Compounds as LPAR1 antagonists, pharmaceutical compositions and uses thereof

Abstract

A compound as an LPAR1 antagonist, a pharmaceutical composition and uses thereof. The invention relates to a compound as shown in a formula (I), a racemate, a stereoisomer, a tautomer, a nitrogen oxide or pharmaceutically acceptable salts of the compound and the racemate, the stereoisomer, the tautomer and the nitrogen oxide. The compound of the LPAR1 antagonist has a good inhibition effect on LPAR1, and has excellent pharmacokinetic properties and good druggability.

Description

Compounds as LPAR1 antagonists, pharmaceutical compositions and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2023109416134 filed on July 28, 2023, Chinese Patent Application No. 2024101736196 filed on February 7, 2024, and Chinese Patent Application No. 2024105392328 filed on April 30, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to a compound serving as an LPAR1 antagonist, a pharmaceutical composition thereof and use thereof. Background Art

[0003] Lysophosphatidic acid (monoacylglycerol-3-phosphate, LPA) is a bioactive phospholipid produced from lysophosphatidylcholine (LPC). It exerts a wide range of cellular responses, such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis, through a family of seven-membrane-domain G protein-coupled receptors (GPCRs), collectively known as LPA receptors (LPARs). To date, the six LPA receptors (LPARs) identified are LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6. These six LPA receptors are often interchangeably referred to as LPAR1-6 or LPA1-6. Six LPA receptors have been characterized, each with distinct tissue distribution and downstream signaling pathways. LPA receptor-mediated signaling has been shown to influence numerous biological processes, including wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis. Aberrant upregulation of the LPA pathway has been implicated in a variety of diseases, including cancer, inflammatory disorders, infertility, neuropathic pain, psychiatric and neurodegenerative disorders, atherosclerosis, and fibrosis of the skin, kidney, lung, and liver. Therefore, the LPA receptor may be a drug target for a variety of diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease.

[0004] Lysophosphatidic acid receptor 1 (LPAR1) is a G protein-coupled receptor that mediates the growth factor-like activity of lysophosphatidic acid (LPA), playing an important role in the development of cancer, inflammation, fibrotic diseases, neurological diseases, urological diseases, and others. For example, silencing LPA1 with siRNA or using LPA1 antagonists can reduce tumor burden in bone and soft tissues; LPA promotes the migration of human monocytes, which is associated with the proliferation and infiltration of T cells; LPA receptor antagonists can protect individuals from infection-induced inflammation; and upregulation of LPAR1 activity is associated with the fibrosis observed in systemic scleroderma. Studies have shown that in unilateral ureteral ligation mice, an animal model of renal fibrosis, LPA production and LPA1 expression are hyperactive, and renal fibrosis can be inhibited by LPA1 deficiency or administration of LPA receptor antagonists. LPA concentrations are elevated in the alveolar lavage fluid of patients with idiopathic pulmonary fibrosis, and LPA1 is most abundant in fibroblasts, which play an important role in the process of pulmonary fibrosis, and LPA induces fibroblast migration. In scleroderma models, bleomycin is administered subcutaneously to mice, which inhibits skin fibrosis. LPA and LPA1 are also associated with the manifestation of neuropathic pain. LPAR1 can also be involved in urinary system diseases by causing contraction of urethral and prostate specimens and increasing intraurethral pressure.

[0005] LPAR1 antagonists have recently been clinically investigated for fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis, but there are no marketed small-molecule LPAR1 antagonists. Therefore, the development of small-molecule LPAR1 antagonists with desired selectivity, good biological activity, and strong metabolic stability is of great significance for the treatment of these diseases.

[0006] Summary of the Invention

[0007] The technical problem to be solved by the present invention is that there are few small molecule antagonists of LPAR1 in the prior art. Therefore, the present invention provides a compound as an LPAR1 antagonist, a pharmaceutical composition thereof, and uses thereof. The compound as an LPAR1 antagonist provided by the present invention has a good inhibitory effect on LPAR1, excellent pharmacokinetic properties, and good drugability.

[0008] The present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof:

[0009] Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl (the C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are independently optionally substituted by m R1 replace);

[0010] The definitions of Ring B and R1 are selected from one of the following cases (1), (2) and (3):

[0011] Case (1): Ring B is a 5-7 membered heteroarylene group;

[0012] Each R1 is independently OH, COOH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0013] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0014] Case (2): Ring B is an 8-10 membered heteroarylene group;

[0015] Each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1- 6-alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0016] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R areplace;

[0017] Case (3): Ring B is C 6-10 arylene;

[0018] Each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0019] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0020] Each R a Independently C 1-4 Alkyl, C 1-4 Alkoxy, halogen, OH, oxo (=O), CN or NH2; when R a When the number of is 2 or more, the OH and oxo (=O) are not attached to the same carbon atom;

[0021] L1 is C 2-6 Alkynylidene, -C 2-6 Alkynylidene-O- or -C 2-6 Alkynylidene-NH-; the C 2-6 Alkynylidene, -C 2-6 Alkynylidene-O- and -C 2-6 Alkynylidene-NH- is optionally substituted by 1, 2 or 3 R b replace;

[0022] Each R b are independently halogen, COOH or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 COOH groups or halogen;

[0023] Each R2 is independently halogen, NH2, OH, oxo (=O), CN, C 1-4 Alkyl, C 1-4Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogen or deuterium;

[0024] X1, X2, X3 and X4 are independently C, CH, CH2, O, S, N or NH; at the same time, at least one of X1, X2, X3 and X4 is independently O, S, N or NH;

[0025] A double line including a solid line and a dashed line represents a single bond or a double bond; at the same time, Contains at least one double bond;

[0026] Each R3 is independently H, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, NH2, OH, oxo (=O), CN, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogen or deuterium;

[0027] W is or -(CR 12 R 13 ) q -Y2-R 15 ; The carbon atom with * is a chiral carbon atom or an achiral carbon atom; when it is a chiral carbon atom, the configuration of the chiral carbon atom is R and / or S;

[0028] in,

[0029] R6 and R7 are independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Substitution; said C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace;

[0030] Each R c are independently deuterium, halogen, -OH, -CN, -COOH, C 1-6 Alkoxy, C 1-6Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace;

[0031] Each R c-1 are independently deuterium, halogen, -OH, -CN, -COOH, C 1-6 Alkoxy or C 1-6 alkyl;

[0032] R4, R5 and R8 are each independently H, deuterium, halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; the C 1-4 The alkyl group is optionally substituted by 1, 2 or more R j replace;

[0033] Each R j are independently deuterium or halogen;

[0034] Y1 is a chemical bond or C 1-6 Alkylene; the C 1-6 The alkylene group is optionally replaced by 1, 2 or more R d replace;

[0035] Each R d are independently deuterium, halogen or C 3-6 Cycloalkyl;

[0036] R9 and R 10 are independently H, deuterium or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace;

[0037] R 11 C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; the C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl are independently optionally substituted by 1, 2 or more R g replace;

[0038] Each R e、R f and R g are independently deuterium, halogen, -OH, -CN, -COOH, C 1-6 Alkoxy, C 1-6 Alkyl or C 3-6 Cycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more deuterium or halogen;

[0039] Y2 is a chemical bond, N(R 14 )、-C(=O)N(R 14 )- or O;

[0040] R 12 、R 13 and R 14 are independently H, deuterium, halogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or more halogens or deuterium;

[0041] R 15 C 1-6 alkyl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl; said C 1-6 Alkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R i replace;

[0042] Each R i are independently deuterium, halogen, oxo (=O), OH, COOH, NH2, CN, C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or more R i-1 replace;

[0043] Each R i-1 are independently deuterium, halogen, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0044] m is 0, 1, 2, 3, 4 or 5;

[0045] n and p are independently 0, 1, 2, 3 or 4;

[0046] q is 0, 1, 2, or 3;

[0047] The heteroatoms in the 3-10 membered heterocycloalkyl, 5-7 membered heteroarylene, 8-10 membered heteroarylene, 3-6 membered heterocyclyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl and 3-8 membered heterocycloalkyl are independently selected from one, two or three of N, O and S; and the number of heteroatoms is independently one, two or three.

[0048] In a preferred embodiment, in the compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salts thereof, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any embodiment of the present invention (this paragraph is hereinafter referred to as "in a preferred embodiment").

[0049] In a preferred embodiment,

[0050] Ring A is C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0051] In case (1): each R1 is independently OH, COOH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0052] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0053] In case (2): each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0054] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0055] In case (3): each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0056] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0057] R6 and R7 are independently C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Substitution; said C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace.

[0058] In a preferred embodiment, ring A is C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0059] In case (1): each R1 is independently OH, COOH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0060] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0061] In case (2): each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0062] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0063] In case (3): each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0064] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0065] Each R2 is independently halogen, NH2, OH, oxo (=O), CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogens;

[0066] Each R3 is independently H, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, NH2, OH, oxo (=O), CN, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogens;

[0067] R6 and R7 are independently C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Substitution; said C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace;

[0068] Each R c are independently halogen, -OH, -CN, -COOH, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace;

[0069] Each R c-1 are independently halogen, -OH, -CN, -COOH, C 1-6 Alkoxy or C 1-6 alkyl;

[0070] R9 and R 10 are independently H or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace;

[0071] Each R e 、R f and R g are independently halogen, -OH, -CN, -COOH, C 1-6 Alkoxy or C 1-6 Alkyl; the C 1-6 Alkyl and C 1-6 Alkoxy groups are independently optionally substituted with 1, 2 or more halogens;

[0072] Y2 is a chemical bond, NR 14 or O;

[0073] R 12 、R 13 and R 14 are independently H, halogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or more halogens;

[0074] R 15 is a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group; the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently optionally substituted by 1, 2 or more R i replace;

[0075] Each R i are independently halogen, oxo (=O), OH, COOH, NH2, CN, C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy; the C 1-6 The alkyl group is optionally substituted by 1, 2 or more Ri-1 replace;

[0076] Each R i-1 are independently halogen, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0077] q is 0, 1, or 2.

[0078] In a preferred embodiment, R1, R2, R3, R4, R5, R8, R 12 、R 13 、R 14 、R a 、R b 、R c 、R c-1 、R d 、R e 、R f 、R g 、R j 、R i and R i-1 wherein each halogen is independently fluorine, chlorine, bromine or iodine.

[0079] In a preferred embodiment, R1, R6, R7, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R b 、R c 、R c-1 、R e 、R f 、R g and R i In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH(C2H5)CH2CH3, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, -CH2C(CH3)3, or -CH(CH3) CH2CH(CH3)2; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH(C2H5)CH2CH3, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2 or -CH2C(CH3)3.

[0080] In a preferred embodiment, R2, R3, R4, R5, R8 and R a In each C 1-4 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0081] In a preferred embodiment, in R1, each C 1-3 Alkylene is independently methylene, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH2-CH3)-, -C(CH3)2-, or -CH2-CH(CH3)-, for example, methylene.

[0082] In a preferred embodiment, in R1, each C 2-3 Alkylene is independently -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH2-CH3)-, -C(CH3)2-, or -CH2-CH(CH3)-.

[0083] In a preferred embodiment, R1, R i 、R c 、R e 、R f 、R g 、R c-1 and R i-1 In each C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0084] In a preferred embodiment, R2, R3 and R a In each C 1-4 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0085] In a preferred embodiment, R2, R3, R4, R5, R8, R d 、R i 、R i-1 、R e 、R f and R g In each C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl; for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0086] In a preferred embodiment, R6, R7, R 11 and R cIn each C 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl or spiro[2.2]pentyl.

[0087] In a preferred embodiment, R6, R7, R 11 and R c In each C 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, spiro[2.2]pentyl or spiro[2.3]hexyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl or spiro[2.2]pentyl.

[0088] In a preferred embodiment, R6, R7, R 11 and R c In each C 6-10 Aryl is independently phenyl or naphthyl, for example phenyl.

[0089] In a preferred embodiment, R6, R7, R 11 and R c In the 5- to 10-membered heteroaryl group, the heteroatom is independently N, O or S, and the number of heteroatoms is independently 1 or 2.

[0090] In a preferred embodiment, the "more" in any embodiment of the present invention is independently 3, 4 or 5.

[0091] In a preferred embodiment, in R2 and R3, the heteroatom of each 3-6 membered heterocyclic group is independently N or O, and the number of heteroatoms is independently 1 or 2.

[0092] In a preferred embodiment, R6, R7 and R c In the above, each 3-10 membered heterocyclic group is independently a 3-6 membered heterocyclic group, the heteroatoms of the 3-6 membered heterocyclic group are independently N, O or S, and the number of heteroatoms is independently 1 or 2.

[0093] In a preferred embodiment, R 11 wherein said optionally 1, 2 or more R g The heteroatom of the 3- to 8-membered heterocycloalkyl group in the substituted 3- to 8-membered heterocycloalkyl group is N, and the number of the heteroatoms is independently 1 or 2.

[0094] In a preferred embodiment, in ring A, the C 3-10 Cycloalkyl is C 3-8 Cycloalkyl, such as cyclopropyl or C 4-8 Cycloalkyl; for example, C 3-6 Cycloalkyl.

[0095] In a preferred embodiment, in ring A, the C 3-10 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, spiro[2.4]heptyl or bicyclo[2.2.2]octyl, for example It can also be For example

[0096] In a preferred embodiment, in ring A, the heteroatom of the 3-10 membered heterocycloalkyl group is N or O, and the number of heteroatoms can be 1 or 2, for example, the number of heteroatoms is 1.

[0097] In a preferred embodiment, in ring A, the 3-10 membered heterocycloalkyl group is a 4-8 membered heterocycloalkyl group, for example a 4-6 membered heterocycloalkyl group.

[0098] In a preferred embodiment, in ring A, the 3-10 membered heterocycloalkyl group is oxirane, oxetanyl, oxolanyl, oxhexyl, oxepanyl, oxocanyl, aziridine, azetidinyl, azepentyl, azetidinyl, azepanyl, azepanyl, or azocinyl; for example For example

[0099] In a preferred embodiment, in ring A, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, the heteroatom of the 5-6 membered heteroaryl group may be N, and the number of heteroatoms may be 1 or 2; for example, a 5-membered heteroaryl group or a 6-membered heteroaryl group.

[0100] In a preferred embodiment, in ring A, the 5-10 membered heteroaryl group is pyridyl; for example

[0101] In a preferred embodiment, in R1, the halogen is fluorine, chlorine or bromine.

[0102] In a preferred embodiment, in R1, each C 1-6 The alkyl groups are independently C 1-4 Alkyl; for example, methyl, ethyl or n-propyl.

[0103] In a preferred embodiment, R a wherein the halogen is fluorine, chlorine or bromine.

[0104] In a preferred embodiment, in R1, the a Substituted C 1-6Alkyl is -CF3, -CHF2,

[0105] In a preferred embodiment, in R1, the optionally substituted 1, 2 or more R a Substituted C 1-6 C in alkoxy 1-6 The alkoxy groups are independently C 1-3 Alkoxy; for example, methoxy or ethoxy.

[0106] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene COOH is

[0107] In a preferred embodiment, in R1, the a Substituted -C 1-3 Alkylene COOH is

[0108] In a preferred embodiment, in R1, the unsubstituted -NHC(=O)OC 1-6 Alkyl is

[0109] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl is

[0110] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl is

[0111] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene S(=O)2OH is

[0112] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene P(=O)(OH)2 is

[0113] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene-tetrazolyl is

[0114] In a preferred embodiment, in R1, the aSubstituted -NHS(=O)2OH is

[0115] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene-NHS(=O)2OH is

[0116] In a preferred embodiment, in R1, the unsubstituted -C 1-3 Alkylene S(=O)2C 1-6 Alkyl is

[0117] In a preferred embodiment, in L1, each C 2-6 Alkyne groups are independently ethynylene, Pentynylene or hexynylene; preferably, each C 2-6 Alkynylidene groups are independently C 2- 4 Alkynylidene groups, such as

[0118] In a preferred embodiment, R b wherein the C optionally substituted by 1, 2 or 3 COOH or halogen 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1-3 An alkyl group; for example, a methyl group.

[0119] In a preferred embodiment, R b In the case of C substituted by 1, 2 or 3 COOH groups 1-6 Alkyl is

[0120] In a preferred embodiment, L1 is occupied by 1, 2 or 3 R b Substituted C 2-6 Alkynyl is For example Among them, the "1" position is connected to ring A, and the "2" position is connected to ring B.

[0121] In a preferred embodiment, in ring B, the C 6-10 Arylene is phenylene or naphthylene; for example, phenylene.

[0122] In a preferred embodiment, in ring B, the heteroatom of the 8-10 membered heteroarylene group and the 5-7 membered heteroarylene group is N, and the number of heteroatoms is independently 1, 2 or 3.

[0123] In a preferred embodiment, in ring B, the 5-7 membered heteroarylene group is a 6-membered heteroarylene group, the heteroatom of the 6-membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3.

[0124] In a preferred embodiment, the ring B is a pyridylene group, a pyrimidylene group, a pyridazinylene group, a pyrazinylene group or a triazinylene group; for example For example For example

[0125] In a preferred embodiment, in R2, each halogen is independently fluorine, chlorine or bromine, such as fluorine or chlorine.

[0126] In a preferred embodiment, in R2, the C optionally substituted by 1, 2 or more halogen or deuterium 1-4 C in the alkyl group 1-4 Alkyl groups are independently methyl or ethyl.

[0127] In a preferred embodiment, in R2, the C optionally substituted by 1, 2 or more halogens 1-4 C in the alkyl group 1-4 Alkyl groups are independently methyl or ethyl.

[0128] In a preferred embodiment, in R2, the C 1-4 Alkyl is -CD3, -CF3, -CHF2 or -CH2F.

[0129] In a preferred embodiment, in R2, the C 1-4 Alkyl is -CF3, -CHF2 or -CH2F.

[0130] In a preferred embodiment, in R3, the halogen is fluorine, chlorine or bromine.

[0131] In a preferred embodiment, in R3, the C optionally substituted by 1, 2 or more halogen or deuterium 1-4 C in the alkyl group 1-4 Alkyl groups are independently methyl or ethyl.

[0132] In a preferred embodiment, among R6 and R7, the optionally replaced by 1, 2 or more R c Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, n-butyl, n-pentyl, For example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, For example, methyl, ethyl, n-propyl, n-butyl,

[0133] In a preferred embodiment, among R6 and R7, the optionally replaced by 1, 2 or more R e Substituted C 3-8 C in cycloalkyl 3-8 Cycloalkyl is independently C 3-6 Cycloalkyl, for example cyclopentyl.

[0134] In a preferred embodiment, among R6 and R7, the optionally replaced by 1, 2 or more R e The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is a monocyclic ring, for example, independently a 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl may be 1 or 2; for example, independently a pyridyl or thiazolyl, more for example, independently

[0135] In a preferred embodiment, R c wherein the halogen is fluorine, chlorine or bromine.

[0136] In a preferred embodiment, R c wherein said optionally 1, 2 or more R c-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl groups are independently methyl or ethyl.

[0137] In a preferred embodiment, R c wherein said optionally 1, 2 or more R c-1 Substituted C 3-8 C in cycloalkyl 3-8 Cycloalkyl groups are independently monocyclic, bridged, or spirocyclic.

[0138] In a preferred embodiment, R c wherein said optionally 1, 2 or more R c-1 Substituted C 3-8 C in cycloalkyl 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl or spiro[2.2]pentyl; the spiro[2.2]pentyl group may be The bicyclo[1.1.1]pentyl group may be

[0139] In a preferred embodiment, R c wherein said optionally 1, 2 or more R c-1 The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is a monocyclic ring, for example, independently a 5-6 membered heteroaryl, wherein the heteroatom of the 5-6 membered heteroaryl may be 1 or 2; for example, independently a pyridyl, oxazolyl or thiazolyl, and more for example, independently

[0140] In a preferred embodiment, R c-1 wherein the halogen is fluorine, chlorine or bromine.

[0141] In a preferred embodiment, R c-1 In the C 1-6 Alkyl is C 1-3 An alkyl group; for example, a methyl group.

[0142] In a preferred embodiment, R6 and R7 are replaced by 1, 2 or more R c Substituted C 1-6 The alkyl groups are independently It can also be

[0143] In a preferred embodiment, in Y1, the optionally substituted R d Substituted C 1-6 C in the alkylene 1-6 Alkylene is independently methylene, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH2-CH3)-, -C(CH3)2-, -CH2-CH(CH3)-, or butylene, for example methylene.

[0144] In a preferred embodiment, R9 and R 10 wherein said is optionally replaced by 1, 2, 3 or 4 R f Substituted C 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1-3 An alkyl group; for example, a methyl group.

[0145] In a preferred embodiment, R f wherein the halogen is fluorine, chlorine or bromine.

[0146] In a preferred embodiment, R9 and R 10 wherein said 1, 2, 3 or 4 R f Substituted C 1-6 Alkyl is -CD3, -CH2F or -CHF2; for example -CH2F or -CHF2.

[0147] In a preferred embodiment, R 11 wherein said optionally 1, 2 or more R g Substituted C 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1-4Alkyl; for example, ethyl, n-propyl, n-butyl, It can also be methyl; for example ethyl, n-propyl, n-butyl or Another example is ethyl or n-propyl.

[0148] In a preferred embodiment, R 11 wherein said optionally 1, 2 or more R g Substituted C 3-8 C in cycloalkyl 3-8 Cycloalkyl is independently C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is a monocyclic, spirocyclic or bridged ring; 3-8 Cycloalkyl can independently be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, spiro[2.2]pentanyl, spiro[2.3]hexyl or bicyclo[2.1.1]hexyl; for example, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl or bicyclo[2.1.1]hexyl; bicyclo[1.1.1]pentyl can be Spiro[2.3]hexyl can be Bicyclo[2.1.1]hexyl can be

[0149] In a preferred embodiment, R 11 wherein said optionally 1, 2 or more R g Substituted C 3-8 C in cycloalkyl 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl or spiro[2.2]pentyl; for example cyclopropyl, cyclobutyl or cyclopentyl.

[0150] In a preferred embodiment, R g wherein the halogen is fluorine, chlorine or bromine.

[0151] In a preferred embodiment, R 11 wherein said 1, 2 or more R g Substituted C 1-6 Alkyl is For example

[0152] In a preferred embodiment, R 11 wherein said 1, 2 or more R g Substituted C 3-8 Cycloalkyl is For example, For example

[0153] In a preferred embodiment, R 11 wherein said 1, 2 or more R g Substituted C 6-10 Aryl

[0154] In a preferred embodiment, R 11 wherein said optionally 1, 2 or more R g The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl, wherein the heteroatom of the 5-6 membered heteroaryl may be N, and the number of heteroatoms may be 1 or 2; preferably a 6 membered heteroaryl; for example, pyridyl, and for example

[0155] In a preferred embodiment, R 11 wherein said 1, 2 or more R g The substituted 5-10 membered heteroaryl is For example, For example

[0156] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more R i The 3-10-membered heterocyclic group in the substituted 3-10-membered heterocyclic group is independently a 3-10-membered heterocycloalkyl group or a 3-10-membered heterocycloalkenyl group, and the number of double bonds in the 3-10-membered heterocycloalkenyl group is 1 or 2.

[0157] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more R i The heteroatom of the 3- to 10-membered heterocyclic group in the substituted 3- to 10-membered heterocyclic group is independently N or O, and the number of heteroatoms is independently 1 or 2. For example, the heteroatom is N, and the number of heteroatoms is 1.

[0158] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more R i The 3- to 10-membered heterocyclic group in the substituted 3- to 10-membered heterocyclic group is independently a 3- to 8-membered heterocyclic group, for example, a 3- to 6-membered heterocyclic group.

[0159] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more Ri The 3-10 membered heterocyclic groups in the substituted 3-10 membered heterocyclic groups are independently 3-6 membered heterocycloalkyl groups, such as azetidinyl, azetyl or azacyclohexyl, and for example For example

[0160] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more R i The 3-10 membered heterocyclic group in the substituted 3-10 membered heterocyclic group is independently a 3-6 membered heterocycloalkenyl group, and the number of double bonds in the 3-6 membered heterocycloalkenyl group is 1 or 2; for example, the 3-6 membered heterocycloalkenyl group is For example

[0161] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more R i The heteroatoms of the 5- to 10-membered heteroaryl in the substituted 5- to 10-membered heteroaryl are independently N, O or S, for example, N. The number of heteroatoms can be 1, 2 or 3.

[0162] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more R i The 5- to 10-membered heteroaryl group in the substituted 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group, for example, a 6-membered heteroaryl group.

[0163] In a preferred embodiment, R 15 wherein said optionally 1, 2 or more R i The 5-10 membered heteroaryl groups in the substituted 5-10 membered heteroaryl groups are independently For example Or For example

[0164] In a preferred embodiment, R i wherein said optionally 1, 2 or more R i-1 Substituted C 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1-4 Alkyl; for example, methyl, ethyl, n-propyl, n-butyl or isopropyl; preferably, C 1-3 Alkyl; for example, methyl, ethyl or isopropyl.

[0165] In a preferred embodiment, R i In the C1-6 Alkoxy is C 1-3 Alkoxy; for example, ethoxy or isopropoxy.

[0166] In a preferred embodiment, R i wherein said optionally 1, 2 or more R i-1 Substituted C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl; bicyclo[1.1.1]pentyl may be

[0167] In a preferred embodiment, R i In the C 3-6 Cycloalkyl is cyclobutyl.

[0168] In a preferred embodiment, R i-1 In the C 3-6 Cycloalkyl is cyclopropyl or cyclobutyl.

[0169] In a preferred embodiment, R i-1 In the C 1-6 Alkoxy is methoxy or ethoxy; for example methoxy.

[0170] In a preferred embodiment, R i-1 wherein the halogen is F.

[0171] In a preferred embodiment, the ring A is C 3-8 Cycloalkyl, 4-6 membered oxacycloalkyl or 4-6 membered azacycloalkyl; the number of heteroatoms in the 4-6 membered oxacycloalkyl and 4-6 membered azacycloalkyl is 1.

[0172] In a preferred embodiment, the ring A is C 4-8 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein the heteroatoms of the 3-10 membered heterocycloalkyl are selected from one, two or three of N, O and S, and the number of the heteroatoms is one, two or three.

[0173] In a preferred embodiment, the ring A is C 3-8 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the heteroatom of the 4-6 membered heterocycloalkyl is N or O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; for example, ring A is C 3-8 Cycloalkyl.

[0174] In a preferred embodiment, the ring A is a 5-6 membered heteroaryl group, the heteroatoms of the 5-6 membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0175] In a preferred embodiment, the ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, spiro[2.4]heptyl, bicyclo[2.2.2]octyl, oxirane, oxetanyl, oxolanyl, oxhexyl, oxetanyl, oxocanyl, aziridine, azetidinyl, azepentyl, azetidinyl, azepanyl, azepanyl, or pyridyl;

[0176] Preferably, the ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[2.3]hexyl, spiro[2.4]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.2]octyl, oxetanyl, oxolanyl(tetrahydrofuranyl), oxetanyl(tetrahydropyranyl), azetidinyl or pyridyl;

[0177] More preferably, the ring A is It can also be

[0178] In a preferred embodiment, the ring A is For example, cyclopropyl; preferably, for

[0179] In a preferred embodiment, in case (1), each R1 is independently OH, COOH, F, Cl, Br, CN, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-3 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene C(=O)NHC(=O)C 1-3 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-3 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3Alkylene P(=O)(OH)2, -C 1-3 Alkylene-tetrazolyl or -C 1-3 Alkyl C(=O)C 1-3 alkyl;

[0180] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-3 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene C(=O)NHC(=O)C 1-3 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-3 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2, -C 1-3 Alkylene-tetrazolyl and -C 1-3 Alkylene C(=O)C 1-3 The alkyl group is optionally substituted by 1, 2 or more R a Preferably, the R1 is -C 1-3 AlkyleneCOOH.

[0181] In a preferred embodiment, in case (1), each R a are independently methyl, oxo (=O), OH, F, Cl or CN;

[0182] In a preferred embodiment, in case (1), each R1 is independently CN, oxo (=O), halogen, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)NHC(=O)C 1- 6-alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkyl-tetrazolyl;

[0183] The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace.

[0184] In a preferred embodiment, in case (3), each R1 is independently -NHS(=O)2OH or -C 1-3 Alkylene-NHS(=O)2OH; said-NHS(=O)2OH and -C 1-3 Alkylene-NHS(=O)2OH is optionally substituted by 1, 2 or more Ra Replace; each R a Independently C 1-4 alkyl.

[0185] In a preferred embodiment, each R1 is independently COOH or -C 1-3 AlkyleneCOOH.

[0186] In a preferred embodiment, in case (1), each R1 is independently OH, COOH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3, For example, OH, COOH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3,

[0187] In a preferred embodiment, in case (2), each R1 is independently OH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3,

[0188] In a preferred embodiment, in case (3), each R1 is independently OH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3, For example

[0189] In a preferred embodiment, m is 0, 1, 2 or 3, for example 1.

[0190] In the present invention, Also for R 1-1 The definition of is the same as that of R1 in any embodiment of the present invention, and the definition of m2 is the same as that of m or m1 in any embodiment of the present invention; (R1) m1 The definition of R1 and R 1-2 The same as the definition of R1 in any embodiment of the present invention or the same as the definition of R in any embodiment of the present invention 1-2 Definition; preferably, each R 1-2 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, OH or CN; the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally substituted independently by 1, 2 or more R a Replace; for example, each R 1-2 are independently halogen, C1-4 Alkyl, C 1-4 Alkoxy, OH or CN; the C 1-4 Alkyl and C 1-4 Alkoxy groups are optionally substituted independently by 1, 2 or more R a replace.

[0191] In a preferred embodiment, for In case (1), ring B is a 6-membered heteroarylene group; R 1-1 OH, COOH, C 1-6 alkyl, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH or -C 1-3 Alkylene S(=O)2C 1-6 Alkyl; the C 1-6 Alkyl, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH and -C 1-3 Alkylene S(=O)2C 1-6 The alkyl group is optionally substituted by 1, 2 or more R a replace;

[0192] Or, R 1-1 COOH, Tetrazolyl, -C 1-3 AlkyleneCOOH, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; the-C 1-3 AlkyleneCOOH, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1- 3Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0193] R 1-1 In each R a Independently C 1-4 Alkyl, halogen, OH, oxo (=O) or CN; when R a When the number of is 2 or more, the OH and oxo (=O) are not attached to the same carbon atom;

[0194] Each R 1-2 are independently halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH or CN; the C 1-4 Alkyl and C 1-4 Alkoxy groups are optionally substituted independently by 1, 2 or more R a replace;

[0195] R 1-2 In each R a In a preferred embodiment, each R a are independently halogen.

[0196] In a preferred embodiment, for m1 is 0, 1, or 2; for example For example

[0197] In a preferred embodiment, for m1 is 0, 1, or 2; for example It can also be For example

[0198] In a preferred embodiment, for It can also be

[0199] In a preferred embodiment, for It can also be

[0200] In a preferred embodiment, for Z3 and Z4 are independently C, CH or N.

[0201] In a preferred embodiment, each R2 is independently halogen, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Preferably, each R2 is independently halogen, C 1-4 Alkyl, methoxy or cyclopropyl; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens or deuterium.

[0202] In a preferred embodiment, each R2 is independently halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; the C 1-4 Alkyl and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more halogen or deuterium; for example, each R2 is independently C 1-4 alkyl.

[0203] In a preferred embodiment, each R2 is independently methyl, ethyl, F, Cl, Br, -CD3, -CF3, -CHF2, -CH2F, -NH2, -OCH3 or cyclopropyl; for example, methyl, ethyl, F, Cl, -CD3, -CF3, -CH2F, -CHF2, -OCH3 or cyclopropyl; for example, methyl, ethyl, F, Cl, -CD3, -CF3, -CHF2, -OCH3 or cyclopropyl.

[0204] In a preferred embodiment, each R2 is independently methyl, ethyl, F, Cl, Br, -CF3, -CHF2, -CH2F or -NH2; for example, methyl, ethyl, F, Cl, -CF3 or -CHF2.

[0205] In a preferred embodiment, n is 0 or 1.

[0206] In a preferred embodiment, the for For example n is 0 or 1; for example Preferably, for Preferably, for The "1" bit is connected to L1, and the "2" bit is connected to X1 connection in.

[0207] In a preferred embodiment, the for For example n is 0 or 1; preferably, for Preferably, for The "1" bit is connected to L1, and the "2" bit is connected to X1 connection in.

[0208] In a preferred embodiment, for Preferably, for The "1" bit is connected to L1, and the "2" bit is connected to X1 connection in.

[0209] In a preferred embodiment, the L1 is C 2-6 Alkynylidene, the C 2-6 The alkynylene group is optionally substituted by 1, 2 or 3 R b Preferably, L1 is unsubstituted C 2-6 Alkynylidene.

[0210] In a preferred embodiment, each R b Independently C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 COOH groups; preferably, the C 1-6 The alkyl group is optionally substituted with 1 COOH.

[0211] In a preferred embodiment, the L1 is For example Among them, the "1" position is connected to ring A, and the "2" position is connected to ring B.

[0212] In a preferred embodiment, X1, X2, X3 and X4 are independently C, CH, CH2, O, S, N or NH; at the same time, two or three of X1, X2, X3 and X4 are independently O, S, N or NH.

[0213] In a preferred embodiment, X1 is C or N.

[0214] In a preferred embodiment, X2 is CH, O, S or N.

[0215] In a preferred embodiment, X3 is C, CH2, O, S or N.

[0216] In a preferred embodiment, X4 is C, CH, N or NH.

[0217] In a preferred embodiment, the is triazolyl, pyrazolyl, imidazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, furazolyl, thiadiazolyl, oxathiazolyl, thienyl, furyl or pyrrolyl;

[0218] Preferably, the for More preferably, the for Among them, the "1" position is connected to ring B, and the "2" position is connected to W.

[0219] In a preferred embodiment, each R3 is independently H, C 1-4 Alkyl, oxo (=O), F, Cl, Br; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens or deuterium; preferably, each R3 is independently H, C 1-4 Alkyl, F, Cl or oxo (=O); the C 1-4 Alkyl is optionally substituted with 1, 2 or more halogen or deuterium; or, each R3 is independently C 1-4 Alkyl, F, Cl, Br or oxo, for example, each R3 is independently C 1-4 alkyl.

[0220] Or; each R3 is independently H, C 1-4 Alkyl, oxo (=O), F, Cl or Br; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens; preferably, each R3 is independently H, C 1-4 Alkyl, F, Cl or oxo (=O); the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens.

[0221] In a preferred embodiment, each R3 is independently H, methyl, ethyl, oxo (=O), F, Cl, -CD3, -CF3, -CHF2 or -CH2F; preferably, each R3 is independently H, methyl, ethyl, -CD3, oxo (=O) or Cl;

[0222] Alternatively, each R3 is independently H, methyl, ethyl, oxo (=O), F, Cl, -CF3, -CHF2 or -CH2F; preferably, each R3 is independently H, methyl, ethyl, oxo (=O) or Cl.

[0223] In a preferred embodiment, p is 0, 1, 2 or 3, for example 1 or 2.

[0224] In a preferred embodiment, for Preferably, for More preferably, for Among them, the "1" position is connected to ring B, and the "2" position is connected to W.

[0225] In a preferred embodiment, W is

[0226] In a preferred embodiment, R4 and R5 are each independently H, halogen or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens; or R4 and R5 are independently H or deuterium; for example, R4 and R5 are H; R6 and R7 have the definitions described in any of the embodiments of the present application; preferably, W is

[0227] In a preferred embodiment, R6 is H or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c replace.

[0228] In a preferred embodiment, in R6, each R c is independently halogen, such as fluorine, chlorine or bromine.

[0229] In a preferred embodiment, R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Substitution; said C3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e Preferably, R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Substitution; said C 3-8 Cycloalkyl, phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or more R e Substitution; the heteroatom of the 5-6 membered heteroaryl group is selected from one or two of N, O and S, and the number of heteroatoms is 1 or 2; more preferably, R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c replace.

[0230] In a preferred embodiment, in R7, each R c are independently deuterium, halogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace.

[0231] In a preferred embodiment, each R c are independently deuterium, halogen, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 substituted; preferably, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group; the heteroatoms of the 5-6 membered heteroaryl group are selected from one or two of N, O and S, and the number of heteroatoms is 1 or 2.

[0232] In a preferred embodiment, in R7, each R c-1 are independently deuterium, halogen or C 1-6 alkyl.

[0233] In a preferred embodiment, in R7, each R e are independently halogen or C 1-6 Alkyl, such as fluorine, chlorine, bromine or methyl, or deuterium or halogen.

[0234] In a preferred embodiment, each R c are independently F, methyl, -CF3, -CHF2, methoxy, cyclopropyl, cyclobutyl, cyclopentyl,

[0235] In a preferred embodiment, R6 is H, methyl, ethyl, For example, methyl, ethyl,

[0236] In a preferred embodiment, R7 is

[0237] In a preferred embodiment, for

[0238] In a preferred embodiment, for

[0239] In a preferred embodiment, for

[0240] In a preferred embodiment, R8 is H, deuterium, halogen or C 1-4 Alkyl; for example, H or deuterium; also for example, H.

[0241] In a preferred embodiment, Y1 is a chemical bond.

[0242] In a preferred embodiment, Y1 is C 1-6 Alkylene; the C 1-6 The alkylene group is optionally replaced by 1, 2 or more R d Preferably, Y1 is unsubstituted C 1-4 Alkylene.

[0243] In a preferred embodiment, Y1 is a single bond or C 1-6 Alkylene.

[0244] In a preferred embodiment, R f is halogen or deuterium; for example, halogen.

[0245] In a preferred embodiment, R9 is H or deuterium; for example, H.

[0246] In a preferred embodiment, R 10 H, deuterium or C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f Substitution; for example, R 10 H or C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace;

[0247] In a preferred embodiment, R 10 H, methyl, ethyl, n-propyl, isopropyl, -CD3, Preferably, R 10 H, methyl, -CD3,

[0248] Or, R 10 is H, methyl, ethyl, n-propyl, isopropyl, Preferably, R 10 H, methyl,

[0249] In a preferred embodiment, W is Preferably, the W is

[0250] In a preferred embodiment, middle, for When the carbon atom with * is a chiral carbon atom, for More preferably, for

[0251] In a preferred embodiment, R 11 C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is a monocyclic, spirocyclic or bridged ring; 1-6 Alkyl, phenyl, 5-6 membered heteroaryl and C 3-6 The cycloalkyl groups are optionally substituted independently by 1, 2 or more R g Substitution; the heteroatom of the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; preferably, R 11 is phenyl or 5-6 membered heteroaryl; the phenyl or 5-6 membered heteroaryl is independently optionally substituted by 1, 2 or more R g replace.

[0252] In a preferred embodiment, R 11 C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl or C 3-8 Cycloalkyl; the C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl and C 3-8 The cycloalkyl groups are optionally substituted independently by 1, 2 or more R g preferably, R 11 C 1-6 Alkyl, C 3-4 Cycloalkyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl or bicyclo[2.1.1]hexyl; said C 1-6 Alkyl, C 3-4 Cycloalkyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl and bicyclo[2.1.1]hexyl are independently optionally substituted by 1, 2 or more R g Replacement; or R 11 is cyclopentyl, cyclohexyl, phenyl or 5-6 membered heteroaryl; the cyclopentyl, cyclohexyl, phenyl or 5-6 membered heteroaryl is independently optionally replaced by 1, 2 or more R g replace.

[0253] In a preferred embodiment, R 11 C 1-6 Alkyl or C 3-4 Cycloalkyl; the C 1-6 Alkyl and C 3-4 The cycloalkyl groups are optionally substituted independently by 1, 2 or more R g replace.

[0254] In a preferred embodiment, each R g are independently deuterium, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; the C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or more deuterium or halogen; preferably, each R g is independently deuterium or a halogen.

[0255] In a preferred embodiment, each R g are independently halogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or more halogens; preferably, each Rg are independently halogen.

[0256] In a preferred embodiment, each of the R g Deuterium, F, Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CD3, For example, deuterium, F, Cl, -CD3, In a preferred embodiment, each of the R g is F, Cl, methyl, ethyl, -CH2F, CHF2 or CF3, for example F or Cl.

[0257] In a preferred embodiment, R 11 for R 11 for

[0258] In a preferred embodiment, for For example

[0259] In a preferred embodiment, for For example

[0260] In a preferred embodiment, R 12 and R 13 are independently H, deuterium or halogen.

[0261] In a preferred embodiment, R 14 H, deuterium or C 1-6 alkyl.

[0262] In a preferred embodiment, R 12 、R 13 and R 14 is independently H, methyl or F; for example, H.

[0263] In a preferred embodiment, Y2 is a chemical bond, NH, -C(=O)N(CH3)- or O.

[0264] In a preferred embodiment, q is 0, 1, 2 or 3; for example, q is 0 or 1.

[0265] In a preferred embodiment, when q is 0, Y2 is N(R 14 )、-C(=O)N(R 14 )-or O.

[0266] In a preferred embodiment, W is -(CR 12 R 13 ) q -Y2-R 15 Preferably, W is -N(R 14 )-R 15 、-C(R 12 R 13 )-R 15 、-C(R 12 R 13 )-N(R 14 )-R 15 、-C(R 12 R 13 )-OR 15 or -(CR 12 R 13 )2-C(=O)-N(R 14 )-R 15 More preferably, the W is -NH-R 15 、-CH2-R 15 、-CH2-NH-R 15 、-CH2-OR 15 or

[0267] In a preferred embodiment, R 15 C 1-6 Alkyl, 3-6 membered heterocyclic group or 5-6 membered heteroaryl; the C 1-6 Alkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or more R i substituted; the heteroatoms of the 3-6 membered heterocyclic group are independently N or O, and the number of heteroatoms is independently 1 or 2; the heteroatoms in the 5-6 membered heteroaryl group are independently N, O or S, and the number of heteroatoms is independently 1, 2 or 3.

[0268] In a preferred embodiment, each R i are independently halogen, oxo (=O), C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The alkoxy group is optionally substituted by 1, 2 or more R i-1 replace.

[0269] In a preferred embodiment, each R i-1 are independently halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy.

[0270] In a preferred embodiment, each R i are independently methyl, n-propyl, isopropyl, F, oxo (=O),

[0271] In a preferred embodiment, the R 15 for It can also be

[0272] In a preferred embodiment, the compound represented by formula (I) has a structure represented by formula (II):

[0273] wherein Z1, Z2, Z3 and Z4 are independently N or CH; at least one of Z1, Z2, Z3 and Z4 is N; n is 0, 1 or 2; ring A, ring B, L1, R1, R2, R3, W, X1, X2, X3, X4, m, p and The definition of is as described in any embodiment of the present invention.

[0274] In a preferred embodiment, the compound represented by formula (I) has a structure represented by formula (I-II), (I-III) or (I-IV):

[0275] Among them, L1 is

[0276] Ring A, Y1, Y2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 15 , X1, X2, X3, X4, m, n, p, q and The definition of is as described in any embodiment of the present invention.

[0277] In a preferred embodiment, the compound represented by formula (I) has a structure represented by formula (IV), (I-VI) or (I-VII):

[0278] Ring A, Y2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 、R 11 、R 12 、R 13 、R 15 , X1, X2, X3, X4, m, n, p, q and The definition of is as described in any embodiment of the present invention.

[0279] In a preferred embodiment, the compound represented by formula (I) is a compound represented by formula (I-VIII):

[0280] Among them, R 1-1 COOH, Tetrazolyl, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0281] Said-C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1- 6-alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1- 6-alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0282] Each R 1-2 are independently OH, CN, oxo (=O), halogen, NH2, C 1-4 Alkyl or C 1-4 Alkoxy; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens;

[0283] Each R a Independently C 1-4 Alkyl, C 1-4 Alkoxy or halogen;

[0284] Z3 and Z4 are independently N or CH;

[0285] m2 is 0, 1, 2, or 3;

[0286] Ring A, R2, R3, W, X1, X2, X3, X4, n, p and The definition of is as described in any embodiment of the present invention.

[0287] In a preferred embodiment, the compound represented by formula (I) is a compound represented by formula (I-VIII),

[0288] Among them, R 1-1 COOH, Tetrazolyl, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl;

[0289] Said-C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1- 6-alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1- 3Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1- 3 alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace.

[0290] In a preferred embodiment, the compound represented by formula (I) is a compound represented by formula (I-VIII-1):

[0291] The carbon atom with * is a chiral carbon atom or an achiral carbon atom; when it is a chiral carbon atom, the configuration of the chiral carbon atom is R and / or S;

[0292] Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0293] m2 is 0, 1, or 2;

[0294] R 1-1 OH, COOH, C 1-6 alkyl, -C 1-3 Alkylene COOH, -NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH or -C 1-3 Alkylene S(=O)2C 1-6 Alkyl; the C 1-6 Alkyl, -C 1-3 Alkylene COOH, NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH and -C 1-3 Alkylene S(=O)2C 1-6 The alkyl group is optionally substituted by 1, 2 or more R a replace;

[0295] R 1-1 In each R a Independently C 1-4 Alkyl, halogen, OH, oxo (=O) or CN; when R a When the number of is 2 or more, the OH and oxo (=O) are not attached to the same carbon atom;

[0296] Each R 1-2 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, OH or CN; the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally substituted independently by 1, 2 or more R a replace;

[0297] R 1-2 In each R a are independently halogen;

[0298] Z3 and Z4 are independently C, CH or N;

[0299] Each R2 is independently halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; the C 1-4 Alkyl and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more halogen or deuterium;

[0300] n is 0 or 1;

[0301] X1 is C or N;

[0302] X2 is CH, O, S or N;

[0303] X3 is C, CH2, O, S or N;

[0304] X4 is C, CH, N or NH;

[0305] and at least one of X1, X2, X3 and X4 is independently O, S or N;

[0306] A double line including a solid line and a dashed line represents a single bond or a double bond; at the same time, Contains at least one double bond;

[0307] Each R3 is independently halogen, C 1-4 Alkyl or oxo;

[0308] p is 1 or 2;

[0309] Y1 is a chemical bond or C 1-6 alkylene;

[0310] R8 is H or deuterium;

[0311] R9 is H or deuterium;

[0312] R 10 are independently H, deuterium or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 Rf Replace; each R f are independently deuterium or halogen;

[0313] R 11 C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl or C 3-8 Cycloalkyl; the C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl and C 3-8 The cycloalkyl groups are optionally substituted independently by 1, 2 or more R g replace;

[0314] Each R g are independently deuterium, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; the C 1-6 Alkyl and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more deuterium or halogen;

[0315] The heteroatoms in the 3-10 membered heterocycloalkyl group and the 5-10 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently one, two or three.

[0316] In a preferred embodiment, the compound represented by formula (I) is a compound represented by formula (I-VIII-2):

[0317] Ring A is C 3-8 Cycloalkyl, 4-6 membered oxacycloalkyl or 4-6 membered azacycloalkyl; the number of heteroatoms in the 4-6 membered oxacycloalkyl and 4-6 membered azacycloalkyl is 1;

[0318] m2 is 0, 1, or 2;

[0319] R 1-1 COOH, Tetrazolyl, -C 1-3 AlkyleneCOOH, -C 1-3 Alkylene C(=O)NHC(=O)C 1- 6-alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; the-C 1-3 AlkyleneCOOH, -C 1-3Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH or -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 Alkylene-tetrazolyl is optionally substituted by 1, 2 or more R a replace;

[0320] Each R 1-2 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, OH or CN; the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally substituted independently by 1, 2 or more R a replace;

[0321] Each R a are independently halogen;

[0322] Z3 and Z4 are independently C, CH or N;

[0323] Each R2 is independently halogen, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl; the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more halogen or deuterium;

[0324] n is 0 or 1;

[0325] R4 and R5 are each independently H or deuterium;

[0326] R6 is C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c replace;

[0327] In R6, each R c are independently halogen;

[0328] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Substitution; said C 3-8 Cycloalkyl, C 6-10Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace;

[0329] In R7, each R c are independently deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace;

[0330] Each R c-1 are independently deuterium, halogen or C 1-6 alkyl;

[0331] Each R e are independently deuterium or halogen;

[0332] The heteroatoms in the 5-10 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently one, two or three.

[0333] In a preferred embodiment, the compound represented by formula (I) is a compound represented by formula (I-VIII-3):

[0334] Ring A is C 3-8 Cycloalkyl;

[0335] R1 is COOH or -C 1-3 AlkyleneCOOH;

[0336] Each R2 is independently C 1-4 alkyl;

[0337] n is 0 or 1;

[0338] Z3 and Z4 are independently C, CH or N;

[0339] X2 is CH or N;

[0340] R 12 and R 13 are independently H, deuterium or halogen;

[0341] When q is 0, Y2 is N(R 14 )、-C(=O)N(R 14 )- or O;

[0342] When q is 1, 2 or 3, Y2 is a chemical bond, N(R 14)、-C(=O)N(R 14 )- or O;

[0343] R 14 H, deuterium or C 1-6 Alkyl; R 15 C 1-6 alkyl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl; said C 1-6 Alkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R i replace;

[0344] Each R i are independently halogen, oxo (=O), C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 Alkoxy groups are optionally substituted independently by 1, 2 or more R i-1 replace;

[0345] Each R i-1 are independently halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkoxy;

[0346] The heteroatoms in the 3-10 membered heterocycloalkyl group and the 5-10 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently one, two or three.

[0347] In a preferred embodiment, R 1-1 COOH, For example, COOH, Alternatively, for example, COOH,

[0348] In a preferred embodiment, R 1-2 are independently OH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3, For example, OH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3,

[0349] In a preferred embodiment, the compound represented by formula (I) is any one of the following compounds:

[0350] or its hydrochloride, or its hydrochloride, or its hydrochloride,

[0351] Preferably, the compound represented by formula (I) is any one of the following compounds:

[0352] In a preferred embodiment, the compound may also be any of the following compounds:

[0353] The compound The compound with a retention time of 13.097 min or 20.769 min under the following conditions;

[0354] Chiral column: CHIRAL ART Amylose-C NEO, AD-H column, 30*250 mm; mobile phase A: n-hexane; mobile phase B: ethanol; volume ratio of mobile phase A to B: 83:17; isocratic elution; flow rate: 30 mL / min; column temperature: 25-28°C; detection wavelength: 220 nm;

[0355] The compound The compound with a retention time of 5.550 min or 6.336 min under the following conditions;

[0356] Chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol and diethanolamine, with the volume percentage of diethanolamine in mobile phase B being 0.05%; the volume ratio of mobile phases A to B was 80:20; isocratic elution; flow rate: 55 g / min, column temperature: 25-28°C, detection wavelength: 220 nm;

[0357] The compound The compound with a retention time of 4.963 or 5.364 under the following conditions;

[0358] Chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol and diethanolamine, with the volume percentage of diethanolamine in mobile phase B being 0.05%; the volume ratio of mobile phases A to B was 80:20; isocratic elution; flow rate: 55 g / min; column temperature: 25-28°C; detection wavelength: 220 nm;

[0359] The compound The compound with a retention time of 8.410 or 7.53 under the following conditions;

[0360] Chiral column: CHIRALART Cellulose-SC, IC column, 30*250 mm; mobile phase A: n-hexane and diethylamine, with 0.1% ethylenediamine by volume in mobile phase A; mobile phase B: ethanol; volume ratio of mobile phases A to B: 7:3; isocratic elution; flow rate: 30 mL / min; column temperature: 25-28°C; detection wavelength: 220 nm;

[0361] The compound The compound with a retention time of 3.241 or 3.424 under the following conditions;

[0362] Chiral column: CHIRALART Amylose-CNEO, AD-H column, 30*250 mm; mobile phase A: supercritical carbon dioxide; mobile phase B: 80% n-hexane and 20% ethanol by volume, with a volume ratio of mobile phases A to B of 80:20; isocratic elution; flow rate: 55 g / min; column temperature: 25-28°C; detection wavelength: 220 nm;

[0363] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropyl alcohol (IPA) and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 80:20; isocratic elution; flow rate: 60 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 9.353 min;

[0364] A compound that elutes later under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropyl alcohol (IPA) and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 80:20; isocratic elution; flow rate: 60 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes later is 10.778 min;

[0365] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 85:15; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 11.977 min;

[0366] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 85:15; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 14.219 min;

[0367] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×25 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B, and a volume ratio of mobile phases A to B of 85:15; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 9.181 min;

[0368] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×25 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B, and a volume ratio of mobile phases A to B of 85:15; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 11.647 min;

[0369] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B, and a volume ratio of mobile phases A to B of 85:15; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 10.806 min;

[0370] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B, and the volume ratio of mobile phases A to B being 85:15; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 12.817 min;

[0371] The compound that elutes first under the following HPLC conditions: chiral column: YMC CHIRALART Cellulose-SC, IC column, 30*250 mm; mobile phase A: n-hexane; mobile phase B: isopropanol, with a volume ratio of mobile phases A to B of 33:67; isocratic elution; flow rate: 38 mL / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 10.566 min;

[0372] The compound eluting later under the following HPLC conditions: chiral column: YMC CHIRALART Cellulose-SC, IC column, 30*250 mm; mobile phase A: n-hexane; mobile phase B: isopropanol, with a volume ratio of mobile phases A to B of 33:67; isocratic elution; flow rate: 38 mL / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 13.500 min;

[0373] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 83:17; isocratic elution; flow rate: 58 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 7.463 min;

[0374] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 83:17; isocratic elution; flow rate: 58 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 8.014 min;

[0375] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiral IG column, 250*30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 80:20; isocratic elution; flow rate: 60 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 10.152 min;

[0376] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiral IG column, 250*30mm ID, 5μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 80:20; isocratic elution; flow rate: 60g / min; preferably, column temperature: 25-28°C; detection wavelength: 220nm; preferably, the retention time of the compound eluting later is 12.037min;

[0377] The compound that elutes first under the following HPLC conditions: chiral column: YMC CHIRALART cellulose-SC, 30*250mm; mobile phase A: n-hexane, mobile phase B: isopropanol, with a volume ratio of mobile phases A to B of 33:67; isocratic elution; flow rate: 30 mL / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 13.546 min;

[0378] The compound eluting later under the following HPLC conditions: chiral column: YMC CHIRALART cellulose-SC, 30*250mm; mobile phase A: n-hexane, mobile phase B: isopropanol, the volume ratio of mobile phases A and B is 33:67; isocratic elution; flow rate: 30mL / min; preferably, column temperature: 25-28°C; detection wavelength: 220nm; preferably, the retention time of the compound eluting later is 15.910min;

[0379] The compound that elutes first under the following HPLC conditions;

[0380] Chiral column: Daicel Chiral IG column, 250*30mm ID, 5μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B; the volume ratio of mobile phases A to B is 60:40; isocratic elution; flow rate: 70g / min; preferably, column temperature: 25-28°C; detection wavelength: 220nm; preferably, the retention time of the first-eluting compound is 12.749min;

[0381] Compounds that elute later under the following HPLC conditions;

[0382] Chiral column: Daicel Chiral IG column, 250*30mm ID, 5μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B; the volume ratio of mobile phases A to B is 60:40; isocratic elution; flow rate: 70g / min; preferably, column temperature: 25-28°C; detection wavelength: 220nm; preferably, the retention time of the late-eluting compound is 14.022min;

[0383] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak IK column, 250×25 mm ID, 10 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B; volume ratio of mobile phases A to B: 82:18; isocratic elution; flow rate: 57 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 15.825 min;

[0384] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiralpak IK column, 250×25 mm ID, 10 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol and NH3H2O, with NH3H2O ​​accounting for 0.1% by volume of mobile phase B; the volume ratio of mobile phases A to B is 82:18; isocratic elution; flow rate: 57 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 16.274 min;

[0385] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak OX column, 250×25 mm ID, 10 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%; the volume ratio of mobile phases A to B being 80:20; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 16.445 min;

[0386] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiralpak OX column, 250×25 mm ID, 10 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: EtOH and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%; the volume ratio of mobile phases A to B being 80:20; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 18.880 min;

[0387] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 88:12; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 13.164 min;

[0388] The compound eluting later under the following HPLC conditions: chiral column: Daicel Chiralpak IG column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 88:12; isocratic elution; flow rate: 55 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound eluting later is 13.847 min;

[0389] The compound that elutes first under the following HPLC conditions: chiral column: Daicel Chiralpak OD column, 250×30 mm ID, 5 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: EtOH and NH3H2O, with the volume percentage of NH3H2O ​​in mobile phase B being 0.1%, and the volume ratio of mobile phases A to B being 88:12; isocratic elution; flow rate: 53 g / min; preferably, column temperature: 25-28°C; detection wavelength: 220 nm; preferably, the retention time of the compound that elutes first is 9.828 min;

[0390] Compounds that elute later under the following HPLC conditions;

[0391] Chiral column: Daicel Chiralpak OD column, 250×30mm ID, 5μm; mobile phase A: supercritical carbon dioxide, mobile phase B: EtOH and NH3H2O, the volume percentage of NH3H2O ​​in mobile phase B is 0.1%, and the volume ratio of mobile phases A to B is 88:12; isocratic elution; flow rate: 53g / min; preferably, column temperature: 25-28°C; detection wavelength: 220nm; preferably, the retention time of the late-eluting compound is 10.576min.

[0392] The present invention also provides a method for preparing the compound represented by formula (I), which is the following method 1, method 2, method 3 or method 4:

[0393] Method 1: In a solvent, in the presence of a base, subjecting the compound represented by formula I'-1A to ester hydrolysis reaction to obtain the compound represented by formula (I);

[0394] Each R 1a -C(=O)OC 1-6 Alkyl or 1, 2 or more R 1a-1 Substituted C 1-6Alkyl; each R 1a-1 -C(=O)OC 1-6 Alkyl; each R1 is COOH or C substituted by 1, 2 or more COOH 1-6 Alkyl; m is 1, 2, 3, 4 or 5;

[0395] Ring A, Ring B, L1, R2, X1, X2, X3, X4, R3, W, m, n and p are as defined in any embodiment of the present invention;

[0396] Method 2: In a solvent, in the presence of a base, a phosphine ligand and a catalyst, the compound represented by formula I'-1B and the compound represented by formula I'-1C are reacted as shown in the following formula to obtain the compound represented by formula (I);

[0397] X is a halogen (e.g., iodine); Ring A, Ring B, R1, L1, R2, X1, X2, X3, X4, R3, W, m, n, and p are as defined in any embodiment of the present invention; V is H, -TMS, or TBDMS;

[0398] Method 3: reacting the compound represented by formula I'-1D in a solvent in the presence of cyanide and a catalyst to obtain the compound represented by formula (I);

[0399] The cyanide is trimethylsilyl cyanide, potassium cyanide or sodium cyanide;

[0400] Each R 1a C substituted by 1, 2 or more -OM 1-6 Alkyl; each R1 is COOH or C substituted by 1, 2 or more cyano groups 1-6 Alkyl; wherein M is selected from methanesulfonyl (Ms), p-toluenesulfonyl (Ts) or p-nitrobenzenesulfonyl (Ns);

[0401] Ring A, Ring B, L1, R2, X1, X2, X3, X4, R3, W, m, n and p are as defined in any embodiment of the present invention;

[0402] Method 4:

[0403] Step 1) reacting a compound represented by Formula I'-1E with a compound represented by Formula I'-1F or a salt thereof in the presence of an acylating agent to obtain a compound represented by Formula I'-1G;

[0404] Step 2) In a solvent, in the presence of a base, subjecting the compound represented by Formula I'-1G to ester hydrolysis to obtain a compound represented by Formula (I-I');

[0405] Each R1a -C(=O)OC 1-6 Alkyl or 1, 2 or more R 1a-1 Substituted C 1-6 Alkyl; each R 1a-1 -C(=O)OC 1-6 Alkyl; each R1 is COOH or C substituted by 1, 2 or more COOH 1-6 Alkyl; m is 1, 2, 3, 4 or 5;

[0406] Ring A, Ring B, L1, R2, X1, X2, X3, X4, R3, R4, R5, R6, R7, m, n and p are defined as described in any embodiment of the present invention.

[0407] In a preferred embodiment, in method 1 or method 4, the solvent is a mixed solvent of an alcohol solvent and water, or an alcohol solvent and tetrahydrofuran; for example, a mixed solvent of methanol and water, for example, a mixed solvent in which the volume ratio of methanol to water is 5:2, 4:1, 3:1, 2:1 or 1:1; for example, a mixed solvent of methanol and tetrahydrofuran, for example, a mixed solvent in which the volume ratio of methanol to water is 1:1 or 2:1.

[0408] In a preferred embodiment, in method 1 or method 4, the base is an inorganic base, such as lithium hydroxide monohydrate and / or lithium hydroxide, and another example is lithium hydroxide monohydrate.

[0409] In a preferred embodiment, in method 1 or method 4, the temperature of the ester hydrolysis reaction is 20-70°C, such as 25°C, 40°C, 50°C or 60°C.

[0410] In a preferred embodiment, in method 1 or method 4, the ester hydrolysis reaction time is 0.5-20 h, such as 1 h, 2 h, 4 h or 16 h.

[0411] In a preferred embodiment, in method 1 or method 4, the ester hydrolysis reaction further comprises the following post-treatment after completion: adjusting the pH value to acidic or neutral, for example, using dilute hydrochloric acid (dilute hydrochloric acid (1 M)) to adjust the pH value to 3, 5, 6 or 7.

[0412] In a preferred embodiment, in method 2, the solvent is an ether solvent, such as 1,4-dioxane.

[0413] In a preferred embodiment, in method 2, the base is potassium carbonate and / or triethylamine.

[0414] In a preferred embodiment, in method 2, the phosphine ligand is bis(triphenylphosphine)palladium dichloride.

[0415] In a preferred embodiment, in method 2, the catalyst is cuprous iodide and / or cesium fluoride.

[0416] In a preferred embodiment, in method 2, the reaction is carried out under an inert atmosphere, such as a nitrogen atmosphere.

[0417] In a preferred embodiment, in method 2, the reaction temperature is 50-100°C, such as 50°C, 70°C, 80°C, 90°C or 100°C.

[0418] In a preferred embodiment, in method 2, the reaction time is 0.5-6 hours, preferably 0.5-5 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours.

[0419] In a preferred embodiment, in method 3, the solvent is a nitrile solvent, such as acetonitrile.

[0420] In a preferred embodiment, in method 3, the catalyst is an ammonium catalyst, such as tetrabutylammonium fluoride.

[0421] In a preferred embodiment, in method 3, the reaction temperature is 50-100°C, for example 80°C.

[0422] In a preferred embodiment, in method 3, the reaction time is 1-3 hours, such as 1 hour or 2 hours.

[0423] In a preferred embodiment, in method 4, the acylating agent connects the -OH of the compound represented by formula I'-1E and the -NH- in the compound represented by formula I'-1F through the carbonyl group in the reaction system to generate a compound represented by formula I'-1G; preferably, the acylating agent is p-nitrophenyl chloroformate, N,N'-disuccinimidyl carbonate, p-nitrophenyl chloroformate, di(p-nitrophenyl) carbonate, 2,2,2-trichloroethyl chloroformate, isopropenyl chloroformate, phenyl chloroformate, dimethyl carbonate, triphosgene or N,N'-carbonyldiimidazole.

[0424] In a preferred embodiment, in step 1) of method 4, the acylating agent forms an active ester with the compound of formula I'-1E, which then reacts with the compound of formula I'-1F to form the compound of formula I'-1G.

[0425] In a preferred embodiment, in method 4, the salt of the compound represented by formula I'-1F is the hydrochloride salt of the compound represented by formula I'-1F.

[0426] The compounds of formula (I) of the present invention, their racemates, stereoisomers, tautomers, nitrogen oxides, or pharmaceutically acceptable salts or prodrugs thereof may also be synthesized by methods similar to those known in the chemical field, the steps and conditions of which may be referenced to the steps and conditions of similar reactions in the art, particularly as described herein. The starting materials are typically obtained from commercial sources or can be readily prepared using methods known to those skilled in the art (e.g., as available from SciFinder or Reaxys online databases).

[0427] The present invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a substance U and a pharmaceutical excipient, wherein the substance U is a compound represented by formula (I) according to any one of the present invention, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof.

[0428] According to the present invention, the pharmaceutical composition of the present invention can be prepared into a dosage form suitable for administration by methods known in the art.

[0429] The present invention further provides a use of the above-mentioned substance U or the above-mentioned pharmaceutical composition in the preparation of an LPAR1 antagonist; the LPAR1 antagonist can be used in mammalian organisms; it can also be used in vitro, for example, for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of LPAR1 antagonists.

[0430] The present invention further provides a use of the above-mentioned substance U or the above-mentioned pharmaceutical composition in preparing a drug.

[0431] In a preferred embodiment, the drug is a drug for diagnosing, preventing and / or treating diseases or conditions mediated by LPAR receptors.

[0432] In a preferred embodiment, the drug is a drug for diagnosing, preventing and / or treating diseases or conditions mediated by LPAR1 receptor.

[0433] In a preferred embodiment, the drug is an LPAR1 antagonist.

[0434] In a preferred embodiment, the disease or condition is fibrotic disease, respiratory disease, pain, nervous system disease, cardiovascular and cerebrovascular disease, inflammatory disease, kidney disease, liver disease, eye disease, cancer, gastrointestinal disease, urinary system disease, metabolic disease or transplant rejection.

[0435] In a preferred embodiment, the fibrotic disease includes but is not limited to: pulmonary fibrosis (especially idiopathic pulmonary fibrosis, progressive pulmonary fibrosis), kidney fibrosis, liver fibrosis, skin fibrosis, intestinal fibrosis, eye fibrosis, cardiac fibrosis, and pancreatic fibrosis.

[0436] In a preferred embodiment, the respiratory diseases include but are not limited to interstitial lung disease (ILD), idiopathic interstitial pneumonia (IIP), asthma, chronic obstructive pulmonary disease (COPD), bronchospasm, cough, chronic cough, respiratory failure, silicosis, acute lung injury, and acute respiratory distress.

[0437] In a preferred embodiment, the kidney disease includes but is not limited to: acute kidney injury, chronic kidney disease, and diabetic nephropathy.

[0438] In a preferred embodiment, the liver disease includes but is not limited to alcoholic steatohepatitis, non-alcoholic fatty liver disease (NAFLD), acute hepatitis, chronic hepatitis, cirrhosis, hepatic dysfunction, primary biliary cirrhosis and other liver diseases; the non-alcoholic fatty liver disease (NAFLD) may be non-alcoholic steatohepatitis (NASH).

[0439] In a preferred embodiment, the inflammatory disease includes but is not limited to: autoimmune disease, inflammation, arthritis, rheumatoid arthritis, scleroderma, Raynaud's phenomenon, chronic pruritus, lupus, cryptogenic fibrosing alveolitis, psoriasis, systemic sclerosis, and collagen vascular disease.

[0440] In a preferred embodiment, the nervous system diseases include but are not limited to: Alzheimer's disease, Parkinson's disease, neurodegenerative diseases, traumatic brain injury, epilepsy, mental illness, and sleep disorders.

[0441] In a preferred embodiment, the cardiovascular and cerebrovascular diseases include but are not limited to: collagen vascular disease, myocardial infarction, stroke, thrombosis, atherosclerosis, heart failure, and hypertension.

[0442] In a preferred embodiment, the gastrointestinal diseases include but are not limited to: colon syndrome, inflammatory bowel disease, digestive tract diseases, and gastrointestinal dysfunction.

[0443] In a preferred embodiment, the pain includes but is not limited to cancer pain, neuropathic pain, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain caused by burns, migraine, or cluster headache, and chronic pain.

[0444] In a preferred embodiment, the urinary system diseases include urinary incontinence, dysuria, cystitis, benign prostatic hyperplasia, urination disorder associated with benign prostatic hyperplasia, bladder neck sclerosis, and underactive bladder.

[0445] In a preferred embodiment, the eye disease includes macular degeneration and diabetic retinopathy.

[0446] In a preferred embodiment, the cancer includes but is not limited to: breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, liver cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, and tumor metastasis.

[0447] In a preferred embodiment, the metabolic disease includes but is not limited to osteoporosis.

[0448] In a preferred embodiment, the disease or disorder is interstitial lung disease, pulmonary fibrosis (particularly idiopathic pulmonary fibrosis), liver fibrosis, kidney fibrosis, non-alcoholic fatty liver disease (such as non-alcoholic steatohepatitis), psoriasis, or scleroderma.

[0449] The present invention also provides a method for diagnosing, preventing and / or treating a disease or condition, which comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of formula (I) according to any one of the present invention, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition, alone or in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0450] The disease or condition is as described in any embodiment of the present invention.

[0451] The compounds of the present invention may be used in combination with additional therapeutic agents.

[0452] Definitions and Explanations of Terms

[0453] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0454] The term "optionally" means that it may be substituted or unsubstituted. Unless otherwise specified, the type and number of the substituents can be any on the basis of chemical practicability. 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Substitution means unsubstituted C 1- 6 alkyl or 1, 2 or more R c Substituted C 1-6 alkyl.

[0455] When any variable (such as R a 、C 1-6When an alkyl group appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition of the other positions. Their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by one, two or more R a Group substitution, that is, the group may be replaced by 3 or more R a Replace, the position R a Definition and other positions R a In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0456] When a substituent appears multiple times in the definition of a compound, these multiple occurrences of the same substituent are collectively referred to as "each" in the unified definition. For example, C 1-6 Alkyl groups appear multiple times in the definition of compounds. When unifying the definition, these multiple occurrences of C 1-6 Alkyl groups are collectively referred to as "each C 1-6 Alkyl", their meanings are independent of each other and do not affect each other.

[0457] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0458] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site. For example, -C 2-3 Alkylene COOH refers to the C 2-3 The alkylene group is linked to other fragments in the molecule, not the COOH group.

[0459] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0460] Unless otherwise indicated, the term "cis-trans isomers" refers to isomers resulting from the inability to rotate freely about double bonds or single bonds of ring carbon atoms.

[0461] The "room temperature" described in this specification should be understood as the ambient temperature during the experiment, for example, 10-35° C., preferably 25° C.±5° C. The "room temperature" described in this specification is represented as "rt" in the reaction flow chart.

[0462] In this application specification, "more" means 3 or more, such as 3, 4, 5 or 6.

[0463] In the claims of this application, the term "multiple" in the phrase "satisfies one or more of the following conditions" refers to 2, 3, 4, or more conditions. The maximum value of "more" is the maximum number of conditions recited in each claim. For example, if a claim recites 8 conditions, the term "one or more" in the phrase "satisfies one or more of the following conditions" in that claim can be any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7, or 8.

[0464] The term "C n-m ” and “C n -C m ", where n and m are integers, represents a group containing n to m carbon atoms. Examples include C 1-6 、C 1-3 etc. The term is intended to specifically disclose each member within the scope, i.e., C n 、C n+1 、C n+2 ......C m-2 、C m-1 、C m For example, C 1-6 Intended to disclose C1, C2, C3, C4, C5 and C6. n-m " means the same as "C n -C m "same.

[0465] The term "n-membered," where n is an integer, generally describes a ring wherein the number of atoms forming the ring is n.

[0466] The term "nm-membered," where n and m are integers, describes a range in which the number of ring atoms is n to m. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, and pyridinyl is an example of a 6-membered heteroaryl ring.

[0467] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to reciting each integer value in the numerical range "1-10", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0468] The term "oxo (=O)" refers to the replacement of hydrogen or lone electron pairs on non-oxygen atoms with oxygen, for example, After being oxygenated After being oxygenated

[0469] The term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group. 1-6 Alkyl, C 1-3 Alkyl, C 1-4 Alkyl, C 3- 4 alkyl, C 4-6 Alkyl, etc. Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, 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, 1,2-dimethylbutyl, etc., or isomers thereof.

[0470] The term "alkylene" refers to a substituent formed by eliminating two hydrogen atoms from a straight or branched alkane. The two hydrogen atoms eliminated can be on the same carbon atom or on different carbon atoms (for example, the two hydrogen atoms eliminated are on the carbon atoms at the two ends). The alkylene group includes C 1-6 Alkylene, C 1-3 Alkylene, C 1-4 Alkylene, C 3-4 Alkylene, C 4-6 Alkylene, C 2-3 Thus, C1 alkylene (i.e., methylene) refers to -CH2-, C2 alkylene (i.e., ethylene) refers to -CH2-CH2- or -CH(CH3)-, and C3 alkylene (i.e., propylene) refers to -CH2-CH2-CH2-, -CH(CH2-CH3)-, -C(CH3)2-, -CH2-CH(CH3)-.

[0471] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0472] The term "C 2-6 "Alkynylene" refers to a substituent formed by eliminating two hydrogen atoms from a straight or branched alkyne having 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. The one or more carbon-carbon triple bonds may be internal or terminal. The alkynyl group includes, but is not limited to, ethynylene, 1-propynylene, 2-propynylene, 2-pentynylene, 3-butynylene, 1-butynylene, and the like.

[0473] The term "cycloalkyl" refers to a cyclic alkyl group having a specified number of ring atoms, including monocyclic, bicyclic or tricyclic alkyl groups, wherein the bicyclic and tricyclic alkyl groups include fused rings, bridged rings or spiro rings. 3-10 Cycloalkyl, C 3-8 Cycloalkyl, C 4-8 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 4-6 Cycloalkyl, C 3-4 Cycloalkyl, C 5-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, spiro[2.4]heptyl, bicyclo[2.2.2]octyl, and the like.

[0474] The term "heterocycloalkyl" refers to a saturated ring or ring system having a specified number of ring atoms (e.g., 3-10 members, 3-8 members) and containing 1, 2 or 3 heteroatoms selected from O, S and N, with the remaining ring atoms being carbon atoms, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)- or -S(=O)2-. The 3-10 membered heterocycloalkyl may be a 3-, 4-, 5-, 6- or 7-membered monocyclic ring, a 5-, 6-, 7-, 8-, 9- or 10-membered bicyclic ring or a 10-membered tricyclic ring system, wherein the bicyclic and tricyclic ring systems include fused rings, bridged rings or spiro rings. The heterocycloalkyl includes 3-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 4-5 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, and the like. Examples of the heterocycloalkyl group include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl (oxolanyl), pyrrolidinyl (azacyclopentyl), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl (oxhexyl), piperidinyl (azepanyl), oxirane, oxepanyl, oxocanyl, aziridine, azepanyl or azocanyl, and the like.

[0475] The term "C 6-10 "Aryl" means an aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, wherein the bicyclic and tricyclic hydrocarbon rings may be fused rings. Among them, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indenyl; or a ring having 10 carbon atoms ("C 10 Aryl "), such as naphthyl. When the C 6-10When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0476] The term "C 6-10 "Arylene" means a group formed by eliminating two hydrogen atoms from a monocyclic, bicyclic or tricyclic aromatic hydrocarbon having 6, 7, 8, 9 or 10 carbon atoms, wherein the bicyclic and tricyclic aromatic hydrocarbons may be fused rings. The ring having 6 carbon atoms ("C6 arylene"), for example, phenylene; or a ring having 9 carbon atoms ("C9 arylene"), for example, indenylene; or a ring having 10 carbon atoms ("C 10 arylene”), such as naphthylene. When the C 6-10 When the arylene group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution position, and for example, the substitution may be at the ortho, para, or meta position.

[0477] The term "5-10 membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group having 5-10 ring atoms, wherein the ring atoms include 1-3 heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms. The bicyclic and tricyclic aromatic groups may be fused rings. In the case of a bicyclic or tricyclic aromatic group, at least one ring is aromatic. The 5-10 membered heteroaryl group preferably has 1-2 heteroatoms. The 5-10 membered heteroaryl group includes a 4-9 membered heteroaryl group, a 5-9 membered heteroaryl group, a 6-9 membered heteroaryl group, a 5-7 membered heteroaryl group, an 8-10 membered heteroaryl group, a 5-6 membered heteroaryl group, a 6 membered heteroaryl group, and the like. The example of heteroaryl includes but is not limited to oxazolyl, pyrazolyl, triazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, furazolyl, thiadiazolyl, oxathiazolyl, furyl, pyrrolyl etc., and their benzo derivatives.When described 5-10 yuan heteroaryl is substituted, it can be monosubstituted or polysubstituted.And, its substitution site is not limited, for example, can be that the hydrogen that is connected to carbon atom on heteroaryl ring is substituted, or the hydrogen that is connected to heteroatom on heteroaryl ring is substituted.

[0478] Optionally, the bicyclic and tricyclic aromatic groups independently may be benzo-fused, such as, but not limited to, benzopiperidinyl, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, and the like. The "5-10 membered heteroaryl" may be bicyclic, for example but not limited to: a 5,5 membered ring, such as 4,6-dihydro-1H-furo[3,4-c]pyrazolyl, 2,6-dihydro-4H-furo[3,4-c]pyrazolyl, 5,6-dihydro-1H-furo[3,2-c]pyrazolyl, 5,6-dihydro-2H-furo[3,2-c]pyrazolyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 2,4,5,6-tetracyclopenta[c]pyrazolyl, etc.; a 5,6 membered ring, such as 6,7-dihydro-5H-cyclopentadienyl[d]pyrimidinyl, etc.

[0479] The term "heteroarylene" refers to a monocyclic, bicyclic, or tricyclic heteroaromatic hydrocarbon containing a specified number of ring atoms (e.g., 5-7, 5-6, 8-10 members) and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon atoms, formed by eliminating two hydrogen atoms. The bicyclic and tricyclic heteroarylene groups may be fused rings. At least one ring in the bicyclic and tricyclic heteroarylene groups is aromatic. The heteroarylene groups include 5-7 membered heteroarylene groups, 5-6 membered heteroarylene groups, 6 membered heteroarylene groups, 8-10 membered heteroarylene groups, and the like. Examples of the heteroarylene group include, but are not limited to, oxazolylene, pyrazolylene, triazolylene, thienylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, imidazolylene, tetrazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, furazanylene, thiadiazolylene, oxathiazolylene, furanylene, pyrrolylene, triazinylene, and the like, and benzo derivatives thereof.

[0480] The term "heterocyclyl" refers to a saturated or partially unsaturated non-aromatic ring or ring system having a specified number of ring atoms (e.g., 3-10, 3-8, 3-6), and its ring atoms contain 1-5 heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein N and S can also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2-. The heterocyclyl can be a 3-, 4-, 5-, 6-, or 7-membered monocyclic, a 5-, 6-, 7-, 8-, 9-, or 10-membered bicyclic or 10-membered tricyclic ring system, and the bicyclic and tricyclic ring systems include fused rings, bridged rings, or spirocycles. The 3-10 membered heterocyclyl includes a 3-6 membered heterocyclyl, a 4-8 membered heterocyclyl, a 4-6 membered heterocyclyl, a 4-5 membered heterocyclyl, and the like. The heterocyclic group may be attached to the rest of the molecule via any carbon atom or nitrogen atom (if present) in the ring. Examples of heterocyclic groups include, but are not limited to, 4-membered rings such as azetidinyl and oxetanyl, 5-membered rings such as tetrahydrofuranyl, dihydrofuranyl, dioxolyl, 2,3-dihydro-1H-imidazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or 6-membered rings such as dihydropyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0481] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0482] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0483] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0484] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0485] It will be appreciated by those skilled in the art 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 base addition salts; 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 internal salts.

[0486] According to its molecular structure, the compound of the present invention can be chiral (having one or more stereocenters), so various enantiomeric forms or diastereomeric forms may exist. Thus these compounds can exist in racemic form or optically active form. The compound of the present invention encompasses isomers or mixtures thereof, racemates in which each chiral carbon is in R or S configuration. The compound of the present invention or its intermediate can be separated into enantiomeric compounds by chemical or physical methods well 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 reacting with an optically active resolution agent.

[0487] In some embodiments, the compounds of the present invention have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds having more than one chiral center, unless otherwise indicated, each chiral center in the compound can independently be (R) or (S). In some embodiments, the compounds of the present invention are trans isomers. In other embodiments, the compounds of the present invention are cis isomers.

[0488] The compounds described herein may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0489] 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.

[0490] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit 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) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents 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) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

[0491] The term "pharmaceutical excipients" refers to excipients and additives used in the production of medicines and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations in addition to the active ingredients.

[0492] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0493] The reagents and raw materials used in the present invention are commercially available.

[0494] The positive progress of the present invention is that the present invention provides a class of LPAR1 antagonist compounds represented by formula (I), which have good LPAR1 antagonist activity and selectivity, as well as excellent pharmacokinetic and pharmacodynamic properties, have good drug development prospects, and can be used to prevent or treat diseases or conditions related to LPAR1. DETAILED DESCRIPTION

[0495] The following will further describe in detail the general formula compounds of the present invention, their preparation methods, and applications with reference to specific examples. The following examples are intended only to illustrate and explain 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 encompassed within the scope of protection intended by the present invention.

[0496] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0497] Method summary:

[0498] The chiral purity of the compounds of the present invention was tested using the following HPLC method:

[0499] HPLC method A: CHIRALPAK CHIRALPAK AD-H, 4.6*250 mm 5 μm, 30% isopropanol / n-hexane, 0.8 mL / min, 30°C.

[0500] Nouns and representative reagents

[0501] Unless otherwise specified, the nouns used in the following experimental descriptions represent the following reagents:

[0502] TMS: tetramethylsilane; DPPA: diphenylphosphoryl azide; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DHP: 3,4-dihydro-2H-pyran; DIPEA: N,N-diisopropylethylamine; DCM: dichloromethane; THF: tetrahydrofuran; T3P: 1-propylphosphoric anhydride; Et3N or TEA: triethylamine; TMSN3: trimethylsilyl azide; Ag NTf2: silver bis(trifluoromethanesulfonyl imide); TsNHNH2: 4-toluenesulfonylhydrazine; MeI: iodomethane; KI: potassium iodide; CuI: cuprous iodide; NaI: sodium iodide; NaH: sodium hydride; CsF: cesium fluoride; TBHP: tert-butyl peroxide; n-BuLi: n-butyl lithium; BF3-Et2O: boron trifluoride etherate; PPTS: 4-methylbenzenesulfonate pyridinium; MeONa: sodium methoxide; A cONa: sodium ethoxide; MeOH: methanol; MeCN: acetonitrile; AcOH: ethanol; PPh3: triphenylphosphine; BnBr: benzyl bromide; DMSO: dimethyl sulfoxide; Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium dichloride; Ru(PPh3)2(CP)2Cl: pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride; DAST: diethylaminosulfur trifluoride; NHBn2: dibenzylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; PIDA: iodophenyldiacetic acid; TEMPO: 2,2,6,6-tetramethylpiperidinium oxide; TMSCHN2: trimethylsilylated diazomethane; TMSCH2N3: trimethylsilylmethyl azide; TBAF: tetrabutylammonium fluoride; TBAI: tetrabutylammonium iodide; (HCHO) n : paraformaldehyde; (COCl)2: oxalyl chloride; MsCl: methanesulfonyl chloride; TMSCN: trimethylsilyl cyanide; NaBH4: sodium borohydride; MeMgBr: methylmagnesium bromide; DEA: diethanolamine; TBDMSCl: tert-butyldimethylchlorosilane; NaHCO3: sodium bicarbonate; K2CO3: potassium carbonate; Py: pyridine; BzCl: benzoyl chloride; DMP: (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoyl-3(1H)-one; BAST: bis(2-methoxy)-1,1-dihydro-1,2-benzidoyl-3(1H)-one The following ingredients are used as the raw materials: (a) 1-(3-dimethylaminopropyl)aminosulfur trifluoride; (b) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (c) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (d) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (e) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (e) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (e) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (f) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (g) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (h ...

[0503] Preparation Example

[0504] Preparation Example 1 Preparation of methyl 2-(1-((trimethylsilyl)ethynyl)cyclopropyl)acetate (M001) and methyl 2,2-difluoro-2-(1-((trimethylsilyl)ethynyl)cyclopropyl)acetate (M001')

[0505] (1) At room temperature, (cyclopropylethynyl)trimethylsilane (20 g, 140 mmol) was dissolved in diethyl ether (250 mL). The reaction solution was cooled to -78°C and n-butyllithium solution (58 mL, 145 mmol, 2.5 M in n-hexane) was added dropwise. After the addition was complete, the reaction solution was stirred at -78°C for 1 hour and then heated to room temperature and stirred for 16 hours. The reaction solution was then cooled to -78°C and ethylene oxide (47 mL, 180 mmol, 4 M in tetrahydrofuran) was added dropwise. The reaction solution was stirred at -78°C for 0.5 hour and then heated to room temperature and stirred for another hour. The reaction solution was poured into a saturated ammonium chloride solution (200 mL) to quench the mixture and extracted with diethyl ether (50 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound M001-1 (10.6 g).

[0506] (2) Compound M001-1 (12.7 g, 69.6 mmol) was dissolved in acetonitrile (130 mL) and water (130 mL) at room temperature. After the reaction solution was cooled to 0°C, PIDA (56.1 g, 174.1 mmol) and 2,2,6,6-tetramethylpiperidinyl oxide (2.2 g, 13.9 mmol) were slowly added in batches. The reaction solution was heated to 40°C and stirred for 4 hours. The resulting reaction solution was poured into a sodium sulfite aqueous solution (200 mL) for quenching, extracted with ethyl acetate (100 mL), and the organic phases were combined. The resulting organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M001-2 (5.6 g).

[0507] (3) Compound M001-2 (5.6 g, 28.5 mmol) was dissolved in methanol (50 mL) and dichloromethane (100 mL) at room temperature. In a nitrogen atmosphere, the reaction solution was cooled to 0°C, and trimethylsilylated diazomethane solution (28 mL, 57.0 mmol, 2 M n-hexane solution) was added dropwise. After the addition was completed, the reaction solution was stirred at this temperature for 0.5 hours. Then, the temperature was raised to room temperature and the stirring was continued for 1 hour. The resulting reaction solution was diluted with water (200 mL), extracted with dichloromethane (100 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M001 (5.1 g). LC-MS [M+H] + =211.10.

[0508] 1 H NMR (400MHz, CD3OD): δ3.71(s,3H),2.38(s,2H),1.05–1.02(m,2H),0.80–0.77(m,2H),0.11(s,9H).

[0509] (4) Compound M001 (1 g, 4.75 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature. The reaction solution was cooled to -78°C (dry ice-ethyl acetate bath) in a nitrogen atmosphere, and then lithium bis(trimethylsilyl)amide (5.7 mL, 5.7 mmol, 1 M tetrahydrofuran solution) was added dropwise. The reaction solution was stirred at this temperature for 0.5 hour, and then a solution of N-fluorobisbenzenesulfonamide (1647.65 mg, 5.23 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction solution was warmed to room temperature and stirred for 1 hour. The reaction mixture was then cooled again to -78°C (dry ice-ethyl acetate bath) and lithium bis(trimethylsilyl)amide (5.7 mL, 5.7 mmol, 1 M solution in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at this temperature for 0.5 hours, followed by the addition of a solution of N-fluorobisbenzenesulfonamide (1647.65 mg, 5.23 mmol) in tetrahydrofuran (10 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched by pouring into saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to yield compound M001' (320 mg, crude product). LC-MS: [M+H]+ = 247.09.

[0510] Preparation Example 2 Preparation of 3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (M003)

[0511] (1) At room temperature, 3,6-dibromo-2-methylpyridine (50 g, 199.27 mmol) and 2-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (41.9 g, 298.9 mmol) were dissolved in acetonitrile (500 mL), and bis(triphenylphosphine)palladium dichloride (7.0 g, 9.96 mmol), cuprous iodide (2.0 g, 9.96 mmol) and triethylamine (60.0 g, 597.8 mmol) were added. The reaction mixture was heated to 50°C under a nitrogen atmosphere and stirred for 1.5 hours. The resulting reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M002-1 (60.0 g). LC-MS: [M+H] + =311.95.

[0512] (2) Compound M002-1 (60.0 g, 0.19 mol) and trimethylsilylmethyl azide (50 g, 0.38 mol) were dissolved in anhydrous tetrahydrofuran (600 mL) at room temperature, and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride (15 g, 0.019 mol), tetrabutylammonium iodide (7.0 g, 0.019 mol) and cuprous iodide (3.6 g, 0.019 mol) were added. The reaction solution was heated to 40°C in a nitrogen atmosphere and stirred for 16 hours. The resulting reaction solution was cooled to room temperature and then directly concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M002 (68.0 g). LC-MS: [M+H] + =439.00.

[0513] (3) Compound M002 (68.0 g, 155.21 mmol) was dissolved in tetrahydrofuran (600 mL) at room temperature, and tetrabutylammonium fluoride (48.7 g, 186.26 mmol) was added in batches. The reaction solution was stirred at room temperature for 1 hour. The resulting reaction solution was directly concentrated under reduced pressure, and the residue was diluted with water (120 mL) and extracted with ethyl acetate (60 mL). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M003 (42.2 g). LC-MS: [M+H] + =367.00.

[0514] Preparation Example 3 Preparation of 4-(5-iodo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (M004) and 4-(5-iodo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (M005)

[0515] (1) At room temperature, M003 (5 g, 13.6 mmol) and N,N'-dimethylethylenediamine (720 mg, 8.2 mmol) were dissolved in 1,4-dioxane (50 mL), and sodium iodide (10.3 g, 68.7 mmol) and cuprous iodide (260 mg, 1.4 mmol) were added. Under a nitrogen atmosphere, the reaction solution was heated to 100°C and stirred for 24 hours. The resulting reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M004-1 (5.5 g). LC-MS: [M+H] + =415.00.

[0516] (2) Compound M004-1 (5.5 g, 13.3 mmol) was dissolved in methanol (60 mL) at room temperature, and 4-methylbenzenesulfonic acid pyridine (3.3 g, 13.3 mmol) was added. The reaction solution was heated to 60°C and stirred for 16 hours. The resulting reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M004 (4.5 g). LC-MS: [M+H] + =330.95.

[0517] (3) Compound M004 (4.5 g, 13.6 mmol) was dissolved in acetonitrile (50 mL) and water (35 mL) at room temperature, and potassium permanganate (4.3 g, 27.2 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. Aqueous sodium hydroxide solution (2 M, 50 mL) was added to the resulting reaction solution, and the mixture was filtered under reduced pressure. The filtrate was extracted with ethyl acetate (50 mL). The combined aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (1 M), filtered under reduced pressure, and the filter cake was rinsed with pure water (30 mL) and dried under reduced pressure to obtain compound M005 (2.8 g). LC-MS: [M+H] + =344.95.

[0518] Preparation Example 4 Preparation of methyl 2-(1-ethynylcyclopropyl)acetate (M006)

[0519] (1) 5-Oxaspiro[2.4]heptan-6-one (2.24 g, 20 mmol) was dissolved in methanol (20 mL) at room temperature. The reaction mixture was cooled to 0°C, and a methanol solution of sodium methoxide (4.8 mL, 5 M) was added. The reaction mixture was stirred at 0°C for 15 minutes, and then ammonium chloride (2.0 g, 37.4 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was directly concentrated under reduced pressure. The residue was diluted with water (30 mL), extracted with dichloromethane (30 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M006-1 (2.88 g, crude product).

[0520] 1 H NMR (400MHz, CDCl3): δ3.66(s,3H),3.46(s,2H),2.73(s,1H),2.41(s,2H),0.55–0.52(m,2H),0.49–0.42(m,2H).

[0521] (2) Oxalyl chloride (5.08 g, 40 mmol) was dissolved in dichloromethane (30 mL) at room temperature. The reaction solution was cooled to -78°C. Then, a solution of dimethyl sulfoxide (6.24 g, 80 mmol) in dichloromethane (10 mL) was added dropwise to the reaction solution, and the reaction temperature was controlled to be no higher than -70°C. After the addition was complete, the reaction solution was stirred at -78°C for 0.5 hours. Then, a solution of M006-1 (2.88 g, 20 mmol) in dichloromethane (10 mL) was slowly added dropwise to the reaction solution, and the reaction temperature was controlled to be no higher than -70°C. The reaction solution was stirred at -78°C for 0.5 hours. At this time, triethylamine (16.16 g, 160 mmol) was added dropwise, and the reaction temperature was controlled to be no higher than -65°C. After the addition was complete, the reaction solution was stirred at -78°C for 0.5 hours, then heated to room temperature and stirred for 0.5 hours. The resulting reaction mixture was poured into dichloromethane (200 mL) and washed with water (200 mL). The resulting organic phase was washed sequentially with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide compound M006-2 (2.4 g, crude product).

[0522] 1 H NMR (400MHz, CDCl3): δ8.66(s,1H), 3.64(s,3H), 3.46(s,2H), 1.29–1.25(m,2H), 1.07–1.03(m,2H).

[0523] (3) M006-2 (2.4 g, 16.9 mmol) was dissolved in methanol (90 mL) at room temperature. The reaction solution was cooled to 0°C and potassium carbonate (4.7 g, 33.8 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (4.9 g, 25.4 mmol) were added. The reaction solution was warmed to room temperature and stirred for 3 hours. The resulting reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M006 (1.3 g).

[0524] 1 H NMR (400MHz, CDCl3): δ3.70(s,3H), 2.37(s,2H), 1.87(s,1H), 1.04–1.01(m,2H), 0.77–0.74(m,2H).

[0525] Preparation Example 5 Preparation of methyl 2-(1-ethynylcyclobutyl)acetate (M007)

[0526] (1) At room temperature, 1,1-cyclobutane dimethanol (4.0 g, 34.44 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and N,N-dimethylformamide (20 mL). The reaction solution was cooled to 0°C, and sodium hydride (1.4 g, 34.44 mmol, 60% dispersed in mineral oil) was added in batches. The reaction solution was heated to room temperature and stirred for 2 hours, and then benzyl bromide (3.5 g, 34.44 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The resulting reaction solution was poured into a saturated aqueous ammonium chloride solution (50 mL) for quenching, extracted with ethyl acetate (50 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5 / 1) to obtain compound M007-1 (5.3 g). LC-MS [M+H] + =207.15.

[0527] (2) Compound M007-1 (5.3 g, 25.69 mmol) was dissolved in dichloromethane (60 mL) at room temperature. After the reaction solution was cooled to 0°C, triethylamine (4.3 mL, 30.83 mmol) and methanesulfonyl chloride (2.2 mL, 28.26 mmol) were added. The reaction solution was stirred at 0°C for 2 hours. The resulting reaction solution was poured into water (50 mL) for quenching, extracted with dichloromethane (50 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M007-2 (7.3 g, crude product).

[0528] (3) Compound M007-2 (7.3 g, 25.67 mmol) was dissolved in N,N-dimethylformamide (80 mL) at room temperature. Trimethylsilyl cyanide (5.1 g, 51.34 mmol) and tetrabutylammonium fluoride (13.4 g, 51.34 mmol) were added. The reaction temperature was raised to 130°C and stirred for 2 hours. The resulting reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M007-3 (4.7 g). LC-MS [M+H] + =216.00.

[0529] (4) Compound M007-3 (2.7 g, 12.54 mmol) was dissolved in a mixed solvent of ethanol (30 mL) and water (30 mL) at room temperature, and potassium hydroxide (2.8 g, 50.16 mmol) was added. The reaction solution was heated to 100°C and stirred for 7 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to remove ethanol. The residue was washed with dichloromethane (30 mL), and the aqueous phases were combined. The aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid (1 M), extracted with ethyl acetate (30 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound M007-4 (1.9 g). LC-MS [M+H] + =235.10.

[0530] (5) Compound M007-4 (3.4 g, 14.51 mmol) was dissolved in methanol (100 mL) at room temperature and cooled to 0°C. Thionyl chloride (5.3 mL, 72.56 mmol) was added dropwise. After the addition was complete, the reaction solution was heated to 80°C and stirred for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M007-5 (3.4 g). LC-MS [M+H] + =249.15.

[0531] (6) Compound M007-5 (3.4 g, 13.69 mmol) was dissolved in methanol (100 mL) at room temperature, and wet palladium on carbon (500 mg, 10%) was added. The reaction mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The resulting reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound M007-6 (2.0 g). LC-MS [M+H] + =139.16.

[0532] (7) Oxalyl chloride (0.2 mL, 2.53 mmol) was dissolved in anhydrous dichloromethane (10 mL) at room temperature. The reaction solution was cooled to -78°C and dimethyl sulfoxide (0.4 mL, 5.06 mmol) was slowly added dropwise while controlling the internal temperature below -70°C. After the addition was complete, the reaction solution was stirred at -78°C for 0.5 h. A solution of compound M007-6 (200 mg, 1.26 mmol) in dichloromethane (4 mL) was then slowly added dropwise while controlling the internal temperature below -70°C. After the addition was complete, the reaction solution was stirred at -78°C for 0.5 h. Triethylamine (1.4 mL, 10.11 mmol) was slowly added dropwise to quench the reaction while controlling the internal temperature below -70°C. After the addition was complete, the reaction solution was stirred at -70°C for 0.5 h. The resulting reaction solution was poured into water (20 mL), extracted with dichloromethane (10 mL), and the organic phases were combined. The obtained organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound M007-7 (190 mg, crude product).

[0533] (8) Compound M007-7 (190 mg, 1.22 mmol) was dissolved in methanol (5 mL) at room temperature. After the reaction solution was cooled to 0°C, dimethyl (1-diazo-2-oxopropyl)phosphonate (351 mg, 1.82 mmol) and potassium carbonate (420 mg, 3.04 mmol) were added. The reaction solution was warmed to room temperature and stirred for 16 hours. The resulting reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M007 (100 mg). LC-MS: [M+H] + =153.15.

[0534] Preparation Example 6 Preparation of (1-ethynylcyclopropyl)methanol (M008)

[0535] (1) At room temperature, (cyclopropylethynyl)trimethylsilane (5.0 g, 36.16 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). The nitrogen atmosphere was replaced, and the reaction solution was cooled to -78°C in a nitrogen atmosphere, and then n-butyllithium (21.7 mL, 54.23 mmol, 2.5 M) was added dropwise. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 16 hours. The reaction solution was then cooled to 0°C, and N,N-dimethylformamide (5.3 g, 72.31 mmol) was added dropwise at this temperature. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 2 hours. The resulting reaction solution was poured into a saturated aqueous ammonium chloride solution (50 mL) for quenching, extracted with ethyl acetate (50 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (pure petroleum ether) to obtain compound M008-1 (4.6 g, crude product).

[0536] (2) Compound M008-1 (4.6 g, 27.66 mmol) was dissolved in methanol (50 mL) at room temperature. The reaction mixture was cooled to 0°C and sodium borohydride (2.1 g, 55.32 mmol) was added in batches. The reaction mixture was stirred at 0°C for 1 hour. The resulting reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL). The organic phases were combined. The resulting organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M008-2 (3.8 g).

[0537] (3) Compound M008-2 (1.8 g, 10.69 mmol) was dissolved in dichloromethane (30 mL) at room temperature. 4-Methylbenzenesulfonic acid pyridine (269 mg, 1.07 mmol) and 3,4-dihydro-2H-pyran (1.2 g, 13.90 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The resulting reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M008-3 (2.6 g). LC-MS [M+H] + =253.42.

[0538] (4) Compound M008-3 (2.6 g, 10.31 mmol) was dissolved in a mixed solvent of methanol (30 mL) and water (10 mL) at room temperature, and ammonium fluoride (1.1 g, 30.93 mmol) was added. The reaction solution was heated to 50°C and stirred for 16 hours. The resulting reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M008 (1.6 g). LC-MS [M+H] + =181.24.

[0539] Preparation Example 7 Preparation of (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol (M009) and 4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (M009')

[0540] Compounds M009 and M009' were prepared by referring to the preparation methods of compounds M004 and M005 in Preparation Examples 2 and 3, except that the raw material was replaced with 5-bromo-2-iodopyridine from 3,6-dibromo-2-methylpyridine to obtain compounds M009 and M009'. LC-MS of compound M009: [M+H] + =270.95, LC-MS of compound M009': [M+H] + =284.93. The specific preparation steps are as follows:

[0541] (1) At room temperature, 5-bromo-2-iodopyridine (10.5 g, 37.1 mmol) and 2-(2-propargyloxy)tetrahydropyran (5.98 g, 42.66 mmol) were dissolved in acetonitrile (100 mL), and bis(triphenylphosphine)palladium dichloride (2.6 g, 3.71 mmol), cuprous iodide (703 mg, 3.70 mmol) and triethylamine (11.2 g, 111.3 mmol) were added. The mixture was heated to 35°C under a nitrogen atmosphere and stirred for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M009-1 (11.2 g). LC-MS: [M+H] + =297.95.

[0542] (2) Compound M009-1 (11.2 g, 38.2 mmol) and trimethylsilylmethyl azide (9.8 g, 76.4 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL) at room temperature, and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride (3.04 g, 3.82 mmol), tetrabutylammonium iodide (1.4 g, 3.82 mmol) and cuprous iodide (725 mg, 3.82 mmol) were added. The reaction was heated to 40°C under a nitrogen atmosphere and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered through celite. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (125 mL × 3). The combined organic phase was washed with saturated brine (200 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound M009-2 (10.0 g). LC-MS: [M+H] + =427.05.

[0543] (3) Compound M009-2 (10.0 g, 23.5 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, and tetrabutylammonium fluoride (9.20 g, 35.2 mmol) was added in batches. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (120 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with saturated brine (150 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M009-3 (6.8 g). LC-MS: [M+H] + =353.00

[0544] (4) At room temperature, compound M009-3 (6.8 g, 19.31 mmol) was dissolved in methanol (70 mL), and 4-methylbenzenesulfonic acid pyridine (4.84 g, 19.31 mmol) was added. The reaction was heated to 60°C and stirred for 1 hour. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with water (60 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phase was washed with saturated sodium bicarbonate aqueous solution (60 mL) and saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M009 (4.3 g). LC-MS: [M+H] + =270.95.

[0545] (5) Compound M009 (2.2 g, 8.18 mmol) was dissolved in acetonitrile (15 mL) and water (15 mL) at room temperature, and potassium permanganate (2.5 g, 16.36 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. Aqueous sodium hydroxide solution (10 mL, 2 M) was added to the reaction solution to adjust the pH to 10-11, and then sodium bisulfite solution (1 M, 20 mL) was added and stirred for 10 minutes. The mixture was filtered, and the filter cake was rinsed with water (30 mL). The filtrate was adjusted to pH 5-6 with dilute hydrochloric acid (1 M), filtered, and the filter cake was rinsed with water (20 mL), ethanol (20 mL), and then petroleum ether (20 mL). The filter cake was concentrated under reduced pressure to obtain compound M009' (2.0 g). LC-MS: [M+H]+ = 284.93.

[0546] Referring to the method of Preparation Example 7, Compound 1 and Compound 2 in the following table were prepared. The raw material 5-bromo-2-iodopyridine needed to be replaced with the corresponding reactants in the following table:

[0547] Preparation Example 8 Preparation of methyl 2-(1-((tert-butyldimethylsilyl)ethynyl)cyclopropyl)acetate (M010)

[0548] (1) At room temperature, cyclopropylacetylene (60 g, 907.7 mmol) was dissolved in anhydrous tetrahydrofuran (240 mL). The reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), and then n-butyllithium (399.4 mL, 998.5 mmol, 2.5 M n-hexane solution) was added dropwise. After the addition was complete, the reaction solution was stirred at -78°C for 1 hour. Then, a solution of tert-butyldimethylsilyl chloride (136.81 g, 907.7 mmol) in tetrahydrofuran (300 mL) was added dropwise. The reaction solution was stirred at -78°C for 0.5 hour, then naturally warmed to room temperature and continued to stir for 1 hour. After the reaction solution was cooled to 0°C, saturated ammonium chloride solution (480 mL) and water (120 mL) were added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0) to obtain compound M010-1 (308 g). LC-MS: [M+H] + =181.36.

[0549] (2) M010-1 (150 g, 831.7 mmol) was dissolved in methyl tert-butyl ether (1500 ml) at room temperature. The reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), and then n-butyl lithium (366 mL, 914.8 mmol, 2.5 M n-hexane solution) was added dropwise. After the addition was completed, the reaction solution was stirred at -78°C for 1 hour. After the reaction solution naturally warmed to room temperature, the stirring reaction was continued for 3 hours. The reaction solution was then cooled to 0°C again, and ethylene oxide (360.4 mL, 1.08 mol, 3 M ether solution) was added dropwise. The reaction solution was stirred at this temperature for 1 hour. Saturated ammonium chloride solution (1200 mL) and water (300 mL) were added to the reaction solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (750 mL × 2). All organic phases were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M010-2 (104 g). LC-MS: [M+H] + =225.1.

[0550] (3) At room temperature, M010-2 (84.0 g, 374.3 mmol) was dissolved in acetonitrile (840 mL) and water (840 mL), and sodium bicarbonate (94.34 g, 1122.9 mmol) and 2,2,6,6-tetramethylpiperidinyl oxide (11.7 g, 74.9 mmol) were added, and then iodophenyl diacetic acid (301.4 g, 935.8 mmol) was added in batches. The reaction solution was stirred at room temperature for 2 hours. Saturated sodium sulfite solution (420 mL) was added to the reaction solution to quench the reaction. The aqueous phase was extracted with ethyl acetate (600 mL × 3), and the combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M010-3 (62 g). LC-MS: [M+H] + =239.40.

[0551] (4) At room temperature, M010-3 (67 g, 281.1 mmol) was dissolved in N,N-dimethylformamide (420 mL), and iodomethane (48.3 g, 340.1 mmol) was added. After the reaction solution was cooled to 0-5°C, powdered potassium carbonate (42.7 g, 309.0 mmol) was added. The reaction solution was stirred at this temperature for 0.5 hours, then heated to room temperature and continued to stir for 2 hours. The reaction solution was poured into water (1.1 L) and extracted twice with ethyl acetate (670 mL × 2). The combined organic phase was washed twice with aqueous solution (670 mL × 2) and saturated brine (670 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:40) to obtain compound M010 (129 g). LC-MS: [M+H] + =253.42.

[0552] Preparation Example 9 Preparation of (R)-4,4-difluoropentan-2-ol (M011)

[0553] (1) At room temperature, (2R,4R)-2,4-pentanediol (10 g, 95.4 mmol) was dissolved in dichloromethane (300 mL), and pyridine (15.1 g, 190.8 mmol) was added. The reaction solution was cooled to 0°C, and benzoyl chloride (12.7 g, 90.6 mmol) was slowly added dropwise. The reaction solution was stirred at 0°C for 0.5 hours, then warmed to room temperature and continued to stir for 2 hours. The reaction solution was poured into dilute hydrochloric acid (200 mL, 1 M) for quenching, and extracted twice with dichloromethane (100 mL × 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M011-1 (13.8 g). LC-MS: [M+H] + =209.10.

[0554] (2) At room temperature, M011-1 (6.8 g, 32.7 mmol) was dissolved in dichloromethane (140 mL) and sodium bicarbonate (13.7 g, 163 mmol) was added. The reaction solution was cooled to 0°C and then (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoyl-3(1H)-one (15.3 g, 36.0 mmol) was added. The reaction solution was warmed to room temperature and stirred for 3 hours. The reaction solution was diluted with dichloromethane (30 mL) and filtered under reduced pressure. The filter cake was rinsed with dichloromethane (60 mL). The filtrate was washed with saturated sodium bicarbonate aqueous solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M011-2 (5.98 g). LC-MS: [M+H] + =207.10.

[0555] (3) At room temperature, M011-2 (5.9 g, 28.6 mmol) was dissolved in bis(2-methoxyethyl)aminosulfur trifluoride (32 g, 143.2 mmol). The reaction solution was heated to 50°C and stirred for 24 hours. After the reaction solution was cooled to room temperature, it was slowly added dropwise to a cold aqueous sodium bicarbonate solution (100 mL) to quench. It was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with a saturated aqueous ammonium chloride solution (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain compound M011-3 (4.6 g). LC-MS: [M+H] + =229.10.

[0556] (4) At room temperature, M011-3 (4.0 g, 17.53 mmol) was dissolved in tetrahydrofuran (30 mL) and methanol (30 mL), and a solution of lithium hydroxide monohydrate (1.84 g, 43.83 mmol) in water (10 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After adding water (15 mL), the reaction solution was directly concentrated under reduced pressure to remove methanol and tetrahydrofuran. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound M011 (3.4 g, crude product). LC-MS: [M+H] + =125.04.

[0557] Preparation Example 10 Preparation of trans-2-ethynylcyclopentane-1-carboxylic acid methyl ester (M012)

[0558] (1) At room temperature, trans-(1S,2S)-cyclopentyl-1,2-dicarboxylic acid (3.7 g, 23.4 mmol, containing a pair of trans-configurations) was dissolved in dichloromethane (60 mL). The reaction solution was cooled to 0°C, 4-dimethylaminopyridine (1.42 g, 11.7 mmol) and benzyl alcohol (2.5 g, 23.4 mmol) were added, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g, 23.4 mmol) was added in batches. The reaction solution was stirred at 0°C for 2 hours. Water (60 mL) was added to the reaction solution for dilution, and the solution was extracted twice with dichloromethane (60 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound M012-1 (3.2 g, containing a pair of trans-configurations). LC-MS: [M+H] + =249.10.

[0559] (2) M012-1 (2.7 g, 11.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) at room temperature. After the reaction solution was cooled to 0°C (ice bath), triethylamine (2.34 g, 23.2 mmol) and isobutyl chloroformate (1.9 g, 13.9 mmol) were added. The reaction solution was stirred at this temperature for 1 hour. Then, a suspension of sodium borohydride (1.3 g, 34.8 mmol) in water (10 mL) was slowly added. After the reaction solution was warmed to room temperature, stirring was continued for 0.5 hours. The reaction solution was diluted with water (30 mL), adjusted to pH = 4 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give compound M012-2 (1.7 g, containing a pair of trans configurations). LC-MS: [M+H] + =235.10.

[0560] (3) M012-2 (700 mg, 2.99 mmol) was dissolved in methanol (15 mL) at room temperature. After nitrogen substitution, wet palladium carbon (70 mg, 10%) was added. Under a hydrogen atmosphere, the reaction solution was stirred at room temperature for 3 hours. The reaction solution was filtered through celite, and the filter cake was rinsed with methanol (30 mL). The filtrate was directly concentrated under reduced pressure to obtain compound M012-3 (600 mg, crude product, containing a pair of trans configurations). LCMS: [M+H] + =144.17.

[0561] (4) M012-3 (600 mg, crude product) was dissolved in dichloromethane (6 mL) and methanol (3 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to 0°C (ice bath), and trimethylsilylated diazomethane (2.0 mL, 5.0 mmol) was slowly added dropwise. The reaction was continued at this temperature with low stirring for 1 hour. Water (10 mL) was added to the reaction solution for dilution, and the solution was extracted twice with dichloromethane (10 mL×2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M012-4 (360 mg, containing a pair of trans configurations). LC-MS: [M+H] + =159.15.

[0562] (5) Oxalyl chloride (546 mg, 4.3 mmol) was dissolved in dichloromethane at room temperature. The reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), and a solution of dimethyl sulfoxide (672 mg, 8.6 mmol) in dichloromethane (5 mL) was slowly added dropwise. The internal temperature of the reaction solution was kept below -70°C. After the addition was complete, the reaction solution was stirred at this temperature for 0.5 hours. Then, a solution of M012-4 (340 mg, 2.15 mmol) in dichloromethane (5 mL) was added dropwise, and the reaction solution was stirred at this temperature for 0.5 hours. Finally, triethylamine (1.74 g, 17.2 mmol) was slowly added dropwise, controlling the internal temperature not to exceed -65°C. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 0.5 hours. The reaction solution was quenched with water (20 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound M012-5 (230 mg, containing a pair of trans configurations). LC-MS: [M+H] + =156.18.

[0563] (6) Potassium carbonate was added to methanol (2.5 mL) at room temperature. The reaction solution was cooled to 0°C under a nitrogen atmosphere, and dimethyl (1-diazo-2-oxopropyl)phosphonate (135 mg, 0.71 mmol) was added. The reaction solution was stirred at this temperature for 10 minutes, and then a solution of M012-5 (130 mg, 0.64 mmol) in methanol (1.5 mL) was added dropwise. The reaction solution was heated to room temperature and continued to stir for 2 hours. Petroleum ether (10 mL) and water (10 mL) were added to the reaction solution, and then the organic layer was separated. The aqueous phase was extracted with petroleum ether (10 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at low temperature (~15°C) to obtain compound M012 (80 mg, containing a pair of trans configurations). LC-MS: [M+H] + =152.19.

[0564] Preparation Example 11 Preparation of trans-2-ethynyl-4,4-difluorocyclopentane-1-carboxylic acid methyl ester (M013)

[0565] (1) At room temperature, trans-(1S,2S)-oxocyclopentyl-1,2-dicarboxylic acid dimethyl ester (5 g, 25.0 mmol) was dissolved in dichloromethane (100 mL), and diethylaminosulfur trifluoride (8.1 g, 50.0 mmol) was added. The reaction solution was heated to 40°C and stirred for 18 hours. After the reaction solution was cooled to room temperature, it was poured into ice water (100 mL) and extracted with dichloromethane (50 mL×2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M013-1 (4.8 g, containing a pair of trans configurations). LC-MS: [M+H] + =223.19.

[0566] (2) At room temperature, M013-1 (4.8 g, 21.6 mmol) was dissolved in methanol (50 mL) and water (10 mL), and sodium hydroxide (0.86 g, 21.6 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The aqueous phase was cooled to 0°C, adjusted to pH 3-4 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M013-2 (3.3 g, containing a pair of trans configurations).

[0567] LC-MS: [M+H] + =209.16

[0568] (3) At room temperature, M013-2 (3.3 g, 15.9 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Under a nitrogen atmosphere, the reaction solution was cooled to 0°C and borane dimethyl sulfide complex (3.2 mL, 31.8 mmol, 10 M) was added dropwise. The reaction solution was stirred at this temperature for 2 hours. Water (50 mL) was added to the reaction solution to quench the reaction solution, and the solution was extracted twice with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M013-3 (2.2 g, containing a pair of trans configurations). LC-MS: [M+H] + =195.18

[0569] (4) At room temperature, dimethyl sulfoxide (1.8 mL, 24.1 mmol) was dissolved in anhydrous dichloromethane (20 mL). Under a nitrogen atmosphere, the reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), and a solution of oxalyl chloride (1.7 mL, 20.1 mmol) in dichloromethane (2 mL) was slowly added dropwise, controlling the internal temperature within -70°C. At this temperature, the reaction was stirred for 0.5 hours, and then a solution of M013-3 (2.6 g, 13.4 mmol) in dichloromethane (5 mL) was added dropwise, controlling the internal temperature within -70°C. The reaction solution was allowed to react at this temperature for 1 hour. Finally, triethylamine (5.7 mL, 33.5 mmol) was slowly added dropwise, controlling the internal temperature at -65°C. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 1 hour. Water (50 mL) was added to the reaction solution for dilution, and the solution was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound M013-4 (1.2 g, containing a pair of trans configurations). LC-MS: [M+H] + =193.16

[0570] (5) At room temperature, M013-4 (1.4 g, 7.3 mmol) was dissolved in methanol (20 mL). The reaction solution was cooled to 0°C, potassium carbonate (1.5 g, 10.9 mmol) was added, and then (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (3.5 g, 18.2 mmol) was slowly added. The reaction solution was heated to room temperature and stirred for 2 hours. Water (30 mL) was slowly added to the reaction solution, and the solution was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M013 (0.6 g, containing a pair of trans configurations). LC-MS: [M+H] + =189.17

[0571] Preparation Example 12 Preparation of trans-2-ethynylcyclopropane-1-carboxylic acid methyl ester (Compound M014)

[0572] Compound M014 was prepared by referring to the preparation method of M013 in Preparation Example 11, except that compound M013-1 was replaced with trans-dimethyl 1,2-cyclopropanedicarboxylate to obtain compound M014 (1.5 g, containing a pair of trans isomers).

[0573] LC-MS: [M+H] + =125.05.

[0574] Preparation Example 13 Preparation of methyl 2-(1-ethynyl-3-methoxycyclobutyl)acetate (Compound M015)

[0575] (1) Benzyl 3-oxocyclobutanecarboxylate (25 g, 122.42 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL) at room temperature. The reaction mixture was cooled to 0°C and a solution of sodium borohydride (5.56 g, 146.90 mmol) in water (60 mL) was slowly added. The reaction mixture was stirred at room temperature for 0.5 hours. Water (200 mL) was added to the reaction mixture to quench the mixture and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M015-1 (22 g). LC-MS [M+H] + =207.05.

[0576] (2) Compound M015-1 (18 g, 87.3 mmol) was dissolved in N,N-dimethylformamide (200 mL) at room temperature, and silver oxide (40.5 g, 174.6 mmol) and iodomethane (105.3 g, 741.9 mmol) were added. The reaction solution was heated to 45°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (200 mL) was added to quench the reaction solution, filtered, and the filtrate was extracted twice with ethyl acetate (200 mL × 2). The combined organic phase was washed with saturated brine (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M015-2 (15 g). LC-MS [M+H] + =221.05.

[0577] (3) Compound M015-2 (15.0 g, 68.1 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to -78°C, and lithium bis(trimethylsilyl)amide (17.1 g, 102.2 mmol, 1 M tetrahydrofuran solution) was added dropwise. The reaction solution was stirred at this temperature for 1 hour, and then allyl iodide (14.9 g, 88.5 mmol) was added dropwise. The reaction solution was warmed to room temperature and stirred for 3 hours. The reaction solution was poured into a saturated ammonium chloride solution (300 mL) for quenching and extracted twice with ethyl acetate (300 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M015-3 (7.3 g, containing cis and trans isomers). LC-MS [M+H] + =261.10.

[0578] (4) Compound M015-3 (7.3 g, 28.1 mmol) was dissolved in acetonitrile (100 mL) and water (100 mL) at room temperature, and sodium periodate (24 g, 112.2 mmol) and ruthenium trichloride (174.5 mg, 84.1 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. Potassium permanganate (13.3 g, 84.1 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for another 2 hours. The reaction solution was filtered, and the filtrate was adjusted to pH 9-10 with sodium hydroxide solution (10%), diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The resulting aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (200 mL × 3). The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound M015-4 (5.2 g, containing cis- and trans-isomers). LC-MS[M+H] + =279.05.

[0579] (5) Compound M015-4 (5.2 g, 18.68 mmol) was dissolved in methanol (100 mL) at room temperature, and thionyl chloride (6.67 g, 56.04 mmol) was slowly added. The reaction solution was refluxed (65°C) for 2 hours. After the reaction solution was cooled to room temperature, it was directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M015-5 (4.4 g, containing cis and trans isomers). LC-MS [M+H] + =293.05.

[0580] (6) Compound M015-5 (4 g, 13.7 mmol) was dissolved in methanol (40 mL) at room temperature, and wet palladium carbon (0.73 g, 0.68 mmol, 10 wt.%) and wet palladium hydroxide carbon (0.48 g, 0.68 mmol, 20 wt.%) were added. Under a hydrogen atmosphere, the reaction solution was heated to 30°C and stirred for 18 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound M015-6 (2.7 g, containing cis and trans isomers). LC-MS: [M+H] + =203.21.

[0581] (7) Compound M015-6 (2.7 g, 13.4 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to 0°C and borane dimethyl sulfide complex (2.67 mL, 26.7 mmol, 10 M) was added dropwise. The reaction solution was warmed to room temperature and stirred for 2 hours. Water (40 mL) was added to the reaction solution to quench the reaction and the solution was extracted with ethyl acetate (40 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M015-7 (2.3 g, containing cis and trans isomers). LC-MS: [M+H] + =189.22.

[0582] (8) Oxalyl chloride (3.1 g, 24.5 mmol) was dissolved in anhydrous dichloromethane (50 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), and a solution of dimethyl sulfoxide (3.8 g, 48.9 mmol) in dichloromethane (20 mL) was slowly added dropwise, controlling the internal temperature within -70°C. The reaction solution was stirred for 0.5 hours at this temperature, and then a solution of compound M015-7 (2.3 g, 12.2 mmol) in dichloromethane (20 mL) was added dropwise, controlling the internal temperature within -70°C. The reaction solution was allowed to react at -78°C for 1 hour. Finally, triethylamine (9.9 g, 97.8 mmol) was slowly added dropwise, controlling the internal temperature within -65°C. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound M015-8 (2.0 g, containing cis and trans isomers). LC-MS: [M+H] + =187.21.

[0583] (9) At room temperature, compound M015-8 (2 g, 10.8 mmol) was dissolved in methanol (20 mL). The reaction solution was cooled to 0°C, potassium carbonate (2.2 g, 16.1 mmol) was added, and then (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (5.2 g, 26.9 mmol) was slowly added. After the reaction solution was warmed to room temperature, stirring and the reaction was continued for 1 hour. Water (20 mL) was slowly added to the reaction solution, and the solution was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M015 (1.5 g, containing cis and trans isomers). LC-MS: [M+H] + =183.22.

[0584] Preparation Example 14 Preparation of 1-ethynyl-1-((methylsulfonyl)methyl)cyclopropane (Compound M016)

[0585] (1) At room temperature, 1,1-cyclopropane dimethanol (5 g, 48.96 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). The reaction solution was cooled to 0°C and sodium hydride (2.35 g, 97.92 mmol, 60% dispersed in mineral oil) was added in batches. After the addition was completed, the reaction solution was stirred at 0°C for 0.5 hours, and then tert-butyldiphenylsilyl chloride (13.46 g, 48.96 mmol) was added. After the reaction solution was warmed to room temperature, the stirring reaction was continued for 2 hours. The reaction solution was quenched with water (20 mL) and extracted twice with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M016-1 (16 g). LC-MS: [M+H] + =341.15.

[0586] (2) Compound M016-1 (10 g, 29.37 mmol) was dissolved in dichloromethane (100 mL) at room temperature. The reaction solution was cooled to 0°C, and N,N-diisopropylethylamine (7.6 g, 58.74 mmol) and methanesulfonyl chloride (4 g, 35.24 mmol) were added at this temperature. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was quenched with water (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M016-2 (11 g, crude product). LC-MS: [M+H] + =419.62.

[0587] (3) Compound M016-2 (11 g, crude product) was dissolved in N,N-dimethylformamide (100 mL) at room temperature, and sodium thiomethoxide (3.68 g, 52.56 mmol) was added. The reaction solution was stirred at room temperature for 48 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed twice with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M016-3 (3.5 g). LC-MS: [M+H] + =371.

[0588] (4) Compound M016-3 (3.5 g, 9.44 mmol) was dissolved in dichloromethane (30 mL) at room temperature. The reaction solution was cooled to 0°C and m-chloroperbenzoic acid (4 g, 23.60 mmol, purity: 85%) was slowly added. After the addition was complete, the reaction solution was allowed to reach room temperature and stirred for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed twice with saturated sodium bicarbonate (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M016-4 (2.8 g). LC-MS: [M+H] + =403.20.

[0589] (5) Compound M016-4 (3 g, 7.45 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) at room temperature. The reaction mixture was cooled to 0°C and tetrabutylammonium fluoride (2.3 g, 8.94 mmol) was slowly added. After the addition was completed, the reaction mixture was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction mixture for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 0) to obtain compound M016-5 (600 mg). LC-MS: [M+H] + =165.22.

[0590] (6) Dimethyl sulfoxide (1.04 mL, 14.60 mmol) was added to dichloromethane (10 mL) at room temperature. The reaction solution was cooled to -78°C under a nitrogen atmosphere, and oxalyl chloride (0.62 mL, 7.30 mmol) was slowly added dropwise. The reaction solution was stirred at -78°C for 0.5 hours. Then a solution of compound M016-5 (600 mg, 3.65 mmol) in dichloromethane (2 mL) was added. After the addition was complete, the reaction solution was stirred at -78°C for 1 hour. Then triethylamine (4.06 mL, 29.20 mmol) was added dropwise, and the internal temperature of the reaction was controlled to be less than -65°C. After the addition was complete, the reaction solution was stirred at -70°C for 0.5 hours, and then naturally warmed to room temperature and continued to stir for 0.5 hours. Water (50 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M016-6 (470 mg). LC-MS: [M+H] + =163.21.

[0591] (7) Compound M016-6 (200 mg, 1.23 mmol) was dissolved in methanol (5 mL) at room temperature. The reaction solution was cooled to 0°C, and potassium carbonate (204 mg, 1.48 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (260 mg, 1.35 mmol) were slowly added. After the reaction solution was warmed to room temperature, the reaction was continued with stirring for 2 hours. Water (10 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M016 (190 mg, crude product). LC-MS: [M+H] + =159.22.

[0592] Preparation Example 15 Preparation of 5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (Compound M017)

[0593] (1) 5-Bromo-6-methylpyridine-2-carbonitrile (5.0 g, 25.38 mmol) was dissolved in a mixed solvent of methanol (50 mL) and water (25 mL) at room temperature, and sodium hydroxide (1 g, 25.38 mmol) was added. The reaction solution was refluxed (85°C) for 5 hours. After the reaction solution was cooled to room temperature, it was directly concentrated under reduced pressure. The residue was diluted with water (20 mL). The pH of the aqueous phase was adjusted to 5-6 with concentrated hydrochloric acid (12 M), filtered, and the filter cake was rinsed with water (20 mL). The filter cake was then dissolved in dichloromethane (40 mL), the resulting solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M017-1 (3.0 g). LC-MS: [M+H] + =215.90.

[0594] (2) Compound M017-1 (2.5 g, 11.57 mmol) was dissolved in dichloromethane (25 mL) at room temperature, and N,N-dimethylformamide (85 mg, 1.16 mmol) was added. After the reaction solution was cooled to 0°C, oxalyl chloride (2.9 g, 23.14 mmol) was added dropwise. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was directly concentrated to obtain compound M017-2 (2.5 g, crude product). LC-MS: [M+H] + =234.10.

[0595] (3) At room temperature, methyl 3-methylaminobut-2-enoate (4.1 g, 31.98 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and pyridine (2.5 g, 31.98 mmol) was added. The reaction solution was cooled to 0°C, and then compound M017-2 (2.5 g, 10.66 mmol) was added. The reaction solution was stirred at room temperature for 48 hours. Water (10 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with dilute hydrochloric acid (20 mL, 1 M), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M017-3 (2.5 g, yield: 66.2%). LC-MS: [M+H] + =328.95.

[0596] (4) At room temperature, compound M017-3 (2.5 g, 7.64 mmol) was dispersed in acetic acid (20 mL), and then hydroxylamine hydrochloride (530 mg, 7.64 mmol) was added. The reaction solution was heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL), and rinsed with water (20 mL × 3). The solution was rinsed with saturated sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M017-4 (1.7 g, crude product). LC-MS: [M+H] + =312.90.

[0597] (5) Compound M017-4 (1.7 g, crude product) was dissolved in a mixed solvent of methanol (20 mL) and water (10 mL) at room temperature, and lithium hydroxide monohydrate (687 mg, 16.38 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with a small amount of water (10 mL) and then concentrated under reduced pressure. The residue was extracted twice with dichloromethane (10 mL × 2), and the resulting aqueous phase was adjusted to pH = 5-6 with dilute hydrochloric acid (1 M), filtered, and the filter cake was rinsed with water (10 mL). The filter cake was concentrated under reduced pressure to obtain compound M017 (1.2 g). LC-MS: [M+H] + =298.90.

[0598] Preparation Example 16 Preparation of 4-(5-bromo-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (Compound M018)

[0599] (1) 5-Bromo-2-chloro-4-methylpyrimidine (5 g, 24.10 mmol) and sodium iodide (6.14 g, 40.97 mmol) were dissolved in chloroform (100 mL) at room temperature. The reaction solution was cooled to 0°C, and hydroiodic acid (4.9 g, 21.69 mmol) was added. The reaction solution was heated to room temperature and stirred for 16 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (100 mL) for quenching and extracted with dichloromethane (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M018-1 (3.3 g). LC-MS: [M+H] + =298.75.

[0600] (2) At room temperature, compound 005-1 (2.4 g, 9.13 mmol) was dissolved in 1,4-dioxane (80 mL) and water (40 mL), and compound M018-1 (3.23 g, 10.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (666 mg, 0.91 mmol) and sodium carbonate (2.9 g, 27.39 mmol) were added. The reaction solution was heated to 80°C under nitrogen protection and stirred for 1 hour. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M018-2 (1.3 g). LC-MS: [M+H] + =312.90.

[0601] (3) Compound M018-2 (1.3 g, 4.18 mmol) was dissolved in methanol (20 mL) and water (10 mL) at room temperature, and lithium hydroxide monohydrate (0.5 g, 12.54 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and then directly concentrated under reduced pressure to remove methanol. The residue was adjusted to pH 3-4 with dilute hydrochloric acid (1 M). The mixture was filtered under reduced pressure, and the filter cake was dried under reduced pressure to obtain compound M018 (700 mg). LCMS: [M+H] + =298.90.

[0602] Preparation Example 17 Preparation of 5-(5-bromo-6-methylpyridin-2-yl)-3-methylisothiazole-4-carboxylic acid (Compound M019)

[0603] (1) 3-Methyl-4-cyano-5-aminoisothiazole (2.0 g, 14.37 mmol) was dissolved in hydrogen bromide solution (46 wt.%, 10 mL) at room temperature. The reaction solution was cooled to 0°C and a solution of sodium nitrite (1.19 g, 17.24 mmol) in water (10 mL) was added. The reaction solution was stirred at 0°C for 0.5 hours. Then, a solution of cuprous bromide (3.09 g, 21.55 mmol) in hydrobromic acid (10 mL) was added. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was diluted with water (20 mL), and the pH of the solution was adjusted to 8-9 with sodium carbonate solution. Ethyl acetate (30 mL) was then added, stirred, and the layers separated. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M019-1 (1.6 g). LC-MS: [M+H] + =302.90.

[0604] (2) 2,5-Dibromo-6-methylpyridine (2.00 g, 8.00 mmol) was dissolved in toluene (100 mL) at room temperature. The reaction mixture was cooled to -70°C (dry ice-ethyl acetate bath). n-Butyl lithium (3.84 mL, 9.61 mmol, 2.5 M n-hexane solution) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at -70°C for 2 hours. Tributyltin chloride (3.39 g, 10.41 mmol) was then added dropwise. The reaction mixture was stirred at -70°C for 1 hour. The reaction mixture was heated to about -10°C and quenched by adding saturated aqueous ammonium chloride (50 mL). The mixture was then extracted twice with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0) to obtain compound M019-2 (1.5 g). LC-MS: [M+H] + =461.00.

[0605] (3) Compound M019-2 (1.25 g, 2.71 mmol) and compound M019-1 (0.55 g, 2.71 mmol) were dissolved in xylene (12 mL) at room temperature, and bis(triphenylphosphine)palladium dichloride (0.19 g, 0.27 mmol) and triphenylphosphine (0.14 g, 0.54 mmol) were added. Under a nitrogen atmosphere, the reaction solution was heated to 120°C and stirred for 20 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M019-3 (440 mg). LC-MS: [M+H] + =294.00.

[0606] (4) At room temperature, compound M019-3 (390 mg, 1.33 mmol) was dissolved in concentrated sulfuric acid (5 mL), and the reaction solution was heated to 120°C and stirred for 1 hour. After the reaction solution was cooled to room temperature, a solution of sodium nitrite (275.31 mg, 3.99 mmol) in water (2.5 mL) was added. The reaction solution was heated to 50°C and stirred for 2 hours. The reaction solution was cooled to room temperature and then added dropwise to ice water (20 mL) to quench the reaction solution, and then washed with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M019 (410 mg). LC-MS: [M+H] + =312.85.

[0607] Preparation Example 18 Preparation of 1-(bicyclo[1.1.1]pentan-1-yl)-N-methylmethanamine (Compound 204-3)

[0608] (1) At room temperature, dicyclo[1.1.1]pentane-1-carboxylic acid (0.9 g, 8.0 mmol) and N-methylbenzylamine (1.1 g, 9.1 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 1-propylphosphonic anhydride (3.8 g, 12.1 mmol, 50% ethyl acetate solution) and N,N-diisopropylethylamine (4.3 mL, 24.1 mmol) were added. The reaction solution was reacted at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the solution was extracted twice with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 8) to obtain compound 204-1 (1.1 g). LC-MS: [M+H] + =216.10.

[0609] (2) Lithium aluminum hydride (354 mg, 9.2 mmol) was dispersed in anhydrous tetrahydrofuran (20 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to 0°C and a tetrahydrofuran solution (5 mL) of compound 204-1 (1 g, 4.6 mmol) was added dropwise. The reaction solution was heated to 70°C and stirred for 2 hours. After the reaction solution was cooled to 0°C, water (2 mL), 15% sodium hydroxide solution (6 mL), tetrahydrofuran (20 mL), water (6 mL), and anhydrous magnesium sulfate (2 g) were added to the reaction solution in sequence. The reaction solution was stirred at room temperature for 15 minutes and filtered. The filtrate was separated and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 2) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain compound 204-2 (591 mg). LC-MS: [M+H] + =202.15.

[0610] (3) At room temperature, compound 204-2 (590 mg, 2.9 mmol) was dissolved in methanol (20 mL), and wet palladium / carbon (60 mg, 10%) and a methanol solution of hydrogen chloride (3.7 mL, 4 M) were added. Under a hydrogen atmosphere, the reaction solution was heated to 70°C and stirred for 2 hours. After cooling to room temperature, the reaction solution was filtered through celite, and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to obtain the crude hydrochloride salt of compound 204-3 (0.8 g). LC-MS: [M+H] + =112.20.

[0611] The compounds and their hydrochlorides in the following table were prepared by referring to the preparation method of Preparation Example 18, except that the raw materials therein were replaced with the corresponding raw materials in the following table from bicyclo[1.1.1]pentane-1-carboxylic acid:

[0612] Preparation Example 19 Preparation of 2,2-difluoro-N-methylbutan-1-amine (Compound 082-3)

[0613] (1) At room temperature, dimethyl sulfoxide (3.7 mL, 51.7 mmol) was dissolved in dichloromethane (50 mL). Under nitrogen atmosphere, the reaction solution was cooled to -78°C. A solution of oxalyl chloride (3.3 mL, 38.8 mmol) in dichloromethane (3 mL) was added dropwise, controlling the internal temperature below -70°C. After the addition was complete, the reaction solution was stirred at -78°C for 0.5 h. A solution of compound 036-1 (5 g, 25.9 mmol) in dichloromethane (10 mL) was then added dropwise. The internal temperature was controlled below -70°C. After the addition was complete, the reaction solution was stirred at -78°C for 0.5 h. Then, triethylamine (10.8 mL, 77.6 mmol) was added dropwise, controlling the internal temperature below -65°C. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 2 h. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 082-1 ​​(3.8 g). LC-MS: [M+H] + =192.10.

[0614] (2) Compound 082-1 ​​(2.8 g, 14.6 mmol) was dissolved in 1,2-dichloroethane (30 mL) at room temperature. Under nitrogen atmosphere, the reaction solution was cooled to 0°C, and bis(2-methoxyethyl)aminosulfur trifluoride (5.4 mL, 29.2 mmol) was added dropwise. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 18 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (30 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound 082-2 (0.95 g). LC-MS: [M+H] + =214.10.

[0615] (3) Compound 082-2 (0.95 g, 4.5 mmol) was dissolved in methanol (10 mL) at room temperature, and wet palladium on carbon (100 mg, 10%) was added. The reaction mixture was heated to 60°C under a hydrogen atmosphere and stirred for 18 hours. The reaction mixture was filtered through celite, and the filter cake was washed with methanol (10 mL). A methanol solution of hydrogen chloride (10 mL, 4 M) was added to the filtrate, and the filtrate was concentrated under reduced pressure to obtain the hydrochloride salt of compound 082-3 (1 g, crude product). LC-MS: [M+H] + =124.15.

[0616] Preparation Example 20 Preparation of (2-fluorocyclobutyl)methylamine (Compound 098-3)

[0617] (1) Compound 026-1 (1.5 g, 5.54 mmol) was dissolved in methanol (30 mL) at room temperature. After the reaction solution was cooled to 0°C, sodium borohydride (203 mg, 5.54 mmol) was added. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 1 hour. Sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 098-1 (900 mg). LC-MS: [M+H] + =282.10.

[0618] (2) Compound 098-1 (800 mg, 2.84 mmol) was dissolved in dichloromethane (10 mL) at room temperature. After the reaction solution was cooled to 0°C, diethylaminosulfur trifluoride (688 mg, 4.26 mmol) was added dropwise. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 2 hours. Sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 098-2 (300 mg). LC-MS: [M+H] + =284.10.

[0619] (3) At room temperature, compound 098-2 (300 mg, 1.06 mmol) was dissolved in methanol (6 mL), and a methanol solution of hydrogen chloride (4 M, 1.06 mL, 4.23 mmol) and palladium hydroxide / carbon (10%, 300 mg) were added. Under a hydrogen atmosphere (hydrogen balloon), the reaction solution was heated to 40°C and stirred for 48 hours. After the reaction solution was cooled to room temperature, it was directly filtered and the filtrate was concentrated under reduced pressure to obtain the hydrochloride salt of compound 098-3 (200 mg, crude product). LC-MS: [M+H] + =104.15.

[0620] Preparation Example 21 Preparation of 1-(3,3-difluorocyclobutyl)ethane-1-ol (Compound 029-3)

[0621] (1) At room temperature, 3,3-difluorocyclobutanecarboxylic acid (4.0 g, 29.39 mmol) was dissolved in dichloromethane (80 mL), and N,N'-diisopropylethylamine (11.40 g, 88.17 mmol), dimethylhydroxylamine hydrochloride (3.93 g, 35.27 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.76 g, 44.09 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. Water (100 mL) was added to the obtained reaction solution, and the mixture was extracted with dichloromethane (100 mL). The organic phases were combined. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 029-1 (5.2 g). LC-MS: [M+H] + =180.10.

[0622] (2) Compound 029-1 (5.2 g, 29.02 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) at room temperature. The reaction mixture was replaced with nitrogen and cooled to 0°C. A tetrahydrofuran solution of methylmagnesium bromide (58 mL, 58.05 mmol, 1 M) was then added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 4 hours. The resulting reaction mixture was poured into a saturated aqueous ammonium chloride solution (100 mL) for quenching, extracted with ethyl acetate (100 mL), and the organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was distilled. The 82°C fraction was collected to obtain compound 029-2 (4.0 g).

[0623] (3) Compound 029-2 (4.0 g) was dissolved in ethanol (20 mL) at room temperature. After the reaction solution was cooled to 0°C, sodium borohydride (564 mg, 11.91 mmol) was added in batches. The reaction solution was warmed to room temperature and stirred for 1 hour. Water (20 mL) was added to the resulting reaction solution, which was diluted and extracted with dichloromethane (10 mL). The organic phases were combined. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 029-3 (440 mg). LC-MS: [M+H] + =137.14.

[0624] The preparation of the compounds in the following table refers to the preparation method of Preparation Example 21, except that the raw materials therein need to be replaced from 3,3-difluorocyclobutanecarboxylic acid with the corresponding raw materials in the following table:

[0625] Preparation Example 22 Preparation of 1-(1,1-difluoroethyl)cyclopropane-1-carboxylic acid (Compound M020)

[0626] (1) At room temperature, 1-acetylcyclopropanecarboxylic acid ethyl ester (5 g, 32.01 mmol) was added to bis(2-methoxyethyl)aminosulfur trifluoride (28.33 g, 128.04 mmol). The reaction solution was heated to 60°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, sodium carbonate aqueous solution (200 mL) was added to quench the solution and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M020-1 (6 g, crude product). LC-MS: [M+H] + =179.05.

[0627] (2) Compound M020-1 (6 g, crude product) was dissolved in methanol (90 mL) and water (30 mL) at room temperature, and lithium hydroxide monohydrate (6.71 g, 159.95 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was adjusted to pH 5-6 with dilute hydrochloric acid (1 M). It was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with water (100 mL), washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was directly concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M020 (4.0 g). LC-MS: [M+H] + =151.05.

[0628] Preparation Example 23 Preparation of 1-(2,5-difluoropyridin-3-yl)ethanol (Compound M021)

[0629] 2,5-Difluoro-3-bromopyridine (1.8 g, 9.32 mmol) was dissolved in tetrahydrofuran (35 mL) at room temperature. The reaction mixture was cooled to 0°C, and isopropylmagnesium chloride-lithium chloride solution (1.3 M, 10.7 mL, 13.9 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 0.5 hours. The reaction mixture was cooled to 0°C again, and acetaldehyde (2.2 mL, 11.0 mmol, 5 M in tetrahydrofuran) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (20 mL), then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain compound M021 (730 mg). LC-MS: [M+H] + =160.05.

[0630] Preparation Example 24 Preparation of 1-(5-fluoro-2-methylpyridin-3-yl)ethanol (Compound M022)

[0631] Compound M022 was prepared by referring to the preparation method of Compound M021 in Preparation Example 23, except that the raw material 2,5-difluoro-3-bromopyridine was replaced with 3-bromo-5-fluoro-2-methylpyridine to obtain Compound M022 (1.0 g). LC-MS: [M+H] + =156.10.

[0632] Preparation Example 25 Preparation of (R)-4,4-difluorohexan-2-ol (Compound M023)

[0633] (1) At room temperature, (R)-methyl 3-hydroxybutyrate (6 g, 50.8 mmol) was dissolved in dichloromethane (90 mL). Under nitrogen atmosphere, the reaction solution was cooled to 0°C, imidazole (6 g, 88.2 mmol) was added and stirred for 10 minutes, and then tert-butyldiphenylsilyl chloride (15.4 g, 56.0 mmol) was added dropwise. After the addition was completed, the reaction solution was warmed to room temperature and continued to stir for 4 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction solution to quench the reaction, and then water (50 mL) was added to dilute it, and it was extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M023-1 (18 g). LC-MS: [M+H] + =357.56.

[0634] (2) Compound M023-1 (18 g, 50.6 mmol) was dissolved in methanol (120 mL) and water (40 mL) at room temperature, and lithium hydroxide (6.0 g, 250.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (80 mL) and then concentrated under reduced pressure to remove methanol. The residue was neutralized with dilute hydrochloric acid (1 M) (pH = 7) and extracted twice with ethyl acetate (60 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M023-2 (14.7 g). LC-MS: [M+H] + =343.51.

[0635] (3) Compound M023-2 (14.7 g, 43 mmol) and dimethylhydroxylamine hydrochloride (12.5 g, 129 mmol) were dissolved in anhydrous tetrahydrofuran (250 mL) at room temperature, and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (49 g, 129 mmol) and N,N-diisopropylethylamine (47.1 g, 365.5 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, and the solution was extracted twice with ethyl acetate (100 mL×2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M023-3 (13.9 g). LC-MS: [M+H] + =386.58.

[0636] (4) Compound M023-3 (6 g, 15.58 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) at room temperature. Under nitrogen atmosphere, the reaction solution was cooled to -78 °C, and then ethyl magnesium bromide (39 mL, 77.9 mmol, 3.0 M ether solution) was added dropwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and the reaction was continued to stir for 1 hour. Saturated ammonium chloride solution (50 mL) was slowly added dropwise to the reaction solution to quench the mixture, and then diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M023-4 (5.5 g). LC-MS: [M+1] + =355.15.

[0637] (5) Compound M023-4 (5 g, 14.10 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) at room temperature, and tetrabutylammonium fluoride (42.3 mL, 42.3 mmol, 1 M tetrahydrofuran solution) was added. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with water (40 mL) and extracted with dichloromethane (30 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound M023-5 (1.4 g). LC-MS: [M+1] + =117.05.

[0638] (6) Compound M023-5 (1.4 g, 12.05 mmol) was dissolved in dichloromethane (15 mL) at room temperature. The reaction mixture was cooled to 0°C and pyridine (2.86 g, 36.15 mmol) and benzoyl chloride (2.54 g, 18.08 mmol) were added. The reaction mixture was slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted twice with dichloromethane (15 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain a crude product (2.5 g), which was then separated and purified by high performance liquid chromatography (0.1% trifluoroacetic acid system) to obtain compound M023-6 (1.4 g). LC-MS: [M+1] + =221.05.

[0639] (7) Compound M023-6 (830 mg, 3.77 mmol) was added to bis(2-methoxyethyl)aminosulfur trifluoride (3.33 g, 15.08 mmol) at room temperature. The reaction solution was heated to 60°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was slowly poured into a saturated sodium bicarbonate aqueous solution (30 mL) cooled to 0°C to quench the solution, and extracted with dichloromethane (30 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain compound M023-7 (400 mg). LC-MS: [M+1] + =243.05.

[0640] (8) Compound M023-7 (400 mg, 1.65 mmol) was dissolved in methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) at room temperature. Lithium hydroxide monohydrate (338.5 mg, 8.25 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (8 mL × 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound M023 (100 mg). LC-MS: [M+1] + =139.16.

[0641] Preparation Example 26 Preparation of (R)-3,3-difluoro-4-methylpentan-2-ol (Compound M024)

[0642] (1) At room temperature, (R)-2-benzyloxypropionic acid (10.0 g, 55.5 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N,N-diisopropylethylamine (21.5 g, 166 mmol) and 1-propylphosphonic anhydride (21.2 g, 66.6 mmol, 50% ethyl acetate solution) were added, followed by the addition of morpholine (5.80 g, 66.6 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 4). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M024-1 (12.6 g). LC-MS: [M+H] + =250.05.

[0643] (2) Compound M024-1 (12.6 g, 50.5 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL) at room temperature. The reaction solution was cooled to -78°C (dry ice-ethyl acetate bath) and isopropylmagnesium chloride (15.6 g, 151.6 mmol) was added dropwise. After the addition was complete, the reaction solution was stirred at this temperature for 0.5 hours, then heated to room temperature and continued to stir for 1 hour. The reaction solution was poured into an aqueous ammonium chloride solution (100 mL) for quenching. The solution was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain product M024-2 (11.3 g). LC-MS: [M+H] + =207.28.

[0644] (3) Compound M024-2 (11.3 g, 50.1 mmol) was dissolved in methanol (110 mL) at room temperature, and wet palladium carbon (1.60 g, 15.0 mmol, 10%) was added. The reaction solution was heated to 60°C and stirred for 3 hours under a hydrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered through celite, and the filter cake was rinsed twice with methanol (30 mL × 2). The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound M024-3 (5.30 g). LC-MS: [M+H] + =117.16.

[0645] (4) Compound M024-3 (5.30 g, 45.6 mmol) was dissolved in dichloromethane (50 mL) at room temperature. After the reaction solution was cooled to 0°C, pyridine (3.61 g, 45.6 mmol) was added, and then benzoyl chloride (6.41 g, 45.6 mmol) was slowly added dropwise. The reaction solution was stirred at 0°C for 30 minutes, then heated to room temperature and continued to stir for 1 hour. The reaction solution was poured into dilute hydrochloric acid (50 mL, 1 M) for quenching. The mixture was extracted with dichloromethane (30 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain compound M024-4 (6.60 g). LC-MS: [M+1] + =221.05.

[0646] (5) Compound M024-4 (6.50 g, 29.5 mmol) was added to bis(2-methoxyethyl)aminosulfur trifluoride (32.6 g, 147 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours, then heated to 60°C and stirred for 16 hours. After the reaction mixture cooled to room temperature, it was added dropwise to a cold aqueous sodium bicarbonate solution (300 mL) for quenching, and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M024-5 (3.50 g). LC-MS: [M+1] + =243.05.

[0647] (6) Compound M024-5 (3.5 g, 14.5 mmol) was dissolved in a mixed solvent of methanol (15 mL) and tetrahydrofuran (15 mL) at room temperature. A solution of lithium hydroxide monohydrate (3.03 g, 72.3 mmol) in water (5 mL) was added. The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, and then the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M024 (2.60 g, crude product). LC-MS: [M+1] + =139.16.

[0648] Preparation Example 27 Preparation of (R)-5,5-difluorohexan-2-ol (Compound M025)

[0649] (1) At room temperature, (2R,5R)-2,5-hexanediol (4.5 g, 38.1 mmol) was dissolved in tetrahydrofuran (150 mL), and imidazole (2.6 g, 38.1 mmol) and tert-butyldiphenylsilyl chloride (9.9 g, 36.2 mmol) were added under ice-water bath. After the addition was completed, the reaction solution was slowly warmed to room temperature and continued to stir for 2 hours. The reaction solution was diluted with aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M025-1 (4.8 g). LC-MS: [M+H] + =357.10.

[0650] (2) Compound M025-1 (4.8 g, 13.5 mmol) was dissolved in dichloromethane (100 mL) at room temperature, and sodium bicarbonate (5.7 g, 67.5 mmol) was added. (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoxyl-3(1H)-one (6.3 g, 14.8 mmol) was added under ice-water bath. The reaction solution was warmed to room temperature and stirred for 3 hours. The reaction solution was directly filtered and the filter cake was rinsed with dichloromethane (100 mL). The filtrate was added with sodium carbonate aqueous solution (100 mL) and stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane (50 mL × 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound M025-2 (4.2 g). LC-MS: [M+H] + =355.15.

[0651] (3) Compound M025-2 (1.5 g, 4.2 mmol) was dissolved in bis(2-methoxyethyl)aminosulfur trifluoride (4.7 g, 21.2 mmol) at room temperature. The reaction solution was heated to 50°C and stirred for 16 hours. The reaction solution was cooled to room temperature and then added dropwise to a cold aqueous sodium bicarbonate solution (40 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M025-3 (1.36 g). LC-MS: [M+H] + =377.20.

[0652] (4) Compound M025-3 (1.36 g, 3.6 mmol) was dissolved in a tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 18 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound M025 (600 mg, crude product). LC-MS: [M+H] + =139.09.

[0653] Preparation Example 28 Preparation of (2R)-4-fluoropentan-2-ol (Compound M026)

[0654] (1) Compound M023-3 (13.9 g, 36.1 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL) at room temperature. Under nitrogen atmosphere, the reaction solution was cooled to -78°C, and then methylmagnesium bromide (60 mL, 3.0 M ether solution) was added dropwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 3 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction solution to quench the mixture, and then diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M026-1 (11.3 g). LC-MS: [M+H] + =341.56.

[0655] (2) Compound M026-1 (5 g, 14.7 mmol) was dissolved in methanol (50 mL) at room temperature. The reaction solution was cooled to 0°C, and sodium borohydride (1.7 g, 44 mmol) was slowly added in batches. After the addition was completed, the reaction solution was warmed to room temperature and continued to stir for 1 hour. Water (50 mL) was slowly added to the reaction solution to quench the solution. The solution was adjusted to pH 2-3 with dilute hydrochloric acid solution (1 M), and then extracted twice with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M026-2 (4.7 g). LC-MS: [M+H] + =343.55.

[0656] (3) Compound M026-2 (4.7 g, 13.7 mmol) was dissolved in dichloromethane (90 mL) at room temperature. In a nitrogen atmosphere, the reaction solution was cooled to 0°C, and diethylaminosulfur trifluoride (11 g, 68.6 mmol) was added dropwise. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 18 hours. The reaction solution was poured into ice water (100 mL) for quenching and extracted with dichloromethane (100 mL). The organic phase was washed with saturated sodium carbonate solution (50 mL) and saturated brine (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to obtain compound M026-3 (2.15 g). LC-MS: [M+H] + =345.52.

[0657] (4) Compound M026-3 (1 g, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) at room temperature, and tetrabutylammonium fluoride (1.1 g, 4.2 mmol) was added. The reaction solution was heated to 60°C and stirred for 3 hours. After the reaction solution was cooled to room temperature, it was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M026 (310 mg). LC-MS: [M+H] + =107.1.

[0658] The preparation of the compounds in the following table refers to the preparation method of Preparation Example 28, except that the compound M026-1 is replaced with the corresponding reactants in the following table:

[0659] Preparation Example 29 Preparation of 1-fluoropentan-2-ol (Compound M029)

[0660] (1) At room temperature, 1,2-pentanediol (3.0 g, 28.80 mmol) and imidazole (2.94 g, 43.21 mmol) were dissolved in dichloromethane (30 mL), and a solution of tert-butyldiphenylsilyl chloride (7.92 g, 28.80 mmol) in dichloromethane (30 mL) was added. The reaction solution was stirred at room temperature for 16 hours. Water (100 mL) was added to the reaction solution for dilution, and the solution was extracted with dichloromethane (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M029-1 (5.8 g). LC-MS: [M+H-78] + =265.10.

[0661] (2) Compound M029-1 (2.3 g, 6.71 mmol), 4-dimethylaminopyridine (82 mg, 0.67 mmol) and pyridine (5.31 g, 67.14 mmol) were dissolved in dichloromethane (30 mL) at room temperature, and benzoyl chloride (1.42 g, 10.07 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M029-2 (2.8 g). LC-MS: [M+H] + =447.10.

[0662] (3) Compound M029-2 (2.6 g, 5.82 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) at room temperature, and tetrabutylammonium fluoride (1.83 g, 6.99 mmol) was added. The reaction solution was stirred at room temperature for 6 hours. Water (30 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M029-3 (1.2 g). LC-MS: [M+H] + =209.10.

[0663] (4) Compound M029-3 (900 mg, 4.32 mmol) was dissolved in dichloromethane (10 mL) at room temperature. After the reaction solution was cooled to 0°C, diethylaminosulfur trifluoride (1.04 g, 6.48 mmol) was added dropwise. After the reaction solution was warmed to room temperature, stirring was continued for 3 hours. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (50 mL) to quench the reaction solution, and extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M029-4 (700 mg). LC-MS: [M+H] + =211.10.

[0664] (5) Compound M029-4 (0.6 g, 2.85 mmol) was dissolved in methanol (4.5 mL) and water (1.5 mL) at room temperature, and lithium hydroxide monohydrate (360 mg, 8.56 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M029 (250 mg).

[0665] Preparation Example 30 Preparation of 4-(5-bromopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (M030)

[0666] Compound M030 was prepared by referring to the preparation method of Compound M018 in Preparation Example 16, except that Compound M018-1 was replaced with 5-bromo-2-iodopyridine to obtain Compound M030 (450 mg). LC-MS: [M+H] + =283.9.

[0667] Preparation Example 31 Preparation of (R)-1-(bicyclo[1.1.1]pentan-1-yl)ethan-1-ol (Compound 237-3A)

[0668] At room temperature, compound 237-3 (21 g, crude product) was dissolved in dichloromethane (210 mL), followed by the addition of (S)-2-methyl-CBS-oxazaborolidine (53 g, 190.65 mmol). The reaction mixture was cooled to 0°C, and borane dimethyl sulfide (95 mL, 2 M in THF) was slowly added dropwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. 1 M dilute hydrochloric acid (100 mL) was added to the reaction mixture, which was quenched, filtered, and the filtrate was extracted twice with dichloromethane (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature. The residue was added with diethyl ether (100 mL), filtered, and the filtrate was concentrated under reduced pressure. This ether reaction was repeated twice. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 237-3A (21 g). LC-MS: [M+H] + =113.17.

[0669] Preparation Example 32 Preparation of 2-chloro-4-(3,3-difluorobutyl)pyrimidine (Compound 255-2)

[0670] (1) 2-Chloropyrimidine (4.0 g, 34.92 mmol) was dissolved in dichloromethane (60 mL) and water (60 mL) at room temperature, and levulinic acid (8.11 g, 69.85 mmol), ammonium persulfate (24 g, 104.77 mmol), silver nitrate (593 mg, 3.50 mmol) and trifluoroacetic acid (7.96 g, 69.85 mmol) were added with stirring. The reaction solution was heated to 45°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was quenched by adding aqueous sodium bicarbonate solution (60 mL), filtered through celite, and the filtrate was rinsed with dichloromethane (180 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 255-1 (600 mg). LC-MS: [M+H] + =185.00.

[0671] (2) Compound 255-1 (550 mg, 2.98 mmol) was dissolved in dichloromethane (10 mL) at room temperature. After the reaction solution was cooled to 0°C, diethylaminosulfur trifluoride (1.44 g, 8.94 mmol) was slowly added dropwise. The reaction solution was heated to 40°C and stirred for 6 hours. The reaction solution was cooled to room temperature, quenched by the addition of aqueous sodium bicarbonate solution (20 mL), and extracted with dichloromethane (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 255-2 (400 mg). LC-MS: [M+H] + =207.00.

[0672] Preparation Example 33 Preparation of 3-(5-bromo-6-methylpyridin-2-yl)-5-methylisoxazole-4-carboxylic acid (M031)

[0673] (1) At room temperature, 5-bromo-6-methylpyridine-2-carboxaldehyde (4 g, 20.0 mmol) was dissolved in ethanol (60 mL) and water (30 mL), and hydroxylamine hydrochloride (1.81 g, 26.0 mmol) and sodium acetate (2.46 g, 30.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound M031-1 (2.8 g). LC-MS: [M+H] + =214.95.

[0674] (2) Compound M031-1 (2.8 g, 15.4 mmol) was dissolved in N,N-dimethylformamide (15 mL) at room temperature, and N-chlorosuccinimide (2.43 g, 18.23 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. Ice water (35 mL) was added to the reaction mixture, filtered, and the filter cake was concentrated under reduced pressure to obtain compound M031-2 (1.2 g). LC-MS: [M+H] + =250.85.

[0675] (3) Ethyl acetoacetate (813.7 mg, 18.14 mmol) was dissolved in anhydrous methanol (30 mL) at room temperature, and compound M031-2 (1.2 g, 4.81 mmol) was added. The reaction solution was cooled to 0°C, and sodium methoxide (0.98 mL, 5.29 mmol, 30% methanol solution) was added. The reaction solution was stirred at 0°C for 0.25 hours, and then sodium methoxide (0.98 mL, 5.29 mmol, 30% methanol solution) was added. The reaction solution was heated to room temperature and continued to stir for 0.5 hours. The reaction solution was diluted with water (40 mL) and extracted twice with ethyl acetate (30 mL×2). The combined organic phase was washed with water (30 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M031-3 (950 mg). LC-MS: [M+H] + =324.95.

[0676] (4) Compound M031-3 (750 mg, 2.31 mmol) was dissolved in methanol (7 mL) and water (3.5 mL) at room temperature, and lithium hydroxide monohydrate (379.2 mg, 9.24 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, and the residue was diluted with water (20 mL). The aqueous phase was adjusted to pH 2-3 with dilute hydrochloric acid (1 M) and extracted twice with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M031 (560 mg). LC-MS: [M+H] + =296.90.

[0677] Preparation Example 34 Preparation of 3-(5-bromo-6-chloropyridin-2-yl)-5-methylisoxazole-4-carboxylic acid (M032)

[0678] Compound M032 was prepared by referring to the preparation method of Compound M031 in Preparation Example 33, except that the raw material 5-bromo-6-methylpyridine-2-carboxaldehyde was replaced with Compound M032-1 to obtain Compound M032 (450 mg). LC-MS: [M+H] + =318.85.

[0679] Among them, the preparation method of compound M032-1 is as follows:

[0680] 3-Bromo-2-chloro-6-iodopyridine (4.8 g, 15.0 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to -15°C and isopropylmagnesium chloride (2 M in tetrahydrofuran, 8.3 mL, 16.6 mmol) was added. The reaction solution was stirred at -15°C for 1 hour. N,N-dimethylformamide (1.65 g, 22.62 mmol) was then added and stirred for 1 hour. The temperature was then raised to room temperature and the reaction was stirred for another 1 hour. The reaction solution was cooled to 0°C and quenched by the addition of dilute hydrochloric acid (10 mL, 3 M). The solution was adjusted to pH 9-10 by the addition of dilute aqueous sodium hydroxide (15%). The solution was diluted with water (100 mL) and extracted twice with ethyl acetate (70 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give compound M032-1 (1.6 g). LCMS: [M+1] + =221.85.

[0681] Referring to the method of Preparation Example 34, the compounds in the following table were prepared. The raw material 3-bromo-2-chloro-6-iodopyridine needed to be replaced with the corresponding reactants in the following table:

[0682] Preparation Example 35 Preparation of 5-(5-bromopyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (M033)

[0683] Compound M033 was prepared by referring to the preparation method of Compound M017 in Preparation Example 15, except that Compound M017-1 was replaced with 5-bromo-2-pyridinecarboxylic acid to obtain Compound M033 (600 mg). LC-MS: [M+H] + =284.85.

[0684] Preparation Example 36 Preparation of 5-(5-bromo-6-chloropyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (M034)

[0685] (1) Compound M033-3 (2 g, 6.73 mmol) was dissolved in dichloromethane (20 mL) at room temperature. After the reaction solution was cooled to 0°C, m-chloroperbenzoic acid (7.00 g, 33.65 mmol, 85%) was added in batches. The reaction solution was stirred at room temperature for 6 hours. The reaction solution was quenched by adding saturated sodium sulfite (50 mL). It was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain compound M034-1 (1.6 g). LC-MS: [M+H] + =312.95.

[0686] (2) Compound M034-1 (1.6 g, 5.11 mmol) was dissolved in 1,2-dichloroethane (16 mL) at room temperature. The reaction mixture was cooled to 0°C and phosphorus oxychloride (4.70 g, 30.66 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 0.5 hours. The temperature was then raised to 50°C and the reaction mixture was stirred for 12 hours. After the reaction mixture was cooled to room temperature, it was quenched by adding a saturated aqueous sodium sulfite solution (30 mL), diluted with saturated brine (30 mL), and extracted twice with ethyl acetate (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound M034-2 (0.9 g).

[0687] LC-MS: [M+H] + =332.90.

[0688] (3) Compound M034-2 (0.9 g, 2.71 mmol) was dissolved in methanol (9 mL) and tetrahydrofuran (9 mL) at room temperature, and a solution of lithium hydroxide (0.33 g, 13.55 mmol) in water (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 mL) and concentrated under reduced pressure to remove methanol and tetrahydrofuran. The residue was extracted with ethyl acetate (15 mL), and the aqueous phase was adjusted to pH = 5 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M034 (850 mg). LC-MS: [M+H] + =318.90.

[0689] Preparation Example 37 Preparation of Compound M035

[0690] (1) At room temperature, trimethylsilyl cyanide (5.6 g, 56.28 mmol) was added to tetrabutylammonium fluoride (14.7 g, 56.28 mmol). The reaction solution was stirred at room temperature for 0.5 hours, and then a solution of 2-(oxetane-3-ylidene)acetic acid methyl ester (4.0 g, 28.14 mmol) in tetrahydrofuran (25 mL) was added. The reaction solution was heated to 50°C and stirred for 3 hours. After the reaction solution was cooled to room temperature, it was poured into water (50 mL) and diluted. The solution was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M035-1 (4.4 g). LC-MS: [M+H] + =170.07.

[0691] (2) Compound M035-1 (500 mg, 2.96 mmol) was dissolved in pyridine (6 mL), glacial acetic acid (2 mL) and water (2 mL) at room temperature, and Raney nickel (174 mg, 2.96 mmol) was added. The reaction solution was heated to 60°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (30 mL), washed with dilute hydrochloric acid (30 mL × 3), and then washed with saturated sodium bicarbonate aqueous solution (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M035-2 (380 mg). LC-MS: [M+H] + =173.07.

[0692] (3) At room temperature, dimethyl (1-diazo-2-oxopropyl)phosphonate (637 mg, 3.31 mmol) was dissolved in methanol (10 mL). After the reaction solution was cooled to 0°C, potassium carbonate (764 mg, 5.53 mmol) was added and the mixture was heated to room temperature and stirred for 0.5 hours. Compound M035-2 (380 mg, 2.21 mmol) was then added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL) and diluted, and extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M035 (130 mg). LC-MS: [M+H] + =155.06.

[0693] Preparation Example 38 Preparation of methyl 2-(3-ethoxy-1-ethynylcyclobutyl)acetate (Compound M036)

[0694] (1) Compound M015-1 (15 g, 72.73 mmol) was dissolved in N,N-dimethylformamide (150 mL) at room temperature. The reaction solution was cooled to 0°C, and sodium hydride (4.36 g, 109.09 mmol, 60% dispersion in mineral oil) was added in batches. The reaction solution was stirred at 0°C for 0.5 hours, and then iodoethane (22.69 g, 145.46 mmol) was added. The reaction solution was warmed to room temperature and continued to stir for 2 hours. The reaction solution was slowly added dropwise to a dilute hydrochloric acid solution (100 mL, 1 M) to quench, and then extracted with ethyl acetate (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M036-1 (8.1 g). LC-MS: [M+H] + =235.05.

[0695] (2) At room temperature, compound M036-1 (8.1 g, 34.57 mmol) was dissolved in ultra-dry tetrahydrofuran (400 mL), allyl iodide (14.52 g, 86.42 mmol) was added, the reaction solution was cooled to -78 °C (dry ice-ethyl acetate bath), and lithium bis(trimethylsilyl)amide (69.14 mL, 69.14 mmol, 1 M tetrahydrofuran solution) was slowly added. The reaction solution was slowly warmed to room temperature and the reaction was continued for 2 hours. The reaction solution was poured into saturated ammonium chloride (150 mL) for quenching and extracted with ethyl acetate (200 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M036-2 (7.5 g, containing cis and trans isomers). LC-MS: [M+H] + =275.10.

[0696] (3) Compound M036-2 (5.5 g, 20.05 mmol) was dissolved in acetonitrile (50 mL) and water (50 mL) at room temperature, and sodium periodate (17.15 g, 80.2 mmol) and ruthenium trichloride (420 mg, 2.01 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and then potassium permanganate (3.17 g, 20.05 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated sodium bicarbonate solution (30 mL), filtered, and saturated sodium sulfite (20 mL) was added to the filtrate and stirred for 15 minutes. The mixture was filtered again, and the filtrate was adjusted to pH 5-6 with dilute hydrochloric acid (1 M) aqueous solution and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound M036-3 (3.5 g, containing cis and trans isomers). LC-MS: [M+H] + =293.05.

[0697] (4) Compound M036-3 (3.5 g, 11.97 mmol) was dissolved in methanol (30 mL) at room temperature, and thionyl chloride (4.27 g, 35.91 mmol) was slowly added. The reaction solution was refluxed (65°C) for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M036-4 (3.5 g, containing cis and trans isomers). LC-MS: [M+H] + =307.10

[0698] (5) Compound M036-4 (3.5 g, 11.42 mmol) was dissolved in tetrahydrofuran (35 mL) at room temperature, and wet palladium carbon (350 mg, 3.31 mmol, 10%) and wet palladium hydroxide carbon (350 mg, 2.51 mmol, 20%) were added. Under a hydrogen atmosphere, the reaction solution was heated to 40°C and stirred for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound M036-5 (2.3 g, crude product, containing cis and trans isomers). LC-MS: [M+H] + =217.05.

[0699] (6) Compound M036-5 (2.3 g, crude product) was dissolved in ultra-dry tetrahydrofuran (25 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to 0°C and borane dimethyl sulfide complex (2.13 mL, 21.23 mmol, 10 M tetrahydrofuran solution) was added dropwise. The reaction solution was heated to room temperature and stirred for 2 hours. Water (20 mL) was added to the reaction solution to quench the reaction and the solution was extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound M036-6 (1.3 g, containing cis and trans isomers). LC-MS: [M+H] + =203.05.

[0700] (7) Oxalyl chloride (1.34 mL, 15.82 mmol) was dissolved in anhydrous dichloromethane (10 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), and dimethyl sulfoxide (2.25 mL, 31.64 mmol) was slowly added dropwise, controlling the internal temperature within -70°C. At this temperature, the reaction solution was stirred for 0.5 hours, and then a solution of compound M036-6 (1.6 g, 7.91 mmol) in dichloromethane (10 mL) was added dropwise, controlling the internal temperature within -70°C. The reaction solution was continued to react at -78°C for 1 hour. Finally, triethylamine (8.80 mL, 63.28 mmol) was slowly added dropwise, controlling the internal temperature within -65°C. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 1 hour. Water (50 mL) was added to the reaction solution for dilution, and the solution was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound M036-7 (1.5 g, containing cis and trans isomers). LC-MS: [M+H] + =201.05

[0701] (8) At room temperature, compound M036-7 (1.5 g, 7.49 mmol) was dissolved in methanol (15 mL). The reaction solution was cooled to 0°C, potassium carbonate (1.24 g, 8.99 mmol) was added, and then (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (1.58 g, 8.24 mmol) was slowly added. The reaction solution was heated to room temperature and stirred for 2 hours. Water (15 mL) was slowly added to the reaction solution, and the solution was extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M036 (1.3 g, containing cis and trans isomers). LC-MS: [M+H] + =197.05

[0702] Preparation Example 39 Preparation of methyl 2-(1-ethynyl-3,3-difluorocyclobutyl)acetate (Compound M037)

[0703] (1) At room temperature, diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (20 g, 82.55 mmol) was dissolved in dichloromethane (300 mL). The reaction solution was cooled to 0°C and diethylaminosulfur trifluoride (33.3 g, 206.4 mmol) was slowly added. The reaction solution was slowly heated to room temperature and stirred for 24 hours. The reaction solution was slowly poured into a cold (0°C) saturated sodium carbonate solution (200 mL) for quenching and extracted with dichloromethane (200 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M037-1 (18.6 g). LC-MS [M+H] + =265.12.

[0704] (2) At room temperature, lithium aluminum tetrahydride (4.0 g, 105.6 mmol) was dissolved in anhydrous tetrahydrofuran (190 mL). Under a nitrogen atmosphere, the reaction solution was cooled to 0°C and compound M037-1 (18.6 g, 70.4 mmol) was slowly added. The reaction solution was heated to 25°C and stirred for 16 hours. Water (50 mL), 50% sodium hydroxide solution (20 mL), and water (100 mL) were added to the reaction solution in sequence to quench the reaction. The reaction solution was filtered under reduced pressure, and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was extracted with ethyl acetate (200 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 0) to obtain compound M037-2 (6.8 g). LC-MS [M+H] + =153.06.

[0705] (3) Compound M037-2 (6.8 g, 44.7 mmol) was dissolved in anhydrous tetrahydrofuran (70 mL) and N,N-dimethylformamide (70 mL) at room temperature. The reaction solution was cooled to 0°C, and sodium hydride (1.8 g, 44.7 mmol, 60% dispersion in mineral oil) was slowly added in batches. The reaction solution was stirred at 0°C for 2 hours, and then benzyl bromide (7.65 g, 44.7 mmol) was added dropwise. The reaction solution was warmed to room temperature and stirred for 1 hour. Saturated ammonium chloride solution (100 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (80 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M037-3 (5 g). LC-MS [M+H] + =243.11.

[0706] (4) Compound M037-3 (5 g, 20.7 mmol) was dissolved in dichloromethane (50 mL) at room temperature. The reaction solution was cooled to 0°C, and triethylamine (2.5 g, 24.8 mmol) and methylsulfonyl chloride (2.6 g, 22.7 mmol) were added. The reaction solution was stirred at 0°C for 2 hours. The reaction solution was quenched with water (100 mL) and extracted with dichloromethane (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M037-4 (6 g). LC-MS [M+H] + =321.09.

[0707] (5) At room temperature, compound M037-4 (6 g, 18.7 mmol) was dissolved in N,N-dimethylformamide (80 mL), and trimethylsilyl cyanide (3.72 g, 37.5 mmol) and tetrabutylammonium fluoride (9.8 g, 37.5 mmol) were added. The reaction solution was heated to 130°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M037-5 (3.8 g). LC-MS [M+H] + =252.11.

[0708] (6) Compound M037-5 (3.8 g, 15.2 mmol) was dissolved in ethanol (50 mL) and water (50 mL) at room temperature, and potassium hydroxide (5.1 g, 90.8 mmol) was added. The reaction solution was heated to 100°C and stirred for 4 days. Potassium hydroxide (1.5 g, 26.8 mmol) was added, and the reaction solution was stirred at 100°C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove ethanol. The residue was washed with ethyl acetate (60 mL × 3). The aqueous phase was adjusted to pH = 3-4 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (60 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M037-6 (4 g). LC-MS [M+H] + =271.11.

[0709] (7) Compound M037-6 (4 g, 14.8 mmol) was dissolved in methanol (90 mL) at room temperature. The reaction mixture was cooled to 0°C, and thionyl chloride (8.7 g, 73.1 mmol) was slowly added. The reaction mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M037-7 (3.7 g). LC-MS [M+H] + =285.12.

[0710] (8) Compound M037-7 (3.7 g, 13.0 mmol) was dissolved in methanol (40 mL) at room temperature, and wet palladium on carbon (0.69 g, 0.65 mmol, 10%) was added. The reaction mixture was heated to 30°C under a hydrogen atmosphere and stirred for 48 hours. The reaction mixture was filtered through celite under reduced pressure, the filter cake was washed with methanol (40 mL), and the filtrate was concentrated under reduced pressure to obtain compound M037-8 (2.8 g, crude product). LC-MS: [M+H] + =195.08.

[0711] (9) Oxalyl chloride (1.3 g, 10.3 mmol) was dissolved in anhydrous dichloromethane (20 mL) at room temperature. Under a nitrogen atmosphere, the reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), and a solution of dimethyl sulfoxide (1.6 g, 20.6 mmol) in dichloromethane (2 mL) was slowly added dropwise, controlling the internal temperature within -70°C. The reaction was stirred for 0.5 hours at this temperature, and then a solution of compound M037-8 (1.0 g, 5.15 mmol) in dichloromethane (2 mL) was added dropwise, controlling the internal temperature within -70°C. The reaction solution was allowed to react for 1 hour at this temperature. Triethylamine (4.2 g, 4.12 mmol) was then slowly added dropwise, controlling the internal temperature within -65°C. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 1 hour. Water (30 mL) was added to the reaction solution for dilution, and the solution was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound M037-9 (0.72 g). LC-MS: [M+H] + =193.06.

[0712] (10) At room temperature, compound M037-9 (0.72 g, 3.75 mmol) was dissolved in methanol (15 mL). The reaction solution was cooled to 0°C, potassium carbonate (0.78 g, 5.63 mmol) was added, and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.8 g, 9.4 mmol) was slowly added. After the reaction solution was warmed to room temperature, stirring was continued for 1 hour. Water (20 mL) was slowly added to the reaction solution to dilute it, and it was extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M037 (0.45 g). LC-MS: [M+H] + =189.06.

[0713] Preparation Example 40 Preparation of diethyl (5-ethynylspiro[2.3]hexan-5-yl)phosphonate (Compound M038)

[0714] (1) At room temperature, diethyl cyanomethylphosphonate (1.0 g, 5.60 mmol) was dissolved in acetonitrile (10 mL), and 1,1-bisbromomethylcyclopropane (1.23 g, 5.6 mmol), benzyltriethylammonium chloride (130 mg, 0.56 mmol, TBAC) and potassium carbonate (2.3 g, 16.80 mmol) were added. The reaction solution was heated to 80°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was poured into water (30 mL) and diluted. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound M038-1 (0.9 g). LCMS: [M+H] + =244.05.

[0715] (2) At room temperature, M038-1 (1.6 g, 6.58 mmol) was dissolved in pyridine (20 mL), glacial acetic acid (10 mL) and water (10 mL), and Raney nickel (386 mg, 6.58 mmol) was added. The reaction solution was heated to 60°C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with dilute hydrochloric acid (50 mL × 3, 1 M), and then washed with saturated sodium bicarbonate aqueous solution (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M038-2 (1.6 g crude product). LCMS: [M+H] + =247.10.

[0716] (3) At room temperature, dimethyl (1-diazo-2-oxopropyl)phosphonate (1.3 g, 6.71 mmol) was dissolved in methanol (30 mL). After the reaction solution was cooled to 0°C, potassium carbonate (1.5 g, 11.17 mmol) was added. The reaction solution was warmed to room temperature and stirred for 0.5 hours. Compound M038-2 (1.1 g, 4.47 mmol) was then added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into water (50 mL) for quenching and extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M038 (800 mg). LCMS: [M+H] + =243.11.

[0717] Preparation Example 41 Preparation of methyl 2-(5-ethynylspiro[2.3]hexane-5-yl)acetate (Compound M039)

[0718] Compound M039 was prepared by referring to the preparation method of compound M015 in Preparation Example 13, except that intermediate M015-2 was replaced with intermediate M039-2 to obtain compound M039 (1 g). LC-MS: [M+H] + =179.05.

[0719] Among them, the preparation method of intermediate M039-2 is as follows:

[0720] (1) At room temperature, 3-methylenecyclobutanecarboxylic acid (5 g, 44.59 mmol) was dissolved in N,N-dimethylformamide (50 mL), and benzyl bromide (9 g, 53.51 mmol) and potassium carbonate (9 g, 66.89 mmol) were added. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M039-1 (9 g). LC-MS: [M+H] + =203.10.

[0721] (2) Diethylzinc (11 g, 89.00 mmol) was dispersed in dichloromethane (100 mL) at room temperature. The reaction solution was cooled to 0°C under a nitrogen atmosphere, and trifluoroacetic acid (3.3 mL, 44.50 mmol) was added dropwise. The reaction solution was stirred at 0°C for 15 minutes, and then diiodomethane (48 g, 178.00 mmol) was added. The reaction solution was stirred at 0°C for 30 minutes, and finally a dichloromethane solution of M039-1 (9 g, 44.50 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution to quench the reaction, and then the solution was extracted with dichloromethane (60 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M039-2 (8 g). LC-MS: [M+H] + =217.05.

[0722] Preparation Example 42 Preparation of 5-(5-bromo-6-(fluoromethyl)pyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (Compound M040)

[0723] (1) Compound M017-4 (2.4 g, 7.71 mmol) was dissolved in dichloromethane (50 mL) at room temperature. The reaction solution was cooled to 0°C, and m-chloroperbenzoic acid (4.0 g, 23.13 mmol, 85% purity) was added. The reaction solution was heated to room temperature and stirred for 16 hours. The reaction solution was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M040-1 (1.7 g). LCMS: [M+H] + =328.90.

[0724] (2) Compound M040-1 (1.7 g, 5.20 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and trifluoroacetic anhydride (5.5 g, 26 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL). Then, saturated sodium bicarbonate solution (100 mL) was added. The mixture was stirred at room temperature for 16 hours, and then the liquids were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M040-2 (1.5 g). LCMS: [M+H] + =326.85.

[0725] (3) Compound M040-2 (500 mg, 1.53 mmol) was dissolved in dichloromethane (5 mL) at room temperature. The reaction solution was cooled to 0°C and diethylaminosulfur trifluoride (247 mg, 1.53 mmol) was added. The reaction solution was stirred at 0°C for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (30 mL) for quenching and extracted with dichloromethane (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M040-3 (250 mg). LCMS: [M+H] + =328.85.

[0726] (4) Compound M040-3 (250 mg, 0.76 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL) at room temperature, and lithium hydroxide monohydrate (96 mg, 2.28 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water (10 mL) and concentrated under reduced pressure to remove methanol. The residue was washed with dichloromethane (10 mL × 3), and the aqueous phase was adjusted to pH = 3-4 with dilute hydrochloric acid (1 M). The mixture was filtered under reduced pressure, and the filter cake was dried under reduced pressure to obtain compound M040 (230 mg). LCMS: [M+H] +=316.90.

[0727] Preparation Example 43 Preparation of 4-(5-bromo-6-(difluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Compound M041)

[0728] (1) Compound M003 (6.0 g, 16.34 mmol) was dissolved in methanol (60 mL) at room temperature, and 4-methylbenzenesulfonic acid pyridine (4.1 g, 16.34 mmol) was added. The reaction solution was heated to 60°C and stirred for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was diluted with water (60 mL) and extracted with ethyl acetate (40 mL×2). The combined organic phase was washed with saturated sodium bicarbonate aqueous solution (60 mL) and saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M041-1 (4.5 g). LC-MS: [M+H] + =282.95.

[0729] (2) Compound M041-1 (600 mg, 2.1 mmol) was dissolved in acetonitrile (6 mL) and water (4.5 mL) at room temperature, and potassium permanganate (664 mg, 4.2 mmol) was added. The reaction solution was stirred at room temperature for 22 hours. Aqueous sodium hydroxide solution (10 mL, 2 M) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The aqueous phase was adjusted to pH = 2-3 with dilute hydrochloric acid (1 M), filtered, and the filter cake was rinsed with water (10 mL) and concentrated under reduced pressure to obtain compound M041-2 (476 mg, crude product). LC-MS: [M+H] + = 298.85.

[0730] (3) Compound M041-2 (1.0 g, 3.37 mmol) was dissolved in methanol (5 mL) and dichloromethane (5 mL) at room temperature, and a solution of trimethylsilyldiazomethane in n-hexane (3.37 mL, 6.74 mmol, 2 M) was slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M041-3 (800 mg). LC-MS: [M+H] + =310.90.

[0731] (4) At room temperature, compound M041-3 (800 mg, 2.57 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (443.5 mg, 2.57 mmol, 85% purity) was slowly added. The reaction solution was stirred at room temperature for 16 hours. Sodium carbonate solution (20 mL) was added to the reaction solution to quench the reaction solution, and the solution was washed with dichloromethane (20 mL × 3). The combined organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound M041-4 (700 mg). LC-MS: [M+H] + =326.95.

[0732] (5) Compound M041-4 (600 mg, 1.83 mmol) was dissolved in dichloromethane (18 mL) at room temperature, and trifluoroacetic anhydride (1921.77 mg, 9.15 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 16 hours. Methanol (10 mL) and saturated sodium bicarbonate solution (30 mL) were added to the reaction solution, and the mixed solution was stirred at room temperature for 2 hours, then extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound M041-5 (470 mg). LC-MS: [M+H] + =326.90.

[0733] (6) Compound M041-5 (420 mg, 1.28 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and Dess-Martin reagent (651 mg, 1.54 mmol) was slowly added. The reaction solution was stirred at room temperature for 6 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, stirred at room temperature for 2 hours, and then extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound M041-6 (330 mg). LC-MS: [M+H] + =324.90.

[0734] (7) Compound M041-6 (280 mg, 0.86 mmol) was dissolved in dichloromethane (6 mL) at room temperature, and diethylaminosulfur trifluoride (555 mg, 3.44 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was added to a saturated sodium bicarbonate solution (10 mL) for quenching. The mixture was then extracted with dichloromethane (10 mL × 3), and the combined organic phase was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound M041-7 (260 mg). LC-MS: [M+H] + =346.90.

[0735] (8) Compound M041-7 (260 mg, 0.75 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL) at room temperature, and lithium hydroxide monohydrate (157 mg, 3.75 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was diluted with water (5 mL) and concentrated under reduced pressure. The pH of the residual solution was adjusted to 5-6 with dilute hydrochloric acid (1 M). The solution was filtered under reduced pressure, and the filter cake was rinsed with water (10 mL). The filter cake was dried under reduced pressure to obtain compound M041 (220 mg). LC-MS: [M+H] + =332.90.

[0736] Preparation Example 44 Preparation of 3-(5-bromo-6-methylpyridin-2-yl)-5-methylisothiazole-4-carboxylic acid (Compound M042)

[0737] (1) At room temperature, ethyl 2-diazo-3-oxobutanoate (1 g, 6.4 mmol) was dissolved in toluene (15 mL), and Lawesson's reagent (3.11 g, 7.68 mmol) was added. The reaction solution was heated to 100°C and stirred in a nitrogen atmosphere for 16 hours. After the reaction solution was cooled to room temperature, it was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound M042-1 (0.82 g). LC-MS: [M+H] + =172.95.

[0738] (2) Compound M042-1 (600 mg, 3.48 mmol), 5-bromo-6-methylpyridine-2-carbonitrile (686 mg, 3.48 mmol), cyclooctadiene ruthenium (II) dichloride (24.4 mg, 0.0870 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (116 mg, 0.210 mmol) were added to chlorobenzene (9 mL) at room temperature. The reaction solution was heated to 130°C and stirred for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with saturated brine (15 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain compound M042-2 (1.08 g). LC-MS: [M+H] + =342.90.

[0739] (3) Compound M042-2 (800 mg, 2.34 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL) at room temperature, and a solution of lithium hydroxide monohydrate (295 mg, 7.02 mmol) in water (2.5 mL) was added. The reaction solution was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution for dilution, and the solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL). The aqueous phase was adjusted to pH = 5 with 1 M hydrochloric acid, filtered under reduced pressure, and the filter cake was rinsed with water (5 mL × 2), ethanol (5 mL × 2), and petroleum ether (5 mL × 2) in sequence. The solution was dried under reduced pressure to obtain compound M042 (560 mg). LC-MS: [M+H] + =314.85.

[0740] Preparation Example 45 Preparation of 5-(5-bromo-6-ethylpyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (Compound M043)

[0741] Compound M043 was prepared by referring to the preparation method of compound M017 in Preparation Example 15, except that the raw material 5-bromo-6-methylpyridine-2-carbonitrile was replaced with M043-1 to obtain compound M043 (500 mg). LC-MS: [M+H] + =310.95.

[0742] Among them, the preparation method of compound M043-1 is as follows:

[0743] At room temperature, 5-bromo-6-methylpyridine-2-carbonitrile (5.00 g, 25.4 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Under a nitrogen atmosphere, the mixture was cooled to -50°C and lithium bistrimethylsilylamide (8.37 g, 50.0 mmol, 1 M solution in tetrahydrofuran) was slowly added dropwise. The reaction mixture was stirred at -50°C for 0.5 hours. The temperature was lowered to -70°C and the reaction continued for 1 hour. Then, iodomethane (7.20 g, 50.8 mmol) was added dropwise. The reaction mixture was continued at -70°C for 1 hour. The reaction mixture was slowly warmed to 0°C and quenched by the addition of saturated aqueous ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1), and then purified by high performance liquid chromatography (0.1% ammonia water) to obtain compound M043-1 (1.09 g). LC-MS: [M+H] + =212.90.

[0744] Preparation Example 46 Preparation of 5-(5-bromo-6-(trifluoromethyl)pyridin-2-yl)-3-methylisoxazole-4-carboxylic acid (Compound M044)

[0745] Compound M044 was prepared by referring to the preparation method of compound M017 in Preparation Example 15, except that compound M017-1 was replaced with compound M044-3 to obtain compound M044 (400 mg). LC-MS: [M+H] + =352.90.

[0746] Among them, the preparation method of compound M044-3 is as follows:

[0747] (1) At room temperature, 5-bromo-6-(trifluoromethyl)pyridin-2-amine (20 g, 83.1 mmol) was dissolved in tetrahydrofuran (200 mL), and cuprous iodide (23.7 g, 124.2 mmol), diiodomethane (177.3 g, 53.3 mmol) and tert-butyl nitrite (34.1 g, 331.2 mmol) were added. The reaction solution was heated to 80°C and stirred for 1 hour. The reaction solution was cooled to room temperature and filtered. Ethyl acetate (400 mL) was added to the filtrate and diluted, and the filtrate was washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0) to obtain compound M044-1 (9 g). LC-MS: [M+H] + =351.84.

[0748] (2) Compound M044-1 (8 g, 22.8 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature. The reaction mixture was cooled to -15°C (ice-salt bath) under nitrogen atmosphere, and then isopropylmagnesium chloride (25 mL, 25.0 mmol, 1 M tetrahydrofuran solution) was added dropwise. The reaction mixture was stirred at this temperature for 1 hour, and N,N-dimethylformamide (2.5 g, 34.1 mmol) was added dropwise. After stirring for 1 hour, the mixture was warmed to room temperature and the reaction was continued for 1 hour. The reaction mixture was quenched with dilute hydrochloric acid (20 mL, 3 M), adjusted to pH = 9 with sodium hydroxide solution (15%), diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound M044-2 (4.1 g). LC-MS: [M+H] + =253.94.

[0749] (3) Compound M044-2 (1.40 g, 5.51 mmol) was dissolved in acetonitrile (14 mL) and water (14 mL) at room temperature, and potassium permanganate (1.74 g, 11.0 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. Ethyl acetate (20 mL) was added to the reaction solution, and a saturated sodium sulfite solution was added dropwise until the purple-red color faded. Then, a 15% aqueous sodium hydroxide solution (4 mL) was added dropwise and stirred vigorously for 10 minutes. The reaction solution was filtered under reduced pressure, the filter cake was rinsed with water (50 mL × 2), the filtrate was separated, the aqueous phase was adjusted to pH = 5 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M044-3 (1.26 g). LC-MS: [M+H] + =270.00.

[0750] Preparation Example 47 Preparation of 3,3-difluoropentan-2-ol (Compound M045)

[0751] (1) At room temperature, 3-pentanone (125 mL, 1.18 mol), benzoic acid (6.0 g, 49.13 mmol) and 1,2-dibromoethane (13.84 g, 73.70 mmol) were added to a reaction flask, followed by potassium iodide (1.63 g, 9.83 mmol) and potassium carbonate (10.19 g, 73.70 mmol). In an oxygen atmosphere, the reaction solution was heated to 60°C and stirred for 20 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M045-1 (2.9 g). LC-MS: [M+H] + =207.10.

[0752] (2) Compound M045-1 (2.9 g, 14.06 mmol) was dissolved in dichloromethane (30 mL) at room temperature. After the reaction solution was cooled to 0°C, diethylaminosulfur trifluoride (6.8 g, 42.18 mmol) was added dropwise. After the addition was completed, the reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into a saturated sodium bicarbonate solution (50 mL) for quenching. It was extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M045-2 (2.4 g). LC-MS: [M+H] + =229.06.

[0753] (3) Compound M045-2 (1.0 g, 4.3 g) was dissolved in methanol (7 mL) and water (3 mL) at room temperature, and lithium hydroxide monohydrate (0.92 g, 21.91 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to dilute the reaction solution, and the solution was extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at room temperature to obtain compound M045 (335 mg). C-MS: [M+H] + =125.07.

[0754] Preparation Example 48 Preparation of 4-fluoro-N,4-dimethylpentan-2-amine (Compound M046) Hydrochloride

[0755] (1) At room temperature, diacetone alcohol (5 g, 43.04 mmol) and methylamine hydrochloride (7.56 g, 111.90 mmol) were dissolved in dichloromethane (100 mL). Triethylamine (11.32 g, 111.90 mmol) was added to the reaction solution with stirring, followed by glacial acetic acid (5.17 g, 86.08 mmol). The reaction solution was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (25.54 g, 120.51 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was poured into a saturated solution of sodium bicarbonate (100 mL) for quenching and extracted with dichloromethane (100 mL × 3). The combined organic phase was washed with water (100 mL) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M046-1 (2 g, crude product). LC-MS: [M+H] + =132.10.

[0756] (2) Compound M046-1 (2 g, 15.24 mmol) and triethylamine (2.31 g, 22.86 mmol) were dissolved in dichloromethane (20 mL) at room temperature. The reaction solution was cooled to 0°C and di-tert-butyl dicarbonate (3.99 g, 18.29 mmol) was added dropwise with stirring. The reaction was allowed to react at room temperature for 1 hour. The reaction solution was quenched with water (50 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound M046-2 (1.3 g). LC-MS: [M+H] + =232.15.

[0757] (3) Compound M046-2 (300 mg, 1.3 mmol) was dissolved in dichloromethane (2 mL) at room temperature. After the reaction solution was cooled to -78°C (dry ice-ethyl acetate bath), diethylaminosulfur trifluoride (314 mg, 1.95 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at -78°C for 1 hour. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution to quench the reaction solution, and the solution was extracted with dichloromethane (20 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound M046-3 (400 mg). LC-MS: [M+H] + =234.10.

[0758] (4) Compound M046-3 (400 mg, 1.71 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and a solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound M046 (200 mg, crude product). LC-MS: [M+H] + =134.15.

[0759] Example 1 Preparation of 2-(1-((6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)ethynyl)cyclopropyl)acetic acid (Compound 001)

[0760] (1) At room temperature, trimethylsilyl acetylene (3.70 g, 37.75 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Nitrogen was replaced and the reaction solution was cooled to -78°C in a nitrogen atmosphere. Then, n-butyl lithium (16.4 mL, 40.90 mmol, 2.5 M) was added dropwise. After the addition was completed, the reaction solution was stirred at -78°C for 1 hour. At this temperature, a solution of bromomethylcyclopropane (4.25 g, 31.46 mmol) and hexamethylphosphoric triamide (6.20 g, 34.61 mmol) in tetrahydrofuran (20 mL) was added dropwise. The internal temperature was controlled within -70°C. After the addition was completed, the reaction solution was stirred at -78°C for 1 hour, then warmed to room temperature and continued to stir for 16 hours. The resulting reaction solution was quenched with saturated aqueous ammonium chloride solution (30 mL), diluted with water (10 mL), extracted with ether (40 mL), and the organic phases were combined. The resulting organic phase was washed with saturated aqueous sodium chloride solution (50 mL), washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (pure petroleum ether) to obtain compound 001-1 (3.4 g, crude product).

[0761] (2) Compound 001-1 (2.90 g, 19.08 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) at room temperature, and tetrabutylammonium fluoride (8.8 g, 28.62 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The resulting reaction mixture was washed with saturated aqueous ammonium chloride (30 mL), and the resulting organic phase was dried over anhydrous sodium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure to obtain a tetrahydrofuran solution of compound 001-2 (30 mL).

[0762] (3) Compound M004 (980 mg, 2.97 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) at room temperature. After the reaction solution was cooled to 0°C, diphenylphosphoryl azide (1.22 g, 4.45 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (677 mg, 4.45 mmol) were added in sequence. The reaction solution was warmed to room temperature and stirred for 16 hours. The resulting reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL), and the organic phases were combined. The resulting organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 001-3 (1.00 g). LC-MS [M+H] + =355.95.

[0763] (4) At room temperature, compound 001-3 (1.00 g, 2.82 mmol) was dissolved in a mixed solvent of tert-butanol (10 mL), tetrahydrofuran (10 mL) and water (10 mL), and compound 001-2 (the tetrahydrofuran solution of compound 001-2 obtained in the second step) was added. The reaction solution was stirred at room temperature for 48 hours. The resulting reaction solution was directly concentrated under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (20 mL), and the organic phases were combined. The resulting organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 001-4 (110 mg). LC-MS [M+H] + =436.05.

[0764] (5) Compound 001-4 (110 mg, 0.25 mmol) was dissolved in 1,4-dioxane (3 mL) at room temperature, and M001 (212 mg, 1.01 mmol), bis(triphenylphosphine)palladium dichloride (18 mg, 0.03 mmol), potassium carbonate (70 mg, 0.56 mmol), triethylamine (77 mg, 0.76 mmol), cuprous iodide (10 mg, 0.05 mmol), and cesium fluoride (154 mg, 1.01 mmol) were added. The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C under a nitrogen atmosphere and stirred for 5 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL), and the organic phases were combined. The resulting organic phase was washed with a saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 001-5 (100 mg). LC-MS [M+H] + =446.15.

[0765] (6) Compound 001-5 (100 mg, 0.23 mmol) was dissolved in a mixed solvent of methanol (3 mL) and water (1 mL) at room temperature, and lithium hydroxide monohydrate (50 mg, 1.13 mmol) was added. The reaction solution was heated to 50°C and stirred for 1 hour. The resulting reaction solution was cooled to room temperature, adjusted to pH 6-7 with dilute hydrochloric acid (1 M), and concentrated under reduced pressure. The resulting residue was separated and purified by high performance liquid chromatography (0.1% hydrochloric acid) and freeze-dried to obtain compound 001 (7.5 mg). LC-MS: [M+H] + =432.15.

[0766] 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.86(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),6.18(s,2H),4.16(s,3H),2 .62(s,3H),2.50(s,2H),2.38(s,2H),1.01(s,2H),0.95(s,3H),0.41(d,J=7.2Hz,2H),0.12(d,J=4.4Hz,2H).

[0767] Example 2 Preparation of (R)-2-(1-((6-(5-((((1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)ethynyl)cyclopropyl)acetic acid (Compound 002)

[0768] (1) Compound M009 (2.0 g, 7.5 mmol) was dissolved in dichloromethane (20 mL) at room temperature. The resulting solution was cooled to 0°C and then 4-nitrophenyl chloroformate (3.0 g, 14.9 mmol) and pyridine (1.2 g, 14.9 mmol) were added. The reaction solution was heated to room temperature and stirred for 2 hours. The resulting reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL), and the organic phases were combined. The resulting organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 002-1 (3.8 g). LC-MS: [M+H] + =433.95.

[0769] (2) Compound 002-1 (400 mg, 0.92 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and N,N-diisopropylethylamine (178 mg, 1.38 mmol) and (R)-1-cyclopropylethylamine hydrochloride (140 mg, 1.15 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction solution to dilute it, and the mixture was extracted with dichloromethane (5 mL). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 002-2 (290 mg) as a powder. LC-MS: [M+H] + =382.00.

[0770] (3) Compound 002-2 (290 mg, 0.77 mmol) was dissolved in acetonitrile (3 mL) at room temperature, and potassium hydroxide (129 mg, 2.3 mmol) and iodomethane (327 mg, 2.3 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was filtered under reduced pressure, and the filter cake was rinsed with acetonitrile (15 mL). The resulting filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 002-3 (190 mg). LC-MS: [M+H] + =394.00.

[0771] (4) At room temperatur...

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof: Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; The definitions of ring B and R1 are selected from one of the following situations (1), (2) and (3): Case (1): Ring B is a 5-7 membered heteroarylene group; Each R1 is independently OH, COOH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; Case (2): Ring B is an 8-10 membered heteroarylene group; Each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1- 6-alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 alkyl,- C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; Case (3): Ring B is C 6-10 arylene; Each R1 is independently OH, CN, oxo (=O), halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1- 6-alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1- 6-alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; Each R a Independently for C 1-4 Alkyl, C 1-4 Alkoxy, halogen, OH, oxo, CN or NH2; when R a When the number of is 2 or more, the OH and oxo groups are not attached to the same carbon atom; L1 is C 2-6 Alkynylidene, -C 2-6 Alkynylidene-O- or -C 2-6 Alkyne-NH-; the C 2-6 Alkynylidene, -C 2-6 Alkynylidene-O- and -C 2-6 Alkyne-NH- is optionally substituted by 1, 2 or 3 R b replace; Each R b are independently halogen, COOH or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 COOH or halogen; Each R2 is independently halogen, NH2, OH, oxo, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogen or deuterium; X1, X2, X3 and X4 are independently C, CH, CH2, O, S, N or NH; at the same time, at least one of X1, X2, X3 and X4 is independently O, S, N or NH; A double line including solid and dashed lines represents a single bond or a double bond; at the same time, Contains at least one double bond; Each R3 is independently H, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, NH2, OH, oxo, CN, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogen or deuterium; W is or -(CR 12 R 13 ) q -Y2-R 15 ; The carbon atom with * is a chiral carbon atom or an achiral carbon atom; when it is a chiral carbon atom, the configuration of the chiral carbon atom is R and / or S; in, R6 and R7 are independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Replacement; said C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace; Each R c are independently deuterium, halogen, -OH, -CN, -COOH, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace; Each R c-1 are independently deuterium, halogen, -OH, -CN, -COOH, C 1-6 Alkoxy or C 1-6 alkyl; R4, R5 and R8 are each independently H, deuterium, halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; said C 1-4 The alkyl group is optionally substituted by 1, 2 or more R j replace; Each R j are independently deuterium or halogen; Y1 is a chemical bond or C 1-6 Alkylene; said C 1-6 The alkylene group is optionally substituted by 1, 2 or more R d replace; Each R d are independently deuterium, halogen or C 3-6 Cycloalkyl; R9 and R 10 are independently H, deuterium or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace; R 11 C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl are independently optionally substituted by 1, 2 or more R g replace; Each R e , R f and R g are independently deuterium, halogen, -OH, -CN, -COOH, C 1-6 Alkoxy, C 1-6 Alkyl or C 3-6 Cycloalkyl; said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more deuterium or halogen; Y2 is a chemical bond, N(R 14 )、-C(=O)N(R 14 )-or O; R 12 , R 13 and R 14 are independently H, deuterium, halogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or more halogens or deuterium; R 15 C 1-6 alkyl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl; said C 1-6 The alkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl groups are independently optionally substituted by 1, 2 or more R i replace; Each R i are independently deuterium, halogen, oxo, OH, COOH, NH2, CN, C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The alkoxy groups are optionally substituted by 1, 2 or more R i-1 replace; Each R i-1 are independently deuterium, halogen, C 1-6 Alkoxy or C 3-6 Cycloalkyl; m is 0, 1, 2, 3, 4 or 5; n and p are independently 0, 1, 2, 3 or 4; q is 0, 1, 2, or 3; The heteroatoms in the 3-10 membered heterocycloalkyl, 5-7 membered heteroarylene, 8-10 membered heteroarylene, 3-6 membered heterocyclyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl and 3-8 membered heterocycloalkyl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently one, two or three.

2. The compound of formula (I) according to claim 1, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: Ring A is C3-10 cycloalkyl or 3-10 membered heterocycloalkyl; In case (1): each R1 is independently OH, COOH, CN, oxo, halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; In case (2): each R1 is independently OH, CN, oxo, halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; In case (3): each R1 is independently OH, CN, oxo, halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 alkyl,- C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; R6 and R7 are independently C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Replacement; said C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace; Preferably; Ring A is C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; In case (1): each R1 is independently OH, COOH, CN, oxo, halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; In case (2): each R1 is independently OH, CN, oxo, halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkane C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; In case (3): each R1 is independently OH, CN, oxo, halogen, NH2, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 2-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; Each R2 is independently halogen, NH2, OH, oxo, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogens; Each R3 is independently H, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, NH2, OH, oxo (=O), CN, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2 or more halogens; R6 and R7 are independently C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Replacement; said C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace; Each R c are independently halogen, -OH, -CN, -COOH, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace; Each R c-1 are independently halogen, -OH, -CN, -COOH, C 1-6 Alkoxy or C 1-6 alkyl; R9 and R 10 are independently H or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace; Each R e , R f and R g are independently halogen, -OH, -CN, -COOH, C 1-6 Alkoxy or C 1-6 Alkyl; the C 1-6 Alkyl and C 1-6 Alkoxy groups are independently optionally substituted with 1, 2 or more halogens; Y2 is a chemical bond, NR 14 or O; R 12 , R 13 and R 14 are independently H, halogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or more halogens; R 15 is a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl; the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl are independently and optionally substituted by 1, 2 or more R i replace; Each R i are independently halogen, oxo, OH, COOH, NH2, CN, C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy; the C 1-6 The alkyl group is optionally substituted by 1, 2 or more R i-1 replace; Each R i-1 are independently halogen, C 1-6 Alkoxy or C 3-6 Cycloalkyl; q is 0, 1, or 2.

3. The compound of formula (I) as claimed in claim 1 or 2, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) R2, R3, R4, R5, R8, R d , R i , R i-1 , R e , R f and R g In each C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl; (2) R6, R7, R 11 and R c In each C 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, spiro[2.2]pentyl or spiro[2.3]hexyl; (3) R6, R7, R 11 and R c In each C 6-10 Aryl is independently phenyl or naphthyl, for example phenyl; (4) In R2 and R3, the heteroatom of each 3-6 membered heterocyclic group is independently N or O, and the number of heteroatoms is independently 1 or 2; (5) R6, R7 and R c In the above, each 3-10 membered heterocyclic group is independently a 3-6 membered heterocyclic group, the heteroatom of the 3-6 membered heterocyclic group is independently N, O or S, and the number of heteroatoms is independently 1 or 2; (6)R 11 wherein said optionally 1, 2 or more R g The heteroatom of the 3-8-membered heterocycloalkyl in the substituted 3-8-membered heterocycloalkyl is N, and the number of heteroatoms is independently 1 or 2; (7) In ring A, the C 3-10 Cycloalkyl is C 3-8 Cycloalkyl, such as cyclopropyl or C 4-8 Cycloalkyl; for example C 3-6 Cycloalkyl; (8) In ring A, the 3-10 membered heterocycloalkyl is a 4-8 membered heterocycloalkyl, for example a 4-6 membered heterocycloalkyl; (9) In ring A, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, such as a 5-membered heteroaryl group or a 6-membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group, the 5-membered heteroaryl group and the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; (10) In L1, each C 2-6 Alkyne groups are independently ethynylene, Pentylenyl or hexynyl; preferably, each C 2-6 The alkynylene groups are independently C 2-4 Alkyne groups, such as (11) In ring B, the C 6-10 Arylene is phenylene or naphthylene; (12) In ring B, the 5-7 membered heteroarylene group is a 6 membered heteroarylene group; the heteroatom of the 6 membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; (13)R 15 wherein said optionally 1, 2 or more R i The 3-10-membered heterocyclic group in the substituted 3-10-membered heterocyclic group is independently a 3-10-membered heterocycloalkyl group or a 3-10-membered heterocycloalkenyl group, and the number of double bonds in the 3-10-membered heterocycloalkenyl group is 1 or 2; (14)R 15 wherein said optionally 1, 2 or more R i The 3-10-membered heterocyclic group in the substituted 3-10-membered heterocyclic group is independently a 3-8-membered heterocyclic group, for example a 3-6-membered heterocyclic group; (15)R 15 wherein said optionally 1, 2 or more R i The 5-10-membered heteroaryl in the substituted 5-10-membered heteroaryl is a 5-6-membered heteroaryl, for example a 6-membered heteroaryl.

4. The compound of formula (I) according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) In ring A, the C 3-10 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, spiro[2.4]heptyl or bicyclo[2.2.2]octyl. Base, for example (2) In ring A, the 3-10 membered heterocycloalkyl group is oxirane, oxetanyl, oxolanyl, oxhexyl, oxepanyl, oxocanyl, aziridine, azetidinyl, azopentyl, azohexyl, azepanyl or azooctanyl; for example (3) In ring A, the 5-10 membered heteroaryl group is pyridyl; for example (4) In R1, the halogen is fluorine, chlorine or bromine; (5) In R1, each C 1-6 The alkyl groups are independently C 1-4 Alkyl; for example, methyl, ethyl or n-propyl; (6) In R1, the optionally substituted a Substituted C 1-6 C in alkoxy 1-6 The alkoxy groups are independently C 1-3 Alkoxy; for example methoxy or ethoxy; (7) In R1, the unsubstituted -C 1-3 Alkylene COOH is (8) In R1, the unsubstituted -NHC(=O)OC 1-6 The alkyl group is (9) In R1, the unsubstituted -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 The alkyl group is (10) In R1, the unsubstituted -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 The alkyl group is (11) In R1, the unsubstituted -C 1-3 Alkylene S(=O)2OH is (12) In R1, the unsubstituted -C 1-3 Alkylene P(=O)(OH)2 is (13) In R1, the unsubstituted -C 1-3 Alkylene-tetrazolyl is (14) In R1, the a Substituted -NHS(=O)2OH is (15) In R1, the unsubstituted -C 1-3 Alkylene-NHS(=O)2OH is (16) In R1, the unsubstituted -C 1-3 Alkylene S(=O)2C 1-6 The alkyl group is (17)R a wherein the halogen is fluorine, chlorine or bromine; (18)R b wherein the C optionally substituted by 1, 2 or 3 COOH or halogen 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1- 3 alkyl; for example methyl; (19) Ring B is pyridylene, pyrimidylene, pyridazinylene, pyrazinylene or triazinylene; for example Another example Another example (20) In R2, each halogen is independently fluorine, chlorine or bromine; (21) In R2, the C optionally substituted by 1, 2 or more halogen or deuterium 1-4 C in the alkyl group 1-4 Alkyl is methyl or ethyl; (22) In R3, the halogen is fluorine, chlorine or bromine; (23) In R3, the C optionally substituted by 1, 2 or more halogen or deuterium 1-4 C in the alkyl group 1-4 Alkyl is independently methyl or ethyl; (24) Among R6 and R7, the optionally substituted R c Substituted C 1-6 C in the alkyl group 1-6 The alkyl groups are independently methyl, ethyl, n-propyl, n-butyl, n-pentyl, (25) Among R6 and R7, the optionally substituted e Substituted C 3-8 C in cycloalkyl 3-8 The cycloalkyl groups are independently C 3- 6-cycloalkyl, such as cyclopentyl; (26) Among R6 and R7, the optionally substituted R e The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is a monocyclic ring, for example, independently a 5-6 membered heteroaryl; for example, independently a pyridyl or thiazolyl; for example, independently (27)R c wherein the halogen is fluorine, chlorine or bromine; (28)R c wherein said optionally 1, 2 or more R c-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl or ethyl; (29)R c wherein said optionally 1, 2 or more R c-1 Substituted C 3-8 C in cycloalkyl 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl or spiro[2.2]pentyl; the spiro[2.2]pentyl is The bicyclo[1.1.1]pentyl group is (30)R c wherein said optionally 1, 2 or more R c-1 The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is a monocyclic ring, for example, independently a 5-6 membered heteroaryl; for example, independently a pyridyl, oxazolyl or thiazolyl; for example, independently (31)R c-1 wherein the halogen is fluorine, chlorine or bromine; (32)R c-1 In the C 1-6 Alkyl is C 1-3 Alkyl; for example, methyl; (33) R9 and R 10 wherein said is optionally substituted by 1, 2, 3 or 4 R f Substituted C 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1-3 Alkyl; for example, methyl; (34)R f wherein the halogen is fluorine, chlorine or bromine; (35)R 11 wherein said optionally 1, 2 or more R g Substituted C 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1-4 Alkyl; for example, methyl, ethyl, n-propyl, n-butyl, Another example is ethyl or n-propyl; (36)R 11 wherein said optionally 1, 2 or more R g Substituted C 3-8 C in cycloalkyl 3-8 The cycloalkyl groups are independently C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is a monocyclic, spirocyclic or bridged ring; C 3-8 The cycloalkyl group may independently be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, spiro[2.2]pentyl, spiro[2.3]hexyl or bicyclo[2.1.1]hexyl; for example, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl or bicyclo[ 2.1.1]hexyl; bicyclo[1.1.1]pentyl may be Spiro[2.3]hexyl may be Bicyclo[2.1.1]hexyl may be (37)R 11 wherein said optionally 1, 2 or more R g The 5-10-membered heteroaryl in the substituted 5-10-membered heteroaryl is independently a 5-6-membered heteroaryl; preferably a 6-membered heteroaryl; for example, pyridyl, (38)R g wherein the halogen is fluorine, chlorine or bromine; (39)R 15 wherein said optionally 1, 2 or more R i The 3-10-membered heterocyclic group in the substituted 3-10-membered heterocyclic group is independently a 3-6-membered heterocycloalkyl group; for example, azetidinyl, aziridine or azacyclohexyl, and for example (40)R 15 wherein said optionally 1, 2 or more R i The 3-10-membered heterocyclic group in the substituted 3-10-membered heterocyclic group is independently a 3-6-membered heterocycloalkenyl group, and the number of double bonds in the 3-6-membered heterocycloalkenyl group is 1 or 2; for example, the 3-6-membered heterocycloalkenyl group is Another example (41)R 15 wherein said optionally 1, 2 or more R i The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is independently Another example (42)R i wherein said optionally 1, 2 or more R i-1 Substituted C 1-6 C in the alkyl group 1-6 The alkyl groups are independently C 1-4 Alkyl; for example, methyl, ethyl, n-propyl, n-butyl or isopropyl; preferably, C 1-3 Alkyl; for example, methyl, ethyl or isopropyl; (43)R i In the C 1-6 Alkoxy is C 1-3 Alkoxy; for example ethoxy or isopropoxy; (44)R i wherein said optionally 1, 2 or more R i-1 Substituted C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl or bicyclo[1.1.1] Pentyl; bicyclo[1.1.1]pentyl may be The C 3-6 Cycloalkyl may be cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl; (45)R i-1 In the C 3-6 Cycloalkyl is cyclopropyl or cyclobutyl; and (46)R i-1 In the C 1-6 Alkoxy is methoxy or ethoxy.

5. The compound of formula (I) according to any one of claims 1 to 4, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) In R1, the a Substituted C 1-6 Alkyl is -CF3, -CHF2, (2) In R1, the a Replaced-C 1-3 Alkylene COOH is (3)R b wherein the C substituted by 1, 2 or 3 COOH 1-6 The alkyl group is Preferably, the b Substituted C 2-6 Alkynyl is For example Among them, the "1" position is connected to ring A, and the "2" position is connected to ring B; (4) In R2, the C substituted by 1, 2 or more halogen or deuterium 1-4 Alkyl is -CD3, -CF3, -CHF2 or -CH2F; (5) Among R6 and R7, the c Substituted C 1-6 The alkyl groups are independently (6) R9 and R 10 wherein the R f Substituted C 1-6 Alkyl is -CD3, -CH2F or -CHF2; (7)R 11 wherein said one, two or more R g Substituted C 3-8 Cycloalkyl is (8)R 11 wherein said one, two or more R g Substituted C 6-10 Aryl (9)R 11 wherein said one, two or more R g The substituted 5-10 membered heteroaryl is and (10)R 11 wherein said one, two or more R g Substituted C 1-6 The alkyl group is 6. The compound of formula (I) according to claim 1, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) The ring A is C 3-8 cycloalkyl, 4-6 membered oxacycloalkyl or 4-6 membered azacycloalkyl; the number of heteroatoms in the 4-6 membered oxacycloalkyl and 4-6 membered azacycloalkyl is 1; or, the ring A is C 4-8 The ring A is a cycloalkyl or a 3-10 membered heterocycloalkyl, wherein the heteroatoms of the 3-10 membered heterocycloalkyl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; or the ring A is a 5-6 membered heteroaryl, wherein the heteroatoms of the 5-6 membered heteroaryl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3. The number of sub-groups is 1, 2 or 3; or, the ring A is C 3-8 Cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the heteroatom of the 4-6 membered heterocycloalkyl is N or O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; for example, ring A is C 3-8 Cycloalkyl; (2) In case (1), the R1 is independently OH, COOH, F, Cl, Br, CN, Tetrazolyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1- 3 alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene C(=O)NHC(=O)C 1-3 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-3 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2, -C 1-3 Alkylene-tetrazolyl or -C 1-3 Alkylene C(=O)C 1-3 alkyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-3 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene C(=O)NHC(=O)C 1-3 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-3 Alkyl, -C 1- 3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2, -C 1-3 Alkylene-tetrazolyl and -C 1-3 Alkylene C(=O)C 1-3 The alkyl group is optionally substituted by 1, 2 or more R a Preferably, the R1 is -C 1-3 AlkyleneCOOH; or, each R1 is independently COOH or -C 1-3 AlkyleneCOOH; Or, in case (1), each R1 is independently CN, oxo, halogen, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1- 3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1- 3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; (3) In case (3), each R1 is independently -NHS(=O)2OH or -C 1-3 Alkylene-NHS(=O)2OH; said-NHS(=O)2OH and -C 1-3 Alkylene-NHS(=O)2OH is optionally substituted by 1, 2 or more R a Replace; each R a Independently for C 1-4 alkyl; (4) In case (1), each R a are independently methyl, oxo, OH, F, Cl or CN; (5) m is 0, 1, 2 or 3, for example, 1; (6) Each R2 is independently halogen, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; 1-4 alkyl The group is optionally substituted by 1, 2 or more halogen or deuterium; preferably, each R2 is independently halogen, C 1-4 Alkyl, methoxy or cyclopropyl; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogen or deuterium; or, each R2 is independently halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; said C 1-4 Alkyl and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more halogen or deuterium; for example, each R2 is independently C 1-4 alkyl; (7)n is 0 or 1; (8) L1 is C 2-6 Alkyne, the C 2-6 The alkynylene group is optionally substituted by 1, 2 or 3 R b Preferably, L1 is unsubstituted C 2-6 Alkyne; (9) Each R b Independently for C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 COOH groups; preferably, the C 1-6 The alkyl group is optionally substituted with 1 COOH; (10) X1, X2, X3 and X4 are independently C, CH, CH2, O, S, N or NH; at the same time, two or three of X1, X2, X3 and X4 are independently O, S, N or NH; for example, X1 can be C or N; X2 can be CH, O, S or N; X3 can be C, CH2, O, S or N; X4 can be C, CH, N or NH; (11) Each R3 is independently H, C 1-4 alkyl, oxo, F, Cl or Br; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens or deuterium; preferably, each R3 is independently H, C 1-4 Alkyl, F, Cl or oxo; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens or deuterium; more preferably, each R3 is independently C 1-4 alkyl, F, Cl, Br or oxo, preferably each R3 is independently C 1-4 alkyl; (12) p is 0, 1, 2 or 3; (13) R4 and R5 are each independently H, halogen or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens; or, R4 and R5 are independently H or deuterium, such as H; (14) R6 is H or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c replace; (15) In R6, each R c are independently halogen, such as fluorine, chlorine or bromine; (16) R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Replacement; said C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e Preferably, R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Replacement; said C 3-8 Cycloalkyl, phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or more R e The heteroatoms of the 5-6 membered heteroaryl group are selected from one or two of N, O and S, and the number of heteroatoms is 1 or 2; more preferably, R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c replace; (17) In R7, each R c are independently deuterium, halogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace; (18) In R7, each R c-1 are independently deuterium, halogen or C 1-6 alkyl; (19) In R7, each R e are independently halogen or C 1-6 Alkyl such as fluorine, chlorine, bromine or methyl; (20) R8 is H, deuterium, halogen or C 1-4 Alkyl; such as H or deuterium; such as H; (21) Y1 is a chemical bond; (22) Y1 is C 1-6 Alkylene; said C 1-6 The alkylene group is optionally substituted by 1, 2 or more R d Preferably, Y1 is unsubstituted C 1-4 Alkylene; (23) R f is a halogen or deuterium; (24) R9 is H or deuterium; for example, H; (25) R 10 H, deuterium or C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f replace; (26) R 11 C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl or C 3-8 Cycloalkyl; said C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl and C 3-8 The cycloalkyl groups are optionally substituted by 1, 2 or more R g preferably, R 11 C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl or C 3-6 Cycloalkyl; said C 3-6 The cycloalkyl group is a monocyclic, spirocyclic or bridged ring; 1-6 Alkyl, phenyl, 5-6 membered heteroaryl and C 3- 6 cycloalkyl groups are independently optionally substituted by 1, 2 or more R g The heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; preferably, the R 11 C 1-6 Alkyl, C 3-4 Cycloalkyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl or bicyclo[ 2.1.1] hexyl; said C 1-6 Alkyl, C 3-4 Cycloalkyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl and bicyclo[2.1.1]hexyl are independently optionally substituted by 1, 2 or more R g Replacement, such as R 11 C 1-6 Alkyl or C 3-4 Cycloalkyl; said C 1-6 Alkyl and C 3-4 The cycloalkyl groups are optionally substituted by 1, 2 or more R g replace; Or, the R 11 is cyclopentyl, cyclohexyl, phenyl or 5-6 membered heteroaryl; the cyclopentyl, cyclohexyl, phenyl and 5-6 membered heteroaryl are independently and optionally replaced by 1, 2 or more R g substituted; for example, phenyl or 5-6 membered heteroaryl; the phenyl or 5-6 membered heteroaryl is independently optionally substituted by 1, 2 or more R g replace; (27) Each R g are independently deuterium, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; said C 1-6 Alkyl and C 3-6 The cycloalkyl groups are optionally substituted independently with 1, 2 or more deuterium or halogen, for example, each R g is independently deuterium or halogen; or each R g are independently halogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with 1, 2 or more halogens; preferably, each R g is a halogen; (28)q is 0 or 1; (29) Y2 is a chemical bond, NH, -C(=O)N(CH3)- or O; (30)R 12 and R 13 are independently H, methyl or F; or R 12 and R 13 are independently H, deuterium or halogen; (31)R 14 is H, methyl or F; or is H, deuterium or C 1-6 alkyl; (32)R 15 C 1-6 alkyl, 3-6 membered heterocyclic group or 5-6 membered heteroaryl; the C 1-6 Alkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or more R i Substitution; the heteroatom of the 3-6 membered heterocyclic group is N or O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-6 membered heteroaryl group is N, O or S, and the number of heteroatoms can be 1, 2 or 3; (33) Each R i are independently halogen, oxo, C 3-6 Cycloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The alkoxy groups are optionally substituted by 1, 2 or more R i-1 Replacement; and (34) Each R i-1 are independently halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy.

7. The compound of formula (I) according to claim 6, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) The ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, spiro[2.4]heptyl, bicyclo[2.2.2]octyl, oxirane, oxetanyl, oxolanyl, oxhexyl, oxetanyl, oxocanyl, aziridine, azetidinyl, azopentyl, azocyclopentyl, azocyclohexyl, oxetanyl, oxetanyl, aziridine ... Preferably, the ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[2.3]hexyl, spiro[2.4]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.2]octyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl or pyridyl; More preferably, the ring A is For example, cyclopropyl; (2) In case (1), each R1 is independently OH, COOH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3, For example, OH, COOH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3, (3) In case (2), each R1 is independently OH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3, (4) In case (3), each R1 is independently OH, F, Cl, CN, methyl, -CH2F, -CHF2, -CF3, For example (5) each R2 is independently methyl, ethyl, F, Cl, Br, -CD3, -CF3, -CHF2, -CH2F, -NH2, -OCH3 or cyclopropyl; for example, methyl, ethyl, F, Cl, -CD3, -CF3, -CHF2, -CH2F, -OCH3 or cyclopropyl; for example, methyl, ethyl, F, Cl, -CD3, -CF3, -CHF2, -OCH3 or cyclopropyl; or, each R2 is independently methyl, ethyl, F, Cl, Br, -CF3, -CHF2, -CH2F or -NH2; for example, methyl, ethyl, F, Cl, -CF3 or -CHF2; (6) L1 is For example Among them, the "1" position is connected to ring A, and the "2" position is connected to ring B; (7) is triazolyl, pyrazolyl, imidazolyl, oxazolyl, tetrazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, furazolyl, thiadiazolyl, oxathiazolyl, Thienyl, furyl or pyrrolyl; preferably, the for More preferably, the for Among them, the "1" position is connected to ring B, and the "2" position is connected to W; (8) Each R3 is independently H, methyl, ethyl, oxo, F, Cl, -CD3, -CF3, -CHF2 or -CH2F; preferably, each R3 is independently H, methyl, ethyl, -CD3, oxo or Cl; or, each R3 is independently H, methyl, ethyl, oxo, F, Cl, -CF3, -CHF2 or -CH2F; preferably, each R3 is independently H, methyl, ethyl, oxo or Cl; (9) Each R c are independently F, methyl, -CF3, -CHF2, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, (10) R 10 H, methyl, ethyl, n-propyl, isopropyl, -CD3, Preferably, the R 10 H, methyl, -CD3, Or, R 10 is H, methyl, ethyl, n-propyl, isopropyl, Preferably, R 10 H, methyl, (11) Each R g Deuterium, F, Cl, methyl, ethyl, -CH2F, CHF2, CF3, -CD3, For example, deuterium, F, Cl, -CD3, Or each R g is F, Cl, methyl, ethyl, -CH2F, CHF2 or CF3, for example F or Cl; (12) R 11 for For example, R 11 for (13)W is -(CR 12 R 13 ) q -Y2-R 15 , for example -N(R 14 )-R 15 ,-C(R 12 R 13 )-R 15 ,-C(R 12 R 13 )-N(R 14 )-R 15 ,-C(R 12 R 13 )-OR 15 or -(CR 12 R 13 )2-C(=O)-N(R 14 )-R 15 Preferably, W is -NH-R 15 、-CH2-R 15 、-CH2-NH-R 15 、-CH2-OR 15 or and (14) Each R i are independently methyl, n-propyl, isopropyl, n-butyl, F, oxo, 8. The compound of formula (I) according to any one of claims 6 to 7, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) for m1 is 0, 1, or 2; for example Another example is Preferably, the for (2) for Z3 and Z4 are independently C, CH or N; preferably, for For example n is 0 or 1; for example or, for For example Preferably, the for Preferably, the for The "1" bit is connected to L1, and the "2" bit is connected to X1 connection in; (3) for Preferably, the for More preferably, the for Among them, the "1" position is connected to ring B, and the "2" position is connected to W; (4) R6 is H, methyl, ethyl, (5) R7 is (6) for (7) In for When the carbon atom with * is a chiral carbon atom, for and / or Preferably for For example More preferably, the for (8) R 15 for 9. The compound of formula (I) according to claim 8, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It meets one or both of the following conditions: (1) for m1 is 0, 1, or 2; for example Preferably, the for (2) for Preferably, the for for 10. The compound of formula (I) according to claim 1, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: for R 1-1 and R 1-2 The definition of is independently the definition of R1 as claimed in any one of claims 1 to 9, the definition of m2 is the definition of m as claimed in any one of claims 1 to 9 or the definition of m1 as claimed in any one of claims 8 to 9; Preferably, each R 1-2 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, OH or CN; the C 1-6 Alkyl and C 1-6 The alkoxy groups are optionally substituted by 1, 2 or more R a Replace; for example, each R 1-2 are independently halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH or CN; the C 1-4 Alkyl and C 1-4 The alkoxy groups are optionally substituted by 1, 2 or more R a replace; More preferably, in case (1), ring B is a 6-membered heteroarylene group; R 1-1 OH, COOH, C 1-6 alkyl, -C 1-3 AlkyleneCOOH, NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH or -C 1-3 Alkylene S(=O)2C 1-6 Alkyl; the C 1-6 Alkyl, -C 1- 3 Alkylene COOH, NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH and -C 1-3 Alkylene S(=O)2C 1-6 The alkyl group is optionally substituted by 1, 2 or more R a replace; Or, R 1-1 For COOH, Tetrazolyl, -C 1-3 AlkyleneCOOH, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; the -C 1-3 AlkyleneCOOH, C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; R 1-1 In each R a Independently for C 1-4 Alkyl, halogen, OH, oxo or CN; when R a When the number of is 2 or more, the OH and oxo groups are not attached to the same carbon atom; Each R 1-2 are independently halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH or CN; the C 1-4 Alkyl and C 1-4 The alkoxy groups are optionally substituted by 1, 2 or more R a replace; R 1-2 In each R a are independently halogen.

11. The compound of formula (I) according to claim 1, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It is any of the following: Scheme 1: The compound represented by formula (I) has a structure represented by the following formula (II): wherein Z1, Z2, Z3 and Z4 are independently N or CH; at least one of Z1, Z2, Z3 and Z4 is N; n is 0, 1 or 2; ring A, L1, R1, R2, R3, W, X1, X2, X3, X4, m, p and The definition as described in any one of claims 1 to 10; Scheme 2: The compound represented by formula (I) has a structure represented by the following formula (I-II), (I-III) or (I-IV): Among them, L1 is Ring A, Y1, Y2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 15 , X1, X2, X3, X4, m, n, p, q, and The definition as described in any one of claims 1 to 10; Scheme 3: The compound represented by formula (I) has a structure represented by the following formula (IV), (I-VI) or (I-VII): Ring A, Y2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 15 , X1, X2, X3, X4, m, n, p, q, and The definition as described in any one of claims 1 to 10; Scheme 4: The compound represented by formula (I) is a compound represented by formula (I-VIII): Among them, R 1-1 For COOH, Tetrazolyl, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1-6 Alkyl, -C 1- 3Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 or -C 1-3 Alkylene-tetrazolyl; The-C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHC(=O)C 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene -NHS(=O)2OH, -C(=O)NHC 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHC(=O)C 1- 6-alkyl, -C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C(=O)NHS(=O)C 1- 6-alkyl, -C 1-3 Alkylene C(=O)NHS(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene S(=O)2C 1-6 Alkyl, -S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replaced; Each R 1-2 are independently OH, CN, oxo (=O), halogen, NH2, C 1-4 Alkyl or C 1-4 Alkoxy; the C 1-4 The alkyl group is optionally substituted with 1, 2 or more halogens; Each R a Independently for C 1-4 Alkyl, C 1-4 Alkoxy or halogen; Z3 and Z4 are independently N or CH; m2 is 0, 1, 2 or 3; Ring A, R2, R3, W, X1, X2, X3, X4, n, p and The definition as described in any one of claims 1-10.

12. The compound of formula (I) according to claim 10, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: It is any of the following: Scheme 1: The compound represented by formula (I) is a compound represented by formula (I-VIII-1): The carbon atom with * is a chiral carbon atom or an achiral carbon atom; when it is a chiral carbon atom, the configuration of the chiral carbon atom is R and / or S; Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; m2 is 0, 1 or 2; R 1-1 OH, COOH, C 1-6 alkyl, -C 1-3 AlkyleneCOOH, -NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH or -C 1-3 Alkylene S(=O)2C 1-6 Alkyl; the C 1-6 Alkyl, -C 1-3 AlkyleneCOOH, NHC(=O)OC 1-6 Alkyl, -NHS(=O)2OH, -C 1-3 Alkylene-NHS(=O)2OH, -C 1-3 Alkylene S(=O)2OH and -C 1-3 Alkylene S(=O)2C 1-6 The alkyl group is optionally substituted by 1, 2 or more R a replace; R 1-1 In each R a Independently for C 1-4 Alkyl, halogen, OH, oxo or CN; when R a When the number of is 2 or more, the OH and oxo groups are not attached to the same carbon atom; Each R 1-2 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, OH or CN; the C 1-6 Alkyl and C 1-6 The alkoxy groups are optionally substituted by 1, 2 or more R a replace; R 1-2 In each R a are independently halogen; Z3 and Z4 are independently C, CH or N; Each R2 is independently halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; said C 1-4 Alkyl and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more halogen or deuterium; n is 0 or 1; X1 is C or N; X2 is CH, O, S or N; X3 is C, CH2, O, S or N; X4 is C, CH, N or NH; and at least one of X1, X2, X3 and X4 is independently O, S or N; A double line including solid and dashed lines represents a single bond or a double bond; at the same time, Contains at least one double bond; Each R3 is independently halogen, C 1-4 Alkyl or oxo; p is 1 or 2; Y1 is a chemical bond or C 1-6 Alkylene; R8 is H or deuterium; R9 is H or deuterium; R 10 H, deuterium or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 R f Replace; each R f are independently deuterium or halogen; R 11 C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl or C 3-8 Cycloalkyl; said C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl and C 3-8 The cycloalkyl groups are optionally substituted by 1, 2 or more R g replace; Each R g are independently deuterium, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; said C 1-6 Alkyl and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more deuterium or halogen; The heteroatoms in the 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Scheme 2: The compound represented by formula (I) is a compound represented by formula (I-VIII-2): Ring A is C 3-8 Cycloalkyl, 4-6-membered oxacycloalkyl or 4-6-membered azacycloalkyl; the number of heteroatoms in the 4-6-membered oxacycloalkyl and 4-6-membered azacycloalkyl is 1; m2 is 0, 1 or 2; R 1-1 is COOH, Tetrazolyl, -C 1-3 AlkyleneCOOH, -C 1-3 Alkylene C(=O)NHC(=O)C 1- 6-alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene P(=O)(OH)2 or -C 1- 3-alkylene-tetrazolyl; said-C 1-3 AlkyleneCOOH, C 1-3 Alkylene C(=O)NHC(=O)C 1-6 Alkyl, -C 1-3 Alkylene C(=O)NHS(=O)2C 1-6 Alkyl, -C 1-3 Alkylene S(=O)2OH, -C 1-3 Alkylene P(=O)(OH)2 and -C 1-3 The alkylene-tetrazolyl group is optionally substituted by 1, 2 or more R a replace; Each R 1-2 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy, OH or CN; the C 1-6 Alkyl and C 1-6 The alkoxy groups are optionally substituted by 1, 2 or more R a replace; Each R a are independently halogen; Z3 and Z4 are independently C, CH or N; Each R2 is independently halogen, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl; said C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or more halogen or deuterium; n is 0 or 1; R4 and R5 are each independently H or deuterium; R6 is C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c replace; In R6, each R c are independently halogen; R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 The alkyl group is optionally substituted by 1, 2 or more R c Replacement; said C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R e replace; In R7, each R c are independently deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2 or more R c-1 replace; Each R c-1 are independently deuterium, halogen or C 1-6 alkyl; Each R e are independently deuterium or halogen; The heteroatoms in the 5-10 membered heteroaryl group are independently selected from N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Scheme 3: The compound represented by formula (I) is a compound represented by formula (I-VIII-3): Ring A is C 3-8 Cycloalkyl; R1 is COOH or -C 1-3 AlkyleneCOOH; Each R2 is independently C 1-4 alkyl; n is 0 or 1; Z3 and Z4 are independently C, CH or N; X2 is CH or N; R 12 and R 13 are independently H, deuterium or halogen; When q is 0, Y2 is N(R 14 )、-C(=O)N(R 14 )-or O; When q is 1, 2 or 3, Y2 is a chemical bond, N(R 14 )、-C(=O)N(R 14 )-or O; R 14 H, deuterium or C 1-6 Alkyl; R 15 C 1-6 alkyl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl; said C 1-6 The alkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl groups are independently optionally substituted by 1, 2 or more R i replace; Each R i are independently halogen, oxo, C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The alkoxy groups are optionally substituted by 1, 2 or more R i-1 replace; Each R i-1 are independently halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy; The heteroatoms in the 3-10 membered heterocycloalkyl group and the 5-10 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of the heteroatoms is independently one, two or three.

13. The compound of formula (I) according to claim 1, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is any of the following compounds: or its hydrochloride, or its hydrochloride, or its hydrochloride, Preferably, the compound represented by formula (I) is any of the following compounds:

14. A method for preparing a compound as represented by formula (I), characterized in that: It is method 1, method 2, method 3 or method 4 below: Method 1: In a solvent, in the presence of a base, subjecting the compound represented by formula I'-1A to ester hydrolysis reaction to obtain a compound represented by formula (I); Each R 1a -C(=O)OC 1-6 Alkyl or 1, 2 or more R 1a-1 Substituted C 1-6 Alkyl; each R 1a-1 -C(=O)OC 1-6 Alkyl; each R1 is COOH or C substituted by 1, 2 or more COOH 1-6 Alkyl; m is 1, 2, 3, 4 or 5; The definitions of ring A, ring B, L1, R2, X1, X2, X3, X4, R3, W, m, n and p are as described in any one of claims 1 to 13; Method 2: In a solvent, in the presence of a base, a phosphine ligand and a catalyst, a compound as shown in formula I'-1B and a compound as shown in formula I'-1C are reacted. The compound is subjected to the reaction shown in the following formula to obtain a compound shown in formula (I); X is halogen, and ring A, ring B, R1, L1, R2, X1, X2, X3, X4, R3, W, m, n and p are defined as described in any one of claims 1 to 13; V is H, TMS or TBDMS; Method 3: reacting the compound represented by formula I'-1D in a solvent in the presence of cyanide and a catalyst to obtain a compound represented by formula (I); The cyanide is trimethylsilyl cyanide, potassium cyanide or sodium cyanide; Each R 1a C substituted with 1, 2 or more -OM 1-6 Alkyl; each R1 is COOH or C substituted by 1, 2 or more cyano groups 1-6 Alkyl; wherein M is selected from methanesulfonyl (Ms), p-toluenesulfonyl (Ts) or p-nitrobenzenesulfonyl (Ns); The definitions of ring A, ring B, L1, R2, X1, X2, X3, X4, R3, W, m, n and p are as described in any one of claims 1 to 13; Method 4: Step 1) reacting a compound represented by formula I'-1E with a compound represented by formula I'-1F or a salt thereof in the presence of an acylating agent to obtain a compound represented by formula I'-1G; Step 2) In a solvent, in the presence of a base, subjecting the compound represented by formula I'-1G to ester hydrolysis reaction to obtain a compound represented by formula (I-I'); Each R 1a -C(=O)OC 1-6 Alkyl or 1, 2 or more R 1a-1 Substituted C 1-6 Alkyl; each R 1a-1 -C(=O)OC 1-6 Alkyl; each R1 is COOH or C substituted by 1, 2 or more COOH 1-6 Alkyl; m is 1, 2, 3, 4 or 5; Ring A, Ring B, L1, R2, X1, X2, X3, X4, R3, R4, R5, R6, R7, m, n and p are defined as described in any one of claims 1 to 13.

15. A pharmaceutical composition comprising a substance U and a pharmaceutical excipient, wherein the substance U is a compound of formula (I) according to any one of claims 1 to 13, a racemate, a stereoisomer, a tautomer, a nitrogen oxide or a pharmaceutically acceptable salt thereof.

16. Use of a substance U or the pharmaceutical composition according to claim 15 in the preparation of an LPAR1 antagonist, wherein the substance U is a compound represented by formula (I) according to any one of claims 1 to 13, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof.

17. Use of a substance U or a pharmaceutical composition as claimed in claim 15 in the preparation of a drug; the substance U is a compound represented by formula (I) as claimed in any one of claims 1 to 13, its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof; Preferably, the drug is a drug for diagnosing, preventing and / or treating a disease or condition mediated by LPAR receptors; Preferably, the drug is an LPAR1 antagonist; Preferably, the disease or condition is a fibrotic disease, a respiratory disease, pain, a nervous system disease, a cardiovascular and cerebrovascular disease, an inflammatory disease, a kidney disease, a liver disease, an eye disease, cancer, a gastrointestinal disease, a urinary system disease, a metabolic disease or a transplant rejection; Preferably, the disease or disorder is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, progressive pulmonary fibrosis), renal fibrosis, liver fibrosis, skin fibrosis, intestinal fibrosis, eye fibrosis, cardiac fibrosis, pancreatic fibrosis, interstitial lung disease, idiopathic interstitial pneumonia, asthma, chronic obstructive pulmonary disease, bronchospasm, cough, chronic cough, respiratory failure, silicosis, acute lung injury, acute respiratory distress, acute kidney injury, chronic kidney disease, diabetic nephropathy, alcoholic fatty liver disease, non-alcoholic fatty liver disease (e.g., non-alcoholic fatty liver disease), acute hepatitis, chronic hepatitis, cirrhosis, hepatic hypofunction, primary biliary cirrhosis, autoimmune disease, inflammation, arthritis, rheumatoid arthritis, scleroderma, Raynaud's phenomenon, chronic pruritus, lupus, cryptogenic fibrosing alveolitis, psoriasis, systemic sclerosis, collagen vascular disease, Alzheimer's disease, Parkinson's disease, Neurodegenerative diseases, traumatic brain injury, epilepsy, mental illness, sleep disorders, collagen vascular diseases, myocardial infarction, stroke, thrombosis, atherosclerosis, heart failure, hypertension, colon syndrome, inflammatory bowel disease, digestive tract disease, gastrointestinal dysfunction, cancer pain, neuropathic pain, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, or cluster headache, chronic pain, urinary incontinence, dysuria, cystitis, prostatic hypertrophy, urination disorder associated with prostatic hypertrophy, bladder neck sclerosis, underactive bladder, macular degeneration, diabetic retinopathy, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, liver cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, tumor metastasis or osteoporosis; Preferably, the disease or disorder is interstitial lung disease, pulmonary fibrosis (particularly idiopathic pulmonary fibrosis), liver fibrosis, kidney fibrosis, non-alcoholic fatty liver disease (eg non-alcoholic steatohepatitis), psoriasis or scleroderma.

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