Fused heterocycle NLRP3 inhibitor compound, pharmaceutical composition, and preparation method and application of fused heterocycle NLRP3 inhibitor compound and pharmaceutical composition

Abstract

The invention provides a fused heterocycle compound as shown in a formula (I), a pharmaceutical composition as well as a preparation method and application of the fused heterocycle compound. The compound has a good NLRP3 inhibiting effect, can be used for regulating NLRP3 protein independently or in combination with other medicines, and is used for treating NLRP3-mediated diseases and / or diseases and preparing medicines for preventing or treating the diseases and / or diseases. # imgabs0 #

Description

[0001] This application claims the priority of the following patent applications:

[0002] A prior application entitled “Fused heterocyclic NLRP3 inhibitor compounds, pharmaceutical compositions, preparation methods and applications thereof”, filed with the State Intellectual Property Office of China on October 17, 2023, with patent application number 202311345849.8;

[0003] A prior application, filed with the State Intellectual Property Office of China on December 7, 2023, with patent application number 202311678229.6 and titled “Fused heterocyclic NLRP3 inhibitor compounds, pharmaceutical compositions, preparation methods and applications thereof”;

[0004] A prior application entitled “Fused heterocyclic NLRP3 inhibitor compounds, pharmaceutical compositions, preparation methods and applications thereof”, filed with the State Intellectual Property Office of China on February 2, 2024, with patent application number 202410154043.9;

[0005] The entirety of said prior application is incorporated into the present application by reference. Technical Field

[0006] The present invention belongs to the field of medicine, and specifically relates to a fused heterocyclic NLRP3 inhibitor compound, a pharmaceutical composition, and a preparation method and application thereof. Background Art

[0007] NOD-like receptor protein 3 (NLRP3) is an important member of the NOD-like receptor family. NLRP3 contains three parts: the pyrin domain (PYD), the nucleotide binding site domain (NBD), and the leucine-rich repeat sequence (LRR). When cells receive stimulation from sterile inflammatory danger signals, NLRP3 interacts with the adaptor protein apoptosis-associated speck-like protein (ASC) and pro-caspase-1 to form the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome leads to the release of IL-1β and IL-18.

[0008] The activation of NLRP3 inflammasome usually requires two steps. The first step involves the initiation signal, in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), and then transmit the signal to the cell, mediating the activation of the NF-κB signaling pathway, and then upregulating the transcriptional levels of NLRP3 inflammasome-related components including inactive NLRP3 and pro-IL-1β. The second step is the activation signal. After receiving ATP, nigericin and other signal stimulation, the P2X7 receptor and other NLRP3 monomers oligomerize to form NLRP3 oligomers, and then recruit ASC and pro-caspase-1 to assemble into the NLRP3 inflammasome complex. This triggers the conversion of pro-caspase-1 to caspase-1, which cleaves pro-IL-1β and pro-IL-18, promoting the production and secretion of mature IL-1β and IL-18.

[0009] Activation of the NLRP3 inflammasome is associated with a variety of diseases, such as autoinflammatory fever syndromes such as cold pyrin-associated periodic syndrome (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury), CNS-related diseases (e.g., Alzheimer's disease, Parkinson's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia), and myelofibrosis.

[0010] Currently, there are few NLRP3 inflammasome inhibitors under development for the treatment of CNS-related diseases (Alzheimer's disease, Parkinson's disease, etc.). Most of them are limited to peripheral inflammatory diseases due to the nature of the molecules not being able to penetrate the blood-brain barrier. Therefore, it is clinically necessary to develop NLRP3 inflammasome inhibitors with higher activity, better drugability, and better brain permeability. Summary of the invention

[0011] In order to improve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound:

[0012]

[0013] in, It means that the ring in which it exists is aromatic;

[0014] X1 is selected from CR1, N;

[0015] X2 Selected from CR 21 , N, NR 22 ;

[0016] X3 is selected from C and N;

[0017] X4 is selected from C and N, and at least one of the atoms at the positions of X1, X2, X3, and X4 on the aromatic ring is N;

[0018] R1, R 21 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl; each R 1a are the same or different and are independently selected from H, OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy;

[0019] Or, R1, R 22 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 22a substituted 5-8 membered heterocyclic ring; each R 22a are the same or different and are independently selected from H, deuterium, OH, halogen, CN, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy;

[0020] Ring A is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; each R a are the same or different and are independently selected from H, deuterium, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R aa Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group; or, two R connected to different carbon atoms aTogether with the atoms to which they are attached, they are unsubstituted or optionally substituted with one, two or more R aa1 Substituted with the following groups: C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring; each R aa are the same or different and are independently selected from H, OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy; each R aa1 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy;

[0021] Ring B is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 3-14 Carbocyclic ring, 3-14 membered heterocyclic ring; each R b are the same or different and are independently selected from H, deuterium, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -(CH2) m1 COR b1 、-(CH2) m2 CONH2, Each R bb are the same or different and are independently selected from H, deuterium, OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy; each R b1 are the same or different and are independently selected from H, deuterium, OH, C 1-12 Alkyl, C 1-12 Alkoxy; R6, R7 are the same or different and are independently selected from H, CN, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl; m1 and m2 are the same or different and are independently selected from 0, 1, 2, 3, 4, 5, 6 or 7;

[0022] W is selected from CR5, N, O, S; when W is selected from O or S, R4 is absent;

[0023] R5 is selected from H, C 1-12 Alkyl, C 1-12Alkoxy, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkoxy;

[0024] R3 is selected from H, deuterium, OH, halogen, CN, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl;

[0025] R4 is absent or selected from H, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkoxy;

[0026] Or, R4, R 22 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 4a substituted 5-8 membered heterocycle;

[0027] Alternatively, R4 is connected to an atom on ring B and together with W forms an unsubstituted or optionally substituted R 4a Substituted C 5-8 A carbocyclic ring or a 5- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring and Ring B together form a spirocyclic or condensed ring structure;

[0028] Each R 4a are the same or different and are independently selected from H, deuterium, OH, halogen, CN, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy.

[0029] According to some embodiments, X1 is selected from CR1, X2 is selected from CR 21 , N, NR 22 , X3 is selected from C, N, X4 is selected from C, N; R1, R 21 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl.

[0030] According to some embodiments, R1 is selected from H, C 1-6 Alkyl, halogen or CN.

[0031] According to some embodiments, R1 is selected from H, methyl, F, Cl, Br or CN.

[0032] According to some embodiments, R 21 Selected from H, C 1-6 Alkyl, halogen or CN.

[0033] According to some embodiments, R 21 is selected from H, F, Cl, Br or CN.

[0034] According to some embodiments, R1, R 22 Together with the atoms to which they are attached they form a 5-6 membered heterocyclic ring.

[0035] According to some embodiments, R1, R 22 Together with the atoms to which they are attached, they form a tetrahydropyridine ring (e.g. ).

[0036] According to some embodiments, Selected from

[0037] According to some embodiments, Selected from

[0038] According to some embodiments, Ring A is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring; each R a are the same or different and are independently selected from H, deuterium, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R aa Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group; or, two R connected to different carbon atoms a Together with the atoms to which they are attached, they are unsubstituted or optionally substituted with one, two or more Raa1 Substitute the following groups: C 5-6 Cycloalkenyl ring, 5-6 membered heterocyclic ring; each R aa are the same or different and are independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; each R aa1 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano C 1-6 Alkyl, cyano C 1-6 Alkoxy;

[0039] According to some embodiments, Ring A is selected from unsubstituted or optionally substituted with one, two or more R a Substituted benzene ring; each R a are the same or different and are independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, halogenated C 1-6 Alkoxy or cyano C 1-6 Alkoxy; or two R attached to different carbon atoms a Together with their respective atoms they form C 5-6 Cycloalkenyl ring.

[0040] According to some embodiments, each R a are the same or different and are independently selected from H, F, Cl, Br, OH, CN, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy; or two R attached to different carbon atoms a Together with the atoms to which they are attached they form a cyclopentene ring.

[0041] According to some embodiments, Ring A is selected from

[0042] According to some embodiments, Ring B is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 3-8 Carbocyclic ring, 3-8 membered heterocyclic ring; each R b are the same or different and are independently selected from H, deuterium, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-6 Alkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl, -(CH2) m1 COR b1 、-(CH2) m2 CONH2, Each R bb are the same or different and are independently selected from H, deuterium, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; each R b1 are the same or different and are independently selected from H, deuterium, OH, C 1-6 Alkyl, C 1-6 Alkoxy; R6, R7 are the same or different and are independently selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl; m1, m2 are the same or different and are independently selected from 0, 1, 2, 3, 4.

[0043] According to some embodiments, Ring B is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 5-7 Cycloalkyl ring, 5-7 membered heterocyclic ring; each R b are the same or different and are independently selected from H, halogen, OH, CN, oxo (=O), C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-CONH2, -COC 1-6 Alkyl or R6 and R7 are the same or different and are independently selected from H, CN and halogen.

[0044] According to some embodiments, R6, R7 are the same or different and are independently selected from H, CN, F, Cl, or Br.

[0045] According to some embodiments, Ring B is selected from unsubstituted or optionally substituted with one, two or more R b The following groups substituted: cyclohexane ring, piperidine ring, pyrrolidine ring (i.e., tetrahydropyrrole ring); each R b are the same or different and are independently selected from H, F, Cl, Br, OH, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-hydroxyethyl, oxo (=O), -CH(CH3)CONH2, -COCH3, 2,2-difluoroethyl,

[0046]

[0047] According to some embodiments, Ring B is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R': wherein each R' is the same or different and is independently selected from H, deuterium, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or amino; R6, R7 have the definitions described herein; R8, R9 are the same or different and are independently selected from H, deuterium, unsubstituted or optionally substituted by one, two or more R 8a Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) s1 COR 81 、-(CH2) s2 CONH2; Each R 8a are the same or different and are independently selected from H, deuterium, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R 81 Selected from H, deuterium, OH, C 1-6 Alkyl, C 1-6 Alkoxy; s1, s2 are the same or different and are independently selected from 0, 1, 2, 3, 4, 5, 6 or 7; n1, n2, n3 are the same or different and are independently selected from 1, 2 or 3.

[0048] According to some embodiments, Ring B is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R': wherein R6, R7, R8, and R9 have the definitions described herein; each R' is the same or different and is independently selected from H, deuterium, OH, CN, halogen, C 1-6 alkyl.

[0049] According to some embodiments, Ring B is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R': wherein R6, R7, R8, and R9 have the definitions described herein; each R' is the same or different and is independently selected from H, deuterium, OH, CN, halogen, C 1-6 alkyl.

[0050] According to some embodiments, Ring B is selected from

[0051] According to some embodiments, Ring B is selected from

[0052]

[0053] According to some embodiments, W is selected from N.

[0054] According to some embodiments, W is selected from O.

[0055] According to some embodiments, R3 is selected from H, deuterium, OH, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0056] According to some embodiments, R3 is selected from H, F, Cl, Br or CN.

[0057] According to some embodiments, R4 is absent or is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, halogenated C 1-6 Alkoxy or cyano C 1-6 Alkoxy.

[0058] According to some embodiments, R4 is absent or is selected from H.

[0059] According to some embodiments, R4, R 22 Together with the atoms to which they are attached they form a 5-8 membered heterocyclic ring.

[0060] According to some embodiments, R4, R 22 Together with the atoms to which they are attached, they form a tetrahydropyrimidine ring (e.g. ).

[0061] According to some embodiments, R4 is connected to an atom on ring B and together with W forms C 5-8 An alkyl ring or a 5- to 8-membered heterocyclic ring, wherein the alkyl ring or the heterocyclic ring and ring B together form a spiro ring or a condensed ring structure.

[0062] According to some embodiments, R4 is connected to an atom on ring B, and together with W forms a pyrrolidine ring, and the pyrrolidine ring and ring B together form a fused ring structure.

[0063] According to some embodiments, Selected from

[0064] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0065]

[0066] Ring A, Ring B, X1, X2, X3, X4, W, R1, R3, R4, R a has the definitions described herein; q1, q2, q3 are the same or different and are independently selected from 1, 2, 3; p1 is selected from 0, 1, 2, 3, 4, 5.

[0067] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0068]

[0069]

[0070] Ring A, Ring B, R1, R3, R4, R8, R a , R b , W, p1 have the definitions described herein, and p2 is selected from 0, 1, 2, 3, 4, 5.

[0071] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0089] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0090] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0091] The present invention also provides a method for treating NLRP3-mediated diseases, comprising administering to a patient a preventive or therapeutically effective amount of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0092] The present invention also provides a method for treating NLRP3-mediated diseases, comprising administering to a patient a preventive or therapeutically effective amount of the above pharmaceutical composition.

[0093] The NLRP3-mediated disease is selected from: autoinflammatory fever syndrome such as cold pyrin-associated periodic syndrome (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, type I and type II diabetes and related complications (such as nephropathy, retinopathy), neuroinflammatory related diseases (such as multiple sclerosis, brain infection, acute injury), CNS related diseases (such as Alzheimer's disease, Parkinson's disease), atherosclerosis and cardiovascular risks (such as hypertension), suppurative hidradenitis, wound healing and scar formation and cancer (such as colorectal cancer, lung cancer, myeloproliferative tumors, leukemia), myelofibrosis.

[0094] In some embodiments, the patient comprises a mammal, preferably a human.

[0095] The present invention also provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or at least one of its prodrug compounds, or a pharmaceutical composition thereof for treating NLRP3-mediated diseases.

[0096] The present invention also provides the use of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a drug.

[0097] According to an embodiment of the present invention, the use may be for preparing a drug for treating NLRP3-mediated disorders and / or diseases, such as for preparing a NLRP3 inhibitor drug.

[0098] According to an embodiment of the present invention, the disease is, for example, autoinflammatory fever syndrome such as cold pyrin-associated periodic syndrome (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory related diseases (e.g., multiple sclerosis, brain infection, acute injury), CNS related diseases (e.g., Alzheimer's disease, Parkinson's disease), atherosclerosis and cardiovascular risks (e.g., hypertension), hidradenitis suppurativa, wound healing and scar formation and cancer (e.g., colorectal cancer, lung cancer, myeloproliferative tumors, leukemia), myelofibrosis.

[0099] Beneficial Effects

[0100] The compounds of the present invention have good NLRP3 inflammasome inhibitory effects and good brain permeability. The compounds can be used alone or in combination with other drugs to regulate NLRP3 protein, to treat NLRP3-mediated disorders and / or diseases, and to prepare drugs for treating such disorders or diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Figure 1 : Bar graph showing the time required for MPTP-induced PD model animals to climb from the top to the bottom of the pole in the pole climbing test.

[0102] Figure 2 : Bar graph of the time spent on the balance beam by MPTP-induced PD model animals.

[0103] Definition and explanation of terms

[0104] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0105] Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to recording each integer value in the numerical range "1-14", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.

[0106] The term "optional" (or "optionally", "optionally") in the general formula definitions of the present application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be selectively substituted by one, two or more R.

[0107] "More" means three or more.

[0108] The term "carbocycle" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as a bicyclo[1.1.1]pentane ring, a bicyclo[2.2.1]heptane ring, a bicyclo[3.2.1]octane ring or a bicyclo[5.2.0]nonane ring, a decalin ring, etc.), which may be optionally substituted with 1 or more (such as 1, 2 or 3) suitable substituents. The term "3-6 membered carbocycle" refers to a carbocycle containing 3, 4, 5 or 6 ring-forming carbon atoms.

[0109] The term "C 1-12 The term "alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms. 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0110] “C 2-12"Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more preferably "C 2-8 "C 2-8 The term "alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3 It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0111] The term "C 2-12 "Alkynyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, for example having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., "C 2-8 alkynyl”), having 2, 3, 4, 5 or 6 carbon atoms (i.e., “C 2-6Alkynyl”), having 2 or 3 carbon atoms (“C 2-3 The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4 In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0112] The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 The term "Cycloalkyl" 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0113] The term "C 3-12 "Cycloalkenyl" is understood to mean a monovalent monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic olefin containing a carbon-carbon double bond, having 3 to 12 carbon atoms, preferably "C3-10 Cycloalkenyl", more preferably "C 3-8 "cycloalkenyl" may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkenyl group may be a monocyclic hydrocarbon group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, or a bicyclic hydrocarbon group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl.

[0114] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-10 The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0115] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbozolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9- 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]oxazolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3 1-, 2-, 3-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-14 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-14 membered heteroaryl ring connected to other groups. When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0116] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, it is a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule by any one of the carbon atoms or the nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group may be bicyclic, for example but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is connected to other groups to form the compounds of the present invention, the carbon atoms on the 3-14-membered heterocyclic group may be connected to other groups, or the heterocyclic atoms on the 3-14-membered heterocyclic group may be connected to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to other groups.

[0117] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0118] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0119] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0120] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0121] "Halo" means substituted with one or more halogens.

[0122] Those skilled in the art will appreciate that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an inner salt.

[0123] The compounds of the present invention may exist in the form of solvates (e.g. hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.

[0124] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0125] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0126] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0127] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0128] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0129] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0130] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0131] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), THERMO Ultimate3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0132] High performance liquid chromatography (HPLC) analysis was performed using Agilent 1260II HPLC and Waters Acquity UPLC H-Class HPLC.

[0133] Chiral HPLC analysis was performed using a Waters Acquity UPCC high performance liquid chromatograph.

[0134] High performance liquid chromatography was performed using Waters MS-triggered Prep-LC with SQD2 detector, Waters MS triggered Prep-LC with Acquity QDA detector, Waters MS-triggered Prep-LCwith QDA detector and GILSON Prep LC with UV detector.

[0135] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0136] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0137] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0138] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0139] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0140] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0141] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0142] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0143] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0144] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0145] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0146] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0147] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0148] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound and the developing solvent system of the thin layer chromatography include: system A: dichloromethane / methanol system, system B: n-hexane / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0149] Example 1

[0150] (R)-3-Methyl-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol (001)

[0151]

[0152] The first step is 5-bromo-4H-1,2,4-triazole-3-amine (001b)

[0153] Dissolve the compound 3,5-diamino-1,2,4-triazole 001a (3g, 0.03mol) in an aqueous solution of hydrobromic acid (45mL), and slowly drop an aqueous solution (10mL) of sodium nitrite (2.5g, 0.04mol) into the reaction system at 0°C. Heat the reaction solution to 60°C and stir for 2 hours. After the reaction, adjust the pH value to 6.5-7.5 with sodium hydroxide. Add ethyl acetate to dissolve, filter, and concentrate the filtrate under reduced pressure. Add 1,4-dioxane (20mL) and stir at 80°C for 1 hour, then cool to room temperature, filter the reaction solution, collect the solid, and obtain the title compound 001b (1.4g, 80%).

[0154] MS m / z(ESI):163(M+1).

[0155] Step 2: 2-Bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (001c)

[0156] Compound 001b (100 mg, 0.61 mmol) was dissolved in acetonitrile (3 mL), and then compound 3-ethoxy ethyl acrylate (88.5 mg, 0.61 mmol) was added and the reaction solution was stirred at 95°C for 12 hours. After the reaction was completed, the reaction solution was directly filtered and the solid was collected to obtain the title compound 001c (100 mg, 75.7%). MS m / z (ESI): 215.0 (M+1).

[0157] Step 3: 2-Bromo-5-((4-methoxybenzyl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine (001d)

[0158] Compound 001c (100 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (5 mL), and p-methoxybenzyl chloride (145.7 mg, 0.93 mmol) and cesium carbonate (454.6 mg, 1.39 mmol) were added. The reaction was stirred at 50°C for 1 hour. After the reaction, a saturated sodium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography system B to obtain the title compound 001d (100 mg, 51.3%).

[0159] MS m / z(ESI):335.0(M+1).

[0160] Step 4: (R)-5-((4-methoxybenzyl)oxy)-N-(1-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (001e)

[0161] Compound 001d (50 mg, 0.15 mmol) was dissolved in 1,4-dioxane (3 mL), and compound 1-methyl-(R)-3-aminopiperidine (20.4 mg, 0.18 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (12.53 mg, 0.015 mmol) and cesium carbonate (145.8 mg, 0.45 mmol) were added. The reaction was stirred at 80°C under nitrogen protection for 4 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography system A to obtain the title compound 001e (40 mg, 72.7%).

[0162] MS m / z(ESI):369.1(M+1).

[0163] Step 5 (R)-5-chloro-N-(1-methylpiperidin-3-yl)[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (001f)

[0164] Compound 001e (40 mg, 0.11 mmol) was dissolved in phosphorus oxychloride (3 mL) and the mixture was stirred at 100°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without purification to obtain the title compound 001f (30 mg).

[0165] MS m / z(ESI):267.1(M+1).

[0166] Step 6: (R)-3-methyl-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol (001)

[0167] Compound 001f (30 mg, 0.11 mmol) was dissolved in a mixed solvent of dioxane and water (3.3 mL, V / V = 10 / 1), and compound (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid (27.3 mg, 0.011 mmol), sodium carbonate (59.6 mg, 0.56 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8.16 mg, 0.011 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatographic column: Xbridge 5um C18 150x 30mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to give the title compound 001 (7.5 mg, yield: 15.6%).

[0168] MS m / z(ESI):407.2(M+1).

[0169] 1H NMR(400MHz,CD3OD)δ8.75(d,1H),7.03-7.00(m,2H),6.94(s,1H),3.90-3.86(m,1H),2.96-2.91(m,1H) ,2.49(s,3H),2.15(s,3H),2.01-1.85(m,3H),1.74-1.65(m,1H),1.52-1.46(m,1H),1.23-1.89(m,2H).

[0170] Example 2

[0171] (R)-3-Methyl-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-5-(trifluoromethyl)phenol

[0172]

[0173] The first step: N-[(6-chloropyridazin-3-yl)carbamic acid ethyl ester (002b)

[0174] The compound 6-chloropyridazine-3-amine 002a (10.00 g, 0.072 mol) was dissolved in dichloromethane (100 mL), and ethoxyhydroxyisothiocyanate (11.97 g, 0.093 mol) was slowly added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, 100 mL of ethanol was added and stirred, and the solid was collected by filtration and dried to obtain the title compound 002b (2.3 g, yield 10%).

[0175] MS m / z(ESI):260.7(M+1).

[0176] Step 2: 6-Chloro-[1,2,4]triazolo[1,5-b]pyridazin-2-amine (002c)

[0177] Compound hydroxylamine hydrochloride (600 mg, 8.60 mmol) was dissolved in a mixed solvent of methanol and ethanol (14 mL, V / V = 1:1), and triethylamine (582 mg, 5.75 mmol) was added. After the reaction solution was stirred at room temperature for 1 hour, compound 002b (500 mg, 1.92 mmol) was added and heated under reflux and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, filtered, rinsed with water, then rinsed with ethanol, and dried to obtain the title compound 002c (190 mg, yield 52.6%).

[0178] MS m / z(ESI):169.5(M+1).

[0179] Step 3: 6-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-b]pyridazin-2-amine (002d)

[0180] Compound 002c (176 mg, 1.04 mmol) was dissolved in a mixed solvent of dioxane and water (5 mL, V / V = 10 / 1), and compound 2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (329 mg, 1.04 mmol), sodium carbonate (330 mg, 3.11 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (150 mg, 0.020 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography system B to obtain the title compound 002d (190 mg, yield: 50.8%).

[0181] MS m / z(ESI):324.2(M+1).

[0182] Step 4: 2-Bromo-6-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-b]pyridazine (002e)

[0183] Dissolve brominated ketone (220 mg, 0.98 mmol) in acetonitrile (10 mL), stir at room temperature, and then slowly add tert-butyl nitrite (101 mg, 0.98 mol). Stir the reaction at 50°C for 1 hour, then add compound 002d (160 mg, 0.49 mmol), and continue to react for 3 hours. After the reaction is completed, add water and dichloromethane to extract, collect the organic phase, dry it, and concentrate it under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography separation system B to obtain the title compound 002e (80 mg, yield 37.6%).

[0184] MS m / z(ESI):388.1(M+1).

[0185] Step 5 (R)-6-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazin-2-amine (002f)

[0186] Compound 002e (20 mg, 0.051 mmol) was dissolved in 1,4-dioxane (3 mL), and compound 1-methyl-(R)-3-aminopiperidine (6 mg, 0.051 mol), cesium carbonate (50 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.010 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (6 mg, 0.010 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 2 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography system A to obtain the title compound 002f (20 mg, 82.9%).

[0187] MS m / z(ESI):421.4(M+1).

[0188] Step 6: (R)-3-methyl-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-5-(trifluoromethyl)phenol (002)

[0189] Compound 002f (20 mg, 0.0047 mmol) was dissolved in dichloromethane (5 mL), and boron tribromide (30 mg, 0.012 mmol) was added at 0°C. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the crude product was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15 minutes gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20mL / min) to obtain the title compound 002 (4 mg, yield: 20.4%).

[0190] MS m / z(ESI):407.4(M+1).

[0191] 1 H NMR(400MHz,CD3OD)δ7.95(d,1H),7.52(d,1H),7.15(s,1H),7.07(s,1H),4.10-3.97(m,1H),3.66-3.43(m,1H),3.28 -3.09(m,1H),2.78(s,3H),2.25(s,3H),2.22-2.01(m,2H),1.99-1.80(m,1H),1.76-1.54(m,1H),1.40-1.27(m,2H).

[0192] Example 3

[0193] 3-Methyl-2-(7-methyl-2-(1-methylpiperidin-3-amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-trifluoromethylphenol (003)

[0194]

[0195] The synthetic route of Example 1 was adopted, and the second step raw material 3-ethoxy ethyl acrylate was replaced with 3-ethoxy but-2-enoic acid. The final product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 20 minutes gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20mL / min) to obtain the title compound 003 (2.08mg, yield: 5%).

[0196] MS m / z(ESI):421.1(M+1).

[0197] 1 H NMR(400MHz,CD3OD)δ8.40(s,1H),7.00(s,1H),6.93(s,2H),4.00-3.98(m,1H),3.15-3.09(m,1H),2.78 -2.77(m,2H),2.66-2.65(m,6H),2.13(s,3H),2.00-1.99(m,2H),1.70-1.69(m,2H),1.23-1.21(m,1H).

[0198] Example 4

[0199] (R)-2-(2-((1-ethylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol

[0200]

[0201] Step 1: (R)-N-(1-ethylpiperidin-3-yl)-5-((4-methoxybenzyl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (011a)

[0202] Compound 001d (200 mg, 0.60 mmol) was dissolved in 1,4-dioxane (5 mL), and compound (R)-1-ethylpiperidin-3-amine (77 mg, 0.60 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (100 mg, 0.12 mmol) and cesium carbonate (583 mg, 1.79 mmol) were added. The reaction was stirred at 80°C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography system A to obtain the title compound 011a (90 mg, yield: 35.5%).

[0203] MS m / z(ESI):397.4(M+1).

[0204] Step 2 (R)-5-chloro-N-(1-ethylpiperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (011b)

[0205] Compound 011a (90 mg, 0.24 mmol) was dissolved in phosphorus oxychloride (3 mL) and the mixture was stirred at 100°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product 011b (60 mg), which was used directly in the next step without purification.

[0206] MS m / z(ESI):281.7(M+1).

[0207] Step 3 (R)-2-(2-((1-ethylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 011

[0208] Compound 011b (30 mg, 0.11 mmol) was dissolved in dioxane and water (3.3 mL, V / V = 10 / 1), and compound (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid (24 mg, 0.11 mmol), sodium carbonate (33 mg, 0.32 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8 mg, 0.011 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20 mL / min) to give the title compound 011 (7 mg, yield: 15.3%).

[0209] MS m / z(ESI):421.4(M+1).

[0210] 1 H NMR(400MHz,CD3OD)δ8.87(d,1H),8.53(s,1H),7.13(d,1H),7.10(s,1H) ,7.04(s,1H),4.16–3.94(m,1H),3.69–3.48(m,1H),3.29–3.19(m,1H),3 .09–2.94(m,2H),2.90–2.69(m,2H),2.24(s,3H),2.18–2.13(m,1H),2.0 9–2.02(m,1H),1.93–1.80(m,1H),1.75–1.56(m,1H),1.39–1.20(m,4H).

[0211] Example 5

[0212] (R)-5-Chloro-2-(2-((1-ethylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methylphenol

[0213]

[0214] Compound 011b (30 mg, 0.11 mmol) was dissolved in a mixed solvent of dioxane and water (3.3 mL, V / V = 10 / 1), and compound (2-hydroxy-6-methyl-4-chloro-phenyl)boric acid (20 mg, 0.11 mmol), sodium carbonate (33 mg, 0.32 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8 mg, 0.011 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μmC18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 17%-100%, flow rate: 20 mL / min) to give the title compound 012 (7.0 mg, yield: 4.5%).

[0215] MS m / z(ESI):387.8(M+1).

[0216] 1 H NMR(400MHz,CD3OD)δ8.85(d,1H),8.54(s,1H),7.14(d,1H),6.84(d,2H),4.08(s,1H),3.71–3.50(m,,1H),3.42–3.28(m,3H ),3.21–3.03(m,2H),3.00–2.81(m,1H),2.20(s,3H),2.18–2.01(m,2H),2.01–1.83(m,1H),1.87–1.62(m,1H),1.33(t,3H).

[0217] Example 6

[0218] (R)-2-(2-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol (013)

[0219]

[0220] Step 1: 2-Bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyrimidine (013a)

[0221] Compound 001d (600 mg, 0.11 mmol) was dissolved in phosphorus oxychloride (3 mL), and the reaction was stirred at 100°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without purification to obtain the title compound 013a (400 mg).

[0222] MS m / z(ESI):232.9(M+1).

[0223] Step 2: 2-(2-Bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol (013b)

[0224] Compound 013a (400 mg, 1.71 mmol) was dissolved in a mixed solvent of dioxane / water (11 mL, V / V=10:1), and compound (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid (414.5 mg, 1.88 mmol), sodium carbonate (544.8 mg, 5.14 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (124.33 mg, 0.17 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography purification system B to obtain the title compound 013b (400 mg, yield: 62.5%).

[0225] MS m / z(ESI):373.1(M+1).

[0226] Step 3: tert-Butyl (R)-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3-yl)carbamate (013d)

[0227] Compound 013c (500 mg, 2.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (517 mg, 3.7 mmol) and compound tert-butyl (2-iodoethoxy) dimethylsilane (858 mg, 3.0 mmol) were added. The mixture was reacted at room temperature for 12 hours, and the reaction mixture was filtered. The filter cake was rinsed twice with ethyl acetate, and the filtrate was collected and dried to obtain a crude product. The crude product was purified by silica gel column separation system A to obtain the title compound 013d (360 mg, yield: 40%).

[0228] MS m / z(ESI):359.6(M+1).

[0229] Step 4 (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol (013e)

[0230] Compound 013d (100 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL), and 4 M dioxane hydrochloride solution (3 mL) was added. The reaction was allowed to react at room temperature for 4 hours. After the reaction was completed, the reaction solution was dried to give the title compound 013e (40 mg, yield: 100%).

[0231] MS m / z(ESI):145(M+1).

[0232] Step 5: (R)-2-(2-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol (013)

[0233] Compound 013e (40 mg, 0.1 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (20 mg, 0.028 mmol) and compound 013b (20 mg, 0.14 mmol) were dissolved in 1,4-dioxane (5 mL), and cesium carbonate (918.8 mg, 2.82 mmol) was added. The reaction was carried out at 80° C. under nitrogen protection for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated, and the crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column Xbridge 5μm C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 20 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20mL / min) to obtain the title compound 013 (1.6 mg, white solid). Yield: 3%.

[0234] MS m / z(ESI):437.4(M+1).

[0235] 1 H NMR(400MHz,CD3OD)δ8.87(d,1H),7.14(d,1H),7.11(s,1H),7.04(s,1H),4.29–3 .38(m,7H),3.14–2.89(m,2H),2.24(s,3H),2.12–2.05(m,2H),1.89–1.58(m,2H).

[0236] Example 7

[0237] (R)-2-(2-((1-ethylpyrrol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 017

[0238]

[0239] Step 1: (R)-5-((4-methoxybenzyl)oxy)-N-(1-ethylpyrrol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine

[0240] Compound 001d (200 mg, 0.60 mmol) was dissolved in 1,4-dioxane (3 mL), and compound (R)-1-ethylpyrrole-3-amine (82.1 mg, 0.72 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (50.1 mg, 0.06 mmol) and cesium carbonate (978 mg, 3.00 mmol) were added. The reaction was stirred at 85°C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography separation system A to obtain the title compound 017a (50 mg, yield: 22.8%).

[0241] MS m / z(ESI):369.1(M+1).

[0242] Step 2 (R)-5-chloro-N-(1-ethylpyrrol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 017b

[0243] Compound 017a (50 mg, 0.136 mmol) was dissolved in phosphorus oxychloride (3 mL) and the mixture was stirred at 110°C for 30 minutes. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product 017b (36 mg), which was directly used in the next step without purification.

[0244] MS m / z(ESI):267.1(M+1).

[0245] Step 3 (R)-3-methyl-2-(2-((1-ethylpyrrol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol 017

[0246] Compound 017b (36 mg, 0.136 mmol) was dissolved in a mixed solvent of dioxane and water (5.5 mL, V / V = 10:1), and compound (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid (30 mg, 0.091 mmol), sodium carbonate (60 mg, 0.57 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8.39 mg, 0.016 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 17%-100%, flow rate: 20 mL / min) to give the title compound 017 (9.7 mg, yield: 17.7%).

[0247] MS m / z(ESI):407.1(M+1).

[0248] 1 H NMR(400MHz,CD3OD)δ8.89(d,1H),8.53(s,1H),7.15(d,1H),7.11(s,1H),7 .04(s,1H),4.53–4.45(m,1H),3.51–3.35(m,2H),3.18–3.13(m,2H),3.11–

[0249] 3.00(m,2H),2.51(dd,1H),2.24(s,3H),2.12(dd,1H),1.34-1.31(m,1H),1.30(t,3H).

[0250] Example 8

[0251] (R)-2-(2-((3-(difluoromethylene)cyclohexyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 031

[0252]

[0253] The synthetic route of Example 7 was adopted, and the first step raw material (R)-1-ethylpyrrole-3-amine was replaced by (R)-3-(difluoromethylene)cyclohexane-1-amine. The final product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatographic column: Gemini 5μm C18 100x 21.2mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minutes gradient, gradient ratio: acetonitrile phase 60%-100%, flow rate: 25mL / min) to obtain the title compound 031 (4.1mg, yield: 6.2%). MS m / z (ESI): 440.2 (M+1).

[0254] 1 H NMR(400MHz,CD3OD)δ8.83(d,1H),7.10–7.08(m,2H),7.03(s,1H),4.58(s,1H),3.75–3.70(m,1H),2.79 –2.75(m,1H),2.37–2.34(m,1H),2.25(s,3H),2.10-2.08(m,1H),1.99-1.87(m,2H),1.54-1.46(m,2H).

[0255] Example 9

[0256] 3-Methyl-2-(2-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol

[0257] 3-Methyl-2-(2-((3aR,7aS)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol

[0258]

[0259] The synthetic route of Example 7 was adopted, and the first step raw material (R)-1-ethylpyrrol-3-amine was replaced with 6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine. The final product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minutes gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20mL / min) to obtain the title compound 033c (45mg, yield: 43%). Compound 033c was subjected to chiral separation (mobile phase: CO2 / MeOH[0.2%NH3(7M Solution in MeOH)]=70 / 30, and compounds 033(t R =1.151min)(10mg), 034(t R =1.394min)(13mg).

[0260] Compound 033:

[0261] MS m / z(ESI):433.2(M+1).

[0262] 1 H NMR(400MHz,CD3OD)δ8.83(dd,1H),7.10(dd,1H),7.08(s,1H),7.03(s,1H),4.16(dd,1H),3.76–3.66(m,1H),3.63–3.57(m,1H),3.0 7(dd,1H),2.57–2.50(m,1H),2.48–2.40(m,2H),2.33–2.35(m,1H),2.29(s,3H),2.25(s,3H),2.13–1.95(m,3H),1.84–1.74(m,1H).

[0263] Compound 034:

[0264] MS m / z(ESI):433.1(M+1).

[0265] 1H NMR(400MHz,CD3OD)δ8.88(d,1H),7.14(d,1H),7.10(s,1H),7.04(s,1H),4.20(dd,1H),3.80–3.61(m,2H),3.21–3.13(m,1H ),2.89–2.80(m,2H),2.58(s,3H),2.58–2.50(m,1H),2.25(s,3H),2.15–2.00(m,3H),2.11–1.86(m,1H),1.33–1.28(m,1H).

[0266] Example 10

[0267] 5-Chloro-3-methyl-2-(2-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol

[0268] 5-Chloro-3-methyl-2-(2-((3aR,7aS)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol

[0269]

[0270] The synthetic route of Example 7 was adopted, and the first step raw material (R)-1-ethylpyrrol-3-amine was replaced by 6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine, and the third step raw material (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid was replaced by (2-hydroxy-6-methyl-4-chloro-phenyl)boric acid. The final product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatographic column: Gemini 5μm C18 100x 21.2mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minutes gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25mL / min) to obtain the title compound 035a (23.37mg, yield: 35%). 。 Compound 035a was subjected to chiral separation (mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 70 / 30) to give Compound 035 (t R =1.215min), (7.18mg), compound 036 (t R =1.890min), (5.47mg).

[0271] Compound 035

[0272] MS m / z(ESI):399.1(M+1).

[0273] 1 H NMR (400MHz, CD3OD) δ8.79(d,1H),7.08(d,1H),6.82(d,1H),6.79(d,1H),4.17–4.12(m,1H),3.73–3.65(m,1H),3.63–3.55( m,1H),3.06(dd,1H),2.54–2.51(m,1H),2.45–2.41(m,2H),2.28(s,3H),2.19(s,3H),2.14–1.92(m,4H),1.84–1.73(m,1H).

[0274] Compound 036

[0275] MS m / z(ESI):399.1(M+1).

[0276] 1 H NMR (400MHz, CD3OD) δ8.80(d,1H),7.09(d,1H),6.83(d,1H),6.79(d,1H),4.18–4.13(m,1H),3.74–3.66(m,1H),3.65–3.56( m,1H),3.09(dd,1H),2.60–2.55(m,1H),2.45–2.37(m,2H),2.32(s,3H),2.19(s,3H),2.12–1.92(m,,4H),1.85–1.76(m,1H).

[0277] Embodiment 11

[0278] (R)-2-(2-((1-isopropylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 045

[0279]

[0280] The synthetic route of Example 4 was adopted, and the first step raw material (R)-1-ethylpiperidin-3-amine was replaced with (R)-1-isopropylpiperidin-3-amine. The final product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatographic column: Gemini 5μm C18 100x 21.2mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 23%-100%, flow rate: 25 mL / min) to give the title compound 045 (8.5 mg, yield: 25.7%).

[0281] MS m / z(ESI):435.2(M+1).

[0282] 1 H NMR(400MHz,CD3OD)δ8.87(d,1H),7.14(d,1H),7.10(s,1H),7.04(s,1H),4.59(s,1H),4.09(dd,1H),3. 45(dd,2H),3.06–2.79(m,2H),2.24(s,3H),2.14(s,2H),1.89(dd,1H),1.66(dd,2H),1.36–1.31(m,6H).

[0283] Example 12

[0284] (R)-3-methyl-2-(2-((1-propylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol 046

[0285]

[0286] The synthetic route of Example 4 was adopted, the first step raw material (R)-1-ethylpiperidin-3-amine was replaced with (R)-1-n-propylpiperidin-3-amine, and the final product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20mL / min) to obtain the title compound 046 (5 mg, yield: 11%).

[0287] MS m / z(ESI):435.1(M+1)

[0288] 1H NMR(400MHz,CD3OD)δ8.88(d,1H),8.56(s,1H),7.15–7.12(m,2H),7.06(s,1H),4.04(t,1H),3.49(d,1H),3.21(d,1H),2.85–2 .80(m,2H),2.71(s,2H),2.27(s,3H),2.15-2.12(m,1H),2.05-2.00(m,1H),1.89-1.81(m,1H),1.72–1.63(m,3H),0.99(t,3H).

[0289] Example 13

[0290] 5-Chloro-2-(2-(((3R,5S)-1-ethyl-5-fluoropiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methylphenol 047

[0291]

[0292] The synthetic route of Example 4 was adopted, the first step raw material (R)-1-ethylpiperidin-3-amine was replaced with (3R, 5S)-1-ethyl-5-fluoropiperidin-3-amine, the third step raw material (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid was replaced with (2-hydroxy-6-methyl-4-chloro-phenyl)boric acid, and the final product was prepared by high performance liquid chromatography (Waters MS-triggeredPrep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 25%-100%, flow rate: 20mL / min) to give the title compound 047 (15 mg, yield: 14.0%).

[0293] MS m / z(ESI):405.8(M+1).

[0294] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),9.15–8.94(m,1H),7.07(d,1H),6.88(s,1H),6.85(s,1H),4.22–3.97(m,1H),3. 93–3.71(m,2H),3.23(s,3H),3.17–2.91(m,1H),2.92–2.70(m,1H),2.09(s,3H),1.92–1.71(m,1H),1.38–1.15(m,5H).

[0295] Embodiment 14

[0296] (R)-2-(2-((1-ethylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 048

[0297]

[0298] Step 1 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 048a

[0299] Compound 013a (300 mg, 1.29 mmol) was dissolved in a mixed solvent of dioxane and water (11 mL, V / V = 10:1), and compound (2-hydroxy-4,6-dimethylphenyl)boric acid (256 mg, 1.54 mmol), sodium carbonate (408.6 mg, 3.86 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8.16 mg, 0.13 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography separation system B to obtain the title compound 048a (300 mg, yield: 73.1%).

[0300] MS m / z(ESI):319.0(M+1).

[0301] Step 2 (R)-2-(2-((1-ethylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 048

[0302] Compound 048a (300 mg, 0.94 mmol) was dissolved in 1,4-dioxane (10 mL), and compound (R)-1-ethylpiperidin-3-amine (132.6 mg, 1.03 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (78.96 mg, 0.094 mmol) and cesium carbonate (918.8 mg, 2.82 mmol) were added. The reaction was stirred at 80°C under nitrogen protection for 12 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μmC18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 17%-100%, flow rate: 20mL / min) to give the title compound 048 (22 mg, yield: 6.4%).

[0303] MS m / z(ESI):367.1(M+1).

[0304] 1 H NMR (400MHz, CD3OD) δ8.77(d,1H),8.51(s,1H),7.12(d,1H),6.63(s,1H),6.60(s,1H),4.04(s,1H),3.59-3.57(m,1H),3.08 (d,2H),2.89-2.86(m,2H),2.27(s,3H),2.17(s,3H),2.12-2.01(m,2H),1.94-1.86(m,1H),1.69-1.68(m,1H),1.30(t,3H).

[0305] Embodiment 15

[0306] (R)-2-(2-((1-(2,2-difluoroethyl)piperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 049

[0307]

[0308] The synthetic route of Example 4 was adopted, and the first step raw material (R)-1-ethylpiperidin-3-amine was replaced with (R)-1-(2,2-difluoroethyl)piperidin-3-amine. The final product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatographic column: Xbridge 5μm C18 150x 30mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 12 min gradient, gradient ratio: acetonitrile phase 23%-100%, flow rate: 25 mL / min) to obtain the title compound 049 (15 mg, yield: 6%).

[0309] MS m / z(ESI):457.1(M+1).

[0310] 1 H NMR(400MHz,CD3OD)δ8.83(d,1H),7.09(d,2H),7.03(s,1H),5.99(tt,1H),3.95–3.82(m,1H),3.12(d,1H),2.81-2.7 5(m,3H),2.43–2.30(m,2H),2.24(s,3H),2.00–1.92(m,1H),1.83–1.75(m,1H),1.72–1.61(m,1H),1.52–1.42(m,1H).

[0311] Example 16

[0312] (R)-2-(2-((1-ethylpiperidin-3-yl)amino)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 050

[0313]

[0314] Step 1: 2-Bromo-5-chloro-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidine 050a

[0315] Compound 003b (220 mg, 0.97 mmol) was dissolved in phosphorus oxychloride (10 mL) and reacted at 110° C. for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and dried to obtain a crude compound 050a (220 mg).

[0316] MS m / z(ESI):246.9(M+1).

[0317] Step 2 2-(2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 050b

[0318] Compound 050a (220 mg, 0.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (61 mg, 0.089 mmol) and (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid (195 mg, 0.89 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (12 mL, V / V=5:1). Sodium carbonate (280 mg, 2.67 mmol) was added to the reaction solution and then heated to 90°C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was filtered and concentrated, and purified by rapid silica gel column purification system A to obtain the title compound 050b (110 mg, yield: 32%).

[0319] MS m / z(ESI):387.7(M+1).

[0320] Step 3 (R)-2-(2-((1-ethylpiperidin-3-yl)amino)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 050

[0321] Compound 050b (110 mg, 0.28 mmol) was dissolved in 1,4-dioxane (10 mL), and cesium carbonate (182 mg, 0.56 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (24 mg, 0.028 mol), and compound (R)-1-ethylpiperidin-3-amine (109 mg, 0.84 mmol) were added to the system, and the reaction was carried out at 85° C. for 16 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product, and the crude product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 20 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20 mL / min) to obtain the title compound 050 (35 mg, yield: 5%).

[0322] MS m / z (ESI): 435.7 (M+1).

[0323] 1H NMR (400MHz, CD3OD) δ8.40(s,1H),6.99(s,1H),6.93-6.92(m,2H),4.03-3.94(m,1H),3.50(s,1H),3.29-3.25( m,2H),2.97(q,2H),2.76(s,1H),2.66(s,3H),2.13(s,3H),2.07-1.91(m,2H),1.81-1.56(m,2H),1.21(t,3H).

[0324] Embodiment 17

[0325] (3S,5R)-1-ethyl-5-((5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)piperidin-3-ol 051

[0326]

[0327] The first step is (3S,5R)-3-hydroxy-5-((5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 051a

[0328] Compound 013b (200 mg, 0.54 mmol) and cesium carbonate (371 mg, 2.68 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (45 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then compound (3R, 5S)-3-amino-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.64 mmol) was added. The reaction was stirred at 85°C for 12 hours under a nitrogen atmosphere and then transferred to room temperature. After the reaction was completed, the crude product was concentrated. The crude product was purified by silica gel column system A to obtain the title compound 051a (150 mg, yield: 49.5%). MS m / z (ESI): 509.2 (M+1).

[0329] Step 2 (3S,5R)-5-((5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)piperidin-3-ol 051b

[0330] Compound 051a (150 mg, 0.29 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (5 mL), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product 051b (150 mg), which was directly used for the next step without purification.

[0331] MS m / z(ESI):409.2(M+1).

[0332] Step 3 (3S,5R)-1-ethyl-5-((5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)piperidin-3-ol 051

[0333] Compound 051b (120 mg, 0.29 mmol) and acetaldehyde (25 mg, 0.59 mmol) were dissolved in 1.2-dichloroethane (5 mL), stirred at 0°C, and then sodium acetate borohydride (94 mg, 0.44 mmol) was added. The reaction was stirred at room temperature for 12 hours. After the reaction was completed, the crude product was concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 12 minutes gradient, gradient ratio: acetonitrile phase 17%-100%, flow rate: 20 mL / min) to obtain the title compound 051 (15 mg, yield: 12%).

[0334] MS m / z(ESI):437.1(M+1).

[0335] 1 H NMR(400MHz,CD3OD)δ8.86(d,1H),8.49(s,1H),7.13(d,1H),7.10(s,1H),7.04(s,1H),4.44(t,1H),4.27(s,1H),3.53(s,1H),3.2 2-3.12(m,1H),3.08-3.04(m,2H),2.98(d,1H),2.81-2.76(m,1H),2.24(s,3H),2.21-2.15(m,1H),1.91-1.85(m,1H),1.30(t,3H).

[0336] Embodiment 18

[0337] (R)-3,5-dichloro-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 052

[0338]

[0339] Step 1 (R)-3,5-dichloro-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 052

[0340] Compound 001f (80 mg, 0.30 mmol) was dissolved in a mixed solvent of dioxane and water (3.3 mL, V / V = 10:1), and compound (2,4-dichloro-6-hydroxyphenyl)boric acid (66 mg, 0.32 mmol), sodium carbonate (64 mg, 0.60 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (15.4 mg, 0.03 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μmC18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 18%-100%, flow rate: 20 mL / min) to give the title compound 052 (6.17 mg, yield: 5.2%).

[0341] MS m / z(ESI):394.1(M+1).

[0342] 1 H NMR (400MHz, CD3OD) δ8.87(d,1H),8.51(s,1H),7.12(d,1H),7.07(d,1H),6.93(d,1H),4.05–3.94(m,1H),3.46–3.37( m,1H),3.16–3.04(m,1H),2.67(s,1H),2.65(s,3H),2.09(dd,1H),2.05–1.93(m,2H),1.81(dd,1H),1.68–1.52(m,1H).

[0343] Embodiment 19

[0344] 2-(2-(((3S,4R)-1-ethyl-4-fluoropiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol 053

[0345]

[0346] The synthetic route of Example 4 was adopted, and the first step raw material (R)-1-ethylpiperidin-3-amine was replaced with (3S, 4R)-1-ethyl-4-fluoropiperidin-3-amine. The final product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20 mL / min) to obtain the title compound 053 (9.3 mg, yield: 21.1%).

[0347] MS m / z(ESI):439.1(M+1).

[0348] 1 H NMR(400MHz,CD3OD)δ8.87(d,1H),7.13(d,1H),7.10(s,1H),7.03(s,1H),4.27-4.17(m,1H),3 .13–3.07(m,2H),2.86(q,2H),2.73-2.67(m,2H),2.24(s,3H),2.21-1.98(m,3H),1.25(t,3H).

[0349] Embodiment 20

[0350] (R)-3,5-dimethyl-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 054

[0351]

[0352] Step 1 (R)-3,5-dimethyl-2-(2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 054

[0353] Compound 001f (180 mg, 0.67 mmol) was dissolved in a mixed solvent of dioxane and water (11 mL, V / V = 10 / 1), and compound (2-hydroxy-4,6-dimethylphenyl)boronic acid (112 mg, 0.67 mmol), sodium carbonate (250 mg, 2.3 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (49 mg, 0.067 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μmC18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 13%-100%, flow rate: 20mL / min) to give the title compound 054 (18.2 mg, 7.7%).

[0354] MS m / z(ESI):353.2(M+1).

[0355] 1 H NMR(400MHz,CD3OD)δ8.79(d,1H),8.48(s,1H),7.14(d,1H),6.65(s,1H),6.61(s,1H),4.05-4.00(m,1H),3.61-3.48(m,1H) ,3.23(s,1H),2.90(s,2H),2.78(s,3H),2.27(s,3H),2.18(s,3H),2.09-1.96(m,2H),1.88-1.85(m,1H),1.72-1.66(m,1H).

[0356] Embodiment 21

[0357] 3,5-Dimethyl-2-(2-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol

[0358] 3,5-Dimethyl-2-(2-((3aR,7aS)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol

[0359]

[0360] first step

[0361] 3,5-Dimethyl-2-(2-(6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 055a

[0362] Compound 033b (50 mg, 0.17 mmol) was dissolved in a mixed solvent of dioxane and water (5.5 mL, V / V = 10:1), and compound (2-hydroxy-4,6-dimethylphenyl)boric acid (34 mg, 0.20 mmol), sodium carbonate (90 mg, 0.85 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (12 mg, 0.017 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μmC18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 18%-100%, flow rate: 20 mL / min) to give the title compound 055a (21 mg, yield: 33%).

[0363] Step 2

[0364] Compound 055a was chiral separated (mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 75 / 25) to give the title compound 055 (t R =1.540min), (7.17mg), title compound 056 (t R =2.174min), (5.99mg).

[0365] Compound 055:

[0366] MS m / z(ESI):379.2(M+1).

[0367] 1H NMR(400MHz,CD3OD)δ8.75(d,1H),7.09(d,1H),6.66(s,1H),6.62(s,1H),4.14(dd,1H),3.71–3.64(m,1H),3.61–3.54(m,1H),3 .06(dd,1H),2.56–2.49(m,1H),2.47–2.39(m,2H),2.28(s,3H),2.26(s,3H),2.19(s,3H),2.15-1.93(m,4H),1.82–1.74(m,1H).

[0368] Compound 056:

[0369] MS m / z(ESI):379.2(M+1).

[0370] 1 H NMR(400MHz,CD3OD)δ8.77(d,1H),7.11(d,1H),6.64(s,1H),6.60(s,1H),4.16(dd,1H),3.73–3.67(m 1H),3.66–3.58(m,1H),3.15(dd,1H),2.70–2.60(m,1H),2.57–2.43(m,2H), 2.39(s,3H),2.27(s,3H),2.20(s,3H),2.14–1.93(m,4H),1.87–1.77(m,1H).

[0371] Embodiment 22

[0372] 2-(2-((((3S,4R)-1-ethyl-4-fluoropiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 057

[0373]

[0374] Step 1 2-(2-((((3S,4R)-1-ethyl-4-fluoropiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 057

[0375] Compound 048a (132 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound (3S,4R)-1-ethyl-4-fluoropiperidin-3-amine (60 mg, 0.41 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (40 mg, 0.041 mmol) and cesium carbonate (700 mg, 1.20 mmol) were added. The reaction was stirred at 80°C under nitrogen protection for 16 hours. After the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25%-100%, flow rate: 20mL / min) to obtain the title compound 057 (11.6 mg, yield: 7.4%).

[0376] MS m / z(ESI):385.2(M+1).

[0377] 1 H NMR(400MHz,CD3OD)δ8.78(d,1H),7.13(d,1H),6.64(s,1H),6.03(s,1H),4.25-4.16(m,1H),3.07 (d,1H),2.86(q,2H),2.72-2.65(m,2H),2.27(s,3H),2.18(s,3H),2.21-1.95(m,4H),1.24(t,3H).

[0378] Embodiment 23

[0379] (R)-1-(3-((5-(2-hydroxy-4,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)piperidin-1-yl)ethan-1-one 058

[0380]

[0381] The first step (R)-1-(3-((5-(2-hydroxy-4,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)piperidin-1-yl)ethan-1-one 058

[0382] Compound (R)-1-(3-aminopiperidin-1-yl)ethane-1-one (26.7 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL), and compound 048a (50 mg, 0.16 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (13.2 mg, 0.016 mmol) and cesium carbonate (255.3 mg, 0.78 mmol) were added. The reaction was stirred at 85°C under nitrogen protection for 12 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Pre LC with QDA detector, chromatographic column: Gemini 5μm C18 100x 21.2mm; mobile phase 1: water (containing 0.05% ammonia water); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30mL / min) to give the title compound 058 (9.31 mg, yield: 15.12%).

[0383] MS m / z(ESI):381.3(M+1).

[0384] 1 H NMR(400MHz,CD3OD)δ8.79(d,1H),7.11(d,1H),6.62(s,1H),6.59(s,1H),4.06–3.97(m,2H),3.79 -3.69(m,2H),3.18-3.08(m,2H),2.27(s,3H),2.18(s,3H),2.13-2.09(m,4H),1.77–1.52(m,2H).

[0385] Embodiment 24

[0386] (R)-2-(2-((1-ethylpiperidin-3-yl)amino)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 059

[0387]

[0388] Referring to the synthesis method of Example 16, according to the above synthesis route, the crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column Xbridge 5μmC18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 20 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20mL / min) to obtain the title compound 059 (3.0 mg).

[0389] MS m / z(ESI):381(M+1).

[0390] 1 H NMR(400MHz,CD3OD)δ7.01(s,1H),6.62(d,2H),3.09(d,2H),2.87(s,1H),2.73(s,3H),2.54(q, 2H),2.40-2.30(m,2H),2.27(s,3H),2.16(s,3H),1.86(s,2H),1.66-1.57(m,2H),1.11(d,3H).

[0391] Embodiment 25

[0392] (R)-4-(2-((1-ethylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-hydroxy-5-methylbenzonitrile 061

[0393]

[0394] The synthetic route of Example 4 was adopted, (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid was replaced by (2-hydroxy-6-methyl-4-cyano-phenyl)boronic acid, and the crude product was purified by high performance liquid chromatography (Waters MS-triggeredPrep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 15%-100%, flow rate: 20mL / min) to obtain the title compound 061 (8.13 mg). MS m / z (ESI): 378.1 (M+1).

[0395] 1H NMR(400MHz,CD3OD)δ8.87(d,1H),8.51(s,1H),7.18(s,1H),7.12(d,1H),7.08(s,1H),4.06(t,1H),3.59(d,1H) ,3.35(s,1H),3.09(q,2H),2.88(s,2H),2.21(s,3H),2.18–2.03(m,2H),1.88(dt,1H),1.70(d,1H),1.31(t,3H).

[0396] Embodiment 26

[0397] (R)-2-(2-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 066

[0398]

[0399] Step 1 (R)-2-(2-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 066

[0400] Compound (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol 013e (20 mg, 0.14 mmol) was dissolved in 1,4-dioxane (5 mL), cesium carbonate (136 mg, 0.42 mmol) was added, and after stirring at room temperature for half an hour, compound 048a (44 mg, 0.14 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (12 mg, 0.014 mmol) were added. The reaction was stirred at 80° C. under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2detector, chromatographic column: Gemini 5μm C18 150x19mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain the title compound 066 (5.62 mg, yield: 10.0%).

[0401] MS m / z(ESI):383.4(M+1).

[0402] 1H NMR(400MHz, CDCl3)δ8.59(d,1H),8.35(s,1H),7.08(d,1H),6.75(s,1H),6.68(s,1H),4.29(s,1H),4.09–3.78 (m,2H),3.15–2.88(m,3H),2.45(s,3H),2.31(s,3H),2.15–1.71(m,4H),1.49–1.11(m,3H),1.10–0.75(m,1H).

[0403] Embodiment 27

[0404] 2-(2-(((3S,4R)-4-fluoro-1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3,5-dimethylphenol 070

[0405]

[0406] Referring to the synthesis method of Example 22, (3S, 4R)-1-ethyl-4-fluoropiperidin-3-amine was replaced with (3S, 4R)-1-methyl-4-fluoropiperidin-3-amine, and the final product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LCwith SQD2 detector, chromatographic column: Xbridge 5μm C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 15%-100%, flow rate: 20 mL / min) to obtain the title compound 070 (4.6 mg, white solid).

[0407] MS m / z(ESI):371.1(M+1).

[0408] 1 H NMR(400MHz,CD3OD)δ8.77(d,1H),7.10(d,1H),6.64(s,1H),6.60(s,1H),4.16-4.07(m,1H),3.13–2.97 (m,2H),2.43-2.41(m,1H),2.41-2.38(m,1H),2.38(s,3H),2.27(s,3H),2.19(s,3H),2.12–1.89(m,3H).

[0409] Embodiment 28

[0410] (R)-3,5-dimethyl-2-(7-methyl-2-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 060

[0411]

[0412] Referring to the synthesis method of Examples 16 and 24, the crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column Xbridge 5μm C18 150×19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 20-minute gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 20mL / min) to obtain the title compound 060 (8 mg, yield: 10%). MS m / z (ESI): 367.2 (M+1).

[0413] 1 H NMR(400MHz,CD3OD)δ6.98(s,1H),6.63(s,1H),6.60(s,1H),4.01(d,1H),3.32(s,1H),2.97(d,1H),2.72 (s,3H),2.50(s,3H),2.49-2.45(m,2H),2.27(s,3H),2.16(s,3H),2.08-1.90(m,2H),1.82-1.52(m,2H).

[0414] Embodiment 29

[0415] (R)-3,5-dimethyl-2-(2-((1-methylpiperidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 071

[0416]

[0417] The first step 5-((4-methoxybenzyl)oxy)-2-(methylthio)-[1,2,4]triazolo[1,5-a]pyrimidine 071b

[0418] Compound 2-(methylthio)-[1,2,4]triazolo[1,5-a]pyrimidin-5-ol 071a (300 mg, 1.6 mmol) was dissolved in N,N-dimethylformamide (5 mL), and p-methoxybenzyl chloride (0.27 mL, 1.9 mmol) and cesium carbonate (1.56 g, 4.8 mmol) were added. The reaction was stirred at 50°C for 1 hour. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The title compound 071b (300 mg, 60%) was obtained by purification by rapid silica gel column chromatography system B.

[0419] MS m / z(ESI):303.1(M+1).

[0420] Step 2 5-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)-[1,2,4]triazolo[1,5-a]pyrimidine 071c

[0421] Dissolve compound 071b (300 mg, 0.99 mmol) in dichloromethane (5 mL), add m-chloroperbenzoic acid (856 mg, 4.95 mmol). Stir at room temperature for 12 hours. After the reaction is completed, the filtrate is concentrated under reduced pressure to obtain a crude product. Purify by rapid silica gel column chromatography system B to obtain the title compound 071c (300 mg, 90%).

[0422] MS m / z(ESI):335.1(M+1).

[0423] Step 3 (R)-5-((4-methoxybenzyl)oxy)-2-((1-methylpiperidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine 071d

[0424] Compound 071c (200 mg, 0.6 mmol) and compound 1-methyl-(R)-3-hydroxypiperidine (84 mg, 0.72 mmol) were dissolved in tetrahydrofuran (5 mL), and sodium hydrogen sulfide (36 mg, 0.9 mmol) was added under ice bath. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water under ice bath and concentrated under reduced pressure to obtain a crude product. The title compound 071d (50 mg, 23%) was obtained by purification by rapid silica gel column chromatography system B.

[0425] MS m / z(ESI):370.2(M+1).

[0426] Step 4 (R)-5-chloro-2-((1-methylpiperidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine 071e

[0427] Compound 071d (50 mg, 0.14 mmol) was dissolved in phosphorus oxychloride (2 mL) and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product 071e (50 mg). The crude product was used directly in the next step without purification.

[0428] MS m / z(ESI):268.1(M+1).

[0429] Step 5 (R)-3,5-dimethyl-2-(2-((1-methylpiperidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol 071

[0430] Compound 071e (50 mg, 0.19 mmol) was dissolved in a mixed solution of dioxane / water (2.2 mL, V / V = 10:1), and compound (2-hydroxy-4,6-dimethylphenyl)boric acid (37 mg, 0.22 mmol), sodium carbonate (201 mg, 1.9 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (14 mg, 0.019 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm C18 150×19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 15%-100%, flow rate: 20mL / min) to give the title compound 071 (2.6 mg, yield: 5.5%).

[0431] MS m / z(ESI):354.2(M+1).

[0432] 1 H NMR(400MHz,CD3OD)δ8.93(d,1H),7.30(d,1H),6.65(s,1H),6.62(s,1H),5.29–5.22(m,1H),3.06–2.98 (m,2H),2.98–2.87(m,1H),2.67(s,3H),2.28(s,3H),2.19(s,3H),2.14–1.94(m,4H),1.88–1.77(m,1H).

[0433] According to the similar method disclosed above, the following compounds were synthesized, and the structural characterization data of these compounds are shown in the following table:

[0434]

[0435]

[0436] Biological evaluation

[0437] Test Example 1 Experiment to reduce the level of IL-1β secretion by THP-1 cells to detect the inhibitory effect of NLRP3 inhibitors

[0438] The chemical names and structural formulas of the compounds of the present invention used in the experiments are given in the preparation examples of the compounds. 1.1. Experimental Principle:

[0439] This experiment uses the human monocytic cell line THP-1 to study the inhibitory activity of NLRP3 inhibitors on cellular IL-Iβ secretion. Human THP-1 cells were treated with crotonyl-12-tetradecanoate-13-acetate (PMA) to differentiate into mature macrophage models. Then, according to the two stages of inflammasome formation in cells (assembly and activation), the cells were stimulated with lipopolysaccharide LPS and nigericin in sequence, which ultimately promoted the release of IL-1β from THP-1 cells outside the cells. The first stage of inflammasome formation is to stimulate cells with LPS (lipopolysaccharide), an agonist of Toll-like receptor TLR4, to activate the protein expression of inflammasome-related proteins NLRP3, caspase 1, and IL-1β precursor pro-IL-1β. The second stage of inflammasome formation is the addition of potassium ion carrier nigericin, which changes a series of membrane potentials in THP-1 cells, destroys the cell membrane structure, causes the efflux of potassium ions, further stimulates the oligomerization of NLRP3 monomers to form NLRP3 oligomers, and begins to recruit ASC and pro-caspase-1 to assemble NLRP3 inflammasome complexes containing a large amount of pro-caspase-1. Pro-caspase-1 on the activated NLRP3 inflammasome is self-activated by its enzymatic hydrolysis to form a large amount of active caspase-1. The activated caspase-1 further enzymatically hydrolyzes and promotes the conversion of pro-IL-1β into mature IL-1β that can be secreted. In this process, NLRP3 inhibitors can effectively inhibit the maturation and activation of NLRP3 induced by nigericin, as well as the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1β.

[0440] 1.2 Experimental reagents and instruments

[0441]

[0442]

[0443] 1.3 Experimental procedures

[0444] (1) Collect the cell suspension. Centrifuge the cells at 1000 rpm for 4 minutes, discard the supernatant, resuspend the cells with 1 mL of test medium, and then gently pipette up and down the cell culture medium with a pipette tip to break up the cell clumps. After counting the cells, resuspend the THP-1 cells with complete RPMI medium 1640 containing PMA and inoculate them into a 96-well plate. Culture them in a 37°C, 5% CO2 incubator for 72 hours.

[0445] (2) Remove the culture medium from each well using an automatic plate washer EL406 and rinse each well twice with PBS. Add 96 μL of RPMI 1640 culture medium containing LPS to each well. Incubate the cells in a 37°C, 5% CO2 incubator for 4 hours.

[0446] (3) Add 2 μL of compound and 2 μL of nigericin sodium salt to each well. The final concentrations of compound screening are: 5000 nM, 1000 nM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0 nM.

[0447] The cells were incubated at 37°C in a 5% CO2 incubator for 1 hour.

[0448] (4) Take out an appropriate amount of supernatant, dilute it 100 times, and use Human IL-1beta Valukine ELISA kit to detect the IL-1β content in the supernatant.

[0449] 1.4 Experimental Results

[0450] IC detection of NLRP3 inhibitors using THP-1 cells 50 and IC 90 The test results of the experiment are shown in Table 1.

[0451] Table 1 Test results of the tested compounds

[0452] Test compound <![CDATA[IC 50 (nM)]]> <![CDATA[IC 90 (nM)]]> Compound 001 9 28 Compound 002 16 105 Compound 003 7 20 Compound 011 4 21 Compound 012 3.1 12.8 Compound 013 43 / Compound 017 61 / Compound 034 1.6 5.4 Compound 036 1.3 3.6 Compound 045 2.5 11 Compound 046 13 43 Compound 048 7 52 Compound 050 10 28 Compound 052 29 132 Compound 053 28 87 Compound 054 25 76 Compound 056 2.5 7.0 Compound 057 21 90 Compound 059 23 87 Compound 060 28 91 Compound 061 31 103 Compound 062 16 55 Compound 063 17 46 Compound 065 37 135 Compound 066 42 154 Compound 072 5 21 Compound 073 51 131 Compound 074 4 14

[0453] Conclusion: The compounds of the present invention have significant inhibitory activity on the maturation and secretion of IL-1β in THP-1 cells.

[0454] Test Example 2: Evaluation experiment of acute peritonitis model in mice

[0455] 2.1 Experimental procedures

[0456] Male C57BL / 6 mice were orally administered with a 3 mg / kg dose of the test compound or control vehicle, and then injected intraperitoneally with 1 μg of E. coli 055:B5 ultrapure lipopolysaccharide (LPS) suspension 1 hour later, followed by intraperitoneal injection of 0.5 ml of 30 mM disodium salt ATP suspension (in PBS, the pH of the ATP solution was adjusted to 7.2 before injection) 2 hours later. All animals were euthanized by carbon dioxide 30 minutes later, and blood and peritoneal lavage fluid were collected. The peritoneal lavage fluid was placed at 4°C.

[0457] Preparation of peritoneal lavage fluid: The peritoneal cavity will be lavaged with ice-cold PBS (3 mL) containing 25 U / mL heparin and 10% heat-inactivated FBS. Before use, a protease inhibitor cocktail is added to each 50 mL buffer. The collected lavage fluid will be centrifuged (centrifugation conditions: 1000 g, 4 ° C, 10 minutes) to remove cells and cell debris, and the clarified samples will be stored at -80 ° C for the measurement of cytokine IL-1β.

[0458] The mouse IL-1β / IL-1F2 DuoSet ELISA kit (R&D Systems) was used to measure the changes in IL-1β cytokine levels in peritoneal lavage fluid and serum, and the inhibition rate of the compound on IL-1β was calculated by comparing with the vehicular group.

[0459] 2.2 Experimental Results

[0460] The experimental results of the mouse acute peritonitis model evaluation are shown in Table 2.

[0461] Table 2: PD efficacy results of acute peritonitis in mice

[0462]

[0463] Conclusion: The compounds of the present invention showed an inhibitory effect on IL-1β in peritoneal lavage fluid and plasma in an in vivo animal model evaluation experiment.

[0464] Test Example 3: Evaluation of the brain-blood ratio of compounds in vivo

[0465] 3.1 Experimental purpose: To obtain the brain-to-blood ratio of the compound.

[0466] 3.2 Experimental plan: The brain-to-blood ratio of the compound was investigated by monitoring the content of the compound in the rat brain and plasma. 3.3 Experimental steps:

[0467] Weigh the compound, add a small amount of DMSO, and then add sodium chloride solution for injection to make a 1mg / mL compound solution for administration. Orally administer at a dose of 14mg / kg, and collect whole blood and whole brain (n=3) 2h after administration. Centrifuge the whole blood at 3500rpm for 15min, and collect the supernatant plasma. Weigh the weight of the centrifuge tube as W1, the weight of the centrifuge tube containing the whole brain as W2, the weight of the centrifuge tube after adding water homogenate as W3, and the weight of the centrifuge tube after taking out 30uL of homogenate as W4. Take 30uL of plasma and 30uL of brain homogenate in a centrifuge tube, add 120uL of 20ng / mL internal standard SAHA acetonitrile precipitation, vortex for 30s, centrifuge at 13000rpm for 15min, take the supernatant and put it in the injection bottle for testing.

[0468] Standard curve range: 10-10000ng / mL

[0469] Drug content in brain = measured value x 0.03 x (W3-W1) / [(W2-W1) x (W3-W4)].

[0470] 3.4 Experimental Results

[0471] The results of the brain-to-blood ratios of the compounds are shown in Table 3 below.

[0472] Table 3: Results of brain-to-blood ratio test in rats after compound administration

[0473] Test compound Brain (ng / g) Plasma (ng / mL) Brain-to-blood ratio Compound 054 818.4 1000.2 0.82

[0474] Conclusion: The compounds of the present invention have the potential to enter the brain, and the brain-to-blood ratio of compound 054 reached 0.82 at 2 hours.

[0475] Test Example 4: Parkinson's disease efficacy experiment in mice

[0476] 4.1 Experimental Purpose

[0477] The MPTP-induced PD (Parkinson's) model pharmacodynamics evaluation was conducted to detect the effects of the test compound on the motor ability of MPTP-induced PD model animals.

[0478] 4.2 Experimental Materials and Methods

[0479] 4.2.1 Experimental animals

[0480] The experimental animals were C57Bl / 6, male, 12-14 weeks old. Rats were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd. They arrived at the facility before the experiment and adapted to the animal facility for more than 5 days (subject to actual conditions). During the adaptation period, 4 rats were kept in a cage. The room temperature was 23-26℃. The light and dark cycle alternates day and night, with the lights on in the breeding room from 07:00 to 19:00 and off from 19:00 to 07:00 the next day.

[0481] Rat feed products comply with GB 14924.1 "General Quality Standard for Compound Feeds for Laboratory Animals", GB 13078 "Feed Hygiene Standard", GB 14924.2 "Compound Feed Hygiene Standard for Laboratory Animals" and GB 14924.3 "Nutritional Composition of Compound Feeds for Laboratory Animals". The main ingredients are: energy grains such as Northeast corn, wheat, and Spanish alfalfa; proteins such as Peruvian fish meal, American chicken meal, and soybean meal; fats such as soybean oil and sunflower oil; amino acids, vitamins, minerals, etc. (subject to actual conditions).

[0482] 4.2.2 Test drugs

[0483] Test compound: Compound 054

[0484] The modeling compound MPTP, the positive compounds L-dopa and Benserazide were purchased from Bidex Pharmaceuticals and Aladdin. The solvent for preparing MPTP, L-doapmine, and Benserazide was physiological sodium chloride solution. Prepared on the day of use. The solvent for preparing compound 054 was 0.5% CMC-Na, prepared on the day of use.

[0485] 4.2.3 Experimental groups and dosing regimen

[0486] The animals were randomly divided into groups according to their body weight. The grouping information and drug administration are shown in Table 4.

[0487] After the animals arrived at the facility, they were adapted for at least 1 week, and the animals were handled and trained for at least 1 week. Then, drug administration, modeling and testing began. The day of drug administration was defined as the first day (D1). After one week of pre-administration, MPTP was intraperitoneally injected at 30 mg / kg for 5 consecutive days, and behavioral evaluation was performed on D14.

[0488] Table 4. Animal grouping information and dosing regimen

[0489]

[0490] 4.2.4 Behavioral assessment

[0491] Behavioral assessments include pole climbing and balance beam tests.

[0492] (1) Pole climbing experiment:

[0493] The mouse was placed on the top of a vertical pole (1 cm in diameter, 60 cm in length). The timer was started from the time the mouse's tail was lowered, and the time required for the mouse to move from the top of the pole to the bottom was measured. The test was repeated 3 times, and the average of the 3 times was used for statistical analysis. The training was continued for at least 3 days before the test, twice a day.

[0494] (2) Balance beam experiment:

[0495] The test evaluates the motor balance and coordination ability of mice. The mice are asked to stand upright and cross a balance beam (1m long and 0.8cm in diameter) to reach a safe platform. The motor coordination ability of the mice is quantified by measuring the time required for the mice to cross the balance beam. The test is performed 3 times, and the average of the 3 times is used for statistical analysis. The training is continuous for at least 3 days before the test, twice a day.

[0496] 4.3 Experimental Results

[0497] The time required for MPTP-induced PD model animals to climb from the top to the bottom of the pole in the pole climbing experiment is shown in the attached figure. Figure 1 As shown in the attached figure, the time spent on the balance beam by MPTP-induced PD model animals was Figure 2 As shown, compound 054 can significantly improve the motor function of MPTP-induced PD model animals and has the potential to treat CNS diseases.

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound: in, It means that the ring in which it exists is aromatic; X1 is selected from CR1, N; X2 Selected from CR 21 , N, NR 22 ; X3 is selected from C and N; X4 is selected from C and N, and at least one of the atoms at the positions of X1, X2, X3, and X4 on the aromatic ring is N; R1, R 21 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl; each R 1a are the same or different and are independently selected from H, OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy; Or, R1, R 22 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 22a substituted 5-8 membered heterocyclic ring; each R 22a are the same or different and are independently selected from H, deuterium, OH, halogen, CN, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy; Ring A is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; each R a are the same or different and are independently selected from H, deuterium, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R aa Substituted with the following groups: amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group; or, two R connected to different carbon atoms a Together with the atoms to which they are attached, they are unsubstituted or optionally substituted with one, two or more R aa1 Substituted with the following groups: C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring; each R aa are the same or different and are independently selected from H, OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy; each R aa1 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy; Ring B is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 3-14 Carbocyclic ring, 3-14 membered heterocyclic ring; each R b are the same or different and are independently selected from H, deuterium, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -(CH2) m1 COR b1 、-(CH2) m2 CONH2, Each R bb are the same or different and are independently selected from H, deuterium, OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy; each R b1 are the same or different and are independently selected from H, deuterium, OH, C 1-12 Alkyl, C 1-12 Alkoxy; R6, R7 are the same or different and are independently selected from H, CN, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl; m1 and m2 are the same or different and are independently selected from 0, 1, 2, 3, 4, 5, 6 or 7; W is selected from CR5, N, O, S; when W is selected from O or S, R4 is absent; R5 is selected from H, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkoxy; R3 is selected from H, deuterium, OH, halogen, CN, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl; R4 is absent or selected from H, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkoxy; Or, R4, R 22 Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R 4a substituted 5-8 membered heterocycle; Alternatively, R4 is connected to an atom on ring B and together with W forms an unsubstituted or optionally substituted R 4a Substituted C 5-8 A carbocyclic ring or a 5- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring and Ring B together form a spirocyclic or condensed ring structure; Each R 4a are the same or different and are independently selected from H, deuterium, OH, halogen, CN, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy.

2. The compound according to claim 1, characterized in that X1 is selected from CR1, X2 is selected from CR 21 , N, NR 22 , X3 is selected from C, N, X4 is selected from C, N; R1, R 21 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl; or, R1, R 22 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic ring; Preferably, R1 is selected from H, C 1-6 Alkyl, halogen or CN; Preferably, R1 is selected from H, methyl, F, Cl, Br or CN; Preferably, R 21 Selected from H, C 1-6 Alkyl, halogen or CN; Preferably, R 21 is selected from H, F, Cl, Br or CN; Preferably, R1, R 22 Together with the atoms to which they are attached, they form a tetrahydropyridine ring (e.g. ); Preferably, Selected from Preferably, Selected from Preferably, W is selected from N; Preferably, R3 is selected from H, deuterium, OH, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; More preferably, R3 is selected from H, F, Cl, Br or CN; Preferably, R4 is absent or selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, halogenated C 1-6 Alkoxy or cyano C 1-6 Alkoxy; More preferably, R4 is absent or selected from H; Or, R4, R 22 , W and the atoms to which they are connected together form a 5-8 membered heterocyclic ring; preferably, R4, R 22 , W and their respective atoms form a tetrahydropyrimidine ring (e.g. ); Alternatively, R4 is connected to an atom on ring B and forms a C 5-8 An alkyl ring or a 5-8 membered heterocyclic ring, wherein the alkyl ring or heterocyclic ring and ring B together form a spiro ring or a condensed ring structure; preferably, R4 is connected to an atom on ring B and together with W forms a pyrrolidine ring, wherein the pyrrolidine ring and ring B together form a condensed ring structure; more preferably, Selected from 3. The compound according to claim 1 or 2, characterized in that Ring A is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring; each R a are the same or different and are independently selected from H, deuterium, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R aa Substituted with the following groups: amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group; or, two R connected to different carbon atoms a Together with the atoms to which they are attached, they are unsubstituted or optionally substituted with one, two or more R aa1 Substitute the following groups: C 5-6 Cycloalkenyl ring, 5-6 membered heterocyclic ring; each R aa are the same or different and are independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; each R aa1 are the same or different and are independently selected from H, deuterium, OH, halogen, CN, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano C 1-6 Alkyl, cyano C 1-6 Alkoxy; Preferably, Ring A is selected from unsubstituted or optionally substituted with one, two or more R a Substituted benzene ring; each R a are the same or different and are independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl, halogenated C 1-6 Alkoxy or cyano C 1-6 Alkoxy; or two R attached to different carbon atoms a Together with their respective atoms they form C 5-6 Cycloalkenyl ring; Preferably, each R a are the same or different and are independently selected from H, F, Cl, Br, OH, CN, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy; or two R attached to different carbon atoms a Together with the atoms to which they are attached they form a cyclopentene ring; More preferably, ring A is selected from 4. The compound according to any one of claims 1 to 3, wherein ring B is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 3-8 Carbocyclic ring, 3-8 membered heterocyclic ring; each R b are the same or different and are independently selected from H, deuterium, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, -(CH2) m1 COR b1 、-(CH2) m2 CONH2, Each R bb are the same or different and are independently selected from H, deuterium, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; each R b1 are the same or different and are independently selected from H, deuterium, OH, C 1-6 Alkyl, C 1-6 Alkoxy; R6, R7 are the same or different and are independently selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl; m1 and m2 are the same or different and are independently selected from 0, 1, 2, 3, 4; Preferably, Ring B is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 5-7 Cycloalkyl ring, 5-7 membered heterocyclic ring; each R b are the same or different and are independently selected from H, halogen, OH, CN, oxo (=O), C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-CONH2, -COC 1-6 Alkyl or R6, R7 are the same or different and are independently selected from H, CN, halogen; Preferably, R6 and R7 are the same or different and are independently selected from H, CN, F, Cl, or Br; Preferably, Ring B is selected from unsubstituted or optionally substituted with one, two or more R b The following groups substituted: cyclohexane ring, piperidine ring, pyrrolidine ring (i.e., tetrahydropyrrole ring); each R b are the same or different and are independently selected from H, F, Cl, Br, OH, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2-hydroxyethyl, oxo (=O), -CH(CH3)CONH2, -COCH3, 2,2-difluoroethyl, Preferably, Ring B is unsubstituted or optionally substituted with one, two or more R's: Each R' is the same or different and is independently selected from H, deuterium, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or amino; R8, R9 are the same or different and are independently selected from H, deuterium, unsubstituted or optionally substituted by one, two or more R 8a Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) s1 COR 81 、-(CH2) s2 CONH2; Each R 8a are the same or different and are independently selected from H, deuterium, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R 81 Selected from H, deuterium, OH, C 1-6 Alkyl, C 1-6 Alkoxy; s1, s2 are the same or different and are independently selected from 0, 1, 2, 3, 4, 5, 6 or 7; n1, n2, n3 are the same or different and are independently selected from 1, 2 or 3; Preferably, ring B is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R': in, R6, R7, R8, R9 have the definitions described herein; each R' is the same or different and is independently selected from H, deuterium, OH, CN, halogen, C 1-6 alkyl; Preferably, ring B is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R': wherein R6, R7, R8, and R9 have the definitions described herein; each R' is the same or different and is independently selected from H, deuterium, OH, CN, halogen, C 1-6 alkyl; Preferably, ring B is selected from Preferably, ring B is selected from 5. The compound according to any one of claims 1 to 4, characterized in that The compound represented by formula (I) is selected from the following structures: Ring A, Ring B, X1, X2, X3, X4, W, R1, R3, R4, R a It has the definition as described in any one of claims 1 to 4; q1, q2, q3 are the same or different and are independently selected from 1, 2, 3; p1 is selected from 0, 1, 2, 3, 4, 5; Preferably, the compound represented by formula (I) is selected from the following structures: Ring A, Ring B, R1, R3, R4, R8, R a , R b , W has the definition as described in any one of claims 1-4, p1 and p2 are the same or different and are independently selected from 0, 1, 2, 3, 4, and 5.

6. The compound according to any one of claims 1 to 5, characterized in that The compound has the following structure: Preferably, the compound represented by formula (I) is selected from the following structures:

7. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof; Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

8. A method for treating a NLRP3-mediated disease, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compounds of any one of claims 1 to 6, their racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, or the pharmaceutical composition of claim 7; Preferably, the NLRP3-mediated disease is selected from: autoinflammatory fever syndrome such as cold pyrin-associated periodic syndrome (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, type I and type II diabetes and related complications (preferably nephropathy, retinopathy), neuroinflammatory related diseases (preferably multiple sclerosis, brain infection, acute injury), CNS related diseases (preferably Alzheimer's disease, Parkinson's disease), atherosclerosis and cardiovascular risk (preferably hypertension), hidradenitis suppurativa, wound healing and scar formation and cancer (preferably colorectal cancer, lung cancer, myeloproliferative tumors, leukemia), myelofibrosis.

9. Use of at least one of the compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or the pharmaceutical composition according to claim 7 in the preparation of a drug; Preferably, the use may be for preparing a drug for treating NLRP3-mediated disorders and / or diseases, such as for preparing a NLRP3 inhibitor drug; Preferably, the disease is selected from autoinflammatory febrile syndromes, such as cold pyrin-associated periodic syndrome (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, type I and type II diabetes and related complications (e.g. nephropathy, retinopathy), neuroinflammatory related diseases, CNS related diseases, atherosclerosis and cardiovascular risks (e.g. hypertension), hidradenitis suppurativa, wound healing and scarring, cancer, myelofibrosis; Preferably, the neuroinflammation-related disease is selected from multiple sclerosis, brain infection or acute injury; Preferably, the CNS-related disease is selected from Alzheimer's disease or Parkinson's disease; Preferably, the atherosclerosis and cardiovascular risk diseases are selected from hypertension; Preferably, the cancer is selected from colorectal cancer, lung cancer, myeloproliferative neoplasms or leukemia.

Images