. After completion of the reaction, the mixture was monitored by TLC and extracted with ethyl acetate and water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography to afford compound F27 as a white solid in a 33% yield. 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=7.4Hz,1H),8.69(s,1H),8.55(d,J=7.9Hz,1H),8.41(s,1H),8.17(s,1H),7.68(d,J=8.7Hz,1 H),7.55(d,J=8.9Hz,1H),7.48–7.33(m,3H),7.27–7.21(m,2H),7.05(t,J=8.8Hz,1H),5.26–5.18(m,1H),1.50(d,J=7.1Hz,7H). MS(ESI),m / z:525.1[M+H] + .

[0209] Example 28

[0210] Preparation of N-((S)-1-(3-fluorophenyl)ethyl)-5-(2-(tetrahydrofuran-3-carboxamide)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F28)

[0211] The preparation of N-((S)-1-(3-fluorophenyl)ethyl)-5-(2-(tetrahydrofuran-3-carboxamide)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F28) was performed using Reference Example 27. 1H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.86(d,J=7.3Hz,1H),8.72(s,1H),8.59(d,J=7.9Hz,1H) ,8.50–8.43(m,2H),7.90–7.82(m,2H),7.48(dd,J=7.3,2.0Hz,1H),7.42–7.34(m,1H),7.28–7. 19(m,2H),7.05(t,J=8.6Hz,1H),5.21(p,J=7.1Hz,1H),3.95(t,J=8.3Hz,1H),3.81(dq,J=9.7, 3.5Hz, 2H), 3.72 (q, J = 7.1Hz, 1H), 3.41–3.35 (m, 1H), 2.20–2.09 (m, 2H), 1.50 (d, J = 7.1Hz, 3H). MS(ESI),m / z:530.2[M+H] + .

[0212] Example 29

[0213] Preparation of (S)-5-(2-(cyclobutanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F29)

[0214] The preparation of (S)-5-(2-(cyclobutanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F29) was performed using Reference Example 27. 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.86(d,J=7.3Hz,1H),8.72(s,1H),8.59(d,J=7.8 Hz,1H),8.49–8.44(m,2H),7.85–7.81(m,2H),7.48(dd,J=7.3,2.0Hz,1H),7.40–7.35(m, 1H),7.27–7.20(m,2H),7.05(dt,J=7.8,4.4Hz,1H),5.21(p,J=8.4,7.6Hz,1H),3.46–3.3 8(m,1H),2.32–2.15(m,4H),2.06–1.94(m,1H),1.91–1.79(m,1H),1.50(d,J=7.1Hz,3H). MS(ESI),m / z:514.3[M+H] + .

[0215] Example 30

[0216] Preparation of (S)-5-(2-(3,3-difluorocyclobutane-1-carboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F30)

[0217] Preparation of (S)-5-(2-(3,3-difluorocyclobutane-1-carboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F30) Reference Example 27. 1 H NMR (400MHz, DMSO-d6) δ8.83(d,J=7.4Hz,1H),8.75(s,1H),8.70–8.60(m,1H),8.45(s,1H),8.37(s,1H),7.76(q,J=8.6Hz,2H),7.47(dd,J=7.4,2.1 Hz,1H),7.43–7.33(m,1H),7.29–7.21(m,2H),7.05(t,J=8.0Hz,1H),5.26 –5.17(m,1H),3.23–3.16(m,1H),2.92–2.74(m,4H),1.51(d,J=7.1Hz,3H). MS(ESI),m / z:550.3[M+H] + .

[0218] Example 31

[0219] Preparation of 5-(2-(2,2-difluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-N-((S)-1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F31)

[0220] The preparation of 5-(2-(2,2-difluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-N-((S)-1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (F31) was performed using Reference Example 27. 1H NMR(400MHz,DMSO-d6)δ8.81(d,J=7.4Hz,1H),8.73(s,1H),8.61(d,J=8.1 Hz,1H),8.45–8.40(m,1H),8.25(s,1H),7.74–7.62(m,2H),7.47(d,J=7.4 Hz,1H),7.41–7.35(m,1H),7.29–7.21(m,2H),7.04(d,J=8.0Hz,1H),5.26 –5.18(m,1H),2.80–2.71(m,1H),2.11–1.96(m,2H),1.50(d,J=7.0Hz,3H). MS(ESI),m / z:536.2[M+H] + .

[0221] Example 32

[0222] Preparation of (S)-N-(1-(3-fluorophenyl)ethyl)-5-(2-(1-(trifluoromethyl)cyclobutane-1-carboxamido)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F32)

[0223] The preparation of (S)-N-(1-(3-fluorophenyl)ethyl)-5-(2-(1-(trifluoromethyl)cyclobutane-1-carboxamido)benzo[d]thiazol-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F32) was performed using Reference Example 27. 1 H NMR (400MHz, DMSO-d6) δ12.95 (s, 1H), 8.87 (d, J = 7.2Hz, 1H), 8.73 (s, 1H), 8. 60(d,J=8.0Hz,1H),8.51(s,1H),8.48(s,1H),7.92–7.83(m,2H),7.49(d,J= 7.1Hz,1H),7.41–7.35(m,1H),7.28–7.20(m,2H),7.06(t,J=8.4Hz,1H),5.2 7–5.16(m,1H),2.83–2.70(m,3H),2.05–1.86(m,3H),1.51(d,J=7.1Hz,3H). MS (ESI), m / z: 582.3 [M+H] + .

[0224] The preparation methods of Examples 33-45 were similar to those of Example 1 to obtain target compounds F33-F45.

[0225] Table 2 Compounds F33-F45

[0226] The preparation methods of Examples 46-87, 163-176, 178-182 and 193-194 were prepared by referring to Example 26 to obtain the target compounds F46-F87, F163-F176, F178-F182 and F193-F194.

[0227] Table 3 Compounds F46-F87, F163-F176, F178-F182 and F193-F194

[0228] Compound F56: 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),10.08(t,J=5.8Hz,1H),8.73(dd,J=8.3,5.2 Hz,2H),8.36(d,J=11.0Hz,1H),8.00(d,J=4.5Hz,1H),7.86(d,J=8.4Hz,1H),7.76 (d,J=8.4Hz,1H),7.46(dd,J=8.4,5.7Hz,2H),7.16(t,J=8.8Hz,2H),6.70(t,J=8. 3Hz, 1H), 5.23 (m, 1H), 2.05–2.00 (m, 1H), 1.51 (d, J = 7.0Hz, 3H), 1.03–0.94 (m, 4H).

[0229] Compound F58: 1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),10.06(d,J=2.2Hz,1H),8.80–8.68(m ,2H),8.36(t,J=5.9Hz,1H),7.99(t,J=8.0Hz,1H),7.85(d,J=8.4Hz,1H),7. 75(dd,J=8.5,1.7Hz,1H),7.20–7.04(m,3H),6.73(t,J=7.5Hz,1H),5.22(m, 1H), 2.02 (dd, J=11.6, 6.2Hz, 1H), 1.50 (t, J=6.8Hz, 3H), 1.02–0.94 (m, 4H).

[0230] Compound F66: 1 H NMR (400MHz, DMSO) δ8.42(s,1H),8.36(d,J=10.2Hz,2H),8.30(d,J=8.4Hz,1H),7.82(s,2H),7.48(dd,J=8.5,5.7Hz,3H),7.32(dd,J=7.4, 1.7Hz,1H),7.14(t,J=8.9Hz,2H),5.25–5.12(m,1H),2.69(s,3H),2.04(dd,J=11.5,6.1Hz,1H),1.51(d,J=7.0Hz,3H),1.03–0.92(m,4H).

[0231] Compound F73: 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),9.62(t,J=1.3Hz,1H),8.95(d,J=8.4Hz, 1H),8.33(d,J=1.8Hz,1H),7.89(dd,J=9.3,1.0Hz,1H),7.84(d,J=8.4Hz,1H),7 .73(dd,J=8.4,1.9Hz,1H),7.46–7.28(m,4H),7.11–7.03(m,1H),5.28–5.15(m ,1H),2.57(s,3H),2.09–2.00(m,1H),1.56(d,J=7.1Hz,3H),1.07–0.93(m,4H).

[0232] Compound F79: 11H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 10.00 (d, J = 2.3 Hz, 1H), 8.66 (t, J = 5.9 Hz, 2H), 8.35 (d, J = 1.6 Hz, 1H), 7.92–7.82 (m, 2H), 7.74 (dd, J = 8.4, 1.8 Hz, 1H), 7.38 (dd, J = 14.2, 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 2H), 7.06 (t, J = 8.6 Hz, 1H), 5.29–5.17 (m, 1H), 2.42 (s, 3H), 2.05–2.00 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.00–0.96 (m, 4H).

[0233] Compound F82: 1 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.04 (d, J = 2.3 Hz, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 4.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.4, 1.9 Hz, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.35–7.26 (m, 2H), 7.20–7.13 (m, 2H), 6.76 (d, J = 4.6 Hz, 1H), 5.62 (m, 1H), 3.63–3.48 (m, 1H), 2.82–2.72 (m, 1H), 2.07–1.96 (m, 1H), 1.03–0.93 (m, 4H).

[0234] Compound F85: 11H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.07 (dd, J = 2.4, 0.8 Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 4.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.4, 1.9 Hz, 1H), 7.44 (td, J = 8.0, 6.0 Hz, 1H), 7.32–7.20 (m, 2H), 7.20–7.07 (m, 1H), 6.78 (dd, J = 4.7, 0.7 Hz, 1H), 5.68 (dd, J = 8.7, 6.4 Hz, 1H), 4.40 (td, J = 7.7, 2.9 Hz, 1H), 3.96 (m, 1H), 2.95 (m, 1H), 2.29 (m, 1H), 2.03 (m, 1H), 0.99 (m, 4H).

[0235] Compound F86: 1 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.07 (d, J = 2.3 Hz, 1H), 8.84 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 4.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.9 Hz, 1H), 7.51–7.41 (m, 2H), 7.27–7.17 (m, 2H), 6.77 (d, J = 4.6 Hz, 1H), 5.66 (dd, J = 8.6, 6.4 Hz, 1H), 4.46–4.35 (m, 1H), 4.04–3.89 (m, 1H), 3.00–2.89 (m, 1H), 2.35–2.23 (m, 1H), 2.09–1.99 (m, 1H), 1.03–0.91 (m, 4H).

[0236] Compound F163: 1 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.90 (s, 1H), 8.61 (s, 1H), 8.46 (s, 2H), 7.85 (s, 2H), 7.52 (d, J = 7.4 Hz, 1H), 7.39–7.30 (m, 2H), 7.17 (d, J = 9.0 Hz, 2H), 5.29 (s, 1H), 4.22 (s, 1H), 3.98 (s, 1H), 2.38 (s, 1H), 2.12–1.89 (m, 3H), 1.78 (s, 1H), 1.06–0.91 (m, 4H).

[0237] Compound F164: 1 H NMR(400MHz,DMSO-d6)δ8.90(d,J=2.1Hz,1H),8.86(d,J=7.4Hz,1H),8.73(s ,1H),8.63(d,J=7.9Hz,1H),8.15(s,2H),7.82(dd,J=7.4,2.1Hz,1H),7.39( td,J=8.0,6.2Hz,1H),7.29–7.21(m,2H),7.06(td,J=8.5,2.7Hz,1H),5.31– 5.18(m,1H),2.07–1.95(m,2H),1.51(d,J=7.1Hz,3H),0.97(d,J=6.0Hz,4H).

[0238] Compound F165: 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.94(d,J=7.2Hz,1H),8.66(s,1H),8.55(d,J=2. 1Hz,1H),8.47(d,J=1.5Hz,1H),7.85(d,J=1.3Hz,2H),7.57(dd,J=7.3,2.2Hz,1H),7.50 –7.41(m,2H),7.25–7.17(m,2H),5.62(dd,J=8.6,6.4Hz,1H),4.46–4.34(m,1H),3.96–3 .86(m,1H),2.99–2.87(m,1H),2.37–2.21(m,1H),2.08–1.96(m,1H),1.04–0.92(m,4H).

[0239] Compound F166: 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),10.04(d,J=2.4Hz,1H),9.27(d,J=9.6Hz,1H),8.80(d,J=2.4Hz,1H),8.39(d,J=1.9Hz,1H),8.19(d,J=4.6Hz, 1H),7.87(d,J=8.4Hz,1H),7.83–7.73(m,3H),7.31(t,J=8.8Hz,2H),6.76 (d,J=4.6Hz,1H),6.23–6.10(m,1H),2.07–1.99(m,1H),1.02–0.94(m,4H).

[0240] Compound F167: 11H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.08 (d, J = 2.3 Hz, 1H), 8.92–8.83 (m, 2H), 8.09–7.98 (m, 1H), 7.93 (d, J = 4.6 Hz, 1H), 7.45–7.35 (m, 3H), 7.16–7.12 (m, 2H), 6.74 (d, J = 4.6 Hz, 1H), 5.59 (dd, J = 8.6, 6.4 Hz, 1H), 4.34 (td, J = 7.6, 2.9 Hz, 1H), 3.89 (m, 1H), 2.87 (m, 1H), 2.25–2.18 (m, 1H), 1.97–1.88 (m, 1H), 0.78 (d, J = 6.4 Hz, 4H).

[0241] Compound F168: 1 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.94 (dd, J = 7.2, 0.8 Hz, 1H), 8.68 (s, 1H), 8.55 (dd, J = 2.2, 0.9 Hz, 1H), 8.47 (t, J = 1.3 Hz, 1H), 7.86 (d, J = 1.3 Hz, 2H), 7.57 (dd, J = 7.3, 2.2 Hz, 1H), 7.44 (td, J = 8.0, 6.1 Hz, 1H), 7.32–7.18 (m, 2H), 7.18–7.08 (m, 1H), 5.64 (dd, J = 8.7, 6.4 Hz, 1H), 4.41 (m, 1H), 3.92 (m, 1H), 2.95 (m, 1H), 2.30 (m, 1H), 2.03 (m, 1H), 0.99 (m, 4H).

[0242] Compound F169: 1 1H NMR (400 MHz, DMSO-d6) δ 10.07 (d, J = 2.5 Hz, 1H), 8.79–8.69 (m, 2H), 8.31 (d, J = 1.9 Hz, 1H), 8.00 (d, J = 4.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.4, 1.9 Hz, 1H), 7.38 (td, J = 8.1, 6.1 Hz, 1H), 7.29–7.20 (m, 2H), 7.06 (m, 1H), 6.71 (d, J = 4.5 Hz, 1H), 5.24 (m, 1H), 3.85 (d, J = 6.2 Hz, 2H), 3.71 (s, 4H), 1.52 (d, J = 7.1 Hz, 3H).

[0243] Compound F170: 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.08 (dd, J = 2.4, 0.8 Hz, 1H), 8.80–8.68 (m, 2H), 8.40 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 4.5 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.38 (td, J = 8.1, 6.1 Hz, 1H), 7.32–7.18 (m, 2H), 7.12–6.99 (m, 1H), 6.72 (dd, J = 4.5, 0.8 Hz, 1H), 5.23 (m, 1H), 4.84–4.65 (m, 4H), 4.14 (m, 1H), 1.52 (d, J = 7.1 Hz, 3H).

[0244] Compound F171: 1 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 10.39 (dd, J = 2.4, 0.8 Hz, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.80 (d, J = 7.9 Hz, 1H), 8.30 (d, J = 0.7 Hz, 1H), 8.16–7.99 (m, 2H), 7.76 (d, J = 9.5 Hz, 1H), 7.39 (td, J = 8.1, 6.2 Hz, 1H), 7.34–7.18 (m, 2H), 7.13–6.99 (m, 1H), 6.77 (dd, J = 4.5, 0.8 Hz, 1H), 5.25 (m, 1H), 1.97 (m, 1H), 1.52 (d, J = 7.0 Hz, 3H), 0.85 (m, 4H).

[0245] Compound F172: 1 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.04 (dd, J = 2.4, 0.8 Hz, 1H), 9.27 (d, J = 9.7 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.4, 1.9 Hz, 1H), 7.65 (m, 1H), 7.61–7.48 (m, 2H), 7.29 (m, 1H), 6.76 (dd, J = 4.6, 0.7 Hz, 1H), 6.21 (m, 1H), 2.02 (m, 1H), 0.98 (m, 4H).

[0246] Compound F173: 11H NMR (400 MHz, DMSO-d6) δ 10.10 (d, J = 2.4 Hz, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 7.0 Hz, 1H), 8.00 (d, J = 4.6 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.43 (td, J = 7.9, 6.0 Hz, 1H), 7.32–7.17 (m, 3H), 7.12 (td, J = 8.6, 2.6 Hz, 1H), 6.79 (d, J = 4.5 Hz, 1H), 6.12 (s, 2H), 5.68 (dd, J = 8.6, 6.4 Hz, 1H), 4.39 (m, 1H), 3.95 (m, 1H), 2.95 (m, 1H), 2.37–2.21 (m, 1H).

[0247] Compound F174: 1 1H NMR (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 10.09 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.40 (m, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 4.6 Hz, 1H), 7.92 (s, 1H), 7.59 (dd, J = 8.5, 1.5 Hz, 1H), 7.44 (td, J = 8.0, 6.0 Hz, 1H), 7.35–7.19 (m, 2H), 7.12 (td, J = 8.5, 2.6 Hz, 1H), 6.79 (d, J = 4.6 Hz, 1H), 5.68 (dd, J = 8.7, 6.4 Hz, 1H), 4.39 (td, J = 7.8, 2.8 Hz, 1H), 4.03–3.89 (m, 1H), 2.95 (m, 1H), 2.84 (d, J = 4.7 Hz, 3H), 2.36–2.23 (m, 1H).

[0248] Compound F175: 1 1H NMR (400 MHz, DMSO-d6) δ 10.13 (d, J = 2.4 Hz, 1H), 8.83–8.77 (m, 2H), 8.63 (d, J = 7.0 Hz, 1H), 8.52 (d, J = 2.9 Hz, 1H), 8.05 (d, J = 4.5 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.70 (td, J = 8.8, 3.0 Hz, 1H), 7.53 (dd, J = 8.7, 4.5 Hz, 1H), 7.19 (dd, J = 7.0, 2.0 Hz, 1H), 6.74 (d, J = 4.5 Hz, 1H), 6.10 (s, 2H), 5.34–5.21 (m, 1H), 1.55 (d, J = 7.1 Hz, 3H).

[0249] Compound F176: 1 H NMR (400MHz, DMSO-d6) δ13.78(s,1H),8.89(d,J=7.2Hz,1H),8.74(s,1H),8.62(d,J=7.9Hz,1H),8.50(d,J=2.1Hz,1H),7.97(d,J=8.9Hz,2H),7.67(d d,J=8.4,1.6Hz,1H),7.55–7.48(m,1H),7.43–7.34(m,2H),7.30–7.19(m, 2H),7.06(td,J=8.5,2.6Hz,1H),5.28–5.16(m,1H),1.51(d,J=7.1Hz,3H).

[0250] Compound F178: 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),10.08(d,J=2.2Hz,1H),8.78(d,J=7.7Hz,1H),8.74(d,J=2 .3Hz,1H),8.52(d,J=2.9Hz,1H),8.36(d,J=1.6Hz,1H),8.03(d,J=4.5Hz,1H),7.85(d,J=8.4Hz, 1H),7.75(dd,J=8.4,1.8Hz,1H),7.69(td,J=8.8,3.0Hz,1H),7.52(dd,J=8.7,4.5Hz,1H),6.73( t,J=7.5Hz,1H),5.34–5.21(m,1H),2.06–1.98(m,1H),1.54(d,J=7.1Hz,3H),1.00–0.94(m,4H).

[0251] Compound F179: 1 H NMR (400MHz, DMSO-d6) δ8.86(d,J=7.3Hz,1H),8.72(s,1H),8.59(d,J=8.0Hz,1H),8.53–8.47(m,2H),7.92–7.85(m,2H),7. 52–7.41(m,3H),7.17(t,J=8.9Hz,2H),5.21(m,1H),3.10–2.95(m,1H),2.17(dd,J=18.4,9.3Hz,2H),1.51(d,J=7.1Hz,3H).

[0252] Compound F180: 11H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 7.3 Hz, 1H), 8.70 (s, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.72–7.61 (m, 3H), 7.43 (t, J = 6.8 Hz, 3H), 7.26 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 7.7 Hz, 1H), 5.22 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H).

[0253] Compound F181: 1 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.86 (d, J = 7.3 Hz, 1H), 8.73 (s, 1H), 8.60 (d, J = 7.9 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H), 8.07 (s, 1H), 7.77–7.65 (m, 2H), 7.48 (dd, J = 7.3, 1.9 Hz, 1H), 7.39 (dd, J = 14.1, 8.0 Hz, 1H), 7.25 (t, J = 9.6 Hz, 2H), 7.06 (td, J = 8.6, 2.4 Hz, 1H), 5.23 (m, 1H), 2.10 (s, 1H), 1.51 (d, J = 7.1 Hz, 3H), 0.94 (s, 4H).

[0254] Compound F182: 1 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.14 (s, 1H), 8.90 (d, J = 7.4 Hz, 1H), 8.73 (s, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.13 (s, 1H), 7.64 (dd, J = 9.4, 1.8 Hz, 1H), 7.55 (d, J = 9.3 Hz, 1H), 7.47–7.34 (m, 2H), 7.25 (t, J = 9.8 Hz, 2H), 7.06 (td, J = 8.6, 2.2 Hz, 1H), 5.22 (m, 1H), 2.00–1.91 (m, 1H), 1.51 (d, J = 7.1 Hz, 3H), 0.88–0.78 (m, 4H).

[0255] Compound F193: 1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),10.05(s,1H),8.81(d,J=7.6Hz,1H),8 .75(s,1H),8.54(s,1H),8.46(d,J=1.9Hz,1H),8.36(s,1H),7.99(d,J=4.4H z,1H),7.85(d,J=8.4Hz,1H),7.75(d,J=7.4Hz,2H),6.72(d,J=4.2Hz,1H),5 .37–5.23(m,1H),2.02(d,J=5.9Hz,1H),1.56(d,J=6.9Hz,3H),0.97(s,4H).

[0256] Compound F194: 1 H NMR(400MHz,DMSO-d6)δ10.00(d,J=2.1Hz,1H),8.69(dd,J=8.8,5.2Hz,2H),8.0 4(d,J=1.8Hz,1H),7.98(d,J=4.6Hz,1H),7.61(s,2H),7.53(dd,J=8.3,1.9Hz,1H ),7.43(d,J=8.3Hz,1H),7.38(dd,J=10.9,4.9Hz,1H),7.24(t,J=8.8Hz,2H),7. 09–7.02(m,1H),6.68(d,J=4.4Hz,1H),5.29–5.17(m,1H),1.51(d,J=7.1Hz,3H).

[0257] The preparation methods of Examples 88-101 were similar to those of Example 27 to obtain target compounds F88-F101.

[0258] Table 4 Compounds F88-F101

[0259] Compound F91: 1 H NMR (400MHz, DMSO) δ8.72(s,1H),8.59(s,1H),8.46(d,J=7.8Hz,1H),8.35(s,2H),7.74(s,2H),7.37–7.28(m,3H),7.03(s,2H),5.13–5. 02(m,1H),4.91(d,J=64.3Hz,1H),2.47–2.40(m,1H),1.56(dd,J=18.5,7.4Hz,1H),1.37(d,J=7.0Hz,3H),1.26(td,J=13.0,6.4Hz,1H).

[0260] Route 3

[0261] Example 102

[0262] Preparation of (S)-5-(2-(cyclopropanecarboxamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)pyrazolo[1.5-a]pyridine-3-carboxamide (F102)

[0263] Step 1: Cyclopropanoyl chloride (2.1 mL, 20.7 mmol) was added to 3-amino-5-bromo-1H-pyrazolo[3,4-B]pyridine (4.0 g, 18.8 mmol) dissolved in pyridine. The solution was heated under reflux for 12 h, and then water was added to obtain a solid, which was filtered and dried to give intermediate 18.

[0264] Preparation of (S)-5-(2-(cyclopropanecarboxamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)pyrazolo[1.5-a]pyridine-3-carboxamide (F102) Reference Example 27. MS (ESI), m / z: 484.1897 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.16(s,1H),8.93(dd,J=7.1,4.4Hz,2H),8.76(s,1H),8.64(d,J=7.9Hz,1H),8.57(d,J=1.3Hz,1H),8.1 3(s,1H),7.59(dd,J=7.3,2.0Hz,1H),7.53(dd,J=7.2,1.8Hz,1H),7.46(dd,J=8.5,5.6Hz,2H),7.17(t,J=8.9Hz,2H),5.23(m 1H), 2.14–1.97 (m, 1H), 1.51 (d, J = 7.1Hz, 3H), 0.85 (d, J = 6.2Hz, 4H).

[0265] The preparation methods of Examples 103-127 and 177 were similar to those of Example 102 to obtain target compounds F103-F127 and F177.

[0266] Table 5 Compounds F103-F127 and F177

[0267] Compound F113:1 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.92 (d, J = 7.4 Hz, 2H), 8.65 (s, 1H), 8.54 (s, 1H), 8.15–8.07 (m, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.51 (dd, J = 7.3, 1.9 Hz, 1H), 7.39–7.28 (m, 2H), 7.14 (t, J = 8.6 Hz, 2H), 5.28 (s, 1H), 4.22 (s, 1H), 3.96 (s, 1H), 2.37 (s, 1H), 2.02 (m, 3H), 1.78 (s, 1H), 0.85 (d, J = 6.2 Hz, 4H).

[0268] Compound F115: 1 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.01 (d, J = 7.2 Hz, 1H), 8.93 (d, J = 7.1 Hz, 1H), 8.70 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.68 (dd, J = 7.3, 2.2 Hz, 1H), 7.52 (dd, J = 7.2, 2.0 Hz, 1H), 7.50–7.42 (m, 2H), 7.26–7.17 (m, 2H), 5.63 (dd, J = 8.6, 6.4 Hz, 1H), 4.45–4.38 (m, 1H), 3.97–3.83 (m, 1H), 3.02–2.89 (m, 1H), 2.35–2.23 (m, 1H), 2.11–1.98 (m, 1H), 0.84 (d, J = 6.2 Hz, 4H).

[0269] Compound F120: 1 1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 10.19 (d, J = 2.2 Hz, 1H), 8.93 (d, J = 7.1 Hz, 1H), 8.83 (d, J = 2.3 Hz, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J = 4.5 Hz, 1H), 7.50–7.40 (m, 3H), 7.16 (t, J = 8.9 Hz, 2H), 6.75 (d, J = 4.5 Hz, 1H), 5.24 (m, 1H), 2.06 (s, 1H), 1.51 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 6.2 Hz, 4H).

[0270] Compound F121: 1H NMR (400MHz, DMSO) δ11.12(s,1H),10.16(d,J=2.2Hz,1H),8.92(d,J=7.1Hz ,1H),8.84(d,J=2.3Hz,1H),8.79(d,J=7.9Hz,1H),8.09(s,1H),8.03(d,J=4 .5Hz,1H),7.45(dd,J=7.1,1.8Hz,1H),7.11(m,3H),6.76(d,J=4.5Hz,1H),5 .36–4.99(m,1H),2.06(s,1H),1.51(d,J=7.1Hz,3H),0.84(d,J=6.2Hz,4H).

[0271] Compound F177: 1 H NMR (400MHz, DMSO) δ11.12(s,1H),10.18(d,J=2.3Hz,1H),8.92(d,J=7.1Hz,1H),8.84(d ,J=2.3Hz,1H),8.78(d,J=8.0Hz,1H),8.09(s,1H),8.04(d,J=4.5Hz,1H),7.45(dd,J=7.1 ,1.8Hz,1H),7.38(dd,J=14.2,8.0Hz,1H),7.25(t,J=8.7Hz,2H),7.11–7.01(m,1H),6.76 (d,J=4.5Hz,1H),5.24(m,1H),2.06(s,1H),1.52(d,J=7.1Hz,3H),0.84(d,J=6.2Hz,4H).

[0272] Route 4

[0273] Example 128

[0274] Preparation of (S)-5-(2-(3-cyclopropylureido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1.5-a]pyridine-3-carboxamide (F128)

[0275] Step 1: Isocyanatocyclopropane (1.7 g, 20.7 mmol) was added to 3-amino-5-bromo-1H-pyrazolo[3,4-B]pyridine (4.0 g, 18.8 mmol) and triethylamine (5.2 mL, 37.6 mmol) in tetrahydrofuran, and the solution was heated at reflux for 12 hours. The crude product was purified by column chromatography to obtain compound Intermediate 19.

[0276] Preparation of (S)-5-(2-(3-cyclopropylureido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1.5-a]pyridine-3-carboxamide (F128) Reference Example 27. MS (ESI), m / z: 499.2 [M+H] + .

[0277] The preparation methods of Examples 129-138 were similar to those of Example 128 to obtain target compounds F129-F138.

[0278] Table 6 Compounds F129-F138

[0279] Compound F137: 1 H NMR (400MHz, DMSO) δ10.94(s,1H),8.84(d,J=7.3Hz,1H),8.70(s,1H),8.56(d,J=7.9Hz,1H),8.45(d,J=1.6Hz,1H),8.36(s,1H),7.77(dd,J=8. 5,1.8Hz,1H),7.71(d,J=8.5Hz,1H),7.45(d,J=8.9Hz,3H),7.16(s,2H) ,6.66(s,1H),5.21(m,1H),2.74(d,J=4.6Hz,3H),1.50(d,J=7.1Hz,3H).

[0280] Route 5

[0281] Example 139

[0282] Preparation of (S)-N-(1-(3-fluorophenyl)ethyl)-5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1.5-a]pyridine-3-carboxamide (F139)

[0283] Step 1: 1-Methyl-4-bromopyrazole (3.3 g, 20.7 mmol) was added to a DMF solution of 3-amino-5-bromo-1H-pyrazolo[3,4-B]pyridine (4.0 g, 18.8 mmol) and cesium carbonate (12 g, 37.6 mmol), and the solution was reacted at 50° C. for 12 hours. The crude product was purified by column chromatography to obtain compound Intermediate 20.

[0284] Preparation of (S)-N-(1-(3-fluorophenyl)ethyl)-5-(2-(((1-methyl-1H-pyrazol-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (F139) Reference Example 27. MS (ESI), m / z: 496.2 [M+H] + .

[0285] The synthesis methods of Examples 140-144 were similar to those of Example 139 to obtain target compounds F140-F144.

[0286] Table 7 Compounds F140-F144

[0287] Route 6

[0288] Example 145

[0289] Preparation of (S)-7-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)-3-methylindolizine-1-carboxamide (F145)

[0290] Step 1: Weigh compound intermediate 21 (5.0 g, 20.50 mmol) and add 50 ml of tetrahydrofuran. Cool to 0-5°C in an ice-water bath. Add sodium hydroxide (0.86 g, 21.50 mmol) in batches and stir for 30 min. Add dropwise a solution of 3-bromopropyne (2.56 g, 21.50 mmol) in tetrahydrofuran (10 ml). After the addition, stir at room temperature for 16 h and monitor with LC-MS. Post-treatment: Add water and extract with ethyl acetate. The organic phase is dried by spin drying. The crude product is purified by column chromatography to obtain compound intermediate 22 (3.30 g). LC-MS: ESI [M+H] + =282.1.

[0291] Step 2: Compound Intermediate 22 (3.30 g, 11.70 mmol) and cesium carbonate (7.63 g, 23.40 mmol) were weighed and added to 33.0 ml of DMSO. The mixture was heated to 100°C and stirred for 16 h. LC-MS monitoring was performed. Post-treatment: water was added, the mixture was extracted with ethyl acetate, and the organic phase was dried by rotary evaporation. The crude product was purified by column chromatography to obtain Compound Intermediate 23 (2.20 g). LC-MS: ESI [M+H] + =282.1.

[0292] Step 3: Compound Intermediate 23 (0.340 g, 1.20 mmol) and lithium hydroxide monohydrate (0.253 g, 6.00 mmol) were weighed and added to a 5.0 ml mixture of methanol:tetrahydrofuran:water (1:1:1). The mixture was heated to 50°C and stirred for 16 h. LC-MS monitoring was performed. Post-treatment: The reaction mixture was adjusted to pH 7-8 with 1N aqueous hydrochloric acid, filtered, and the filter cake was dried to obtain Compound Intermediate 24 (0.250 g). LC-MS: ESI [M+H] + =254.1.

[0293] Step 4: Compound Intermediate 24 (0.250 g, 0.98 mmol), Intermediate 25 (0.164 g, 1.180 mmol), HATU (0.448 g, 1.180 mmol), and DIEA (0.253 g, 1.960 mmol) were weighed and added to 3.0 ml of DMF. The mixture was stirred at 50°C for 16 h and monitored by LC-MS. Post-treatment: Water was added, the mixture was extracted with ethyl acetate, and the organic phase was dried by rotary evaporation. The crude product was purified by column chromatography to obtain Compound Intermediate 26 (0.2 g). LC-MS: ESI [M+H] + =375.2.

[0294] Step 5: Compound Intermediate 26 (0.1 g, 0.26 mmol), Intermediate 7 (0.092 g, 0.26 mmol), Pd(dppf)Cl2 (0.02 g, 0.026 mmol), and cesium carbonate (0.128 g, 0.390 mmol) were weighed, and dioxane:water = 10:1 (3.0 ml) was added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 100°C and stirred for 16 h. LC-MS monitoring was performed. Post-treatment: The crude product was spin-dried and purified by column chromatography to obtain compound F145 (40 mg, white solid). LC-MS: ESI [M+H] + =513.2; 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=2.0Hz,1H),8.29(s,1H),8.18(dd,J=7.7,4.5Hz,2H),7.75(s,2H),7.48–7.41(m,2H),7.30(s,1H),7.25(d d,J=7.4,2.1Hz,1H),7.14(t,J=8.9Hz,2H),5.28–5.16(m,1H),2.52(s,3H),2.04–1.91(m,1H),1.48(d,J=7.0Hz,3H),0.93(t,J=5.3Hz,4H).

[0295] The preparation methods of Examples 146-150 were similar to those of Example 145 to obtain target compounds F146-F150.

[0296] Table 8 Compounds F146-F150

[0297] Route 7

[0298] Example 151

[0299] Preparation of (S)-3-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)-7-methylpyrrolo[1,2-b]pyridazine-5-carboxamide (F151)

[0300] Step 1: Compound Intermediate 27 (0.25 g, 0.98 mmol), Intermediate 8 (0.164 g, 1.18 mmol), HATU (0.448 g, 1.18 mmol), and DIEA (0.253 g, 1.96 mmol) were weighed and added to 3.0 ml of DMF. The mixture was heated to 50°C and stirred for 16 h. LC-MS monitoring was performed. Post-treatment: water was added, the mixture was extracted with ethyl acetate, and the organic phase was dried by rotary evaporation. The crude product was purified by column chromatography to obtain Compound Intermediate 28 (0.24 g). LC-MS: ESI [M+H] + =376.0.

[0301] Step 2: Compound Intermediate 28 (0.1 g, 0.26 mmol), Intermediate 7 (0.092 g, 0.260 mmol), Pd(dppf)Cl2 (0.02 g, 0.026 mmol), and cesium carbonate (0.128 g, 0.390 mmol) were weighed and added with dioxane:water = 10:1 (3.0 ml). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 100°C and stirred for 16 h. LC-MS monitoring was performed. Post-treatment: The crude product was spin-dried and purified by column chromatography to obtain compound F151 (22 mg, white solid). LC-MS: ESI [M+H] + =514.2; 1 H NMR(400MHz,Chloroform-d)δ8.85(d,J=2.5Hz,1H),8.77(d,J=2.5Hz,1H),8.48–8.40(m,2H),7.82(s,2H),7.45(s,1H),7.40–7.32( m,1H),7.22(m,2H),7.07–7.00(m,1H),5.24–5.15(m,1H),2.55(s,3H),2.04–1.93(m,1H),1.48(d,J=7.1Hz,3H),1.01–0.91(m,4H).

[0302] The preparation methods of Examples 152-161 were similar to those of Example 151 to obtain target compounds F152-F161.

[0303] Table 9 Compounds F152-F161

[0304] Route 8

[0305] Example 162

[0306] Preparation of (S)-6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-1-methylimidazo[1,5-a]pyridine-3-carboxamide (F162)

[0307] Step 1: Weigh compound intermediate 29 (1.0 g, 4.97 mmol) and triethylamine (1.28 g, 9.94 mmol) and add 20 ml of dichloromethane. Cool to 0-5°C in an ice-water bath. Add ethyl oxalyl chloride (0.68 g, 4.97 mmol) dropwise. Stir at room temperature for 4 hours after addition and monitor with LC-MS. Post-treatment: Add water, separate the liquids, spin-dry the organic phase, and purify the crude product by column chromatography to obtain compound intermediate 30 (1.13 g). LC-MS: ESI [M+H] + =301.0.

[0308] Step 2: Weigh compound intermediate 30 (1.00 g, 3.32 mmol) and phosphorus pentoxide (2.30 g, 16.60 mmol), add 30.0 ml of phosphorus oxychloride, heat to 110°C, and stir for 16 h. Monitor by LC-MS. Post-treatment: The reaction solution was spin-dried, ethyl acetate and water were added, and the pH was adjusted to 7-8 with 10% aqueous sodium carbonate solution. The layers were separated, and the organic phase was washed with saturated brine and spin-dried. The crude product was purified by column chromatography to obtain compound intermediate 31 (0.82 g). LC-MS: ESI [M+H] + =283.0.

[0309] Step 3: Compound Intermediate 31 (0.70 g, 2.47 mmol) and lithium hydroxide monohydrate (0.519 g, 12.30 mmol) were weighed and added to a 1:1:1 mixture of methanol:tetrahydrofuran:water (21.0 ml). The mixture was heated to 50°C and stirred for 16 h. LC-MS monitoring was performed. Post-treatment: The reaction mixture was adjusted to pH 7-8 with 1N aqueous hydrochloric acid, filtered, and the filter cake was dried to obtain Compound Intermediate 32 (0.56 g). LC-MS: ESI [M+H] + =255.1.

[0310] Step 4: Compound Intermediate 32 (0.360 g, 1.41 mmol), Intermediate 8 (0.236 g, 1.69 mmol), HATU (0.642 g, 1.69 mmol), and DIEA (0.365 g, 2.82 mmol) were weighed and added to 3.0 ml of DMF. The mixture was stirred at 50°C for 16 h and monitored by LC-MS. Post-treatment: Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried by rotary evaporation. The crude product was purified by column chromatography to obtain Compound Intermediate 33 (0.47 g). LC-MS: ESI [M+H] + =376.2.

[0311] Step 5: Weigh compound intermediate 33 (0.100 g, 0.27 mmol), pinacol diboron (0.101 g, 0.400 mmol), Pd(dppf)Cl2 (0.020 g, 0.027 mmol), and potassium acetate (0.053 g, 0.540 mmol), add 3.0 ml of 1,4-dioxane, replace the atmosphere with nitrogen three times, heat to 100°C and stir for 16 h, monitor by LC-MS, and continue the reaction solution to the next step.

[0312] Step 6: To the reaction mixture from the previous step, intermediate 18 (0.065 g, 0.230 mmol), Pd(dppf)Cl2 (0.020 g, 0.023 mmol), and cesium carbonate (0.127 g, 0.390 mmol) were added. Dioxane:water = 10:1 (3.0 ml) was added, and the atmosphere was replaced with nitrogen three times. The mixture was heated to 100°C and stirred for 16 h. LC-MS monitoring was performed. Post-treatment: The crude product was spin-dried and purified by column chromatography to obtain compound F162 (12 mg). LC-MS: ESI [M+H] + =498.2; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.72(s,1H),9.01(d,J=8.5Hz,1H),8.90(d,J=7.1Hz,1H),8.02(s,1H),7.92(d,J=9.4Hz,1H),7.51(d,J =9.5Hz,1H),7.46–7.26(m,4H),7.05(m,1H),5.29–5.15(m,1H),2.56( s, 3H), 2.04–1.95 (m, 1H), 1.54 (d, J = 7.1Hz, 3H), 0.84 (d, J = 6.3Hz, 4H).

[0313] Route 9

[0314] Example 183

[0315] Preparation of (S)-6-(2-acetylaminobenzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)-1-methylindolizine-3-carboxamide (F183)

[0316] Step 1: Weigh MePPh3Br (42.8 g, 120 mmol), add THF (300 mL), cool to 0°C, add n-BuLi (80 mL, 200 mmol) dropwise, stir at 0°C for 30 min, add compound intermediate 35 (20 g, 100 mmol) dissolved in THF (300 mL) dropwise, warm to room temperature and stir for 1 h. Monitor by TLC. The reaction solution is slowly added dropwise to ice water to quench, and extracted three times with EA and H2O. The organic phase is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography to obtain compound intermediate 36 (11 g, white solid). LC-MS: ESI [M+H] + =198.1.

[0317] Step 2: Weigh compound intermediate 36 (10 g, 51 mmol), add acetonitrile (150 mL), add NaOAc (12.5 g, 153 mmol) and NIS (40 g, 178.5 mmol) in batches, add compound intermediate 37 (13.5 g, 102 mmol) dropwise, raise the temperature to 85°C and stir overnight. Monitor by TLC, quench the reaction by adding aqueous Na2SO3 solution, extract three times with EA, combine the organic phases, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 38 (7.6 g, light yellow solid). LC-MS: ESI [M+H] + =282.1; 1 H NMR (400MHz, CDCl3) δ9.52 (s, 1H), 7.27 (d, J = 11.7Hz, 2H), 6.98 (dd, J = 9.4, 1.4Hz, 1H), 4.34 (q, J = 7.1Hz, 2H), 2.29 (s, 3H), 1.37 (t, J = 7.1Hz, 3H).

[0318] Step 3: Weigh compound intermediate 38 (2.6 g, 9.2 mmol), add MeOH (50 mL), THF (10 mL) and H2O (5 mL), add lithium hydroxide monohydrate (1.16 g, 27.6 mmol) in batches, raise the temperature to 40°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, adjust the pH to 6 with 1 mol / L aqueous hydrochloric acid, filter, and dry the filter cake to obtain compound intermediate 39 (1.3 g, yellow solid). LC-MS: ESI [M+H] + =254.1.

[0319] Step 4: Weigh compound intermediate 39 (1.3 g, 5.1 mmol), compound intermediate 25 (0.85 g, 6.12 mmol), and HATU (2.33 g, 6.12 mmol), add DMF (15 mL) and DIPEA (1.3 g, 10.2 mmol), heat to 70°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 40 (1.5 g, dark green solid). LC-MS: ESI [M+H] + =375.2; 1 H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 7.36 (dd, J = 8.5, 5.4Hz, 2H), 7.26 (t, J = 4.7Hz, 2H), 7.03 (t, J = 8 .7Hz,2H),6.96–6.95(m,1H),6.00(d,J=7.2Hz,1H),5.35–5.22(m,1H),2.31(s,3H),1.59(s,3H).

[0320] Step 5: Compound Intermediate 40 (100 mg, 0.27 mmol), Compound Intermediate 7 (93 mg, 0.27 mmol), Pd(dppf)Cl2 (20 mg, 0.027 mmol), and Cs2CO3 (132 mg, 0.405 mmol) were weighed, the atmosphere was replaced with N2, 1,4-dioxane (10 mL) and H2O (1 mL) were added, the atmosphere was replaced with N2, the temperature was raised to 100°C, and the mixture was stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F183 (10 mg, white solid). LC-MS: ESI [M+H] + =513.6; 1 HNMR(400MHz,DMSO)δ12.69(s,1H),9.88(s,1H),8.45(d,J=7.9Hz,1H),8.25(s,1 H),7.82(d,J=8.5Hz,1H),7.68(d,J=10.0Hz,2H),7.64(s,1H),7.45(dd,J=8.2,5 .7Hz,2H),7.35(d,J=9.1Hz,1H),7.14(dd,J=15.1,6.3Hz,2H),5.27–5.14(m,1H) ,2.37(s,3H),2.03(d,J=5.8Hz,1H),1.49(d,J=7.0Hz,3H),0.97(d,J=3.9Hz,4H).

[0321] Example 184

[0322] Preparation of (S)-6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)-1-methylindolizine-3-carboxamide (F184)

[0323] Step 1: Weigh compound intermediate 40 (200 mg, 0.53 mmol), pinacol diboron (269 mg, 1.06 mmol), Pd(dppf)Cl2 (38 mg, 0.053 mmol), and KOAc (104 mg, 1.06 mmol), replace the N2 atmosphere, add 1,4-dioxane (10 mL), replace the N2 atmosphere, heat to 100°C, stir overnight, monitor by TLC, extract three times with EA and H2O, dry the organic phase over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 41 (160 mg, yellow solid). LC-MS: ESI [M+H] + =423.3.

[0324] Step 2: Compound Intermediate 41 (160 mg, 0.38 mmol), Compound Intermediate 18 (79 mg, 0.38 mmol), Pd(dppf)Cl2 (28 mg, 0.038 mmol), and Cs2CO3 (186 mg, 0.57 mmol) were weighed, the atmosphere was replaced with N2, 1,4-dioxane (10 mL) and H2O (1 mL) were added, the atmosphere was replaced with N2, the temperature was raised to 100°C, and the mixture was stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F184 (36 mg, light yellow solid). LC-MS: ESI [M+H] + =497.5; 1 H NMR (400MHz, DMSO) δ11.09(s,1H),10.01(s,1H),8.86(d,J=7.1Hz,1H),8.51(d,J=8.0Hz,1H),7.94(d,J=12.7Hz,1H),7.68(s,2H),7.50–7 .41(m,3H),7.36(dd,J=7.1,1.5Hz,1H),7.15(s,2H),5.22(m,1H),2.36(s,3H),2.08(s,1H),1.50(d,J=7.0Hz,3H),0.85(d,J=6.0Hz,4H).

[0325] Route 10

[0326] Example 185

[0327] Preparation of (S)-7-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)-3-methylimidazo[1,5-a]pyridine-1-carboxamide (F185)

[0328] Step 1: Weigh compound intermediate 42 (10 g, 41 mmol), add AcOH (50 mL), cool to 0°C and stir for 30 min, slowly add NaNO2 (2.8 g, 41 mmol) dissolved in H2O (6 mL) dropwise, warm to room temperature and stir for 1 h, monitor by TLC, concentrate by rotary evaporation, extract three times with EA and H2O, dry the organic phase over anhydrous sodium sulfate, and concentrate by rotary evaporation to obtain compound intermediate 43 (12 g, yellow oily liquid). LC-MS: ESI [M+H] + =273.1.

[0329] Step 2: Weigh compound intermediate 43 (12 g, 44 mmol), add AcOH (50 mL), cool to 0°C, add zinc powder (8.6 g, 132 mmol) in portions, warm to room temperature and stir for 1 h. Monitor by TLC, filter, and concentrate the filtrate by rotary evaporation to obtain compound intermediate 44 (12 g, brown oily liquid). LC-MS: ESI [M+H] + =283.1.

[0330] Step 3: Weigh compound intermediate 44 (10 g, 38 mmol), add toluene (50 mL), add compound intermediate 45 (5.5 g, 43 mmol) dropwise, heat to 110°C and stir for 3 h. Monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 46 (3.5 g, light yellow solid). LC-MS: ESI [M+H] + =254.1; 1 H NMR (400MHz, DMSO) 8.18 (s, 1H), 7.50 (d, J = 7.4Hz, 1H), 6.69 (dd, J = 7.4, 1.8Hz, 1H), 4.27 (q, J = 7.1Hz, 2H), 1.90 (s, 3H), 1.26 (t, J = 7.1Hz, 3H).

[0331] Step 4: Weigh compound intermediate 46 (0.55 g, 1.94 mmol), add MeOH (10 mL), THF (10 mL) and H2O (1 mL), add lithium hydroxide monohydrate (0.24 g, 5.82 mmol) in portions, raise the temperature to 40°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, adjust the pH to 6 with 1 mol / L aqueous hydrochloric acid, filter, and dry the filter cake to obtain compound intermediate 47 (0.39 g, white solid). LC-MS: ESI [M+H] + =255.1.

[0332] Step 5: Weigh compound intermediate 47 (0.39 g, 1.5 mmol), compound intermediate 25 (0.25 g, 1.8 mmol), and HATU (0.68 g, 1.8 mmol), add DMF (5 mL) and DIPEA (0.39 g, 3.0 mmol), heat to 70°C and stir for 3 h, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 48 (0.48 g, yellow solid). LC-MS: ESI [M+H] + =376.2.

[0333] Step 6: Weigh compound intermediate 48 (200 mg, 0.53 mmol), pinacol diboronate (269 mg, 1.06 mmol), Pd(dppf)Cl2 (38 mg, 0.053 mmol) and KOAc (104 mg, 1.06 mmol), replace the N2 atmosphere, add 1,4-dioxane (10 mL), replace the N2 atmosphere, heat to 100°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 49. LC-MS: ESI [M+H] + =424.3.

[0334] Step 7: Compound Intermediate 49 (225 mg, 0.53 mmol), Compound Intermediate 18 (149 mg, 0.53 mmol), Pd(dppf)Cl2 (38 mg, 0.053 mmol), and Cs2CO3 (345 mg, 1.06 mmol) were weighed, the atmosphere was replaced with N2, 1,4-dioxane (10 mL) and H2O (1 mL) were added, the atmosphere was replaced with N2, the temperature was raised to 100°C, and the mixture was stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F185 (33 mg, yellow solid). LC-MS: ESI [M+H] + =498.5; 1HNMR (400MHz, DMSO) δ11.12(s,1H),8.88(d,J=7.2Hz,1H),8.46(s,1H),8.40(dd,J=8.0,4.0Hz,2H),8.08(s,1H),7.54–7.45(m,3 H),7.43(dd,J=7.5,1.7Hz,1H),7.14(s,2H),5.20(m,1H),2.71(s,3H),2.06(s,1H),1.52(d,J=7.0Hz,3H),0.84(d,J=6.2Hz,4H).

[0335] Example 186

[0336] Preparation of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)-1-methylindolizine-3-carboxamide (F186)

[0337] Step 1: Weigh compound intermediate 50 (0.8 g, 3.2 mmol), compound intermediate 8 (0.53 g, 3.8 mmol), and HATU (1.4 g, 3.8 mmol), add DMF (10 mL) and DIPEA (0.83 g, 6.4 mmol), heat to 70°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 51 (0.73 g, dark green solid). LC-MS: ESI [M+H] + =375.2.

[0338] Step 2: Compound Intermediate 51 (150 mg, 0.4 mmol), Compound Intermediate 7 (138 mg, 0.4 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), and Cs2CO3 (196 mg, 0.6 mmol) were weighed, the atmosphere was replaced with N2, 1,4-dioxane (10 mL) and H2O (1 mL) were added, the atmosphere was replaced with N2, the temperature was raised to 100°C, and the mixture was stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F186 (18 mg, light yellow solid). LC-MS: ESI [M+H] + =513.6; 1H NMR (400MHz, DMSO) δ12.71(s,1H),9.89(s,1H),8.49(d,J=8.0Hz,1H),8.26(d,J=1.5Hz,1H),7.83(d,J=8.5Hz,1H),7.69(dd,J=10.4,4.1Hz,3H),7. 43–7.34(m,2H),7.26(t,J=8.4Hz,2H),7.10–7.02(m,1H),5.23(m,1H),2. 38(s,3H),2.08–2.00(m,1H),1.51(d,J=7.1Hz,3H),0.99(d,J=4.3Hz,4H).

[0339] Example 187

[0340] Preparation of (S)-6-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-1-methylindolizine-3-carboxamide (F187)

[0341] Step 1: Weigh compound intermediate 51 (200 mg, 0.53 mmol), pinacol diboronate (269 mg, 1.06 mmol), Pd(dppf)Cl2 (38 mg, 0.053 mmol) and KOAc (104 mg, 1.06 mmol), replace the N2 atmosphere, add 1,4-dioxane (10 mL), replace the N2 atmosphere, heat to 100°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 52. LC-MS: ESI [M+H] + =423.3.

[0342] Step 2: Compound Intermediate 52 (224 mg, 0.53 mmol), Compound Intermediate 18 (149 mg, 0.53 mmol), Pd(dppf)Cl2 (38 mg, 0.053 mmol), and Cs2CO3 (261 mg, 0.80 mmol) were weighed, the atmosphere was replaced with N2, 1,4-dioxane (10 mL) and H2O (1 mL) were added, the atmosphere was replaced with N2, the temperature was raised to 100°C, and the mixture was stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F187 (11 mg, light yellow solid). LC-MS: ESI [M+H] + =497.5; 1H NMR (400MHz, DMSO) δ11.10(s,1H),10.01(s,1H),8.86(d,J=7.1Hz,1H),8.54(d ,J=8.0Hz,1H),7.93(s,1H),7.71(d,J=11.9Hz,2H),7.46(d,J=9.3Hz,1H),7.3 8(dt,J=6.6,5.0Hz,2H),7.25(t,J=8.3Hz,2H),7.11–6.99(m,1H),5.23(m,1H) ,2.38(s,3H),2.16–1.98(m,1H),1.50(d,J=7.0Hz,3H),0.85(d,J=6.1Hz,4H).

[0343] Route 11

[0344] Example 188

[0345] Preparation of (S)-8-chloro-3-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)pyrrolo[1,2-a]pyrimidine-6-carboxamide (F188)

[0346] Step 1: Weigh compound intermediate 53 (30 g, 105.6 mmol), vinyl pinacol borate (18 g, 116.2 mmol), Pd(PPh3)2Cl2 (3.7 g, 5.3 mmol), XPhos Pd G2 (2.1 g, 2.6 mmol), and Cs2CO3 (86 g, 264 mmol), replace the nitrogen atmosphere, add 1,4-dioxane (300 mL) and H2O (60 mL), replace the nitrogen atmosphere, heat to 90°C, stir overnight, monitor by TLC, extract twice with H2O and EA, combine the organic phases, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 54 (17 g, light yellow solid). LC-MS: ESI [M+H] + =185.0.

[0347] Step 2: Weigh compound intermediate 54 (17 g, 92 mmol), add acetonitrile (500 mL), add NaOAc (22.6 g, 276 mmol) and NIS (72.5 g, 322 mmol) in batches, add compound intermediate 37 (24.3 g, 184 mmol) dropwise, raise the temperature to 85°C and stir overnight. Monitor by TLC. Quench the reaction by adding aqueous Na2SO3 solution, extract three times with EA, combine the organic phases, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 55 (7.8 g, light yellow solid). LC-MS: ESI [M+H] +=269.1; 1 H NMR(400MHz, CDCl3) δ9.79(d,J=2.3Hz,1H),8.31(d,J=2.3Hz,1H),7.65(d,J=4 .6Hz, 1H), 6.71 (d, J = 4.5Hz, 1H), 4.40 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 3H).

[0348] Step 3: Weigh compound intermediate 55 (0.5 g, 1.85 mmol), add DCM (20 mL), add NCS (0.3 g, 2.22 mmol), stir at room temperature for 3 h, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 56 (0.43 g, bright yellow solid). LC-MS: ESI [M+H] + =303.5; 1H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 8.36 (t, J = 1.9Hz, 1H), 7.59 (d, J = 2.7Hz, 1H), 4.39 (q, J = 7.1, 2H), 1.41 (t, J = 7.1Hz, 3H).

[0349] Step 4: Weigh compound intermediate 56 (0.43 g, 1.4 mmol), add MeOH (10 mL), THF (2 mL), and H2O (2 mL), add lithium hydroxide monohydrate (0.17 g, 4.2 mmol) in portions, raise the temperature to 40°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, adjust the pH to 6 with 1 mol / L aqueous hydrochloric acid, filter, and dry the filter cake to obtain compound intermediate 57 (0.3 g, yellow solid). LC-MS: ESI [M+H] + =275.5.

[0350] Step 5: Weigh compound intermediate 57 (300 mg, 1.1 mmol), compound intermediate 8 (183 mg, 1.32 mmol), and HATU (501 mg, 1.32 mmol), add DMF (5 mL) and DIPEA (284 mg, 2.2 mmol), raise the temperature to 70°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 58 (0.26 g, bright yellow solid). LC-MS: ESI [M+H] + =396.6.

[0351] Step 6: Compound Intermediate 58 (100 mg, 0.25 mmol), Compound Intermediate 7 (96 mg, 0.28 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), and Cs2CO3 (204 mg, 0.625 mmol) were weighed, the atmosphere was replaced with N2, 1,4-dioxane (10 mL) and H2O (1 mL) were added, the atmosphere was replaced with N2, the temperature was raised to 100°C, and the mixture was stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F188 (14 mg, light yellow solid). LC-MS: ESI [M+H] + =535.0; 1 H NMR (400MHz, DMSO) δ12.74(s,1H),10.05(d,J=2.2Hz,1H),8.81(d,J=2.2Hz,1H),8 .76(d,J=7.8Hz,1H),8.37(d,J=1.6Hz,1H),8.10(s,1H),7.85(d,J=8.4Hz,1H),7. 76(dd,J=8.5,1.8Hz,1H),7.42–7.35(m,1H),7.24(t,J=7.9Hz,2H),7.06(td,J=8. 6, 2.3Hz, 1H), 5.21 (m, 1H), 2.07–1.96 (m, 1H), 1.50 (d, J = 7.0Hz, 3H), 0.97 (s, 4H).

[0352] The preparation methods of Examples 189-190 were similar to those of Example 188 to obtain target compounds F189-F190.

[0353] Table 10 Compounds F189-F190

[0354] Route 12

[0355] Example 191

[0356] Preparation of (S)-3-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-8-methylpyrrolo[1,2-a]pyrimidine-6-carboxamide (F191)

[0357] Step 1: Weigh compound intermediate 53 (1.0 g, 3.5 mmol), isopropenylboronic acid pinacol ester (0.67 g, 4.03 mmol), Pd(PPh3)2Cl2 (123 mg, 0.175 mmol), and Cs2CO3 (2.85 g, 8.75 mmol). Displace the nitrogen atmosphere with 1,4-dioxane (20 mL) and H2O (5 mL). Displace the nitrogen atmosphere with the addition of 1,4-dioxane (20 mL) and H2O (5 mL). Heat to 90°C and stir overnight. Monitor by TLC. Extract twice with H2O and EA. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 59 (0.43 g, white solid). LC-MS: ESI [M+H] + =199.1.

[0358] Step 2: Compound Intermediate 59 (0.43 g, 2.1 mmol) was weighed and added to acetonitrile (10 mL). NaOAc (0.52 g, 6.3 mmol) and NIS (1.65 g, 7.35 mmol) were added portionwise. Compound 3c (0.55 g, 4.2 mmol) was added dropwise. The mixture was heated to 85°C and stirred overnight. TLC was monitored. Aqueous Na2SO3 was added to quench the reaction. The reaction was extracted three times with EA. The combined organic phases were dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound Intermediate 60 (0.37 g, light yellow solid). LC-MS: ESI [M+H] + =283.1.

[0359] Step 3: Weigh compound intermediate 60 (0.4 g, 1.4 mmol), pinacol diboronate (0.53 g, 2.1 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), and KOAc (0.34 g, 3.5 mmol), replace the N2 atmosphere, add 1,4-dioxane (20 mL), replace the N2 atmosphere, heat to 100°C, stir overnight, monitor by TLC, extract three times with EA and H2O, dry the organic phase over anhydrous sodium sulfate, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 61 (0.34 g, yellow oily liquid). LC-MS: ESI [M+H] + =249.0.

[0360] Step 4: Weigh compound intermediate 61 (0.34 g, 1.37 mmol), compound intermediate 18 (0.38 g, 1.37 mmol), Pd(dppf)Cl2 (100 mg, 0.137 mmol) and Cs2CO3 (1.1 g, 3.43 mmol), replace the nitrogen atmosphere, add 1,4-dioxane (20 mL) and H2O (2 mL), replace the nitrogen atmosphere, heat to 100°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, and purify by column chromatography to obtain compound intermediate 62 (130 mg, yellow solid). LC-MS: ESI [M+H] + =405.4.

[0361] Step 5: Weigh compound intermediate 62 (130 mg, 0.32 mmol), add MeOH (10 mL), THF (2 mL) and H2O (2 mL), add lithium hydroxide monohydrate (40 mg, 0.96 mmol) in portions, raise the temperature to 40°C and stir overnight, monitor by TLC, concentrate by rotary evaporation, adjust the pH to 6 with 1 mol / L aqueous hydrochloric acid, filter, and dry the filter cake to obtain compound intermediate 63 (60 mg, yellow solid). LC-MS: ESI [M+H] + =377.4.

[0362] Step 6: Compound Intermediate 63 (30 mg, 0.08 mmol), Compound Intermediate 8 (13 g, 0.096 mmol), and HATU (36 mg, 0.096 mmol) were weighed, DMF (3 mL) and DIPEA (21 mg, 0.16 mmol) were added, and the mixture was heated to 70°C and stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F191 (3 mg, light yellow solid). LC-MS: ESI [M+H] + =498.5; 1 H NMR (400MHz, DMSO) δ11.13(s,1H),10.10(d,J=2.4Hz,1H),8.92(d,J=7.2Hz,1H),8.77(d,J= 2.3Hz,1H),8.71(d,J=8.1Hz,1H),8.08(s,1H),7.92(s,1H),7.44(dd,J=7.1,1.9Hz,1H),7.3 7(dd,J=8.1,6.1Hz,1H),7.25(t,J=8.1Hz,2H),7.07(dd,J=11.9,5.2Hz,1H),5.22(dd,J=14 .5,7.3Hz,1H),2.43(s,3H),2.05–1.99(m,1H),1.51(d,J=7.1Hz,3H),0.85(d,J=6.2Hz,4H).

[0363] Example 192

[0364] Preparation of (S)-3-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)-8-methylpyrrolo[1,2-a]pyrimidine-6-carboxamide (F192)

[0365] Compound Intermediate 63 (30 mg, 0.08 mmol), Compound Intermediate 25 (19 mg, 0.096 mmol), and HATU (36 mg, 0.096 mmol) were weighed, and DMF (3 mL) and DIPEA (21 mg, 0.16 mmol) were added. The mixture was heated to 70°C and stirred overnight. The mixture was monitored by TLC, concentrated by rotary evaporation, and purified by column chromatography to obtain Compound F192 (3 mg, light yellow solid). LC-MS: ESI [M+H] + =552.5; 1 H NMR (400MHz, DMSO) δ11.13(s,1H),10.07(d,J=2.4Hz,1H),9.25(d,J=9.7Hz,1H),8.94(d,J=7.2Hz,1H),8.84(dd,J=8.5,2.4Hz,1H),8.11(s,2H),7.7 9(dd,J=8.6,5.4Hz,2H),7.47(dd,J=7.1,1.9Hz,1H),7.32(t,J=8.9Hz,2H) ,6.21–6.07(m,1H),2.44(s,3H),2.07–1.99(m,1H),0.85(d,J=6.3Hz,4H).

[0366] Biological activity test:

[0367] 1. In vitro kinase activity assay

[0368] In a single reaction tube, a buffer (8mM MOPS, pH 7.0, 0.2mM EDTA, 10mM MnCl₂), the kinase to be tested, its substrate, 10mM magnesium acetate and γ₃⁻P-ATP solution, and various concentrations of the compound are added sequentially. MgATP is then added to initiate the enzymatic reaction and incubated at room temperature for 40 minutes. The reaction is terminated with 5µL of 3% phosphate buffer, and 10µL of the reaction solution is titrated onto a Filtermat A membrane. The membrane is washed three times with 75mM phosphate solution for 5 minutes each, followed by a single wash with methanol. Finally, the membrane is dried and subjected to scintillation counting. The scintillation count value reflects the degree of substrate phosphorylation, thus indicating kinase activity. IC50 The data was obtained by Eurofins.

[0369] Table 11 Inhibition results of test compounds on RIPK1 kinase

[0370] + indicates: IC 50 ≥500nM; ++ means: 500nM>IC 50 ≥100nM;+++ indicates: IC 50 <100nM.

[0371] Conclusion: The compounds of the present invention have significant inhibitory effects on RIPK1 kinase.

[0372] 2. Screening of RIPK1 inhibitors at the cellular level

[0373] HT-29 cells were cultured in DMEM + 10% FBS + 1% penicillin / streptomycin medium, L929 cells were cultured in MEM + 10% FBS + 1% penicillin / streptomycin medium, and U937 cells were cultured in RPMI + 10% FBS + 1% penicillin and streptomycin medium. When the cells were cultured to the logarithmic growth phase, the cells to be tested were collected, resuspended, and counted using a hemocytometer. The cell suspension was added to each well (8000 cells / well for L929 and HT-29, 1000 cells / well for U937). 4 / well) were inoculated into 96-well plates and cultured overnight in a cell culture incubator at 37°C with 5% CO2. The next day, the test drug was diluted with culture medium to the corresponding concentration, and the prepared test compound was added to the corresponding wells of the 96-well plate. Three replicates were set for each sample. An inducer control group (cells + inducer), a cell-containing control group (no drug addition), and a blank group containing only culture medium (no cells) were also set up. After the drug-treated cells were induced with the inducer TNF-α / Smac mimetic / z-VAD-FMK for 24 hours, 20 μl of 5 mg / mL MTT working solution was added to each well and incubated for 2-4 hours. After obvious purple formazan crystals were observed on the bottom of the 96-well plate under a microscope, the culture supernatant in the wells was carefully aspirated with a 5mL syringe. Finally, 100 μL of DMSO was added to each well. After the purple crystals were fully dissolved, the absorbance was measured at a wavelength of 570 nm using a microplate reader. After incubating U937 cells with MTT working solution for 2-4 hours, 50 μl of 20% SDS solution was added to each well and incubated overnight. The absorbance was measured the next day at 570 nm using a microplate reader. Cell viability was calculated as [(A(test drug added) - A(blank)) / (A(0 drug added) - A(blank))] x 100%; A represents the absorbance. Finally, GraphPad Prism 8.0 software was used to fit the cell viability curve and calculate the EC value for the test compound's inhibition of programmed cell death. 50 value.

[0374] Table 12 Results of the anti-necroptosis effects of the test compounds on U937, L929 and HT-29 cells

[0375] + means: EC 50 ≥50nM; ++ means: 50nM>IC 50 ≥10nM; +++ means: <10nM; - means not tested.

[0376] Conclusion: The compounds of the present invention significantly inhibit necroptosis in U937, L929 and HT-29 cells.

[0377] 3. Pharmacokinetic evaluation of the compound in Balb / c mice

[0378] Experimental purpose: To understand the pharmacokinetics of the compound.

[0379] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0380] Experimental protocol: Balb / c mice were intravenously administered (5 mg kg -1 or 10 mg kg -1 ) and oral administration (5 mg·kg -1 or 10 mg kg -1 ), to investigate the pharmacokinetics of the compound.

[0381] Sample preparation: Weigh the compound and dissolve it in DMSO, then add sodium chloride solution for injection to make 1 mg mL -1 The compound solution was prepared for administration. Reference compound 10b was synthesized according to the synthesis method of compound 10b in reference J Med Chem. 2024 Jan 11; 67(1): 754-773 (doi: 10.1021 / acs.jmedchem.3c02102).

[0382] Sample collection: 6 Balb / c mice (Chengdu Dashuo Laboratory Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), male, 3 mice were dosed with 10 mg kg -1 Intravenous administration (IV), 3 at 10 mg kg -1Oral administration (PO) was performed. Approximately 0.05 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected and frozen at -40°C for testing. The plasma concentration was quantitatively analyzed by LC-MS / MS analysis, and pharmacokinetic parameters such as peak time (C max ), area under the drug-time curve (AUC (0-t) ), half-life (T 1 / 2 ), clearance rate (CL), tissue distribution (V dss ), bioavailability (F), etc.

[0383] The results of the pharmacokinetic evaluation are shown in Table 13 below:

[0384] Table 13 Pharmacokinetic test results of the compounds in Balb / c mice

[0385] Conclusion: The compounds of the present invention have good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life and clearance. The pharmacokinetic properties of the preferred compounds are significantly better than those of the reference compound 10b.

[0386] 4. Pharmacodynamic evaluation of compound F20 in SIRS mouse model

[0387] Experimental groups: control group (8 SIRS mice), model group (7 mice), 5 mg / kg GSK2982772 (8 mice), 2.5 mg / kg compound F20 (8 mice), 5 mg / kg compound F20 (8 mice), and 10 mg / kg compound F20 (6 mice); reference compound GSK2982772 was purchased from Shanghai MedChemExpress.

[0388] Experimental plan: 15 minutes before the induction of mice by tail vein injection of mTNFα (6μg / mouse), the mice in the drug group were orally administered 200μl of different doses of the drug, and the control group was given an equal amount of normal saline. The changes in the body temperature of the mice within 8 hours after TNFα injection and the survival rate of the mice within 72 hours were observed.

[0389] The results are shown in Figure 1. Experimental Results: Changes in Mouse Body Temperature: The body temperature of mice in the control group remained almost unchanged, while that of the model group gradually decreased over time. The body temperature of mice in the 5 mg / kg GSK2982772 group dropped to a low temperature and gradually recovered after 6 hours. The body temperature of mice in the RIPK1 compound A67 group initially decreased and then gradually returned to near normal. Survival rate of mice within 72 hours: No mice in the control group died, with a survival rate of 100% (8 / 8); all mice in the model group died, with a survival rate of 0% (7 / 0); 3 mice in the 5 mg / kg GSK2982772 group died, with a survival rate of 62.5% (8 / 5); no mice in the low-dose compound F20 group (2.5 mg / kg) died, with a survival rate of 100% (8 / 8); one mouse in the medium-dose compound F20 group (5 mg / kg) died, with a survival rate of 87.5% (8 / 7); and no mice in the high-dose compound F20 group (5 mg / kg) died, with a survival rate of 100% (6 / 6).

[0390] Experimental conclusion: The compound F20 of the present invention improves the body temperature of SIRS mouse model in a dose-dependent manner and increases the survival rate of mice in TNFα-induced SIRS mouse model.

[0391] 5. Effect of compound F20 on the phosphorylation of RIPK1 and its downstream kinase proteins

[0392] Experimental groups: DMSO and F20 (0.3, 3, 30, 300 nM).

[0393] Experimental protocol: HT-29 cells were co-induced with 40 ng / ml TNFα+100 nM SM-164+20 μM Z-VAD-FMK for 6 hours, and protein expression was analyzed by Western Blot.

[0394] Experimental results: The experimental results are shown in Figure 2.

[0395] Experimental conclusion: The compound F20 of the present invention inhibits the phosphorylation expression of RIPK1 and its downstream MLKL in a dose-dependent manner.

[0396] 6. Evaluation of the compound's inhibitory effect on inflammatory factor IL-6 in TNFα-induced SIRS mouse model

[0397] Experimental Methods: After 3 days of acclimation, 6-8 week-old C57BL / 6 female mice weighing 18-20 g were randomly divided into eight groups, each consisting of six mice: control, model, 2.5 mg / kg 10b, 2.5 mg / kg GSK2982772, 1 mg / kg F20 / F21, and 2.5 mg / kg F20 / F21. Mice were induced with TNFα injection via the tail vein at 8 μg / mouse. Six hours after TNFα injection, ocular blood was collected and serum IL-6 levels were measured. The reference compound, GSK2982772 (Catalog No. HY-101760), was purchased from Shanghai MedChemExpress. Reference compound 10b was synthesized according to the synthesis method of compound 10b in reference J Med Chem. 2024 Jan 11; 67(1): 754-773 (doi: 10.1021 / acs.jmedchem.3c02102).

[0398] Experimental results: The experimental results are shown in Figure 3. The average serum IL-6 levels were: 30.14 pg / ml in the Control group, 21431.29 pg / ml in the Model group, 5051.66 pg / ml in the 2.5 mg / kg 10b group, 5489.02 pg / ml in the 2.5 mg / kg GSK2982772 group, 2646.48 pg / ml in the 1 mg / kg F20 group, 2186.33 pg / ml in the 1 mg / kg F21 group, 1884.81 pg / ml in the 2.5 mg / kg F20 group, and 2090.57 pg / ml in the 2.5 mg / kg F20 group.

[0399] Experimental conclusion: There were significant differences between the model group and all the treatment groups, with P values ​​of 0.0001. Compounds F20 and F21 of the present invention significantly inhibited the production of inflammatory factor IL-6 in the SIRS mouse model and were significantly better than the reference compounds GSK2982772 and 10b.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of Formula I is as follows: Wherein: represents a single bond or a double bond, and the structural unit is a conjugate structure; X1 is selected from CR 7a or N, X2 is selected from CR 7b or N, X3 is selected from CR 7c or N, X4 is selected from CR 7d or N, X5 is selected from CR 7e or N, and at most 3 of X1, X2, X3, X4 and X5 are selected from N; Y and Z are independently selected from C or N, and when one of them is N, the other is C; Ring A is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl; in Ring A, the 5- to 10-membered heteroaryl contains 1 to 6 heteroatoms, and the heteroatoms are selected from N, S, O; L is selected from -CONH, -NHCO-, -NHCONH-, -O(O)CNH-, -SO2NH-, -NHSO2-, -O- or -NH-; R1 is selected from hydrogen, deuterium, or the following substituted or unsubstituted groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered spirocycloalkyl, 5- to 10-membered heterospirocycloalkyl, 6- to 10-membered bridged cycloalkyl, 6- to 10-membered heterobridged cycloalkyl, 6- to 10-membered aryl, or 5- to 6-membered heteroaryl; in R1, the substituents of the following substituted groups are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, or C 1-4 fluoroalkoxy; in R1, the 3- to 6-membered heterocycloalkyl, 5- to 10-membered heterospirocycloalkyl, 6- to 10-membered heterobridged cycloalkyl, 5- to 6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R2 is selected from H, deuterium, halogen, NH2, OH, CN, oxo group or the following substituted or unsubstituted groups: C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl; in R2, the substituents of the following substituted groups are selected from: deuterium, halogen, -OH, -NH2, -CN or 3- to 6-membered cycloalkyl; in R2, the 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, O; R3 is selected from hydrogen or the following substituted or unsubstituted groups: C 1-4 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heteroalkyl, phenyl or 5- to 6-membered heteroaryl; in R3, the substituents of the following substituted groups are selected from: deuterium, halogen, OH, NH2 or CN; in R3, the 4- to 6-membered heteroalkyl or 5- to 6-membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, O; R4 is selected from hydrogen, deuterium or the following substituted or unsubstituted groups: C 1-6 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heteroalkyl, phenyl or 5- to 6-membered heteroaryl; R5 is selected from hydrogen, deuterium or the following substituted or unsubstituted groups: C 1-6 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heteroalkyl, phenyl or 5- to 6-membered heteroaryl; among R4 and R5, the substituents of the following substituted groups are selected from: deuterium, halogen, -OH, -NH2, -CN or 3- to 6-membered cycloalkyl; among R4 and R5, the 4- to 6-membered heteroalkyl and 5- to 6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; Alternatively, R4 and R5 together with the atoms to which they are attached form a substituted or unsubstituted 3- to 6-membered alkyl ring or 4- to 6-membered alkyl heterocycle; when R4 and R5 form a ring with the atoms to which they are attached, the substituents are selected from: deuterium, halogen, OH or NH2; when R4 and R5 form a ring with the atoms to which they are attached, the 4- to 6-membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N, S, O; Alternatively, R3 and R4 or R3 and R5 together with the atoms to which they are attached form a substituted or unsubstituted 5- to 6-membered alkyl heterocycle; when R3 and R4 or R3 and R5 form a ring with the atoms to which they are attached, the substituents are selected from: deuterium, halogen, OH or NH2; when R3 and R4 or R3 and R5 form a ring with the atoms to which they are attached, the 5- to 6-membered alkyl heterocycle contains 0 to 2 heteroatoms selected from at least one of N, S, O in addition to the N shown in Formula I; Ring B is selected from 3- to 10-membered cycloalkyl, 5- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered spiroalkyl, 6- to 10-membered heterospiroalkyl, 6- to 10-membered bridged cycloalkyl, 6- to 10-membered heterobridged cycloalkyl or 5- to 10-membered heteroaryl; in Ring B, the 6- to 10-membered heterospiroalkyl, 6- to 10-membered heterobridged cycloalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl contains 1 to 3 heteroatoms, and the heteroatoms are selected from N, S, O; R6 is selected from H, deuterium, halogen, NH2, OH, CN, oxo group or the following substituted or unsubstituted groups: C 1-4 alkyl, C 1-4 alkoxy, 3-4 membered cycloalkyl or In R6, the substituents of the following substituted groups are selected from deuterium or halogen; R 7a is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7b is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7c is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7d is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; R 7e is selected from hydrogen, deuterium, halogen, amino, cyano, methyl, fluoromethyl, cyclopropyl, methoxy or fluoromethoxy; n1 is selected from 0, 1, 2, 3, 4, 5 or 6; n2 is selected from 0, 1, 2, 3, 4, 5 or 6; The pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs.

2. The compound according to claim 1, wherein: At most 2 of X1, X2, X3, X4 and X5 are selected from N; Preferably, the structural unit Selected from the following structures: More preferably, the structural unit Selected from the following structures:

3. The compound according to claim 1 or 2, wherein: Ring A is selected from 9- to 10-membered heteroaryl; in Ring A, the 9- to 10-membered heteroaryl contains 1 to 4 heteroatoms, the heteroatoms are selected from N, S, O, and at least one heteroatom is N; Preferably, ring A is selected from:

4. The compound according to any one of claims 1 to 3, wherein: R2 is selected from H, deuterium, halogen, NH2, CN, oxo group, methyl, fluoromethyl, methoxy, fluoromethoxy or cyclopropyl; Preferably, R2 is selected from H, fluorine, chlorine, NH2, CN, methyl, fluoromethyl, methoxy or fluoromethoxy; More preferably, R2 is selected from H, fluorine, chlorine or CN.

5. The compound according to any one of claims 1 to 4, characterized in that: L is selected from -CONH, -NHCONH-, -O(O)CNH- or -NH-.

6. The compound according to any one of claims 1 to 5, characterized in that: R1 is selected from H, deuterium or the following substituted or unsubstituted groups: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered spirocycloalkyl, phenyl or 5- to 6-membered heteroaryl; in R1, the substituents of the following substituted groups are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy or C 1-4 fluoroalkoxy; in R1, the 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; Preferably, R1 is selected from H, deuterium, or a substituted or unsubstituted C 1-4 alkyl group, a substituted or unsubstituted 3- to 6-membered cycloalkyl group, a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 6-membered spirocycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group; in R1, the substituted C 1-4 alkyl group substituents are selected from deuterium, fluorine, -OH, -NH2, -CN, methoxy, or fluoromethoxy; in R1, the substituents of the substituted 3- to 6-membered cycloalkyl group, the substituted 4- to 6-membered heterocycloalkyl group, the substituted 5- to 10-membered spirocycloalkyl group, the substituted phenyl group, and the substituted 5- to 6-membered heteroaryl group are selected from deuterium, fluorine, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy, or fluoromethoxy; in R1, the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 2 heteroatoms selected from at least one of N, S, and O; More preferably, R1 is selected from H, deuterium, methyl, fluoromethyl, deuteromethyl, ethyl, fluoroethyl, propyl, fluoropropyl, substituted or unsubstituted 3- to 4-membered cycloalkyl, substituted or unsubstituted In R1, the substituted 3- to 4-membered cycloalkyl group, the substituted The substituents of are selected from deuterium, halogen, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy or fluoromethoxy; Most preferably, R1 is selected from H, deuterium, methyl, fluoromethyl, deuteromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, Cyclobutyl, Or 7. The compound according to any one of claims 1 to 6, characterized in that: Structural unit Selected from the following structures: amino group, Structural unit Selected from the following structures:

8. The compound according to any one of claims 1 to 7, characterized in that: R3 is selected from hydrogen, methyl, fluoromethyl or cyclopropyl; Preferably, R3 is selected from hydrogen.

9. The compound according to any one of claims 1 to 8, characterized in that: R4 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-4 alkyl or 3- to 4-membered cycloalkyl; R5 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-4 alkyl or 3- to 4-membered cycloalkyl; among R4 and R5, the substituent of the substituted C 1-4 alkyl is selected from: deuterium, fluorine, -OH, -NH2 or -CN; or R4 and R5 form a 3- to 6-membered alkyl ring with the atoms to which they are attached; Preferably, R4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl or 3-4 membered cycloalkyl; R5 is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl or 3-4 membered cycloalkyl; or R4 and R5 together with the atoms to which they are attached form a 3-4 membered alkyl ring; More preferably, R4 is selected from H, deuterium, methyl, fluoromethyl, deuterated methyl; R5 is selected from H, deuterium, methyl, fluoromethyl, deuterated methyl; or R4 and R5 together with the atoms to which they are attached form a 3-membered alkyl ring.

10. The compound according to any one of claims 1 to 9, characterized in that: R3 and R4, or R3 and R5, together with the atoms to which they are attached, form a substituted or unsubstituted group selected from the following: Or n3 is selected from 1 or 2; when R3 forms a ring with R4 or R3 forms a ring with R5 together with the atoms to which they are attached, the substituents are selected from: deuterium, fluorine, -OH, -NH2, -CN; Preferably, R3 and R4 or R3, R5 and the atoms to which they are attached form a substituted or unsubstituted group selected from the following groups: Or 11. The compound according to any one of claims 1 to 10, characterized in that: Ring B is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; in ring B, the 5- to 6-membered heterocycloalkyl and 5- to 10-membered heteroaryl contain 1 to 2 heteroatoms, and the heteroatoms are selected from N, S, O; Preferably, ring B is selected from 5- to 6-membered cycloalkyl, piperidinyl, phenyl or pyridyl; More preferably, ring B is selected from phenyl Or 12. The compound according to any one of claims 1 to 11, characterized in that: R6 is selected from H, deuterium, fluorine, chlorine, NH2, OH, CN, oxo group, the following substituted or unsubstituted groups: C 1-4 alkyl, C 1-4 alkoxy, 3- to 4-membered cycloalkyl or In R6, the substituents of the following substituted groups are selected from deuterium or F; Preferably, R6 is selected from H, fluorine, chlorine, cyano, methyl, fluoromethyl, methoxy, fluoromethoxy, cyclopropyl, Or 13. The compound according to any one of claims 1 to 12, characterized in that: Structural unit Selected from the following structures: Structural unit Selected from the following structures: Structural unit Selected from the following structures:

14. The compound according to any one of claims 1 to 13, characterized in that: Structural unit Selected from the following structures: Structural unit Selected from the following structures:

15. The compound according to any one of claims 1 to 14, characterized in that: The compound is selected from:

16. The compound according to claim 1, characterized in that: Structural unit Selected from the following structures:

17. The compound according to claim 1, characterized in that: Ring A is selected from: Structural unit Selected from the following structures: methyl, fluoromethyl, amino, Structural unit Selected from the following structures:

18. The compound according to claim 1, characterized in that: Structural unit Selected from the following structures: Structural unit Selected from the following structures: Structural unit Selected from the following structures:

19. The compound according to claim 1, characterized in that: Structural unit Selected from the following structures: Structural unit Selected from the following structures:

20. The compound according to any one of claims 1 or 16 - 19, characterized in that: The chemical substances are selected from:

21. Pharmaceutical composition, characterized in that: It uses the compound according to any one of claims 1 to 20 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug as the active ingredient, supplemented with a pharmaceutically acceptable carrier.

22. The compound according to any one of claims 1 to 20 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, and the pharmaceutical composition according to claim 21, are used in the preparation of a drug for preventing and / or treating RIPK1 kinase-related diseases.

23. The use according to claim 22, wherein: The RIPK1 kinase-related diseases are inflammatory diseases, immune diseases, neurological diseases or tumors.

24. The use according to claim 22 or 23, characterized in that: The RIPK1 kinase-related diseases are amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, Parkinson's disease, spinal muscular atrophy, stroke, dementia associated with human immunodeficiency virus, autism, schizophrenia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic-onset juvenile idiopathic arthritis, psoriasis, dermatitis, systemic lupus erythematosus, systemic inflammatory response syndrome, pancreatitis, encephalitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, ulcerative colitis, Crohn's disease, retinal degenerative diseases, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, Sjogren's syndrome, systemic scleroderma, solid organ ischemia-reperfusion injury, cerebral ischemia, ischemic heart disease, acute kidney injury, ischemic brain injury, sepsis, diabetes or atherosclerosis.

25. The use according to claim 22 or 23, characterized in that: The RIPK1 kinase-related diseases are leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric oncology, urothelial cancer, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor or myeloma.

26. Use of the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite or prodrug thereof according to any one of claims 1 to 20, and the pharmaceutical composition according to claim 21, in the preparation of an RIPK1 inhibitor.

Images