LPAR1 antagonist and use thereof

Abstract

An LPAR1 antagonist and the use thereof. The present invention relates to a compound as shown in formula (I), or a stereoisomer, a deuterated substance, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, and the use thereof in the preparation of a drug for treating / preventing LPAR1-mediated diseases, wherein each group in formula (I) is as defined in the description.

Description

LPAR1 antagonist and its use Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound with LPAR1 antagonistic activity, its stereoisomers, deuterated substances or pharmaceutically acceptable salts, and use thereof in preparing medicines for treating related diseases. Background Art

[0002] Lysophosphatidic acid (LPA) is a small glycerophosphodiester with a molecular weight of 430–480 Da. LPA is widely present in the human body. Upon binding to receptors, it activates multiple cellular signaling pathways, regulating cell proliferation, differentiation, apoptosis, neurotransmitter release, and other vital processes. It plays a crucial role in diseases such as cancer, fibrosis, neuronal dysfunction, and bone metabolic disorders. LPA is primarily produced by the hydrolysis of lysophospholipids (primarily lysophosphatidylcholine) by autocrine motility factor. In a bleomycin-induced pulmonary fibrosis model, LPA levels in bronchoalveolar lavage fluid are significantly elevated, leading to increased vascular permeability and pulmonary fibrosis. LPA also mediates the production of various paracrine mediators by fibroblasts, which act on epithelial cells, leukocytes, and endothelial cells, regulating tissue remodeling, angiogenesis, inflammation, wound healing, and tumor progression. LPA can even induce the extracellular shedding of epidermal growth factor (EGF) family ligands by fibroblasts, activating the release of soluble factors and, in part through EGFR, stimulating lung epithelial cells and amplifying the local fibroblast response. Recent studies have also found that the LPA-LPA1 signaling pathway can promote apoptosis of lung epithelial cells and inhibit fibroblast apoptosis in idiopathic pulmonary fibrosis (IPF), suggesting that this signaling pathway may regulate the development of fibrosis after lung injury. Studies have shown that LPA is closely associated with organ fibrosis, primarily mediated through the lysophosphatidic acid receptor (LPAR) 1. Currently, six LPARs have been discovered, namely LPAR1 to LPAR6. The function of LPAR1 has been a hot topic of research in recent years. Clinical studies have confirmed that LPAR antagonists have therapeutic effects on idiopathic pulmonary fibrosis. Furthermore, the LPAR1 antagonist BMS-986020 has been found to effectively improve lung function in patients with idiopathic pulmonary fibrosis.

[0003] Summary of the Invention

[0004] The present invention provides a small molecule compound having LPAR1 antagonist activity, and its stereoisomers, deuterated products or pharmaceutically acceptable salts, which have good activity, excellent physicochemical properties, convenient formulation, excellent pharmacokinetic properties, high bioavailability and low toxic side effects. The compound has the structures of formula (I), (I-1), (I-2), (I-2a), (I-2b), (I-2c), (I-3), (I-4), (I-5) and (I-6).

[0005] Ring C is selected from The "*" end is connected to the pyridine ring on the left. The end is connected to L2; in some embodiments, ring C is selected from The "*" end is connected to the pyridine ring on the left. The end is connected to L2;

[0006] Ring A is selected from a 3-12 membered carbocyclic group, a 4-12 membered heterocyclic group or ring A is absent, and the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 R A replace;

[0007] When ring A is absent, L1 is selected from C substituted with one COOH 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl;

[0008] When ring A is absent, L1 is selected from -OC substituted with one COOH 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl;

[0009] When rings A1 and A1b are each independently selected from 1-1 , L 1-1b Each independently selected from -OC substituted with one COOH 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; In some embodiments, Ring A1 is selected from absent, L 1-1 Selected from -OC substituted with one COOH 1-6 Alkyl; In some embodiments, Ring A, Ring A1 or A1b are each independently selected from not present, L1, L 1-1 , L 1-1b Each independently selected from -OCH2C(CH3)2CH2COOH, -OCH2CH2C(CH3)2COOH;

[0010] In some embodiments, ring A is selected from 4-12 membered carbocyclic groups, 4-12 membered heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally further substituted by 1-4 R A replace;

[0011] In some embodiments, Ring A is selected from 4-8 membered monocyclic carbocyclyl, 6-12 membered bicyclic carbocyclyl, 4-8 membered monocyclic heterocyclyl, 6-12 membered bicyclic heterocyclyl, 6-10 membered heterobridged cyclyl; said carbocyclyl, heterocyclyl, heterobridged cyclyl is optionally substituted by 1-4 R A replace;

[0012] In some embodiments, ring A is selected from 4-8 membered monocyclic cycloalkyl, 6-12 membered cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered heterocycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl, wherein the heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl contains 1-3 heteroatoms selected from N, O, and S; the cycloalkyl, heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl is optionally further substituted by 1-4 R A replace;

[0013] In some embodiments, Ring A is selected from the group consisting of A One of the groups formed by the following structures: or ring A is absent;

[0014] Rings A1, A1b, and A1c are each independently selected from a 3-12 membered carbocyclic group, a 4-12 membered heterocyclic group, or are absent, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 R A replace;

[0015] In some embodiments, rings A1, A1b, and A1c are each independently selected from a 3-8 membered monocyclic cycloalkyl, a 6-12 membered paracycloalkyl, a 4-8 membered monocyclic heterocycloalkyl, a 6-12 membered heteroparacycloalkyl, a 6-10 membered heterospirocyclyl, a 6-10 membered heterobridged cyclyl, or are absent, and the heterocycloalkyl, heteroparacycloalkyl, heterospirocyclyl, and heterobridged cyclyl contain 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, heteroparacycloalkyl, heterospirocyclyl, and heterobridged cyclyl are optionally further substituted by 1-4 R A replace;

[0016] Ring A1 is selected from 4-12 membered carbocyclic groups and 4-12 membered heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally further substituted by 1-4 R AReplace; and L 1-1 -A1 is not selected

[0017] In some embodiments, ring A1 is selected from 4-8 membered monocyclic cycloalkyl, 6-12 membered cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered heterocycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl, said heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl containing 1-3 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl optionally further substituted by 1-4 R A Replace; and L 1-1 -A1 is not selected

[0018] In some embodiments, Ring A1 is selected from the group consisting of A One of the groups formed by the following structures: And L 1-1 -A1 is not selected

[0019] In some embodiments, Ring A1 is selected from the group consisting of A One of the groups formed by the following structures: And L 1-1 -A1 is not selected

[0020] Ring A1b is selected from 3-12 membered carbocyclic group, 4-12 membered heterocyclic group or is absent, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 R A Replace; and L 1-1b -A1b is not selected

[0021] In some embodiments, ring A1b is selected from 4-12 membered carbocyclic groups and 4-12 membered heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally further substituted by 1-4 R A Replace; and L 1-1b -A1b is not selected

[0022] In some embodiments, Ring A1b is selected from 4-8 membered monocyclic cycloalkyl, 6-12 membered paracycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered paracycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl, wherein the heterocycloalkyl, paracycloalkyl, heterospirocyclyl, heterobridged cyclyl contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, paracycloalkyl, heterospirocyclyl, heterobridged cyclyl is optionally further substituted by 1-4 R A Replace; and L 1-1b -A1b is not selected

[0023] In some embodiments, Ring A1b is selected from the group consisting of A One of the groups formed by the following structures: or ring A1b is absent; and L 1-1b -A1b is not selected

[0024] In some embodiments, ring A1c is selected from a 3-12 membered carbocyclyl, a 4-12 membered heterocyclyl or is absent, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; the carbocyclyl or heterocyclyl is optionally further substituted with 1-4 R A substituted; and O-A1c is not selected from

[0025] In some embodiments, ring A1c is selected from 4-12 membered carbocyclic groups and 4-12 membered heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally further substituted by 1-4 R A substituted; and O-A1c is not selected from

[0026] In some embodiments, Ring A1c is selected from 4-8 membered monocyclic cycloalkyl, 6-12 membered paracycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered paracycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl, wherein the heterocycloalkyl, paracycloalkyl, heterospirocyclyl, heterobridged cyclyl contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, paracycloalkyl, heterospirocyclyl, heterobridged cyclyl is optionally further substituted by 1-4 R A substituted; and O-A1c is not selected from

[0027] In some embodiments, Ring A1c is selected from the group consisting of A One of the groups formed by the following structures: Or ring A1c is absent; and O-A1c is not selected from

[0028] R A Each independently selected from H, halogen, =O, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -(5-10 membered heterocyclyl), -(3-6 membered carbocyclic ring)-COOR a1 、-(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 , or -(CH2) p -P(O)(OH)2 or selected from =CH2, =CF2, =CH-CH3, =C-(CH3)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0029] In some embodiments, R A Each independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -(5-10 membered heterocyclic group), -(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2)p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 , or -(CH2) p -P(O)(OH)2 or selected from =CH2, =CF2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0030] In some embodiments, R A Each independently selected from H, halogen, =O, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-2 Alkyl, -(CH2) p -(5-8 membered heterocyclic group), -(3-6 membered carbocyclic group)-COOR a1 、-(CH2) p -COOR a1 or selected from =CH2, =CF2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution;

[0031] In some embodiments, R A Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-2 Alkyl, -(CH2) p -(5-8 membered heterocyclic group), -(CH2) p -COOR a1 or selected from =CH2, =CF2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution;

[0032] In some embodiments, R AEach is independently selected from H, halogen, CN, OH, -COOH, -CH2-COOH, -CH2CH2-COOH or selected from =CH2;

[0033] In some embodiments, R A Each is independently selected from H, F, Cl, CN, OH, -COOH, -CH2-COOH, -CH2CH2-COOH or selected from =CH2;

[0034] In some embodiments, Rings A1, A1b, and A1c are each independently selected from the following structures: Or selected from

[0035] Ring A3 is selected from

[0036] L1 is selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace;

[0037] In some embodiments, L1 is selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 replace;

[0038] In some embodiments, L1 is selected from a bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -O-, -OC 1-4 Alkyl-, -S-, -SC 1-4Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 replace;

[0039] In some embodiments, L1 is selected from a bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, the alkyl group is optionally further substituted by 1-4 R L1 replace;

[0040] In some embodiments, L1 is selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-, -NH-, -N(CH3)-, -NHCH(CH3)-;

[0041] In some embodiments, L1 is selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -NHC(O)-, -CH2-, -NH-, -N(CH3)-, -NHCH(CH3)-;

[0042] In some embodiments, L1 is selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-;

[0043] In some embodiments, L1 is selected from -O-, -N(CH3)-;

[0044] L 1-1 Selected from bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace;

[0045] In some embodiments, L 1-1 Selected from bond, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1 Selected from bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -O-, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1 Selected from bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, Ethyl, propenyl, ethynyl, -C(O)NH-, wherein the alkyl group is optionally further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1 Selected from bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, the alkyl group is optionally further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1 Selected from bond, -OCH2-, -OCH2CH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-; In some embodiments, L 1-1 Selected from bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-;

[0046] L 1-1a Selected from bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-、 -NR L1 -、-NRL1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1a Selected from bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1a Each independently selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-, -NH-, -N(CH3)-, -NHCH(CH3)-; In some embodiments, L 1-1a Selected from bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -C(=O)-, -CH2-;

[0047] L 1-1 Selected from bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace;

[0048] In some embodiments, L 1-1b Selected from bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1b Selected from bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -O-, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1b Selected from bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, Ethyl, propenyl, ethynyl, -C(O)NH-, -NHC(O)-, wherein the alkyl group is optionally further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1b Selected from bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, the alkyl group is optionally further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1b Selected from bond, -OCH2-, -OCH2CH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-; In some embodiments, L 1-1b Selected from bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-;

[0049] R L1 Each independently selected from H, halogen, =O, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl groups are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2; in some embodiments, R L1 Each independently selected from H, halogen, =O, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, the alkyl, cycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2; in some embodiments, RL1 Each independently selected from H, halogen, =O, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, 3-6 membered cycloalkyl, the alkyl, cycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2; in some embodiments, R L1 Each independently selected from H, halogen, =O, OH, C 1-2 alkyl, 3-6 membered cycloalkyl; in some embodiments, R L1 Each is independently selected from H, F, Cl, Br, =O, OH, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; in some embodiments, R L1 are independently selected from H, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl groups are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2; in some embodiments, R L1 Each independently selected from H, halogen, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl groups are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2; in some embodiments, R L1 Each independently selected from H, halogen, OH, C 1-2 Alkyl, 3-6 membered cycloalkyl; L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0050] In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(RL25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0051] In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0052] In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、 -N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 RL22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), Cy is selected from 4-7 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27)(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-N(R L31 )-C(=O)OR L32 In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 );

[0053] In some embodiments, R a1 、R a2 、R L1 、R L2 、RL21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, -(CH2) p -OC 3-10 Cycloalkyl, -OC 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -SCF3, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 radical substitution of cycloalkyl groups;

[0054] R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p-(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, -OC 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 radical substitution of cycloalkyl groups;

[0055] In some embodiments, R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 radical substitution of cycloalkyl groups;

[0056] In some embodiments, R a1 、Ra2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-10 membered heterocycloalkyl, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are optionally further substituted by 1-4 halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 radical substitution of cycloalkyl groups;

[0057] In some embodiments, R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0058] In some embodiments, R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0059] In some embodiments, R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、RL29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0060] In some embodiments, R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-10 membered heterocycloalkyl, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are optionally further substituted by 1-4 halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0061] In some embodiments, R a1 、R a2 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0062] In some embodiments, R a1 、R a2 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;

[0063] In some embodiments, each R L21 、R L22 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0064] In some embodiments, each R L21 、R L22 Each independently selected from H, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0065] In some embodiments, each R L21 、R L22 Each independently selected from H, C 1-2 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally further substituted by 1-4 groups selected from F, Cl, OH, NH2, and CN;

[0066] In some embodiments, each L21 、R L22 Each is independently selected from H, methyl, ethyl, cyclopropyl;

[0067] In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, S, S(O), S(O)2; the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0068] And when R L21 、R L22 When both are H and L1 is O, at least one R L23 Selected from -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2) p -OC 3-6 Cycloalkyl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 3-6 Cycloalkyl, the heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0069] In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 3-6Cycloalkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, S, S(O), S(O)2; the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0070] In some embodiments, each R L23 Each independently selected from -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2) p -OC 3-6 Cycloalkyl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 3-6 Cycloalkyl, the heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0071] In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, -OCF3, NH2, CN, acetyl, -S(O)2CH3, and when R L21 、R L22When both are H, at least 1 R L23 -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, quilt Substituted 5-6 membered heteroaryl, -CH2CH2OCF3, -OC 3-6 Cycloalkyl,

[0072] In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, The heterocycloalkyl group contains 1-3 heteroatoms selected from N, O, and S; the alkyl group and the heterocycloalkyl group are optionally further substituted by 1-4 groups selected from =O, halogen, OH, NH2, CN, acetyl, and -S(O)2CH3; and when R L21 、R L22 When both are H, at least 1 R L23 -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl,

[0073] In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, NH2, CN, acetyl, -S(O)2CH3, and when R L21 、R L22 When both are H, at least 1 R L23 -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, quilt substituted 5-6 membered heteroaryl;

[0074] In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p-(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, The heterocycloalkyl group contains 1-3 heteroatoms selected from N, O, and S; the alkyl group and the heterocycloalkyl group are optionally further substituted by 1-4 groups selected from =O, halogen, OH, NH2, CN, acetyl, and -S(O)2CH3; and when R L21 、R L22 When both are H, at least 1 R L23 -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl,

[0075] In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, 6-12 membered bicyclic heterocycloalkyl, the heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S; the alkyl, heterocycloalkyl optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, acetyl; and when R L21 、R L22 When both are H, at least 1 R L23 is a 6-12 membered bicyclic heterocycloalkyl group;

[0076] In some embodiments, each R L23 Each independently selected from methyl, ethyl, propyl,

[0077] R L23-1 is selected from methyl, ethyl; in some embodiments, R L23-1 selected from methyl;

[0078] R L23-2 Selected from -(CH2) p -(4-7 membered heterocycloalkyl), -(CH2) p -C 4-6 Monocyclic cycloalkyl, -OC 3-6 Cycloalkyl, -CH2CH2OCF3, the heterocycloalkyl contains 1-2 N atoms; wherein the heterocycloalkyl is optionally further substituted by 1-2 -S(O)2CH3, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2 groups, the cycloalkyl is further substituted by 1-2 =CH2, =CF2, =CH-CH3, =C-(CH3)2 groups; in some embodiments, R L23-2 Selected from -CH2CH2OCF3,

[0079] RL23-1a is selected from H, methyl, ethyl; in some embodiments, R L23-1a is selected from H, methyl; in some embodiments, R L23-1a Selected from methyl and ethyl;

[0080] R L23-2a Selected from -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2) p -OC 3-6 Cycloalkyl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 3-6 Cycloalkyl, the heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, In some embodiments, R L23-2a Selected from 4-7 membered heterocycloalkyl, -CH2-(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, C substituted by 1-4 groups selected from -OCF3, -OCHF2, -SCF3 2-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2)2-OC 3-6 Cycloalkyl, 1 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 3-6 Cycloalkyl, the heterocycloalkyl, heteroaryl may be further substituted by 1, 2, or 3 groups selected from: =O, F, Cl, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0081] In some embodiments, R L24 Each independently selected from H, C 2-6 Alkenyl, C 2-6Alkynyl, the alkenyl, alkynyl optionally further 1-4 selected from halogen, OH, NH2, CN, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0082] In some embodiments, each R L25 、R L27 、R L28 Each independently selected from C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0083] In some embodiments, each R L25 、R L27 、R L28 Each independently selected from C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0084] In some embodiments, each R L25 、R L27 、R L28 Each is independently selected from methyl, ethyl, and propyl;

[0085] In some embodiments, R L29 Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN; in some embodiments, R L29 Selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN; in some embodiments, R L29 Selected from H, methyl, ethyl;

[0086] In some embodiments, R L30 is selected from a 6-14 membered bicyclic or tricyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, CN, OH, NH2, C 1-4 Alkyl, halogenated C 1-4 alkyl group substituted; and R L30 Not for In some embodiments, R L30 Selected from

[0087] The compound is not

[0088] L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0089] In some embodiments, L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25)2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0090] In some embodiments, L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29)-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0091] In some embodiments, L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、 -(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)RL21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), Cy is selected from 4-7 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0092] In some embodiments, L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 );

[0093] In some embodiments, L 2-1 Selected from

[0094] In some embodiments, L 2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from

[0095] L 2-2 , L 2-2c Each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 ;

[0096] In some embodiments, L2-2 , L 2-2c Each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 ;

[0097] In some embodiments, L 2-2 , L 2-2c Each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -OC(O)-R L23 ;

[0098] In some embodiments, L 2-2 , L 2-2c Each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 );

[0099] In some embodiments, L 2-2c Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 );

[0100] In some embodiments, L 2-2 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 RL22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 );

[0101] In some embodiments, L 2-2 , L 2-2c Each independently selected from or L 2-2 , L 2-2c Each independently selected from

[0102] In some embodiments, L 2-2 , L 2-2c Each independently selected from

[0103] R L32 Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), -C 1-4 Alkyl-(6-10 membered aryl), wherein the heteroaryl and aryl groups are optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Substitution of alkynyl groups by substituents;

[0104] In some embodiments, R L32 Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halo 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Substitution of alkynyl groups by substituents;

[0105] In some embodiments, R L32 Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halo 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6Alkenyl or C 2-6 Substitution of alkynyl groups by substituents;

[0106] In some embodiments, R L32 Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from F, Cl, CN, OH, NO2, NH2, halogenated C 1-2 Substitution of alkyl groups;

[0107] In some embodiments, R L32 Selected from -C 1-2 Alkyl-(5-6 membered monocyclic heteroaryl), -C 1-2 Alkyl-(8-10 membered bicyclic heteroaryl), wherein the heteroaryl is optionally further substituted with 1-3 substituents selected from F, Cl, CN, OH, NO2, NH2, -CH2F, -CHF2, -CF3;

[0108] R L33 Selected from C 1-4 Alkyl, halogen, OH, NH2, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)H, -C(=O)OH, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, N3, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0109] In some embodiments, R L33 Selected from C 1-4 Alkyl, wherein the alkyl is optionally further substituted by 1-2 groups selected from halogen, OH, NH2, CN, N3, C 1-2 Alkoxy, fluorinated C 1-2 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0110] Alternatively, R L24 With R L25 or R L26 With R L27Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0111] Alternatively, R L24 With R L25 or R L26 With R L27 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, acetyl group substitution;

[0112] Alternatively, two R L23 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted with 1-3 groups selected from =O, OH, NH2, CN, and acetyl;

[0113] p is independently selected from 0, 1, 2, 3, 4;

[0114] In some embodiments, p is selected from 0, 1 or 2;

[0115] In some embodiments, p is selected from 0 or 1;

[0116] The conditions are:

[0117] (1) For formula (I-2), when L 2-2 Selected from When L 1-1 -A1 is not selected

[0118] (2) For formula (I-2), when L 2-2 Selected from When L 1-1 -A1 is not selected

[0119] (3) For formula (I-2b), L 1-1b -A1b is not selected

[0120] (4) For formula (I-2c), O-A1c is not selected from

[0121] And the compound is not

[0122] Specifically, in the first technical solution of the present invention, the compound of formula (I), its stereoisomers, deuterated substances, or pharmaceutically acceptable salts,

[0123] Ring C is selected from The "*" end is connected to the pyridine ring on the left. The end is connected to L2; in some embodiments, ring C is selected from The "*" end is connected to the pyridine ring on the left. The end is connected to L2;

[0124] Ring A is selected from a 3-12 membered carbocyclic group, a 4-12 membered heterocyclic group or ring A is absent, and the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 R A In some embodiments, ring A is selected from 4-12 membered carbocyclic groups, 4-12 membered heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally further substituted with 1-4 R A replace;

[0125] R A Each independently selected from H, halogen, =O, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -(5-10 membered heterocyclyl), -(3-6 membered carbocyclic ring)-COOR a1 、-(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 , or -(CH2) p-P(O)(OH)2 or, =CH2, =CF2, =CH-CH3, =C-(CH3)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 In some embodiments, R A Each independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -(5-10 membered heterocyclic group), -(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 , or -(CH2) p -P(O)(OH)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0126] L1 is selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 In some embodiments, L1 is selected from a bond, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 replace;

[0127] R L1 Each independently selected from H, halogen, =O, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl groups are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2; in some embodiments, R L1 Each independently selected from H, halogen, =O, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2;

[0128] When ring A is absent, L1 is selected from C substituted with one COOH 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl;

[0129] In some embodiments, when Ring A is absent, L1 is selected from -OC substituted with one COOH. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; In some embodiments, Ring A is selected from absent, L1 is selected from -OCH2C(CH3)2CH2COOH, -OCH2CH2C(CH3)2COOH;

[0130] L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6cycloalkyl, 5-7 membered heterocyclic group; or

[0131] L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 )p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group; or

[0132] L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CRL21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group; or

[0133] L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(RL29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), Cy is selected from 4-7 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group substitution;

[0134] In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 ;

[0135] R a1 、R a2、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, -(CH2) p -OC 3-10 Cycloalkyl, -OC 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -SCF3, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 cycloalkyl radical substitution; or

[0136] R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 cycloalkyl radical substitution; or

[0137] R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), The heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally further substituted by 1-4 heteroatoms selected from halogen, =O, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0138] In some embodiments, R a1 、R a2 、R L1 、R L2 、R L21 、R L22、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、 R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0139] In some embodiments, R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 、R L30 、R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10cycloalkyl, 5-12 membered heterocyclic group substitution;

[0140] R L32 Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), -C 1-4 Alkyl-(6-10 membered aryl), wherein the heteroaryl and aryl groups are optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 In some embodiments, R L32 Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), wherein the heteroaryl is optionally further substituted by 1-3 groups selected from halogen, CN, OH, NO2, NH2, halo 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Substitution of alkynyl groups by substituents;

[0141] R L33 Selected from C 1-4 Alkyl, halogen, OH, NH2, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)H, -C(=O)OH, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, N3, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0142] Alternatively, R L24 With R L25 or R L26 With R L27 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0143] Alternatively, R L24 With R L25 or R L26 With R L27 or two R L23Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, acetyl group substitution;

[0144] p is independently selected from 0, 1, 2, 3, and 4.

[0145] In the second technical solution of the present invention, the compound of formula (I), its stereoisomers, deuterated substances, or pharmaceutically acceptable salts have the structure of formula (I-1), wherein:

[0146] L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、 -(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 RL22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group; or

[0147] L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group; or

[0148] L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p-C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclic group; or

[0149] L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29)(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), Cy is selected from 4-7 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclyl; in some embodiments, L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 );

[0150] R L21 、R L22 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0151] Each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, S, S(O), S(O)2; the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0152] And when R L21 、R L22 When both are H and L1 is O, at least one R L23 Selected from -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2) p -OC 3-6 Cycloalkyl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C3-6 Cycloalkyl, the heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, or

[0153] Each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, NH2, CN, acetyl, -S(O)2CH3, and when R L21 、R L22 When both are H, at least 1 R L23 -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, quilt substituted 5-6 membered heteroaryl; or

[0154] Each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, The heterocycloalkyl group contains 1-3 heteroatoms selected from N, O, and S; the alkyl group and the heterocycloalkyl group are optionally further substituted by 1-4 groups selected from =O, halogen, OH, NH2, CN, acetyl, and -S(O)2CH3; and when R L21 、R L22 When both are H, at least 1 R L23 -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, or

[0155] Each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, The heterocycloalkyl group contains 1-3 heteroatoms selected from N, O, and S; the alkyl group and the heterocycloalkyl group are optionally further substituted by 1-4 groups selected from =O, halogen, OH, NH2, CN, acetyl, and -S(O)2CH3; and when R L21 、R L22 When both are H, at least 1 R L23 -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, In some embodiments, each R L23 Each independently selected from C 1-4 Alkyl, 6-12 membered bicyclic heterocycloalkyl, the heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S; the alkyl, heterocycloalkyl optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, acetyl; and when R L21 、R L22 When both are H, at least 1 R L23 is a 6-12 membered bicyclic heterocycloalkyl group; or

[0156] Each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, S, S(O), S(O)2; the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0157] And when R L21 、R L22 When both are H and L1 is O, at least one R L23 Selected from -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2) p -OC 3-6 Cycloalkyl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 3-6 Cycloalkyl, the heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution;

[0158] R L24 Each independently selected from H, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkenyl, alkynyl optionally further 1-4 selected from halogen, OH, NH2, CN, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0159] Each R L25 、R L27 、R L28 Each independently selected from C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0160] R L26 Each independently selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, the alkenyl, alkynyl, cycloalkyl may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0161] R L29 Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0162] R L30is selected from 6-14 membered bicyclic or tricyclic heterocyclic groups, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, CN, OH, NH2, C 1-4 Alkyl, halogenated C 1-4 Alkyl radical substitution;

[0163] p is selected from 0, 1, 2, 3, 4;

[0164] Alternatively, R L24 With R L25 or R L26 With R L27 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0165] Alternatively, R L24 With R L25 or R L26 With R L27 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, acetyl group substitution;

[0166] Alternatively, two R L23 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted with 1-3 groups selected from =O, OH, NH2, CN, and acetyl;

[0167] The conditions are, (1), R L30 Not for

[0168] (2) The compound is not

[0169] The definitions of other groups are consistent with those of the first technical solution.

[0170] The third technical solution of the present invention is the compound of formula (I-1), its stereoisomers, deuterated substances, or pharmaceutically acceptable salts, wherein:

[0171] L 2-1 Selected from

[0172] In some embodiments, L2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from or L 2-1 Selected from

[0173] L1 is selected from a bond, -OCH2-, -OCH2CH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -NHC(O)-, -CH2-, -NH-, -N(CH3)-, -NHCH(CH3)-; In some embodiments, L1 is selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -NHC(O)-, -CH2-;

[0174] The definitions of other groups are consistent with those of the second technical solution.

[0175] In the fourth technical solution of the present invention, the compound of formula (I), its stereoisomers, deuterated substances, or pharmaceutically acceptable salts have the structures of formula (I-2), (I-2a), (I-2b), or (I-2c), wherein:

[0176] Rings A1, A1b, and A1c are each independently selected from a 3-12 membered carbocyclic group, a 4-12 membered heterocyclic group, or are absent, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 R A In some embodiments, ring A1, A1b, A1c are each independently selected from a 4-12 membered carbocyclic group, a 4-12 membered heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and the heterocyclic group are optionally further substituted by 1-4 R A replace;

[0177] R A Each independently selected from H, =O, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2)p -5-10 membered heterocyclic group, -(3-6 membered carbocyclic ring)-COOR a1 、-(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 , or -(CH2) p -P(O)(OH)2 or =CH2, =CF2, =CH-CH3, =C-(CH3)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 In some embodiments, R A Each independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -5-10 membered heterocyclic group, -(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 , or -(CH2) p-P(O)(OH)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 alkyl group substituted; and L 1-1 -A1, L 1-1b -A1b, O-A1c are not selected

[0178] L 1-1 , L 1-1b Each independently selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1 , L 1-1b Each independently selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 replace;

[0179] L 1-1a Selected from bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)- -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1Substitution; in some embodiments, L 1-1a Selected from bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 replace;

[0180] R L1 Each independently selected from H, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl groups are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2;

[0181] In some embodiments, when rings A1 and A1b are each independently selected from 1-1 , L 1-1b Each independently selected from -OC substituted with one COOH 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; in some embodiments, R L1 Each independently selected from H, halogen, =O, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2;

[0182] L 2-2 , L 2-2c Each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29)(R L30 ),-(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 ;or

[0183] L 2-2 , L 2-2c Each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -OC(O)-R L23 ;or

[0184] L 2-2 , L 2-2c Each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 R L22 ) p N(R L26 )C(O)N(R L27)(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 );

[0185] R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-10 membered heterocycloalkyl, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, -(CH2) p -OC 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are optionally further substituted by 1-4 halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, -SCF3, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 cycloalkyl radical substitution; or

[0186] R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-10 membered heterocycloalkyl, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are optionally further substituted by 1-4 halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 cycloalkyl radical substitution; or

[0187] R a1 、R a2 、R L1 、R L2 、R L21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-10 membered heterocycloalkyl, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 heteroatoms selected from halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0188] In some embodiments, R a1 、R a2 、R L1 、R L2 、RL21 、R L22 、R L23 、R L24 、R L25 、R L26 、R L27 、R L28 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-10 membered heterocycloalkyl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 cycloalkyl, 5-12 membered heterocyclic group substitution;

[0189] R L29 Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0190] R L30 is selected from 6-14 membered bicyclic or tricyclic heterocyclic groups, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, CN, OH, NH2, C 1-4 Alkyl, halogenated C 1-4 Alkyl radical substitution;

[0191] Alternatively, R L24 With R L25 or R L26 With R L27 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution;

[0192] p is independently selected from 0, 1, 2, 3, 4;

[0193] The conditions are:

[0194] (1) For formula (I-2), when L 2-2 Selected from When L1-1 -A1 is not selected

[0195] (2) For formula (I-2), when L 2-2 Selected from When L 1-1 -A1 is not selected

[0196] (3) For formula (I-2b), L 1-1b -A1b is not selected

[0197] (4) For formula (I-2c), O-A1c is not selected from

[0198] The definitions of other groups are consistent with those of the first technical solution.

[0199] The fifth technical solution of the present invention is the compound of formula (I-2), (I-2b), (I-2c), its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, wherein:

[0200] Ring A1, A1b, A1c is selected from 3-8 membered monocyclic cycloalkyl, 6-12 membered paracycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered paracycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl or absent, said heterocycloalkyl, paracycloalkyl, heterospirocyclyl, heterobridged cyclyl contains 1-3 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl, paracycloalkyl, heterospirocyclyl, heterobridged cyclyl is optionally further substituted by 1-4 R A In some embodiments, ring A1, A1b, A1c is selected from 4-8 membered monocyclic cycloalkyl, 6-12 membered cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered heterocycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl, said heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl contains 1-3 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl is optionally further substituted by 1-4 R A replace;

[0201] R A Each independently selected from H, halogen, =O, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-2 Alkyl, -(CH2) p -(5-8 membered heterocyclic group), -(3-6 membered carbocyclic group)-COORa1 、-(CH2) p -COOR a1 or =CH2, =CF2, =CH-CH3 or =C-(CH3)2, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, and heterocyclic group are optionally further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 In some embodiments, R A Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-2 Alkyl, -(CH2) p -(5-8 membered heterocyclic group), -(CH2) p -COOR a1 The heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, and heterocyclic group are optionally further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution;

[0202] L 1-1 , L 1-1b Each independently selected from a bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -O-, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl group may be further substituted by 1-4 R L1 replace;

[0203] R L1 Each independently selected from H, halogen, =O, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl groups are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2; in some embodiments, R L1 Each independently selected from H, halogen, =O, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, 3-6 membered cycloalkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2;

[0204] The definitions of other groups are consistent with those of the fourth technical solution.

[0205] The sixth technical solution of the present invention is the compound of formula (I-2), its stereoisomers, deuterated substances, or pharmaceutically acceptable salts, wherein:

[0206] Rings A1, A1b, and A1c are each independently selected from the group consisting of A One of the groups formed by the following structures:

[0207] R A Each independently selected from H, C 1-2 Alkyl, halogen, CN, OH, -COOH, -CH2-COOH, -CH2CH2-COOH, =CH2, =CF2, =CH-CH3, or =C-(CH3)2; in some embodiments, R A Each independently selected from H, C 1-2 Alkyl, halogen, CN, OH, -COOH, -CH2-COOH, -CH2CH2-COOH; In some embodiments, R A Each is independently selected from H, halogen, CN, OH, -COOH, -CH2-COOH, -CH2CH2-COOH;

[0208] L 1-1 , L 1-1b Each independently selected from a bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, Ethyl, propenyl, ethynyl, -C(O)NH-, -NHC(O)-, wherein the alkyl group is optionally further substituted by 1-4 R L1 Substitution; in some embodiments, L 1-1 , L 1-1b Each independently selected from a bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, -NHC(O)-, wherein the alkyl group is optionally further substituted by 1-4 R L1 replace;

[0209] R L1 Each independently selected from H, halogen, =O, OH, C 1-2 Alkyl, 3-6 membered cycloalkyl;

[0210] L 2-2 , L 2-2c Each independently selected from or

[0211] L2-2 , L 2-2c Each independently selected from or

[0212] L 2-2 , L 2-2c Each independently selected from

[0213] The definitions of other groups are consistent with those of the fifth technical solution.

[0214] The seventh technical solution of the present invention is the compound of formula (I-2), (I-2a), (I-2b), (I-2c), its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, wherein:

[0215] Rings A1, A1b, and A1c are each independently selected from the following structures: Or selected from Or selected from

[0216] L 1-1 , L 1-1b Each independently selected from a bond, -OCH2-, -OCH2CH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-; In some embodiments, L 1-1 , L 1-1b Each independently selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-;

[0217] L 1-1a Each independently selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-, -NH-, -N(CH3)-, -NHCH(CH3)-; In some embodiments, L 1-1a Each independently selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -C(=O)-, -NHC(O)-, -CH2-;

[0218] The definitions of other groups are consistent with those of the sixth technical solution.

[0219] In the eighth technical solution of the present invention, the compound of formula (I), its stereoisomers, deuterated substances, or pharmaceutically acceptable salts have the structure of formula (I-6),

[0220] in

[0221] Ring A1 is selected from 3-12 membered carbocyclic group, 4-12 membered heterocyclic group or is absent, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 R A In some embodiments, ring A1 is selected from 3-8 membered monocyclic cycloalkyl, 6-12 membered cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered heterocycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl or ring A1 is absent, and the heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl, heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl is optionally further replaced by 1-4 R A In some embodiments, ring A1 is selected from 4-8 membered monocyclic cycloalkyl, 6-12 membered cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered heterocycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl, said heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl containing 1-3 heteroatoms selected from N, O, S, said cycloalkyl, heterocycloalkyl, heterocycloalkyl, heterospirocyclyl, heterobridged cyclyl optionally further substituted by 1-4 R A Substitution; In some embodiments, Ring A1 is selected from the following structures:

[0222] In some embodiments, when Ring A1 is absent, L 1-1 Selected from -OC substituted with one COOH 1-6 alkyl;

[0223] L 1-1 Selected from bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 Substitution; in some embodiments, L1-1 Selected from bond, -OCH2-, -OCH2CH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-;

[0224] R A Each independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -(5-10 membered heterocyclic group), -(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 、-(CH2) p -P(O)(OH)2, =CH2, =CF2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group may be further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 In some embodiments, R A Each is independently selected from H, halogen, CN, OH, -COOH, -CH2-COOH, -CH2CH2-COOH or =CH2;

[0225] L 2-2 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2、-(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2、-(CR L21 RL22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2、-(CR L21 R L22 ) p -SC(O)-N(R L25 )2、-(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23, Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 5-7 membered heterocyclyl; in some embodiments, L 2-2 Selected from -(CR L21 R L22 ) p -OC(O)-N(CH3)R L23 、-(CR L21 R L22 ) p -OC(O)-NHR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 ;

[0226] R L23 Selected from -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 groups selected from =CH2, =CF2, =CH-CH3, and =C-(CH3)2;

[0227] R L21 、R L22 、R L24 、R L25 、R L26 、R L27 、R L28 、R L29 Each independently selected from H, C 1-4 alkyl.

[0228] The ninth technical solution of the present invention is a compound of formula (I), a stereoisomer, a deuterated substance, or a pharmaceutically acceptable salt thereof, having a structure of formula (I-3),

[0229] wherein ring A3 is selected from

[0230] L1 is selected from -O-, -N(CH3)-, -NHC(O)-;

[0231] R L23-1 Selected from methyl and ethyl;

[0232] R L23-2 Selected from -(CH2) p -(4-7 membered heterocycloalkyl), -(CH2) p -C 4-6 Monocyclic cycloalkyl, -(CH2)2-OC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -CH2CH2OCF3, the heterocycloalkyl contains 1-2 N atoms; wherein the heterocycloalkyl is optionally further substituted by 1-2 -S(O)2CH3, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2 groups, the cycloalkyl is further substituted by 1-2 =CH2, =CF2, =CH-CH3, =C-(CH3)2 groups; in some embodiments, R L23-2 Selected from -CH2CH2OCF3,

[0233] p is selected from 0, 1, and 2.

[0234] The tenth technical solution of the present invention is a compound of formula (I), a stereoisomer, a deuterated substance, or a pharmaceutically acceptable salt thereof, having a structure of formula (I-5),

[0235] wherein ring A1 is selected from 4-8 membered monocyclic cycloalkyl, 6-12 membered cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered heterocycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl or is absent. In some embodiments, ring A1 is selected from or does not exist;

[0236] L 1-1 Selected from -OCH2-, -OCH2CH2-, -O-; or

[0237] When ring A1 is absent, L 1-1 Selected from -OCH2CH2C(CH3)2-COOH, -OCH2C(CH3)2CH2-COOH;

[0238] R L26 Selected from H, C 1-4 alkyl;

[0239] R L23 Selected from -(CH2) p -(4-7 membered heterocycloalkyl), -(CH2) p -C 4-6Monocyclic cycloalkyl, the heterocycloalkyl contains 1-2 N atoms; wherein the heterocycloalkyl is optionally further substituted by 1-2 =CH2, =CF2, =CH-CH3, =C-(CH3)2, =CHF, or a haloalkoxy group; the cycloalkyl is further substituted by 1-2 =CH2, =CH-CH3, =C-(CH3)2, =CF2, =CHF, or a haloalkoxy group; in some embodiments, R L23 Selected from

[0240] p is selected from 0, 1, and 2.

[0241] The eleventh technical solution of the present invention relates to a compound represented by formula (I-6), its stereoisomers, deuterated substances, or pharmaceutically acceptable salts,

[0242] in,

[0243] L 2-2 Selected from -(CR L21 R L22 ) p -OC(O)-N(CH3)R L23 、-(CR L21 R L22 ) p -OC(O)-NHR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 ;

[0244] R L21 、R L22 、R L26 Each independently selected from H, C 1-4 alkyl;

[0245] R L23 Selected from -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the cycloalkyl and heterocyclic groups are further substituted by 1-4 groups selected from =CH2, =CF2, =CH-CH3, and =C-(CH3)2;

[0246] Ring A1 is selected from 3-12 membered carbocyclic group, 4-12 membered heterocyclic group or is absent, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 RA replace;

[0247] When ring A1 is absent, L 1-1 Selected from -OC substituted with one COOH 1-6 alkyl;

[0248] L 1-1 Selected from bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace;

[0249] R A 、R L1 , pAs described in the first or eighth technical solution above.

[0250] More specifically, the compound of formula (I) of the present invention, its stereoisomers, deuterated substances, or pharmaceutically acceptable salts are selected from but not limited to the structures in Table 1 and Table 2 below:

[0251] Table 1

[0252] Table 2

[0253] Secondly, the present invention also provides a pharmaceutical composition, which contains the compound described in any one of the aforementioned schemes, its stereoisomers, deuterated substances, or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0254] Furthermore, the pharmaceutical composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any one of the aforementioned schemes, its stereoisomers, deuterated substances, or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0255] Furthermore, the present invention also provides the use of a compound according to any of the aforementioned embodiments, or a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating / preventing an LPAR1-mediated disease. Furthermore, the LPAR1-mediated disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, and neuralgia, preferably idiopathic pulmonary fibrosis and progressive pulmonary fibrosis.

[0256] The present invention also provides a method for treating a disease in a mammal or human, comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, or a composition of the present invention, as described in any of the preceding schemes. The disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, and neuralgia. In some embodiments, the mammal described herein does not include a human.

[0257] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5 -800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60 mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 1 0-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1500mg, 20-1000mg, 20-900mg, 20-8 00mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20- 150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0258] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer, deuterated substance, or pharmaceutically acceptable salt thereof.

[0259] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer, a deuterated form thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably idiopathic pulmonary fibrosis or progressive pulmonary fibrosis.

[0260] A method for treating a disease in a mammal or a human, comprising administering a compound of the present invention, a stereoisomer, a deuterated substance, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0261] The present invention relates to a kit, which can include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance, or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0262] The amount of the compound of the present invention or its stereoisomer, deuterated substance, or pharmaceutically acceptable salt in the present invention is in each case calculated based on the free base form.

[0263] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0264] Synthesis route

[0265] Those skilled in the art can prepare the compounds of the present invention by combining this document with known organic synthesis techniques, using commercially available chemicals and / or compounds described in the chemical literature as starting materials. "Commercially available chemicals" are obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0266] The ACS Chemical Abstracts Service index of known chemical substances allows for the selective identification of specific and similar

[0267] Reactants are indexed to a wide variety of reagents, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which (e.g., those listed above) offer custom synthesis services.

[0268] the term

[0269] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0270] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0271] "Halo" or "halogen substituted" means that a hydrogen atom is replaced by one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be the same or different halogens.

[0272] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one isotope, deuterium. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms, more preferably 1-10 deuterium atoms, more preferably 1-6 deuterium atoms, and even more preferably 1-3 deuterium atoms.

[0273] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, further preferably an alkyl group having 1 to 4 carbon atoms, and further preferably an alkyl group having 1-2 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof.

[0274] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0275] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", non-limiting examples of which include cyclopropylene, cyclobutylene, and the like.

[0276] "Carbocycle" or "carbocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocycles, bicyclic bridged rings, bicyclic cyclic rings and bicyclic spirocycles, etc., unless otherwise specified, and has 3 to 12 carbon atoms, preferably 3-10 carbon atoms, and more preferably 3-6 carbon atoms. Its definition includes cycloalkyl and aryl. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc., the bicyclic bridge ring includes etc., double ring and ring include etc., bicyclic spiro ring includes wait.

[0277] "Cycloalkyl" refers to a monovalent non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group, which, unless otherwise specified, usually has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and further preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Or cycloheptyl, etc.

[0278] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0279] "Alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, etc.

[0280] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, the alkenyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0281] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, -OC 1-8 Alkyl, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl, more preferably -OC 1-2 Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0282] "Haloalkoxy" refers to -O-haloalkyl, unless otherwise specified, -O-haloC 1-8 Alkyl, preferably -O-halogenated C 1-6 Alkyl, more preferably -O-halogenated C 1-4 Alkyl, more preferably -O-halogenated C 1-2 Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0283] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0284] "Heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which, unless otherwise specified, contains 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, and includes monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles. Unless otherwise specified, it is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. This definition includes heterocycloalkyl and heteroaryl groups. The nitrogen and sulfur atoms in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxane, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dithio ... hydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, wait.

[0285] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolyl, piperidinyl, aziridinyl, and the like.

[0286] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furyl, and the like.

[0287] "Heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic carbon ring containing 1, 2, 3, 4, or 5 heteroatoms selected from N, S, O, P, and Si. Heterocycloalkyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic groups can be bridged, fused, spirocyclic, or a combination thereof. Bicyclic or polycyclic groups can include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic, and the attachment point is on the non-aromatic ring. Heterocycloalkyl groups are usually 3 to 20-membered rings. When they are monocyclic heterocycloalkyl groups, they are usually 3 to 15-membered rings, or 3-10-membered rings, or 3-8-membered rings, or 3-6-membered rings; when they are bicyclic or polycyclic heterocycloalkyl groups, they are usually 5-12-membered rings, or 5-11-membered rings, or 6-9-membered rings. The heteroatoms N, S, and P include their oxidation states of C=O, NO, S=O, S(=O)2, P=O, and P(=O)2. When the heterocycloalkyl group is bicyclic or polycyclic, at least one of the rings contains at least one heteroatom, and the heterocycloalkyl group may be a bicyclic or polycyclic ring formed by a ring containing a heteroatom and a ring not containing a heteroatom, or a bicyclic or polycyclic ring formed by a ring containing a heteroatom and a ring containing a heteroatom; when connected to other groups, the connection point may be a heteroatom or a carbon atom; non-limiting examples of heterocycloalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azopentyl, azohexenyl, oxolenyl, oxetanyl, etc. The heterocycloalkyl group may be optionally substituted by a substituent.

[0288] "Spiro" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the rings, which may contain 0 or more double bonds or triple bonds, and may contain 0 to 5 heteroatoms selected from N, O, S and their oxidation states. Typically, the spiro ring is a 5- to 14-membered ring, or a 5- to 12-membered ring, or a 5- to 10-membered ring. Typically, the spiro ring is a trispirotri (representing a three-membered ring spirotricyclic ring), a trispirotetra, a trispiropenta, a trispirohexa, a tetraspirotetra, a tetraspiropenta, a tetraspirohexa, a pentaspiropenta or a pentaspirohexa. Non-limiting examples of spiro rings include , the spiro ring may be optionally substituted by a substituent.

[0289] "Parallel ring" refers to a polycyclic group in which the rings share two adjacent ring atoms and a chemical bond, and may contain one or more double bonds or triple bonds, and the rings may contain 0 to 5 heteroatoms selected from N, S, O and their oxidation states. Usually, the ring is a 5- to 20-membered ring, or a 5- to 14-membered ring, or a 5- to 12-membered ring, or a 5- to 10-membered ring. Usually, the ring is a three- to four-membered ring (representing a ring formed by a three-membered ring and a four-membered ring. According to the IUPC naming rules, it may be a three-membered ring as the basic ring or a four-membered ring as the basic ring. The same applies below), a three- to five-ring ring, a three- to six-ring ring, a four- to four-ring ring, a four- to five-ring ring, a four- to six-ring ring, a five- to five-ring ring, a five- to six-ring ring, and a six- to six-ring ring. Non-limiting examples of parallel rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, ; The ring may be optionally substituted by a substituent.

[0290] "Bridged ring" means two rings that share two non-adjacent ring atoms and may contain one or more double or triple bonds. A bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, and oxidation states thereof. Typically, the number of ring atoms in a bridged ring is 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings include adamantane,

[0291] "Carbocyclyl," "cycloalkyl," "carbocyclyl," or "carbocyclyl" refers to a "cyclyl" whose ring system consists only of carbon atoms. As used herein, "carbocyclyl," "cycloalkyl," "carbocyclyl," or "carbocyclyl" has the same definition as for cyclocyclyl.

[0292] "Heterocyclyl", "heterocyclyl group", "heterocyclylalkyl", "heterocyclyl group" or "heterocyclyl group" refers to a "cyclyl group" containing a heteroatom. The heterocyclyl, "heterocyclyl group", "heterocyclylalkyl", "heterocyclyl group" or "heterocyclyl group" appearing herein have the same definition as for heterocyclyl.

[0293] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom. Heterospirocycle, "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" appearing herein have the same definition as spirocycle.

[0294] "Heterobridged ring," "heterobridged cyclyl," "bridged heterocyclyl," or "heterobridged cyclyl" refers to a "bridged ring" containing a heteroatom. As used herein, heterobridged ring, "heterobridged cyclyl," "bridged heterocyclyl," or "heterobridged cyclyl" have the same definition as for bridged ring. "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes instances where the event or circumstance occurs and where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0295] When the listed linking groups do not specify their connection direction, their connection direction includes the direction of connection from left to right and from right to left. For example, when ALB and L are selected from -MW-, AMWB and AWMB are included. For example, AC(O)NR L1 -B, including AC(O)NR L1 -B and A-NR L1 C(O)-B.

[0296] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0297] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0298] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0299] "Excipient" refers to a substance that is not itself a therapeutic agent and is used as a diluent, adjuvant, binder, and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0300] "Isomers" include "stereoisomers" and "tautomers". "Stereoisomers" refer to isomers produced by the same order of connection of atoms or atomic groups in a molecule, but different arrangements in space. Stereoisomers include cis-trans isomers and optical isomers. "Tautomers" refer to compounds that can be converted into each other through a reversible chemical reaction called tautomerization, usually caused by the concomitant migration of hydrogen atoms and π bonds (double or triple bonds). For example, the following pairs of compounds: aldehyde / keto-enol, imine-enamine. DETAILED DESCRIPTION

[0301] The present invention will be described in detail below through examples. Where specific conditions are not specified in the examples, the experimental methods are carried out according to conventional conditions. The examples are provided to better illustrate the present invention, but it should not be understood that the present invention is limited to the examples. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention are still within the scope of protection of the present invention.

[0302] Test Method

[0303] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0304] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0305] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C 18 100 × 4.6 mm, 3.5 μM);

[0306] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0307] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0308] Example 1

[0309] Step 1: Ethyl 2-(diethoxyphosphoryl)acetate (2.31 g, 10.32 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of sodium hydride (0.37 g, 15.33 mmol). The mixture was then purged with nitrogen three times and allowed to react at 0°C for half an hour. 1A (1.5 g, 7.37 mmol) was then dissolved in tetrahydrofuran and slowly added to the reaction mixture. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate three times. The combined organic phases were concentrated and purified by normal phase purification (petroleum ether:ethyl acetate = 20:1) to afford product 1B (1.6 g, 79%).

[0310] LC-MS (ESI): m / z = 274.2 [M+H] + .

[0311] Step 2: 1B (0.5 g, 1.83 mmol) was dissolved in ethanol (8 mL) and 1 M dilute hydrochloric acid solution (2 mL). Palladium on carbon (0.19 g, 1.83 mmol) was then added. The mixture was replaced with hydrogen three times and hydrogenated overnight at room temperature. After completion of the reaction, the reaction solution was filtered through celite, rinsed repeatedly with dichloromethane and methanol, and the filtrate was dried and redissolved in 10 mL of dichloromethane. Excess potassium carbonate was added until the solution pH was weakly alkaline. The mixture was filtered and the filtrate was concentrated to dryness to obtain the free product 1C (0.3 g, 88%).

[0312] LC-MS (ESI): m / z = 186.1 [M+H] + .

[0313] Step 3: 1D (0.5 g, 1.31 mmol, synthesized according to the literature Journal of Medicinal Chemistry, 2021, vol. 64, # 21, p. 15549-15581), 1C (0.32 g, 1.73 mmol), cesium carbonate (0.85 g, 2.62 mmol), Ruphos Pd G3 (0.11 g, 0.13 mmol) were dissolved in 1,4-dioxane (15 mL), replaced with nitrogen three times, and then reacted at 90 degrees for 6 hours. After the reaction was completed, it was concentrated to dryness and purified by normal phase (petroleum ether: ethyl acetate = 2: 1) to give the product 1E (35 mg, 5.5%).

[0314] LC-MS (ESI): m / z = 487.1 [M+H] + .

[0315] Step 4: 1E (0.035 g, 0.072 mmol) was dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide (0.0069 g, 0.29 mmol) was then added and the mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to a weakly acidic state. A small amount of water was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated and purified by preparative HPLC to afford compound 1 trifluoroacetate (4 mg, 12%).

[0316] LC-MS (ESI): m / z = 459.3 [M+H] + .

[0317] 1 H NMR(400MHz,Chloroform-d)δ7.96(s,1H),7.80(d,1H),5.61(s,2H),4.18(s,3H),3.29-3.10(m,11 H),2.88-2.73(m,3H),2.36-2.20(m,3H),1.90-1.78(m,3H),1.56-1.41(m,3H),0.90-0.74(m,3H).

[0318] Example 2:

[0319] Step 1: Dissolve compound 2A (1.00 g, 4.49 mmol, HCl salt) in anhydrous tetrahydrofuran (20 mL). Add triethylamine (682 mg, 6.74 mmol) and methanesulfonyl chloride (617 mg, 5.39 mmol) sequentially with stirring. React at room temperature for 4 hours. After TLC analysis, the starting material disappears. The reaction solution is concentrated to approximately 5 mL and added dropwise to 15 mL of ice water. Extraction is performed twice with 20 mL of ethyl acetate. The organic phases are combined and concentrated. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford compound 2B (680 mg, 57%).

[0320] 1 H NMR (400MHz, CDCl3) δ4.78 (s, 1H), 4.15-4.03 (m, 4H), 2.91-2.87 (m, 6H), 1.46 (s, 9H).

[0321] Step 2: Dissolve compound 2B (300 mg, 1.13 mmol) in 4 mL of a mixture of dichloromethane and trifluoroacetic acid (3:1) and react at room temperature for 2 hours. After TLC analysis, the reaction mixture was concentrated to afford crude product 2C (220 mg, TFA salt), which was used directly in the next step.

[0322] LC-MS (ESI): m / z = 165.2 [M+H] + .

[0323] Step 3: Compound 2D (200 mg, 0.36 mmol, prepared according to the method of patent WO2017223016A1) and crude product 2C (220 mg) were dissolved in 10 mL of tetrahydrofuran. DIPEA (140 mg, 1.08 mmol) was added and reacted at room temperature for 2 hours. After the disappearance of the starting material by LCMS monitoring, the reaction solution was concentrated to 2 mL and added dropwise to 15 mL of ice water. The extracted solution was extracted twice with 20 mL of ethyl acetate. The organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain compound 2E (120 mg, 57%).

[0324] LC-MS (ESI): m / z = 579.3 [M+H] + .

[0325] Step 4: Dissolve compound 2E (120 mg, 0.21 mmol) in 5 mL of a mixture of tetrahydrofuran and water (THF:H2O = 4:1). Add lithium hydroxide monohydrate (28 mg, 0.63 mmol) and react at room temperature for 16 hours. After the disappearance of the starting material as monitored by LCMS, filter the mixture, concentrate the filtrate, and separate it on a C18 reverse-phase column to obtain the trifluoroacetic acid salt of target compound 2 (21 mg, 17%).

[0326] LC-MS (ESI): m / z = 537.5 [M+H] + .

[0327] 1 H NMR (400MHz, DMSO-d6) δ7.87-7.82(m,1H),7.52-7.46(m,1H),5.68(s,2H),4.78(s,1H),4.10(s,3H),4.02-3.84(m ,4H),3.05-2.80(m,7H),2.69-2.60(m,1H),2.41(s,3H),2.08-2.07(m,1H),1.91-1.73(m,3H),1.68-1.44(m,4H).

[0328] Example 3

[0329] Step 1: Compound 2D (204 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), and 3-methyleneimidine (38 mg, 0.55 mmol) and excess pyridine were added. The reaction was carried out at room temperature for 4 h. After the complete disappearance of the starting material, the mixture was concentrated. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to obtain the target compound 3A (164 mg, yield: 91.6%).

[0330] LC-MS (ESI): m / z = 484.3 [M+1] + .

[0331] Step 2: Compound 3A (163 mg, 0.34 mmol) was dissolved in tetrahydrofuran (10 mL), and 1 M lithium hydroxide aqueous solution (2 mL) was added. 0 The mixture was reacted at 40°C for 48 h. Excess citric acid was added until the mixture became weakly acidic, and the mixture was concentrated. The resulting residue was separated by silica gel column chromatography (dichloromethane:anhydrous methanol = 1:0 to 10:1) to obtain compound 3 (48 mg, yield: 33.1%).

[0332] LC-MS (ESI): m / z = 442.3 [M+1] + .

[0333] 1 H NMR(400MHz,DMSO-d6)δ7.83(d,1H),7.46(d,1H),5.74(s,2H),5.66(s,2H),4.81-4.73(m,1H),4.4 8-4.38(m,4H),4.07(s,3H),2.40(s,3H),2.04-1.96(m,1H),1.89-1.71(m,4H),1.68-1.43(m,4H).

[0334] Example 4

[0335] Step 1: Compound 4A (500 mg, 2.73 mmol) was added to a reaction flask and dissolved in DMF (10 ml). NaH (160 mg, 4.10 mmol) was added at 0°C and maintained at this temperature for 30 min. Then, iodomethane (775 mg, 5.46 mmol) was added and the mixture was allowed to warm to room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was diluted with water (50 ml) and extracted twice with ethyl acetate (50 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 4B (475 mg, 88.29% yield).

[0336] 1H NMR (400MHz, DMSO-d6) δ4.84-4.80(m,2H),4.50-4.24(m,1H),2.90-2.80(m,2H),2.78-2.70(m,2H),1.39(s,9H).

[0337] Step 2: Compound 4B (470 mg, 2.38 mmol) was added to a reaction flask and dissolved in dichloromethane (10 ml). Trifluoroacetic acid (0.5 ml) was then added and allowed to react at room temperature for 1 h. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure to afford crude compound 4C (250 mg, TFA salt), which was used directly in the next step.

[0338] LC-MS (ESI): m / z = 98.1 [M+H] + .

[0339] Step 3: Compound 2D (200 mg, 0.36 mmol, synthesized according to the method of patent WO2017223016A1) and crude compound 4C (250 mg) were added to a reaction flask and dissolved in dichloromethane (10 ml). DIPEA (0.62 ml, 3.6 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 4D (120 mg, 64.93% yield).

[0340] LC-MS (ESI): m / z = 512.3 [M+H] + .

[0341] Step 4: Compound 4D (120 mg, 0.23 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 3:1:1 (15 ml). Anhydrous lithium hydroxide (22 mg, 0.92 mmol) was then added and the mixture was allowed to react at 50°C for 16 hours. After completion of the reaction, monitored by TLC, the mixture was concentrated under reduced pressure, and the resulting residue was separated by a C18 reverse-phase column to afford the trifluoroacetic acid salt of compound 4 (35 mg, 32.40% yield).

[0342] LC-MS (ESI): m / z = 470.4 [M+H] + .

[0343] 1H NMR(400MHz,DMSO-d6)δ7.87-7.82(m,1H),7.52-7.47(m,1H),5.64(s,2H),4.79(s,3H),4.10(s ,3H),2.88-2.59(m,9H),2.41(s,3H),2.06-1.98(m,1H),1.91-1.73(m,3H),1.68-1.45(m,4H).

[0344] Example 5

[0345] Step 1: Lithium aluminum hydride (815 mg, 21.48 mmol) was dissolved in tetrahydrofuran (10 ml), followed by dissolving compound 5A (1.0 g, 10.74 mmol) in tetrahydrofuran (10 ml). The mixture was added to the above system at room temperature and allowed to react at 70°C for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was cooled to room temperature, quenched with water (1 ml), stirred at room temperature for 30 minutes, filtered, and the filtrate was collected and concentrated under reduced pressure to afford compound 5B (0.9 g, 86.54% yield).

[0346] LC-MS (ESI): m / z = 98.2 [M+H] + .

[0347] Step 2: Compound 5B (900 mg, 9.26 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (10 ml). Di-tert-butyl dicarbonate (2.0 g, 9.26 mmol) and triethylamine (2.5 ml, 18.52 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to afford compound 5C (1.36 g, 95.10% yield).

[0348] 1 H NMR (400MHz, DMSO-d6) δ6.86(s,1H),4.75-4.69(m,2H),3.03-2.94(m,2H),2.70-2.57(m,2H),2.39-2.26(m,3H),1.37(s,9H).

[0349] Using compound 5C as starting material, referring to steps 1 to 4 of Example 4, trifluoroacetic acid salt of compound 5 (40 mg, yield: 34.48%) was obtained.

[0350] LC-MS (ESI): m / z = 484.4 [M+H] + .

[0351] 1H NMR(400MHz,DMSO-d6)δ7.87-7.82(m,1H),7.53-7.47(m,1H),5.63(s,2H),4.82-4.52(m,3H),4.10(s,3H),3.36-3.14(m,2H), 2.82-2.72(m,3H),2.70-2.57(m,2H),2.42(s,3H),2.39-2.28(m,2H),2.22-2.10(m,1H),2.06-1.98(m,1H),1.93-1.42(m,8H).

[0352] Example 6:

[0353] Step 1: Compound 6A (5.00 g, 28.6 mmol) and 70 mL of glacial acetic acid were placed in a 200 mL autoclave. Platinum dioxide (1.62 g, 7.15 mmol) was added and the mixture was filled with 2 MPa of hydrogen. The mixture was heated to 70°C and stirred for 48 hours. The mixture was filtered and concentrated. The pH was neutralized with sodium bicarbonate solution to approximately 8. The crude product was purified by column chromatography (dichloromethane:anhydrous methanol = 70 / 10) to obtain the target compound 6B (2.2 g, 42%).

[0354] LC-MS (ESI): m / z = 184.1 [M+H] + .

[0355] Step 2: Intermediate 6C (1 g, 2.72 mmol) (synthesized by referring to patent WO2017223016A1), intermediate 6B (1 g, 5.44 mmol), BrettPhos-G3-Pd (270 mg, 0.25 mmol) and cesium carbonate (1.77 g, 5.44 mmol) were added to 1,4-dioxane (30 mL), and nitrogen was replaced three times. The mixture was heated to 95 ° C for 12 h, cooled to room temperature, filtered, concentrated, and column chromatography (PE / EA = 2 / 1) was performed to obtain intermediate 6D (700 mg, 55%).

[0356] LC-MS (ESI): m / z = 470.3 [M+H] + .

[0357] Step 3: Intermediate 6D (0.7 g, 1.49 mmol) was dissolved in anhydrous methanol (20 mL), followed by the addition of pyridine p-toluenesulfonate (750 mg, 2.98 mmol). After the addition was complete, the reaction was stirred at 65°C for 4 h, concentrated, diluted with water (40 mL), and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 80) to afford Intermediate 6E (400 mg, 70%).

[0358] LC-MS (ESI): m / z = 386.2 [M+H] + .

[0359] Step 4: Intermediate 6E (0.4 g, 1.04 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of pyridine (410 mg, 5.18 mmol) and p-nitrophenyl chloroformate (630 mg, 3.13 mmol). After the addition was complete, the reaction was stirred at room temperature for 2 h, diluted with water (40 mL), and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 60) to afford Intermediate 6F (500 mg, 87% yield).

[0360] LC-MS (ESI): m / z = 551.2 [M+H] + .

[0361] Step 5: Compound 6F (500 mg, 0.91 mmol) and methyl-n-propylamine (200 mg, 0.73 mmol) were added to a reaction flask and dissolved in tetrahydrofuran (20 ml). DIPEA (750 mg, 2.71 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 70) to afford compound 6G (400 mg, 91% yield).

[0362] Step 6: Compound 6G (400 mg) was further chirally resolved to obtain compounds 6G-P1 (150 mg) and 6G-P2 (150 mg).

[0363] Analytical methods: Instrument: SHIMADZU LC-30AD, Column: Chiral AD Column; Mobile phase: A: CO2, B: 0.05% DEA in MeOH; Gradient: 5-10% B in A; Flow rate: 3 mL / min; Column temperature: 35°C; Wavelength: 220 nm.

[0364] Preparation: Instrument: Waters 150Prep-SFC, Column: Chiral AD Column; Mobile Phase: A: CO2, B: 0.1% NH3·H2O in ETOH; Gradient: 12% B gradient elution, Flow rate: 80 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 10.5 min. Sample preparation: Sample concentration: 10 mg / mL, ethanol solution injection: 1.5 mL per injection. After separation, the fraction was dried on a rotary evaporator at 35°C to yield compounds 6G-P1 (70 mg, retention time 1.558 min) and 6G-P2 (80 mg, retention time 1.799 min).

[0365] Step 7: Compound 6G-P1 (150 mg, 0.31 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (15 ml). Anhydrous lithium hydroxide (52 mg, 1.24 mmol) was then added and allowed to react at 25°C for 16 hours. After completion of the reaction, the pH was adjusted to approximately 7 with 1M HCl and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:anhydrous methanol = 10:1) to afford compound 6-1 (50 mg, 34% yield).

[0366] LC-MS (ESI): m / z = 471.4 [M+H] + .

[0367] 1 H NMR(400MHz,DMSO-d6)δ7.74(d,1H),7.30(d,1H),5.64-5.67(m,2H),4.08(s,3H) ,3.82-3.87(m,1H),3.60-3.64(m,1H),3.15-3.17(m,1H),3.04-3.07(m,1H),2.9 5-3.00(m,1H),2.74-2.80(m,3H),2.44(s,3H),2.37-2.44(m,1H),2.16-2.19(m, 1H),1.88-1.93(m,1H),1.72-1.80(m,2H),1.33-1.64(m,7H),0.65-0.82(m,3H).

[0368] Compound 6G-P2 (150 mg, 0.31 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (15 ml). Anhydrous lithium hydroxide (52 mg, 1.24 mmol) was then added and allowed to react at 25°C for 16 hours. After completion of the reaction, as monitored by TLC, the pH was adjusted to approximately 7 with 1M HCl and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:anhydrous methanol = 10:1) to isolate compound 6-2 (40 mg, 27% yield).

[0369] LC-MS (ESI): m / z = 471.4 [M+H] + .

[0370] 1 H NMR(400MHz,DMSO-d6)δ7.74(d,1H),7.30(d,1H),5.64-5.67(m,2H),4.08(s,3H) ,3.82-3.87(m,1H),3.60-3.64(m,1H),3.15-3.17(m,1H),3.04-3.07(m,1H),2.9 5-3.00(m,1H),2.74-2.80(m,3H),2.44(s,3H),2.37-2.44(m,1H),2.16-2.19(m, 1H),1.88-1.93(m,1H),1.72-1.80(m,2H),1.33-1.64(m,7H),0.65-0.82(m,3H).

[0371] Example 7

[0372] Step 1: Ethyltriphenylphosphonium bromide (25 g, 67.48 mmol) was added to a reaction flask, dissolved in tetrahydrofuran (300 ml), cooled to -45°C, and then KHMDS (70 ml, 1 mol / L in THF) was added dropwise. The reaction was maintained at this temperature for 30 min. Compound 7A (10 g, 53.99 mmol) was then dissolved in THF (100 ml) and added dropwise to the reaction at -45°C. The temperature was then slowly warmed to room temperature and allowed to react for 16 hours. After completion of the reaction, as monitored by TLC, saturated ammonium chloride solution (200 ml) was added to quench the reaction. The mixture was then extracted twice with ethyl acetate (150 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 7B (5.1 g, 47.89% yield).

[0373] 1H NMR(400MHz,DMSO-d6)δ7.24-7.14(m,1H),5.19-5.09(m,1H),3.97-3.84(m ,1H),2.88-2.72(m,2H),2.57-2.40(m,2H),1.47-1.42(m,3H),1.37(s,9H).

[0374] Using compound 7B as starting material, referring to steps 1 to 4 of Example 4, trifluoroacetic acid salt of compound 7 (53 mg, yield: 40.77%) was obtained.

[0375] 1 H NMR(400MHz,DMSO-d6)δ7.89-7.82(m,1H),7.56-7.50(m,1H),5.67-5.58(m,3H),5.20-5.11(m,1H),4.82-4 .76(m,1H),4.10(s,3H),2.76(s,3H),2.72-2.55(m,4H),2.43(s,3H),2.06-1.74(m,4H),1.71-1.35(m,8H).

[0376] LC-MS (ESI): m / z = 484.4 [M+H] + .

[0377] Example 8:

[0378] Step 1: Compound 6F (300 mg, 0.54 mmol) and intermediate 4C (100 mg, 1.03 mmol) were added to a reaction flask and dissolved in tetrahydrofuran (20 ml). DIPEA (140 mg, 1.62 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, monitored by TLC, the product was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 70) to afford compound 8A (300 mg, 91% yield).

[0379] LC-MS (ESI): m / z = 509.3 [M+H] + .

[0380] Step 2: Compound 8A (300 mg, 0.59 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (10 ml). Anhydrous lithium hydroxide (120 mg, 2.96 mmol) was then added and allowed to react at 25°C for 16 hours. After completion of the reaction, the pH was adjusted to approximately 7 with 1M HCl and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:anhydrous methanol = 10:1) to isolate compound 8B (230 mg, 79% yield).

[0381] LC-MS (ESI): m / z = 495.3 [M+H] + .

[0382] Step 3: Compound 8B (400 mg) was further subjected to chiral separation to obtain compounds 8-1 (100 mg) and 8-2 (100 mg).

[0383] Analytical methods: Instrument: SHIMADZU LC-30AD, Column: Chiral AD Column; Mobile phase: A: CO2, B: 0.05% DEA in MeOH; Gradient: 5-10% B in A; Flow rate: 3 mL / min; Column temperature: 35°C; Wavelength: 220 nm.

[0384] Preparation: Instrument: SFC Prep 150AP, Column: Daicel IG (19 mm × 250 mm); Mobile Phase: A: CO2, B: 0.05% NH3·H2O in ETOH; Gradient: 12% B gradient elution, Flow rate: 80 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 20 min. Sample Preparation: Sample concentration: 10 mg / mL. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare a sample solution. After separation, the fraction was dried on a rotary evaporator at 35°C to yield compounds 8-1 (100 mg, retention time 10.0 min) and 8-2 (100 mg, retention time 16.7 min).

[0385] 8-1: (retention time 10.0 min), 1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),7.75(d,1H),7.31(d,1H),5.71-5.63(m ,2H),4.79(s,2H),4.43-4.39(m,1H),4.08(s,3H),3.87-3.83(m,1H),3.66-3. 60(m,1H),2.99-2.92(m,1H),2.87-3.58(m,7H),2.43(s,3H),2.41-2.32(m,1H ),2.24-2.21(m,1H),1.92-1.87(m,1H),1.80-1.71(m,2H),1.63-1.51(m,5H).

[0386] 8-2: (retention time 16.7min), 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),7.75(d,1H),7.31(d,1H),5.71-5.63(m ,2H),4.79(s,2H),4.43-4.39(m,1H),4.08(s,3H),3.87-3.83(m,1H),3.66-3. 60(m,1H),2.99-2.92(m,1H),2.87-3.58(m,7H),2.43(s,3H),2.41-2.32(m,1H ),2.24-2.21(m,1H),1.92-1.87(m,1H),1.80-1.71(m,2H),1.63-1.51(m,5H).

[0387] Example 9:

[0388] Using compound 6F as starting material, referring to the first to third steps of Example 8, compounds 9-1 (25 mg) and 9-2 (22 mg) were obtained.

[0389] Analytical methods: Instrument: SHIMADZU LC-30AD, Column: Chiral AD Column; Mobile phase: A: CO2, B: 0.05% DEA in MeOH; Gradient: 5-10% B in A; Flow rate: 3 mL / min; Column temperature: 35°C; Wavelength: 220 nm.

[0390] Preparation: Instrument: SFC Prep 150AP, Column: Daicel IG (19 mm × 250 mm); Mobile Phase: A: CO2, B: 0.05% NH3·H2O in ETOH; Gradient: 12% B; Flow Rate: 80 mL / min; Column Temperature: 25°C; Wavelength: 220 nm; Cycle Time: 25 min. Sample Preparation: Sample concentration: 10 mg / mL. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare a sample solution. After separation, the fraction was dried on a rotary evaporator at 35°C to yield compounds 9-1 (100 mg, retention time 12.0 min) and 9-2 (100 mg, retention time 19.6 min).

[0391] 9-1: (retention time 12.0 min) 1 H NMR(400MHz,DMSO-d6)δ11.68(s,1H),7.75(d,1H),7.31(d,1H),5.70-5.63(m,2H),4.74- 4.59(m,2H),4.08(s,3H),3.87-3.83(m,1H),3.66-3.60(m,1H),3.33-3.29(m,1H),3.25- 3.19(m,1H),2.99-2.93(m,1H),2.80-2.65(m,4H),2.53-2.50(m,1H),2.44(s,3H),2.44- 2.32(m,3H),2.26-2.14(m,2H),1.94-1.87(m,1H),1.80-1.71(m,2H),1.63-1.51(m,5H).

[0392] 9-2: (retention time 19.6 min) 1 H NMR(400MHz,DMSO-d6)δ11.68(s,1H),7.75(d,1H),7.31(d,1H),5.70-5.63(m,2H),4.74- 4.59(m,2H),4.08(s,3H),3.87-3.83(m,1H),3.66-3.60(m,1H),3.33-3.29(m,1H),3.25- 3.19(m,1H),2.99-2.93(m,1H),2.80-2.65(m,4H),2.53-2.50(m,1H),2.44(s,3H),2.44- 2.32(m,3H),2.26-2.14(m,2H),1.94-1.87(m,1H),1.80-1.71(m,2H),1.63-1.51(m,5H).

[0393] Example 10:

[0394] Step 1: Dissolve compound 10A (200 mg, 0.52 mmol, prepared according to the method of patent WO2017223016A1) in anhydrous tetrahydrofuran (8 mL). Add 60% sodium hydride (31 mg, 0.77 mmol) under ice-cooling. Stir for 10 minutes, then add 2,4-dibromothiazole (150 mg, 0.62 mmol). React at room temperature for 1 hour. After completion, the reaction solution was slowly added dropwise with 0.5 M aqueous hydrochloric acid (20 mL) to quench the reaction. Extract with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to obtain 10B (145 mg, 51%).

[0395] LC-MS (ESI): m / z = 550.1 [M+H] + .

[0396] Step 2: Dissolve 10B (145 mg, 0.27 mmol), cyclopropylacetylene (52 mg, 0.79 mmol), bis(triphenylphosphine)palladium dichloride (19 mg, 0.027 mmol), cuprous iodide (10 mg, 0.05 mmol), and triethylamine (80 mg, 0.79 mmol) in anhydrous tetrahydrofuran (8 mL), purge with nitrogen, and react at 40°C overnight. After the reaction is complete, cool to room temperature, add 20 mL of water, and extract with ethyl acetate (15 mL x 3). The combined organic layers are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford 10C (85 mg, 60%).

[0397] LC-MS (ESI): m / z = 536.3 [M+H] + .

[0398] Step 3: Dissolve 10C (85 mg, 0.16 mmol) in 5 mL of a mixture of tetrahydrofuran and water (THF:H₂O (v / v) = 4:1) and add lithium hydroxide monohydrate (20 mg, 0.48 mmol). Allow to react overnight at room temperature. After the reaction is complete, filter and concentrate the filtrate. The residue is purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to yield compound 10 (15 mg, 19%).

[0399] LC-MS (ESI): m / z = 494.1 [M+H] + .

[0400] 1 H NMR (400MHz, CDCl3) δ8.04-8.01(m,1H),7.54-7.51(m,1H),6.76(s,1H),6.03-5.93(m,2H),4.78(s,1H),4.18(s,3H),2.90 -2.85(m,1H),2.62(s,3H),2.13-1.91(m,4H),1.80-1.64(m,4H),1.43-1.35(m,1H),0.91-0.83(m,2H),0.81-0.74(m,2H).

[0401] Example 11:

[0402] Step 1: Compound 11A (1.0 g, 10.19 mmol) was added to 20 ml of tetrahydrofuran, followed by the addition of pyridine (4030 mg, 50.95 mmol) and phenylmethyl p-nitrochloroformate (6160 mg, 30.57 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=5 / 1) to obtain compound 11B (870 mg, yield: 32%).

[0403] LC-MS (ESI): m / z = 264.1 [M+H] + .

[0404] Step 2: Compound 11C (220 mg, 0.61 mmol, prepared according to the method of patent WO2017223016A1) and ammonium acetate (470 mg, 6.1 mmol) were added to a reaction flask, followed by the addition of anhydrous methanol (20 ml). After reacting at room temperature for 1 hour, sodium cyanoborohydride (77 mg, 1.22 mmol) was added and stirred at room temperature for 16 hours. After completion of the reaction monitored by TLC, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOH=10 / 1) to obtain compound 11D (45 mg, yield: 20%).

[0405] LC-MS (ESI): m / z = 360.2 [M+H] + .

[0406] Step 3: Compound 11D (45 mg, 0.13 mmol) and compound 11B (51 mg, 0.20 mmol) were added to a reaction flask and dissolved in tetrahydrofuran (20 ml). DIPEA (50 mg, 0.39 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 70) to afford compound 11E (25 mg, 41% yield).

[0407] LC-MS (ESI): m / z = 484.2 [M+H] + .

[0408] Step 4: Compound 11E (25 mg, 0.052 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (10 ml). Lithium hydroxide monohydrate (11 mg, 0.26 mmol) was then added and allowed to react at 25°C for 16 hours. After completion of the reaction, the pH was adjusted to approximately 7 with 1M HCl and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:anhydrous methanol = 10:1) to isolate compound 11 (15 mg, 62% yield).

[0409] LC-MS (ESI): m / z = 470.3 [M+H] + .

[0410] 1 H NMR(400MHz,CD3OD)δ7.81(d,1H),7.45(d,1H),4.80-4.83(m,1H),4.71-4.73(m,4H),4.15(s,3H),4.05-4.06(m,2H),2.61-2.75(m, 3H),2.54-2.57(m,1H),2.53(s,3H),2.37-2.43(m,2H),2.07-2.11(m,1H),1.87-1.93(m,3H),1.70-1.77(m,1H),1.54-1.67(m,3H).

[0411] Example 12:

[0412] Step 1: Potassium tert-butoxide (5.0 g, 44.56 mmol) was added to a three-necked flask and dissolved in DMF (50 ml). The atmosphere was replaced with nitrogen three times and cooled to -45°C. A solution of 12A (5.0 g, 27.00 mmol) in DMF (25 ml) and difluoromethyl (2-pyridyl) sulfone (4.35 g, 22.95 mmol) in DMF (25 ml) were slowly added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and allowed to react for 16 hours. After TLC monitoring, saturated ammonium chloride solution (50 ml) and 3M aqueous hydrochloric acid (15 ml) were added to the reaction solution and stirred at room temperature for 1 hour. The solution was then diluted with water (100 ml) and extracted twice with ethyl acetate (100 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound 12B (360 mg, yield: 6.08%).

[0413] 1 H NMR (400MHz, DMSO-d6) δ7.40-7.30(m,1H),4.13-4.00(m,1H),2.95-2.84(m,2H),2.65-2.54(m,2H),1.38(s,9H).

[0414] Using compound 12B as starting material, referring to steps 1 to 4 of Example 4, trifluoroacetic acid salt of compound 12 (76 mg, yield: 55.07%) was obtained.

[0415] 1 H NMR (400MHz, DMSO-d6) δ7.87-7.82(m,1H),7.52-7.47(m,1H),5.65(s,2H),4.82-4.75(m,1H),4.70-4.30(m ,1H),4.10(s,3H),2.93-2.69(m,7H),2.67-2.60(m,1H),2.41(s,3H),2.06-1.74(m,4H),1.68-1.45(m,4H).

[0416] LC-MS (ESI): m / z = 506.6 [M+H] + .

[0417] Example 13

[0418] Using compound 13A as starting material, referring to steps 1 to 5 of Example 12, trifluoroacetic acid salt of compound 13 (85 mg, yield: 81.73%) was obtained.

[0419] 1H NMR (400MHz, DMSO-d6) δ7.87-7.82(m,1H),7.52-7.46(m,1H),5.71-5.52(m,2H),4.81-4.75(m,1H),4.10(s,3H ),3.39-3.16(m,2H),2.83-2.56(m,6H),2.42(s,3H),2.39-2.32(m,1H),2.23-1.97(m,2H),1.92-1.40(m,8H).

[0420] LC-MS (ESI): m / z = 520.6 [M+H] + .

[0421] Example 14:

[0422] Step 1: Dissolve 14A (1.3 g, 10 mmol) in dichloromethane (20 ml) at room temperature. Add triethylamine (3.03 g, 30 mmol) and stir until uniform. Then add di-tert-butyl dicarbonate (2.18 g, 10 mmol) and continue the reaction for 16 hours. TLC monitoring confirms the completion of the reaction and the reaction is stopped. EA (30 mL) is added to the reaction solution. The organic phase is washed with water (30 mL × 3) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is isolated and purified by column chromatography (PE:EA = 10:1) to obtain compound 14B (640 mg, 27.73%).

[0423] LC-MS (ESI): m / z = 230.1 [M+H] + .

[0424] Step 2: 14B (640 mg, 2.79 mmol) was dissolved in dry DMF (5 mL) at room temperature. NaH (134 mg, 3.35 mmol) was added under ice-cooling and stirred for 15 minutes. Methyl iodide (439 mg, 3.07 mmol) was then added and allowed to react at room temperature for 1 hour. The reaction was stopped by TLC monitoring of the disappearance of the starting material. Ethyl acetate (15 mL) was added to the reaction solution, and the organic phase was washed with water (20 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by column chromatography (PE:EA = 10:1) to obtain compound 14C (320 mg, 47.12%).

[0425] LC-MS (ESI): m / z = 244.1 [M+H] + .

[0426] Step 3: Dissolve 14C (320 mg, 1.32 mmol) in dichloromethane (5 mL) at room temperature. Add a solution of hydrochloric acid in dioxane (1.32 mL, 5.28 mmol, 4 M). Continue the reaction for 1 hour. Stop the reaction after the disappearance of the starting material as monitored by TLC. Concentrate the reaction mixture to yield compound 14D (180 mg, 95.60%).

[0427] LC-MS (ESI): m / z = 144.1 [M+H] + .

[0428] Step 4: At room temperature, 14E (240 mg, 0.54 mmol) (synthesized according to patent WO2017223016A1) was dissolved in dry dichloromethane (20 mL). Triethylamine (209 mg, 1.62 mmol) was added and stirred. 14D (170 mg, 1.19 mmol) was added under ice-cooling and allowed to react at room temperature for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. Dichloromethane (20 mL) was added to the reaction solution, and the organic phase was washed with water (30 mL × 3) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by column chromatography (PE:EA = 2:1) to obtain compound 14F (230 mg, 94.99%).

[0429] LC-MS (ESI): m / z = 452.4 [M+H] + .

[0430] Step 5: 14F (230 mg, 0.51 mmol) was dissolved in dry tetrahydrofuran (10 mL) at room temperature, and bis(pinacolato)diboron (259 mg, 1.02 mmol), Pd(dppf)Cl2 (83 mg, 0.10 mmol), and potassium acetate (100 mg, 1.02 mmol) were added. The reaction was incubated at 80°C under a nitrogen atmosphere for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. The mixture was cooled to room temperature, and ethyl acetate (20 mL) was added. The organic phase was washed with water (20 mL × 3), then with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield compound 14G (180 mg, 84.84%) without further purification.

[0431] LC-MS (ESI): m / z = 418.5 [M+H] + .

[0432] Step 6: 14G (180 mg, 0.43 mmol) was dissolved in ethyl acetate (5 mL) at room temperature. Hydrogen peroxide (244 mg, 2.15 mmol, 30%) was added dropwise to the reaction mixture under ice-cooling. The reaction was allowed to react at room temperature for two hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. Ethyl acetate (10 mL) was added to the reaction mixture, and the organic phase was washed with water (20 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by column chromatography (PE:EA = 1:1) to obtain compound 14H (90 mg, 53.57%).

[0433] LC-MS (ESI): m / z = 390.3 [M+H] + .

[0434] Step 7: At room temperature, 14H (90 mg, 0.23 mmol) was dissolved in dry toluene (5 mL). 14I (86 mg, 0.46 mmol) (synthesized with reference to patent WO2017223016A1) and tri-n-butylphosphine (140 mg, 0.69 mmol) were added and stirred. Azodicarbonyl dipiperidine (174 mg, 0.69 mmol) was then added. The mixture was reacted at 50°C under a nitrogen atmosphere for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. After cooling to room temperature, ethyl acetate (15 mL) was added to the reaction solution. The organic phase was washed with water (20 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain compound 14J (100 mg, 77.59%).

[0435] LC-MS (ESI): m / z = 558.7 [M+H] + .

[0436] Step 8: Dissolve 14J (100 mg, 0.18 mmol) in tetrahydrofuran (3 mL) at room temperature, add water (3 mL), and stir thoroughly. Add lithium hydroxide (22 mg, 0.9 mmol) and react at room temperature for 16 hours. The reaction is stopped by TLC monitoring of the disappearance of the starting material. Ethyl acetate (10 mL) is added to the reaction solution, and the pH is adjusted to a weakly acidic state with dilute hydrochloric acid. The organic phase is separated and washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is isolated and purified by column chromatography (DCM:MeOH = 15:1) to afford compound 14 (35 mg, 37.86%).

[0437] LC-MS (ESI): m / z = 516.1 [M+H] + .

[0438] 1 H NMR(400MHz,DMSO-d6)δ7.85-7.83(d,1H),7.48-7.46(d,1H),5.69-5.64(d,2H),4.77(s,1H),4.18(s,1H),4.09(s,3H),4.00(s,1 H),3.54-3.44(d,2H),2.86-2.81(d,3H),2.68-2.59(m,1H),2.40(s,3H),2.03-1.99(m,1H),1.88-1.77(m,3H),1.66-1.45(m,4H).

[0439] Example 15

[0440] Step 1: 14E (1.5 g, 3.35 mmol) and N,N-diisopropylethylamine (1.73 g, 13.4 mmol) were added to the reaction mixture at room temperature, followed by 15C (1.1 g, hydrochloride, see ChemMedChem. 2012 Jul; 7(7): 1230-6). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 15F (0.85 g, 64%).

[0441] LC-MS (ESI): m / z = 398.0 [M+H] + .

[0442] Step 2: 15F (850 mg, 2.15 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydroxide (250 mg, 6.45 mmol, 60%) was added at 0°C. After reacting for 0.5 hour, iodomethane (920 mg, 6.45 mmol) was added and the mixture was allowed to react overnight at 40°C. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 15G (0.5 g, 1.22 mmol).

[0443] LC-MS (ESI): m / z = 410.0 [M+H] + .

[0444] Step 3: Dissolve 15G (0.5 g, 1.22 mmol), pinacol diboronate (0.46 g, 1.83 mmol), potassium acetate (0.30 g, 3.05 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (89 mg, 0.12 mmol) in 1,4-dioxane (10 mL) under nitrogen atmosphere at 80°C for 16 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate, washed, concentrated, and used directly in the next step.

[0445] LC-MS (ESI): m / z = 376.1 [M+H] + .

[0446] Step 4: The product from the previous step was dissolved in ethyl acetate (10 mL). Hydrogen peroxide solution (0.61 mL, 6 mmol, 30%) was added at 0°C and allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate, washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the target compound 15I (0.3 g, 72%).

[0447] LC-MS (ESI): m / z = 348.1 [M+H] + .

[0448] Step 5: Dissolve 14I (5 g, 26.85 mmol), tert-butyldiphenylsilyl chloride (8.12 g, 29.54 mmol), and imidazole (5.48 g, 80.55 mmol) in N,N-dimethylformamide (50 mL) and react at 60°C for 16 hours. After completion of the reaction, the reaction solution was extracted (ethyl acetate), washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the target compound 15K (10.3 g, 90%).

[0449] LC-MS (ESI): m / z = 425.3 [M+H] + .

[0450] Step 6: Dissolve 15K (10.3 g, 24.26 mmol) in methanol (40 mL), tetrahydrofuran (40 mL), and water (20 mL). Add lithium hydroxide monohydrate (3.05 g, 72.78 mmol) and allow to react at room temperature for 2 hours. After completion of the reaction, adjust the pH of the reaction mixture to 5-6, extract (ethyl acetate), wash, and concentrate to obtain the target compound 15L (9.2 g, 99%).

[0451] LC-MS (ESI): m / z = 383.3 [M+H] + .

[0452] Step 7: Dissolve 15L (9.2 g, 24.05 mmol) and N,N-dimethylformamide di-tert-butyl acetal (19.56 g, 96.2 mmol) in toluene (150 mL) and react at 110°C for 24 hours. After completion of the reaction, the reaction solution was extracted (ethyl acetate), washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the target compound 15M (4.1 g, 38%).

[0453] LC-MS(ESI):m / z=383.1[M+H-56] + .

[0454] Step 8: Dissolve 15M (4.1 g, 9.35 mmol) in tetrahydrofuran (40 mL), then add tetrabutylammonium fluoride (18.7 mL, 18.7 mmol, 1 M). Allow to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted (ethyl acetate), washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain the target compound 15N (2.2 g, impure).

[0455] Step 9: Dissolve 15I (0.1 g, 0.29 mmol), 15N (0.17 g, 0.87 mmol), and triphenylphosphine (0.15 g, 0.58 mmol) in 1,2-dichloroethane (5 mL). Add diisopropyl azodicarboxylate (0.12 g, 0.58 mmol) dropwise at 0°C. Then, heat to 80°C and react for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain the target compound 15O (30 mg, 19%).

[0456] LC-MS (ESI): m / z = 530.3 [M+1] + .

[0457] Step 10: Dissolve 15O (30 mg, 0.06 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL), and react at room temperature for 1 hour. After the reaction, the reaction solution was concentrated and the residue was purified to obtain the trifluoroacetic acid salt of the target compound 15 (2.09 mg, 7%).

[0458] LC-MS (ESI): m / z = 474.2 [M+1] + .

[0459] 1H NMR(400MHz, CDCl3)δ8.01(d,1H),7.63(d,1H),5.70(dd,2H),4.31(t,1H),4.19(s,3H),3.11(s,3H),2.90(m,1H),2.74(s,3H), 2.15-2.10(m,2H),2.07-2.00(m,4H),1.97-1.91(m,2H),1.80-1.78(m,3H),1.71-1.66(m,2H),1.49-1.46(m,1H),1.26(m,1H).

[0460] Example 16:

[0461] Step 1: Methyl-tert-butyl carbamate (1.3 g, 10 mmol) was dissolved in dry DMF (10 mL) at room temperature. NaH (440 mg, 11 mmol) was added under ice-cooling and stirred for 30 minutes. 16A (1.32 g, 10 mmol) was added and allowed to react at room temperature for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. Ethyl acetate (20 mL) was added to the reaction solution, and the organic phase was washed with water (20 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by column chromatography (PE:EA = 10:1) to obtain compound 16B (1.7 g, 94.90%).

[0462] LC-MS (ESI): m / z = 184.2 [M+H] + .

[0463] Step 2: Dissolve 16B (1.7 g, 9.29 mmol) in dichloromethane (10 mL) at room temperature. Add a solution of hydrochloric acid in dioxane (9.3 mL, 37.15 mmol, 4 M). Continue the reaction for 1 hour. Stop the reaction after the disappearance of the starting material as monitored by TLC. Concentrate the reaction mixture without purification to yield compound 16C (760 mg, 98.54%).

[0464] LC-MS (ESI): m / z = 84.2 [M+H] + .

[0465] Using compound 16C as starting material, referring to steps 4 to 8 of Example 14, compound 16 (25 mg, 24.83%) was obtained.

[0466] LC-MS (ESI): m / z = 456.1 [M+H] + .

[0467] 1H NMR (400MHz, CDCl3) δ7.99-7.96(d,1H),7.37-7.35(d,1H),5.76-5.73(d,2H),4.74(s,1H),4.16(s,3H),4.04-3.92 (d,2H),2.94-2.90(d,4H),2.58(s,3H),2.15-2.11(d,1H),2.01-1.89(m,3H),1.80-1.78(d,3H),1.74-1.64(m,4H).

[0468] Example 17

[0469] Step 1: Compound 17A (synthesized according to patent WO2019 / 126093) (4.68 g, 30 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (9.18 g, 90 mmol), DMAP (366 mg, 3 mmol) and tert-butyldiphenylsilyl chloride (9.1 g, 33 mmol) were added. The reaction was carried out at room temperature for 3 h. After the complete disappearance of the starting material, the mixture was concentrated and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate (v:v) = 20:1) to obtain the target compound 17B (10.9 g, yield: 92.3%).

[0470] Step 2: Compound 17B (10.9 g, 27.6 mmol) was dissolved in anhydrous toluene (100 mL), and trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (34.5 g, 138 mmol) was added. The mixture was reacted at 110°C overnight. The mixture was washed with saturated sodium thiosulfate and then saturated brine. The organic phase was dried and concentrated. The resulting residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 20:1) to obtain the target compound 17C (3.1 g, yield: 25.3%).

[0471] Step 3: Compound 17C (3.1 g, 7.0 mmol) was dissolved in tetrahydrofuran (20 ml), and an excess of tetrabutylammonium fluoride was added. The mixture was stirred at room temperature overnight. After the reaction, ethyl acetate (100 mL) was added, and the mixture was washed with water (100 mL × 4). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to obtain the title target compound 17D (1.1 g, 78.5%).

[0472] Step 4: At room temperature, 17D (1.1 g, 5.3 mmol) was dissolved in dry toluene (100 mL). 17E (1.8 g, 6 mmol) (synthesized according to patent WO2019 / 126093) and tri-n-butylphosphine (3.2 g, 15.9 mmol) were added and stirred. Azodicarbonyl dipiperidine (4.0 g, 15.9 mmol) was then added. The mixture was reacted at 50°C under a nitrogen atmosphere for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. After cooling to room temperature, ethyl acetate (100 mL) was added to the reaction solution. The organic phase was washed with water (100 mL × 3) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound 17F (1.1 g, 43.3%).

[0473] LC-MS (ESI): m / z = 493.2 [M+H] + .

[0474] Using compound 17F as the starting material, following steps 3, 4, 5, and 7 of Example 6, the trifluoroacetic acid salt of compound 17-1 (preparative HPLC elution time: 18.85 min, 9.3 mg) and the trifluoroacetic acid salt of compound 17-2 (HPLC elution time: 19.23 min, 16.5 mg) were obtained. HPLC preparation method: Instrument: Waters 2767 preparative liquid phase, column: Sunfire Prep C18 (19 mm × 250 mm), 5 μm; mobile phase: A: acetonitrile, B: water (containing 1 / 1000th TFA, v / v); gradient: mobile phase A increased from 10% to 60% over 20 minutes, gradient elution flow rate: 15 mL / min.

[0475] Compound 17-1 (preparative HPLC peak time: 18.85 min): LC-MS (ESI): m / z=518.8 [M+H] + .

[0476] Compound 17-2 (preparative HPLC peak time: 19.23 min): 1 H NMR(400MHz,DMSO-d6)δ7.85(d,1H),7.48(d,1H),5.70(s,2H),4.78(s,1H),4.21-4.01(m,6H),3.21- 3.16(m,1H),2.97-2.55(m,5H),2.41(s,3H),2.07-1.97(m,1H),1.91-1.72(m,3H),1.69-1.40(m,4H).

[0477] LC-MS (ESI): m / z = 518.8 [M+H] + .

[0478] Example 18

[0479] Step 1: Compound 7A (5.0 g, 27.0 mmol) and carbon tetrabromide (17.9 g, 54.0 mmol) were added to a reaction flask and mixed with toluene (200 ml). Triphenylphosphine (28.3 g, 108.0 mmol) was then added and reacted at 80°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove toluene. The residue was dissolved in ethyl acetate (200 ml) and washed twice with water (100 ml x 2). The organic phase was collected, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 18A (5.4 g, yield: 59.01%).

[0480] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.26(m,1H),4.01-3.90(m,1H),2.88-2.78(m,2H),2.56-2.51(m,2H),1.38(s,9H).

[0481] Step 2: Compound 18A (2.0 g, 5.90 mmol) was added to a reaction flask, dissolved in tetrahydrofuran (50 ml), and cooled to 0°C. NaH (0.35 g, 8.85 mmol) was then added and the reaction was maintained at this temperature for 30 min. Iodomethane (1.7 g, 11.80 mmol) was then added and the mixture was allowed to warm to room temperature for 2 hours. After completion of the reaction as monitored by TLC, saturated ammonium chloride solution (100 ml) was added to quench the reaction system. The mixture was then extracted twice with ethyl acetate (100 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 30:1) to afford compound 18B (2.02 g, 97.11% yield).

[0482] 1 H NMR (400MHz, DMSO-d6) δ4.39 (s, 1H), 2.86-2.71 (m, 7H), 1.40 (s, 9H).

[0483] Step 3: Cuprous iodide (10.8 g, 57.20 mmol) was added to a reaction flask and mixed with tetrahydrofuran (60 ml). Methyllithium solution (43 ml, 1.6 mol / L in ether) was added dropwise at 0°C. After the addition was complete, a solution of compound 18B (2.02 g, 5.72 mmol) in tetrahydrofuran (60 ml) was added. After the addition was complete, the mixture was warmed to room temperature and reacted for 16 hours. After completion of the reaction, saturated ammonium chloride solution (100 ml) was added to quench the reaction, followed by extraction with ethyl acetate twice (50 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound 18C (800 mg, yield: 62.02%).

[0484] 1 H NMR (400MHz, DMSO-d6) δ4.36(s,1H),2.77-2.64(m,7H),1.50(s,6H),1.39(s,9H).

[0485] Step 4: Compound 18C (300 mg, 1.33 mmol) was added to a reaction flask and dissolved in dichloromethane (6 ml). Trifluoroacetic acid (1 ml) was then added and allowed to react at room temperature for 2 hours. After completion of the reaction, monitored by TLC, the mixture was concentrated under reduced pressure to afford compound 18D (170 mg, TFA salt), which was directly used in the next step.

[0486] LC-MS (ESI): m / z = 126.2 [M+H] + .

[0487] Step 5: Crude compound 18D (170 mg) was added to a reaction flask and dissolved in dichloromethane (10 ml). DIPEA (0.6 ml, 3.60 mmol) and compound 2D (100 mg, 0.18 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 18E (90 mg, 92.78% yield).

[0488] LC-MS (ESI): m / z = 540.6 [M+H] + .

[0489] Step 6: Compound 18E (90 mg, 0.17 mmol) was added to a reaction flask and dissolved in THF:MeOH:H₂O = 1:1:1 (9 ml). Anhydrous lithium hydroxide (17 mg, 0.68 mmol) was then added and allowed to react at room temperature for 16 hours. After completion of the reaction, monitored by TLC, the mixture was concentrated under reduced pressure. The resulting residue was separated by a C₁₈ reverse-phase column to afford the trifluoroacetic acid salt of compound 18 (43 mg, 50.83% yield).

[0490] 1 H NMR (400MHz, DMSO-d6) δ7.89-7.81(m,1H),7.52-7.47(m,1H),5.64(s,2H),4.81-4.75(m,1H),4.09(s,3H),2.75(s ,3H),2.70-2.56(m,5H),2.44-2.31(m,4H),2.06-1.95(m,1H),1.91-1.73(m,3H),1.68-1.50(m,4H),1.45(s,6H).

[0491] LC-MS (ESI): m / z = 498.3 [M+H] + .

[0492] Example 19

[0493] Step 1: Compound 2D (200 mg, 0.36 mmol) and compound 19A (100 mg, 0.72 mmol, synthesized according to the method of patent EP585130A2) were added to a reaction flask and dissolved in dichloromethane (10 ml). DIPEA (0.20 ml, 1.2 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 19B (110 mg, 54.99% yield).

[0494] LC-MS (ESI): m / z = 554.6 [M+H] + .

[0495] Step 2: Compound 19B (110 mg, 0.20 mmol) was dissolved in a tetrahydrofuran / water mixture (8 mL, 3:1, v:v), followed by the addition of lithium hydroxide (35 mg, 0.80 mmol). The reaction mixture was incubated at 30°C for 16 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) and further isolated by a C18 reverse-phase column to afford the target compound 19 (32 mg, 31.48% yield).

[0496] LC-MS (ESI): m / z = 512.4 [M+H] + .

[0497] 1 H NMR (400MHz, CDCl3) δ7.97-7.94(m,1H),7.22-7.19(m,1H),5.76-5.74(m,2H),5. 35-5.21(m,1H),4.70(s,1H),4.62-4.47(m,1H),4.13(s,3H),3.23-3.16(m,1H),3 .06-2.98(m,1H),2.91-2.82(m,4H),2.49(s,3H),2.17-2.13(m,1H),1.98-1.92(m ,4H),1.80-1.74(m,3H),1.70-1.64(m,5H),1.58-1.56(m,2H),1.25-1.07(m,2H).

[0498] Example 20:

[0499] Step 1: Compound 14I (1500 mg, 8.05 mmol, prepared according to the method of patent WO2017223016A1) was added to 40 ml of dichloromethane, followed by the addition of triethylamine (1630 mg, 16.1 mmol) and methanesulfonyl chloride (1200 mg, 10.47 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction monitored by TLC, saturated sodium bicarbonate solution was added for dilution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 20B (1500 mg, yield: 70%).

[0500] Step 2: Compound 20B (1.5 g, 5.67 mmol) and sodium azide (1.11 g, 17.01 mmol) were added to a reaction flask, followed by the addition of DMF (30 ml). The mixture was heated to 110°C for 2 hours, cooled, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 20C (1.1 g, yield: 92%).

[0501] Step 3: Compound 20C (1.1 g, 5.21 mmol) and triphenylphosphine (2.73 g, 10.42 mmol) were added to a mixture of tetrahydrofuran (20 ml) and water (20 ml). The atmosphere was replaced with nitrogen and the mixture was allowed to react at room temperature for 10 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: DCM / MeOH = 100 / 15) to afford compound 20D (710 mg, 74% yield).

[0502] LC-MS (ESI): m / z = 186.1 [M+H] + .

[0503] Step 4: Compound 20D (400 mg, 2.16 mmol) and 6C (190 mg, 2.16 mmol, prepared according to the method of patent WO2017223016A1) were added to 1,4-dioxane (20 ml), followed by RuphosPdG3 (90 mg, 0.11 mmol) and cesium carbonate (1.41 g, 4.32 mmol). The mixture was purged with nitrogen and heated to 110°C for 10 hours. After completion of the reaction as monitored by TLC, the mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE / EA = 1 / 1) to afford compound 20F (500 mg, 49% yield).

[0504] LC-MS (ESI): m / z = 472.3 [M+H] + .

[0505] Step 5: Compound 20F (0.5 g, 1.06 mmol) was dissolved in anhydrous methanol (20 mL), followed by the addition of pyridine p-toluenesulfonate (530 mg, 2.12 mmol). The reaction mixture was stirred at 65°C for 4 h, concentrated, diluted with water (20 mL), and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 80) to afford compound 20G (400 mg, 97%).

[0506] LC-MS (ESI): m / z = 388.2 [M+H] + .

[0507] Step 6: Compound 20G (0.4 g, 1.03 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of pyridine (410 mg, 5.15 mmol) and p-nitrophenyl chloroformate (620 mg, 3.09 mmol). After the addition was complete, the reaction was stirred at room temperature for 2 hours, diluted with water (40 mL), and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product, which was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 60) to afford compound 20H (140 mg, 25% yield).

[0508] LC-MS (ESI): m / z = 553.2 [M+H] + .

[0509] Step 7: Compound 20H (140 mg, 0.25 mmol) and N-methyl-3-methylenecyclobutane-1-amine hydrochloride (43 mg, 0.33 mmol) were added to a reaction flask and dissolved in tetrahydrofuran (10 ml). DIPEA (97 mg, 0.75 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 70) to afford compound 20I (120 mg, 93% yield).

[0510] LC-MS (ESI): m / z = 511.3 [M+H] + .

[0511] Step 8: Compound 20I (120 mg, 0.24 mmol) and iodomethane (51 mg, 0.36 mmol) were dissolved in dry tetrahydrofuran (30 mL). LiHMDS (80 mg, 0.48 mmol) was slowly added under ice-cooling. After the addition was complete, the reaction was stirred for 2 h. TLC confirmed the complete reaction of the starting material. The reaction was quenched by adding saturated ammonium chloride solution and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 60) to obtain compound 20J (80 mg, yield: 73%).

[0512] LC-MS (ESI): m / z = 525.3 [M+H] + .

[0513] Step 9: Compound 20J (80 mg, 0.15 mmol) was added to a reaction flask and dissolved in THF:MeOH:H₂O = 5:1:1 (7 ml). Lithium hydroxide monohydrate (31 mg, 0.75 mmol) was then added and reacted at 25°C for 16 hours. After completion of the reaction, the pH was adjusted to approximately 7 with 1 M HCl and concentrated under reduced pressure. The resulting residue was purified and separated by HPLC to afford compounds 20-1 and 20-2 (separation method: Instrument: SHIMADZU LC-20AP; Reverse Phase Column: C18; Mobile Phase: A: 10 mmol NH₄HCO₃ in water; B: acetonitrile; Gradient: B from 15% to 45% in 16 minutes; Flow Rate: 25 mL / min; Column Temperature: Room Temperature; Wavelength: 210 & 254 nm).

[0514] Compound 20-1: peak time 2.039 min.

[0515] LC-MS (ESI): m / z = 483.3 [M+H] + .

[0516] 1 H NMR(400MHz,CD3OD)δ7.78(d,1H),7.53(d,1H),5.70(s,2H),4.76-4.80(m ,2H),4.17(s,3H),2.93-2.99(m,1H),2.77-2.92(m,6H),2.65-2.78(m,5H) ,2.52(s,3H),2.18-2.23(m,1H),1.99-2.04(m,1H),1.84-1.90(m,2H),1. 76-1.82(m,1H),1.59-1.68(m,1H),1.457-1.52(m,1H),1.28-1.34(m,2H).

[0517] Compound 20-2: peak time 2.141 min.

[0518] LC-MS (ESI): m / z = 483.3 [M+H] + .

[0519] 1 H NMR(400MHz,CD3Cl)δ7.94(d,1H),7.45(d,1H),5.73-5.83(m,2H),4.75-4.89(m,2H),4.13(s,3H),3.23-3.32(m,1H),2 .66-3.00(m,8H),2.62(s,3H),2.55(s,3H),1.97-2.06(m,1H),1.80-1.92(m,2H),1.53-1.80(m,5H),1.37-1.47(m,1H).

[0520] Example 21:

[0521] Step 1: Compound 20I (120 mg, 0.24 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (7 ml). Lithium hydroxide monohydrate (50 mg, 1.20 mmol) was then added and allowed to react at 25°C for 16 hours. After completion of the reaction, the pH was adjusted to approximately 7 with 1M HCl and the mixture was concentrated under reduced pressure. The resulting residue was purified by TLC (DCM:MeOH = 10:1) to afford Compound 21.

[0522] LC-MS (ESI): m / z = 469.2 [M+H] + .

[0523] 1 H NMR(400MHz, CDCl3)δ7.95(d,1H),7.14(d,1H),5.73(s,2H),4.78-4.87(m,2H),4.12(s,3H),3.70-3.79(m,1H ),2.70-2.92(m,8H),2.48(s,3H),2.23-2.33(m,1H),1.87-2.01(m,2H),1.58-1.78(m,5H),1.43-1.56(m,2H).

[0524] Example 22:

[0525] Step 1: Potassium tert-butoxide (9.53 g, 85.13 mmol) was added to a three-necked flask and dissolved in DMF (100 ml). The atmosphere was replaced with nitrogen three times and cooled to -45°C. A solution of 22A (10 g, 56.75 mmol) in DMF (25 ml) and a solution of 2-(difluoromethanesulfonyl)pyridine (9.86 g, 51.08 mmol) in DMF (25 ml) were slowly added dropwise. The mixture was allowed to react at this temperature for one hour. Saturated ammonium chloride solution (30 mL) and aqueous hydrochloric acid (1 N, 50 mL) were then added, and the temperature was slowly warmed to room temperature and allowed to react for 16 hours. After completion of the reaction, the mixture was diluted with water (100 ml) and extracted twice with methyl tert-butyl ether (100 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure at 30°C. The resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 22B (4 g, yield: 33.53%).

[0526] 1 H NMR (400MHz, CDCl3-d) δ7.29-7.20(m,5H),4.36(s,2H),4.11-4.03(m,1H),2.86-2.79(m,2H),2.64-2.55(m,2H).

[0527] Step 2: Compound 22B (4 g, 19.05 mmol) was added to a reaction flask and dissolved in dichloromethane (100 ml). The atmosphere was replaced with nitrogen three times and cooled to -78°C. Boron tribromide (9.52 g, 38.10 mmol) was then added dropwise and maintained at this temperature for one hour. After completion of the reaction, saturated sodium bicarbonate solution (200 ml) was added to adjust the pH to greater than 7 using TLC. The product was extracted with dichloromethane twice (50 ml x 2). The organic phases were combined, dried, and concentrated at 20°C. The resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 22C (1.63 g, 71.33% yield).

[0528] Step 3: Compound 22C (1.63 g, 13.58 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (20 ml). Pyridine (5.37 g, 67.90 mmol) and p-nitrophenyl chloroformate (8.2 g, 40.74 mmol) were then added and allowed to react at room temperature for one hour. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 22D (2.4 g, 62.02% yield).

[0529] 1 H NMR (400MHz, CDCl3-d) δ8.32-8.26(m,2H),7.43-7.36(m,2H),5.23-5.10(m,1H),3.25-3.14(m,2H),3.01-2.88(m,2H).

[0530] Step 4: Compound 22F (100 mg, 0.26 mmol, refer to WO2019126093) was dissolved in tetrahydrofuran (5 mL), and compound 22D (150 mg, 0.52 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol) were added. The mixture was reacted at room temperature for 1 h. After the complete disappearance of the starting material, the mixture was concentrated and the crude product was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the target compound 22E (108 mg, yield: 78.83%).

[0531] LC-MS (ESI): m / z = 534.3 [M+1] + .

[0532] Step 5: Compound 22E (108 mg, 0.20 mmol) was added to a reaction flask and dissolved in THF:MeOH:H₂O = 3:1:1 (15 ml). Anhydrous lithium hydroxide (27 mg, 0.61 mmol) was then added and allowed to react at room temperature for 16 hours. After completion of the reaction, as monitored by LC-MS, the pH was adjusted to 4-5 with aqueous hydrochloric acid (1 mol / L). The mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to afford compound 22 (45.1 mg, 45.31% yield).

[0533] LC-MS (ESI): m / z = 492.2 [M+H] + .

[0534] 1H NMR(400MHz,DMSO-d6)δ7.82(d,1H),7.71(m,1H),7.49(d,1H),4.95-4.92(m,1H),4.77-4.76(m,3H),4.04(s,3 H),3.07-2.99(m,2H),2.73-2.54(m,3H),2.44(s,3H),2.02-1.92(m,1H),1.88-1.74(m,3H),1.70-1.43(m,4H).

[0535] Example 23:

[0536] Compound 23A was used as the starting material, and the first to fifth steps of Example 22 were followed to obtain compound 23 (5.4 mg, 6%).

[0537] LC-MS (ESI): m / z = 506.3 [M+H] + .

[0538] 1 H NMR(400MHz,DMSO-d6)δ7.83(d,1H),7.69-7.63(m,1H),7.49(d,1H),4.80-4.74(m,3H),4.07-3.97(m ,5H),2.77-2.57(m,4H),2.46-2.30(m,5H),2.03-1.95(m,1H),1.88-1.75(m,3H),1.67-1.47(m,4H).

[0539] Example 24:

[0540] Step 1: Compound 24A (3.00 g, 11.70 mmol, synthesized according to the method of patent WO2013090929A1) was added to methanol (30 mL), and then sodium methoxide (2.11 g, 11.70 mmol, 30% methanol solution) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction monitored by TLC, the reaction solution was added to saturated ammonium chloride solution (50 mL) and extracted three times with dichloromethane (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24B (2.90 g, yield: 86%).

[0541] Step 2: Compound 24B (2.90 g, 10.05 mmol) and 3,4-dihydropyran (1.01 g, 12.06 mmol) were added to dichloromethane (30 mL), and p-toluenesulfonic acid (96.0 mg, 0.50 mmol) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give compound 24C (3.10 g, yield: 83%).

[0542] Step 3: Compound 24C (3.10 g, 8.32 mmol) was added to a tetrahydrofuran (30 mL) solution, followed by the addition of tetrabutylammonium fluoride (16.64 mL, 16.64 mmol, 1.0 mol / L tetrahydrofuran solution). The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 24D (1.80 g, yield: 84%).

[0543] Step 4: Compound 24D (1.8 g, 6.97 mmol) was added to dry tetrahydrofuran (40 mL), followed by the addition of p-nitrobenzoic acid (2.33 g, 13.94 mmol) and diisopropyl azodicarboxylate (2.82 g, 13.94 mmol). The mixture was replaced with nitrogen three times, cooled to 0-5°C, and finally triphenylphosphine (3.66 g, 13.94 mmol) was added. The mixture was returned to room temperature and reacted for 6 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PET / EA = 4 / 1) to give compound 24E (2.2 g, yield: 77%).

[0544] Step 5: Compound 24E (2.2 g, 5.40 mmol) and sodium carbonate (1.72 g, 16.20 mmol) were added to methanol (40 mL) and reacted at room temperature for 5 hours. After the completion of the reaction monitored by TLC, the product was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 24F (1.20 g, yield: 86%).

[0545] Step 6: Compound 24G (1.00 g, 3.13 mmol, synthesized according to the method of patent WO2017223016A1) was added to dry toluene (30 mL), followed by the addition of compound 24F (1.13 g, 4.38 mmol) and azodicarbonyl dipiperidine (2.37 g, 9.39 mmol). The mixture was replaced with nitrogen three times, cooled to 0-5°C, and finally tributylphosphine (1.90 g, 9.39 mmol) was added. The temperature was raised to 60°C and the reaction was allowed to proceed for 16 hours. After the reaction was completed, the mixture was diluted with water (40 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain compound 24H (0.95 g, yield: 54%).

[0546] LC-MS (ESI): m / z = 560.3 [M+H] + .

[0547] Step 7: Compound 24H (0.95 g, 1.70 mmol) was added to methanol (10 mL), followed by trifluoroacetic acid (2 mL). The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the product was monitored by TLC and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 6) to obtain compound 24I (0.61 g, yield: 76%).

[0548] LC-MS (ESI): m / z = 476.2 [M+H] + .

[0549] Step 8: Compound 24I (0.61 g, 5.40 mmol) and 2-iodoacylbenzoic acid (1.08 g, 3.84 mmol) were added to ethyl acetate (20 mL), and the temperature was raised to 75° C. for 6 hours. After the completion of the reaction as monitored by TLC, the product was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 5) to obtain compound 24J (0.50 g, yield: 82%).

[0550] LC-MS (ESI): m / z = 474.2 [M+H] + .

[0551] Step 9: Compound 24J (120.0 mg, 0.25 mmol) was added to 5 mL of dry toluene, replaced with nitrogen three times, cooled to -5-0°C, and TEBBE reagent (1.00 mL, 0.50 mmol, 0.5 mol / L toluene solution) was slowly added dropwise. After the addition, the temperature was controlled and the reaction was continued at -5-0°C for 2 hours. After the completion of the reaction monitored by TLC, the reaction mixture was slowly added to 15 mL of saturated sodium bicarbonate solution and extracted three times with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 4) to obtain compound 24K (26.0 mg, yield: 22%).

[0552] LC-MS (ESI): m / z = 472.1 [M+H] + .

[0553] Step 10: 24K (26.0 mg, 0.055 mmol) was dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL), followed by the addition of lithium hydroxide (12 mg, 0.28 mmol) and the reaction was allowed to react at room temperature for 3 hours. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to a weakly acidic state. A small amount of water was then added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were concentrated and purified by HPLC to afford compound 24 (8.0 mg, 32%).

[0554] LC-MS (ESI): m / z = 458.3 [M+H] + .

[0555] 1 H NMR(400MHz, CDCl3)δ8.05(d,1H),7.67(d,1H),5.73-5.49(m,2H),4.93(s,1H),4.89-4.86(m,1H),4.81(s,1H),4.18(s,3H),3.22-3 .18(m,2H),2.99-2.93(m,1H),2.89(s,3H),2.67(s,3H),2.63-2.45(m,4H),2.23-2.06(m,2H),1.55-1.50(m,2H),0.89-0.83(m,3H).

[0556] Example 25

[0557] Step 1: Compound 17E (610 mg, 2.00 mmol), methyl 2,2-difluoro-3-(hydroxymethyl)cyclopropane-1-carboxylate (665 mg, 4.00 mmol, reference: Helvetica Chimica Acta, 1992, vol. 75, #3, pp. 766-772), and tributylphosphine (1.21 g, 6.00 mmol) were added to a reaction flask and dissolved in toluene (50 ml). Azodicarbonyldipiperidine (1.51 g, 6.00 mmol) was then added and reacted at 50°C for 16 hours. After completion of the reaction, as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 2:1) to afford compound 25A (800 mg, 88.40% yield).

[0558] LC-MS (ESI): m / z = 453.3 [M+H] + .

[0559] Step 2: Compound 25A (800 mg, 1.77 mmol) was added to a reaction flask and dissolved in methanol (50 ml). 4-Methylbenzenesulfonate pyridine (490 mg, 1.94 mmol) was then added and reacted at 60°C for 4 hours. After completion of the reaction, as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 1:4) to afford compound 25B (310 mg, 47.55% yield).

[0560] LC-MS (ESI): m / z = 369.2 [M+H] + .

[0561] Step 3: Compound 25B (310 mg, 0.84 mmol) was added to a reaction flask and dissolved in dichloromethane (10 ml). Pyridine (330 mg, 4.2 mmol) and p-nitrophenyl chloroformate (423 mg, 2.1 mmol) were then added and allowed to react at room temperature for 16 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 25C (130 mg, 29.02% yield).

[0562] LC-MS (ESI): m / z = 534.2 [M+H] + .

[0563] Step 4: Compound 25C (130 mg, 0.24 mmol) was added to a reaction flask and dissolved in dichloromethane (10 ml). DIPEA (0.25 ml, 1.44 mmol) and compound 4C (70 mg, 0.72 mmol) were then added and reacted at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:2) to afford compound 25D (115 mg, 96.00% yield).

[0564] LC-MS (ESI): m / z = 492.1 [M+H] + .

[0565] Step 5: Compound 25D (115 mg, 0.23 mmol) was added to a reaction flask and dissolved in THF:MeOH:H₂O = 1:1:1 (9 ml). Lithium hydroxide (22 mg, 0.92 mmol) was then added and allowed to react at room temperature for 4 hours. After completion of the reaction, monitored by TLC, the mixture was concentrated under reduced pressure, and the resulting residue was separated by a C₁₈ reverse-phase column to afford compound 25 (64 mg, 57.29% yield).

[0566] 1 H NMR(400MHz,DMSO-d6)δ7.88-7.83(m,1H),7.51-7.46(m,1H),5.64(s,2H),4.78(s,2H),4.33-4 .26(m,1H),4.21-4.13(m,1H),4.09(s,3H),2.87-2.73(m,5H),2.71-2.53(m,5H),2.39(s,3H).

[0567] LC-MS (ESI): m / z = 478.3 [M+H] + .

[0568] Example 26

[0569] Step 1: Compound 26A (15.0 g, 115.26 mmol) was added to a reaction flask and dissolved in dichloromethane (200 ml). Triethylamine (34.99 g, 345.78 mmol) was added and the atmosphere was replaced with nitrogen three times. The mixture was cooled to 0°C and tert-butyldiphenylsilyl chloride (38.02 g, 138.31 mmol) was slowly added. The mixture was reacted at this temperature for 4 hours. After completion of the reaction, the mixture was diluted with water (500 ml) and extracted twice with methyl tert-butyl ether (300 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure at 40°C. The resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 26B (40 g, yield: 94.17%).

[0570] LC-MS (ESI): m / z = 369.3 [M+H] + .

[0571] Step 2: Compound 26B (10 g, 27.13 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (50 ml). The atmosphere was replaced with nitrogen three times, cooled to 0°C, and lithium borohydride (1.18 g, 54.26 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction as monitored by TLC, saturated ammonium chloride solution (100 ml) was added and extracted twice with ethyl acetate (50 ml x 2). The organic phases were combined, dried, and concentrated at 45°C. The resulting residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 26C (4.0 g, 43.29% yield).

[0572] LC-MS (ESI): m / z = 341.2 [M+H] + .

[0573] Step 3: Compound 26C (2.0 g, 5.87 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (20 ml). 2-Nitrophenyl seryl cyanate (4.00 g, 17.61 mmol) and tri-n-butylphosphine (3.56 g, 17.61 mmol) were added and reacted at room temperature for one hour. The mixture was concentrated under reduced pressure, dissolved in dichloromethane (20 ml), cooled to 0°C, and m-chloroperbenzoic acid (3.04 g, 17.61 mmol) was added. The mixture was stirred for one hour and concentrated under reduced pressure. The mixture was dissolved in toluene (20 ml), and diisopropylamine (1.78 g, 17.61 mmol) was added. The mixture was stirred at 90°C for 16 hours. After completion of the reaction, water (50 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 26D (1.2 g, yield: 63.35%).

[0574] 1 H NMR (400MHz, CDCl3) δ7.64-7.66(m,4H),7.34-7.44(m,6H),4.74-4.76(m,2H),4.27-4.34(m,1H),2.72-2.82(m,4H),1.04(s,9H).

[0575] Step 4: Compound 26D (2.0 g, 6.20 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (12.4 mL, 12.4 mmol) was added and reacted at room temperature for 16 h. After the starting material completely disappeared, the mixture was concentrated to obtain the crude target compound 26E (2 g, crude product), which was used directly in the next step.

[0576] Step 5: Compound 26E (500 mg, 5.94 mmol) was added to a reaction flask and dissolved in dichloromethane (15 ml). Triethylamine (1.80 g, 17.82 mmol) and p-nitrophenyl chloroformate (1.44 g, 7.13 mmol) were added and reacted at room temperature for 16 hours. After completion of the reaction as monitored by TLC, water (20 ml) was added, and the mixture was extracted with dichloromethane (20 ml). The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 26F (0.2 g, 13.15% yield).

[0577] LC-MS (ESI): m / z = 250.1 [M+H] + .

[0578] Step 6: Compound 26F (200 mg, 0.80 mmol) was added to a reaction flask and dissolved in dichloromethane (10 ml). Triethylamine (0.24 g, 2.40 mmol) was added, followed by compound 22F (0.34 g, 0.88 mmol) and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, as monitored by TLC, water (20 ml) was added, and the mixture was extracted with dichloromethane (20 ml). The mixture was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 26G (0.18 g, 45.08% yield).

[0579] LC-MS (ESI): m / z = 498.2 [M+H] + .

[0580] Step 7: Compound 26G (180 mg, 0.27 mmol) was added to a reaction flask and dissolved in methanol (10 ml). Lithium hydroxide monohydrate (45 mg, 1.08 mmol) was added and allowed to react at room temperature for 16 hours. 2N hydrochloric acid was added to adjust the pH to 4. The mixture was concentrated and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the crude title compound. Preparative HPLC yielded compound 26 (40 mg, 24.28%).

[0581] LC-MS (ESI): m / z = 456.2 [M+H] + .

[0582] 1 H NMR(400MHz,DMSO-d6)δ7.85(d,1H),7.68(s,1H),7.55(d,1H),4.73-4.85(m,6H),4.06(s,3H),2.90- 2.97(m,2H),2.61-2.68(m,3H),2.47(s,3H),2.00-2.07(m,1H),1.76-1.88(m,3H),1.49-1.65(m,4H).

[0583] Example 27

[0584] Step 1: In a 250 mL single-necked flask, 27A (2 g, 12.41 mmol), potassium bifluoride (3.88 g, 49.64 mmol), and difluorobromomethyltrimethylsilane (5.04 mg, 24.82 mmol) were added sequentially to a mixture of dichloromethane (20 mL) and water (60 mL). The atmosphere was replaced with nitrogen three times and the mixture was vigorously stirred at room temperature for 4 hours. After completion of the reaction, the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product, which was purified using a Biotage Isolera One (40 g silica gel column, eluent: 0-25% EA / PE) to afford compound 27B (543 mg, 20.72% yield).

[0585] 1 H NMR (400MHz, CDCl3) δ6.41-6.01(m,1H),4.83(s,1H),3.94-3.88(m,2H),3.43-3.35(m,2H),1.45(s,9H).

[0586] Step 2: 27B (535 mg, 2.53 mmol) was dissolved in DMF (10 mL), replaced with nitrogen, and cooled to 0°C with stirring in an ice-water bath. Sodium hydride (121 mg, 3.04 mmol, 60% Wt) was added and stirred for 5 minutes. Methyl iodide (538 mg, 3.79 mmol) was added and stirred for 1 hour after removing the ice-water bath. After completion of the reaction, ice water (30 mL) was added to the reaction flask to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product of compound 27C (800 mg), which was directly used for the next step without further purification.

[0587] Step 3: 27C (800 mg, crude product) was added to a single-necked flask, and dichloromethane (3 mL) was added to dissolve it. A dioxane solution of hydrochloric acid (10 mL, 4 mol / L) was added and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was directly concentrated to dryness under reduced pressure to obtain the crude compound 27D (288 mg). The crude product was used directly in the next step without further purification.

[0588] Step 4: Crude 27D (288 mg) was added to a single-necked flask, followed by dichloromethane (10 mL), DIPEA (567 mg, 4.4 mmol), and compound 2D (120 mg, 0.22 mmol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford the crude product, which was then purified using a Biotage Isolera One (12 g silica gel column, eluent: 0-3% MeOH / DCM) to afford compound 27E (87 mg, 73.30% yield).

[0589] LC-MS (ESI): m / z = 540.2 [M+H] + .

[0590] Step 5: 27E (87 mg, 0.16 mmol) was added to a single-necked flask, tetrahydrofuran (10 mL) was added to dissolve it, and water (5 mL) was added. Lithium hydroxide (33 mg, 0.80 mmol) was added with stirring, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) and ethyl acetate (20 mL) were added, stirred for 10 minutes, and the aqueous phase was separated. The organic phase was extracted twice with water (20 mL). The three aqueous phases were combined and the pH was adjusted to weak acidity with hydrochloric acid (1N). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using a Biotage Isolera One (12 g silica gel column, eluent: 0-6% MeOH / DCM) to obtain compound 27 (41 mg, yield 51.11%).

[0591] LC-MS (ESI): m / z = 498.3 [M+H] + .

[0592] 1 H NMR(400MHz,DMSO-d6)δ7.90-7.80(m,1H),7.56-7.46(m,1H),6.88-6.30(m,1H),5.73-5.61(m,2H),4.78(s,2H),4.09(s,3H),3.9 5-3.76(m,2H),3.46(s,2H),2.90-2.78(m,3H),2.63(s,1H),2.42(s,3H),2.09-1.98(m,1H),1.87-1.76(m,2H),1.70-1.46(m,4H).

[0593] Example 28

[0594] Step 1: Dissolve 28A (500 mg, 2.24 mmol) in acetonitrile (8 mL), then add trifluoromethylthiotetramethylammonium salt (588 mg, 3.36 mmol). Allow to react overnight at room temperature. After completion, the reaction solution was concentrated by rotary evaporation. Dichloromethane (8 mL) and 20% aqueous sulfuric acid (5 mL) were added to the residue and stirred at room temperature for 2 h. The reaction was quenched by the slow addition of saturated sodium bicarbonate solution and extracted with diethyl ether (15 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 25:1) to afford 28B (251 mg, 46%).

[0595] LC-MS(ESI):m / z=190.0[M+H-56] + .

[0596] Compound 28B was used as the starting material, and the second to fifth steps of Example 27 were followed to obtain compound 28 (21 mg, 18%).

[0597] LC-MS (ESI): m / z = 532.0 [M+H] + .

[0598] 1 H NMR (400MHz, CDCl3) δ8.03-8.00(m,1H),7.62-7.54(m,1H),5.77-5.59(m,2H),4.81-4.78(m,1H),4.18(s,3H),3 .57-3.45(m,2H),3.06-3.02(m,1H),2.96-2.85(m,5H),2.70-2.67(m,3H),2.14-1.88(m,4H),1.83-1.61(m,4H).

[0599] Example 29:

[0600] Step 1: Compound 29A (15.00 g, 102.64 mmol) was dissolved in methanol (150 mL), cooled to 0-5°C, and concentrated sulfuric acid (2 mL) was slowly added dropwise. The mixture was returned to room temperature and stirred for 17 hours. After completion of the reaction, the mixture was concentrated under pressure. Saturated aqueous sodium bicarbonate (150 mL) was then added portionwise and the impurities were extracted twice with petroleum ether (100 mL). The aqueous phase was cooled to 0°C, the pH was adjusted to 3-4 with 6N aqueous hydrochloric acid, and the product was extracted twice with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 29B (9.20 g, 56% yield).

[0601] Step 2: Compound 29B (5.00 g, 31.22 mmol) was dissolved in dry tetrahydrofuran (50 mL), replaced with nitrogen three times, and cooled to 0-5°C. Borane tetrahydrofuran solution (62.44 mL, 62.44 mmol, 1.0 mol / L tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the temperature was slowly returned to room temperature and reacted for 3 hours. After the completion of the reaction monitored by TLC, the temperature was lowered to 0°C, and methanol (100 mL) was slowly added dropwise to quench the reaction. After complete quenching, the reaction was concentrated under reduced pressure. The residue was purified by normal phase column to give compound 29C (2.60 g, yield: 57%).

[0602] Step 3: Compound 29C (0.96 g, 6.58 mmol) was added to a dichloromethane (10 mL) solution, followed by the addition of triethylamine (1.33 g, 13.16 mmol). After the addition, the temperature was lowered to 0-5°C and methanesulfonic anhydride (1.20 g, 6.91 mmol) was added in batches. After the addition, the temperature was kept at 0-5°C and the reaction was continued for 2 hours. After the completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure. The residue was dissolved in (10 mL) N,N-dimethylformamide, and compound 17E (1.00 g, 3.29 mmol) and cesium carbonate (3.22 g, 9.87 mmol) were added in sequence. After the addition, the temperature was raised to 100°C and the reaction was continued for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and the product was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the obtained residue was purified by normal phase column to give compound 29E (0.23 g, yield: 16%).

[0603] LC-MS (ESI): m / z = 433.2 [M+H] + .

[0604] Step 4: Compound 29E (0.23 g, 0.53 mmol) was added to methanol (10 mL), followed by trifluoroacetic acid (2 mL). The mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction was monitored by TLC and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to give compound 29F (0.15 g, yield: 81%).

[0605] LC-MS (ESI): m / z = 349.1 [M+H] + .

[0606] Step 5: Compound 29F (0.15 g, 0.43 mmol) was added to dichloromethane (5 mL), followed by pyridine (0.14 g, 1.72 mmol) and 4-nitrophenyl chloroformate (0.13 g, 0.65 mmol). The mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction was monitored by TLC and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to give compound 29G (0.17 g, yield: 77%).

[0607] Step 6: Compound 29G (0.17 g, 0.33 mmol) was added to tetrahydrofuran (5 mL), followed by triethylamine (0.17 g, 1.65 mmol) and compound 4C (100 mg, TFA salt). The mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction was monitored by TLC, and the mixture was concentrated under reduced pressure. The residue was purified by normal phase column chromatography to give compound 29H (0.13 g, yield: 83%).

[0608] LC-MS (ESI): m / z = 472.2 [M+H] + .

[0609] Step 7: Compound 29H (0.13 g, 0.27 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (3 mL), and water (3 mL), followed by the addition of lithium hydroxide (112 mg, 2.71 mmol) and the reaction at room temperature for 15 hours. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to a weakly acidic state. A small amount of water was then added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were concentrated and purified by HPLC to afford compound 29 (11.0 mg, 9%).

[0610] LC-MS (ESI): m / z = 458.3 [M+H] + .

[0611] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),7.84(d,1H),7.41(d,1H),5.65(s,2H),4.79(s,2H),4.44- 4.27(m,1H),4.09(s,3H),3.86(s,2H),2.77-2.67(m,7H),2.41(s,3H),2.34(s,2H),1.12(s,6H).

[0612] Example 30

[0613] Step 1: Dissolve 30A (400 mg, 1.99 mmol), silver trifluoromethanesulfonate (2.04 g, 7.96 mmol), SELECTFLUOR fluorinating agent (1.06 g, 2.98 mmol), potassium fluoride (461 mg, 7.96 mmol), and 2-fluoropyridine (772 mg, 7.96 mmol) in ethyl acetate (30 mL). Stir thoroughly, then add trifluoromethyltrimethylsilane (706 mg, 4.98 mmol) dropwise. Allow to react at room temperature for 36 h. After the reaction is complete, add 60 mL of water, extract with ethyl acetate (25 mL x 3), combine the organic layers, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The residue is purified by silica gel column chromatography to afford 30B (276 mg, 52%).

[0614] LC-MS(ESI):m / z=214.0[M+H-56] + .

[0615] Using compound 30B as starting material, referring to the third to fifth steps of Example 27, compound 30 (48 mg, 40%) was obtained.

[0616] LC-MS (ESI): m / z = 542.3 [M+H] + .

[0617] 1 H NMR (400MHz, CDCl3) δ8.04-8.00(m,1H),7.59-7.56(m,1H),5.70-5.55(m,2H),4.80-4.75(m,1H),4.39-4.31(m,1H),4.17(s,3H),2.87(s, 3H),2.67-2.59(m,4H),2.37-2.28(m,2H),2.09-2.02(m,2H),1.98-1 .87(m,2H),1.82-1.50(m,5H),1.45-1.35(m,1H),0.95-0.90(m,1H).

[0618] Example 31

[0619] Compound 31 (44 mg, 51%) was synthesized using 31A (400 mg, 1.99 mmol) as the starting material and following the procedure of Example 30.

[0620] LC-MS (ESI): m / z = 542.6 [M+H] + .

[0621] 1H NMR (400MHz, CDCl3) δ8.04-8.01(m,1H),7.60-7.57(m,1H),5.69-5.57(m,2H),4.80-4.68(m,2H),4.18(s,3H),2.91-2.83(m,4H) ,2.66(s,3H),2.57-2.44(m,2H),2.09-2.01(m,2H),1.98-1.88(m,2H),1.80-1.50(m,5H),1.44-1.35(m,1H),0.95-0.90(m,1H).

[0622] Example 32

[0623] Step 1: Compound 25 (1.34 g) was subjected to chiral separation to obtain compounds 32-1 (6 mg, retention time 1.07 min), 32-2 (10 mg, retention time 1.22 min), 32-3 (537 mg, retention time 1.46 min) and 32-4 (502 mg, retention time 1.78 min).

[0624] Analytical methods: Instrument: SHIMADZU LC-30AD, Column: Chiral AD Column; Mobile phase: A: CO2, B: 0.05% DEA in MeOH; Gradient: 5-10% B in A; Flow rate: 3 mL / min; Column temperature: 35°C; Wavelength: 220 nm.

[0625] Preparation: Instrument: SFC Prep 150AP, Column: Daicel IG (19 mm × 250 mm); Mobile Phase: A: CO2, B: 0.05% NH3·H2O in ETOH; Gradient: 12% B; Flow Rate: 120 mL / min; Column Temperature: 25°C; Wavelength: 220 nm; Cycle Time: 25 min. Sample Preparation: Sample concentration: 10 mg / mL. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. After separation, the fraction was dried on a rotary evaporator at 35°C to yield compounds 32-1 (6 mg, retention time 1.07 min), 32-2 (10 mg, retention time 1.22 min), 32-3 (537 mg, retention time 1.46 min), and 32-4 (502 mg, retention time 1.78 min).

[0626] 32-1: (retention time 1.07 min), 1H NMR(400MHz,DMSO-d6)δ7.87-7.83(m,1H),7.48-7.44(m,1H),5.64(s,2H),4.79(s,2H) ),4.60-4.53(m,1H),4.50-4.43(m,1H),4.09(s,3H),2.86-2.57(m,10H),2.37(s,3H).

[0627] LC-MS (ESI): m / z = 478.3 [M+H] + .

[0628] 32-2: (retention time 1.22 min), 1 H NMR(400MHz,DMSO-d6)δ7.87-7.84(m,1H),7.50-7.47(m,1H),5.65(s,2H),4.79(s,2H) ),4.58-4.52(m,1H),4.47-4.40(m,1H),4.09(s,3H),2.88-2.63(m,10H),2.37(s,3H).

[0629] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0630] 32-3: (retention time 1.46 min), 1 H NMR(400MHz,DMSO-d6)δ7.87-7.83(m,1H),7.50-7.46(m,1H),5.64(s,2H),4.78(s,2H) ),4.32-4.25(m,1H),4.18-4.11(m,1H),4.09(s,3H),2.88-2.51(m,10H),2.39(s,3H).

[0631] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0632] 32-4: (retention time 1.78 min), 1 H NMR(400MHz,DMSO-d6)δ7.87-7.83(m,1H),7.50-7.45(m,1H),5.64(s,2H),4.78 (s,2H),4.31-4.24(m,1H),4.16-4.06(m,4H),2.90-2.41(m,10H),2.39(s,3H).

[0633] LC-MS (ESI): m / z = 478.2 [M+H]+ .

[0634] Example 33

[0635] Step 1: Compound 33A (600 mg, 2.98 mmol, synthesized according to the method of patent CN 116789556A) was added to a reaction flask and dissolved in dichloromethane (10 ml). Then, 4N hydrochloric acid solution in dioxane (10 ml) was added and allowed to react at room temperature for 18 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure to provide compound 33B (330 mg, 80.44% yield), which was used directly in the next step without further purification.

[0636] LC-MS (ESI): m / z = 102.2 [M+H] + .

[0637] Step 2: Compound 2D (250 mg, 0.45 mmol) and compound 33B (185 mg, 1.35 mmol) were added to a reaction flask and dissolved in dichloromethane (10 ml). DIPEA (645 mg, 5.0 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford compound 33C (180 mg, 77.30% yield).

[0638] LC-MS (ESI): m / z = 516.3 [M+H] + .

[0639] Step 3: Compound 33C (180 mg, 0.35 mmol) was added to a reaction flask and dissolved in DMF (10 ml). The mixture was then cooled to 0°C and NaH (17 mg, 0.42 mmol) was added. The mixture was stirred at this temperature for 20 min, followed by the addition of iodomethane (75 mg, 0.52 mmol). The mixture was allowed to warm to room temperature for 1 hour. After completion of the reaction, as monitored by TLC, saturated ammonium chloride solution (20 ml) was added, followed by extraction with ethyl acetate (20 ml x 2). The organic phases were combined, dried, and concentrated under reduced pressure to afford compound 33D (180 mg, 95.35% yield), which was used directly in the next step without further purification.

[0640] LC-MS (ESI): m / z = 530.3 [M+H] + .

[0641] Step 4: Compound 33D (180 mg, 0.34 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 1:1:1 (9 ml). Anhydrous lithium hydroxide (41 mg, 1.70 mmol) was then added and stirred at room temperature for 18 hours. After completion of the reaction, the pH was adjusted to a weakly acidic state with dilute hydrochloric acid, and ethyl acetate (20 mL x 2) was added. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated by preparative HPLC to afford compound 33 (0.13 mg, 78.46% yield).

[0642] LC-MS (ESI): m / z = 484.4 [M+H] + .

[0643] 1 H NMR (400MHz, CDCl3) δ8.09-8.08(m,1H),7.82-7.81(m,1H),5.67(s,1H),5.54-5.50(m,1H),4.86(s,1H),4.20(s,3H),3.59 -3.24(m,4H),3.24-3.23(m,1H),2.95-2.88(m,4H),2.79(s,3H),2.06-2.00(m,2H),1.92-1.67(m,6H),0.49-0.43(m,4H).

[0644] Example 34

[0645] Step 1: Compound 6C (5 g, 13.62 mmol), tert-butyl carbamate (3.19 g, 27.24 mmol), cesium carbonate (8.88 g, 27.24 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (RuPhos PD G3) (1.14 g, 1.36 mmol) were dissolved in 1,4-dioxane (50 mL). The mixture was then purged with nitrogen three times and reacted at 100°C for 16 hours. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 34B (5.1 g, yield: 92.84%).

[0646] LC-MS (ESI): m / z = 404.2 [M+H] + .

[0647] Step 2: Compound 34B (3 g, 7.44 mmol) was dissolved in methanol (30 mL), and p-toluenesulfonic acid (0.13 g, 0.74 mmol) was added. The mixture was reacted at 40°C for 2 hours. The mixture was concentrated and purified by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 34C (2.1 g, yield: 88.44%).

[0648] LC-MS (ESI): m / z = 320.2 [M+H] + .

[0649] Step 3: Compound 34C (2 g, 6.26 mmol) and pyridine (0.99 g, 12.52 mmol) were dissolved in dichloromethane (15 mL). p-Nitrophenyl chloroformate (1.51 g, 7.51 mmol) was added portionwise and reacted at 25°C for 2 hours. The mixture was concentrated and purified by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 34D (2.5 g, yield: 82.40%).

[0650] LC-MS (ESI): m / z = 485.1 [M+H] + .

[0651] Step 4: Dissolve compound 34D (0.2 g, 0.41 mmol) and triethylamine (0.17 g, 1.64 mmol) in dichloromethane (10 mL), then add compound 4C (0.052 g, 0.53 mmol). React at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 34E (0.15 g, yield: 82.11%).

[0652] LC-MS (ESI): m / z = 443.3 [M+H] + .

[0653] Step 5: Compound 34E (0.15 g, 0.34 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.3 mL) was added and reacted at room temperature for 2 hours. The mixture was directly concentrated to obtain compound 34F for the next step.

[0654] LC-MS (ESI): m / z = 343.1 [M+H] + .

[0655] Step 6: Compound 34F (0.1 g, 0.29 mmol), trans-2,2-difluoro-3-(methoxycarbonyl)cyclopropanecarboxylic acid (0.10 g, 0.58 mmol) (Helvetica Chimica Acta, 1992, vol. 75, #3, pp. 766-772), and N-methylimidazole (0.095 g, 1.16 mmol) were dissolved in acetonitrile (2 mL). Tetramethylchlorouronium hexafluorophosphate (0.24 g, 0.87 mmol) was added and reacted at room temperature for 16 hours. The mixture was concentrated and purified by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 34G (0.1 g, yield: 67.87%).

[0656] LC-MS (ESI): m / z = 505.1 [M+H] + .

[0657] Step 7: Dissolve compound 34G (0.1 g, 0.20 mmol) in tetrahydrofuran (3 mL) and water (1 mL), then add lithium hydroxide monohydrate (0.034 g, 0.80 mmol). React at room temperature for 2 hours. Adjust the pH to 4 with formic acid. Concentrate and purify by reverse-phase column chromatography (acetonitrile:water = 3% to 60%) to afford compound 34 (0.06 g, yield: 61.72%).

[0658] LC-MS (ESI): m / z = 491.3 [M+H] + .

[0659] Step 8: Chiral analysis of compound 34 (400 mg) revealed two isomers: P1 (retention time: 2.699 min, designated as compound 34-1) and P2 (retention time: 3.511 min, designated as compound 34-2). Analytical method: Instrument: Waters UPC2 analytical SFC (SFC-H); Column: ChiralPak IK, 150×4.6 mm ID, 3 μm; Mobile phase: A for CO2 and B for Ethanol (0.05% DEA); Gradient: 40% B gradient elution; Flow rate: 2.5 mL / min; Column pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 4 min.

[0660] Preparation method: Instrument: WATERS150preparative SFC (SFC-26); Column: ChiralPak IH, 250×30mm ID, 10μm; Mobile phase: A for CO2 and B for Ethanol (0.1% NH3H2O); Gradient: 40% B gradient elution; Flow rate: 120mL / min; Column temperature: 38℃; Wavelength: 220nm; Cycle time: 4min; Sample preparation: Compound was dissolved in ~20ml methanol / DCM Injection: 2.2mL each time, to obtain compound 34-1 (142mg) and compound 34-2 (194mg).

[0661] Compound 34-1: 1 H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.01-7.98(m,1H),7.88(d,1H),5.67(s,2H),4.79(s,2H),4. 11(s,3H),3.45-3.41(m,1H),3.38-3.32(d,2H),2.89-2.73(m,6H),2.46(s,3H),2.35-3.30(m,1H).

[0662] LC-MS (ESI): m / z = 491.3 [M+H] +.

[0663] Compound 34-2: 1 H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.02-7.98(m,1H),7.88(d,1H),5.67(s,2H),4.79(s,2H),4. 11(s,3H),3.45-3.41(m,1H),3.38-3.32(d,2H),2.89-2.73(m,6H),2.46(s,3H),2.35-3.30(m,1H).

[0664] LC-MS (ESI): m / z = 491.3 [M+H] + .

[0665] Example 35

[0666] Compound 34D was used as the starting material, following steps 4 to 8 of Example 34, to obtain compounds 35-1 (retention time: 2.609 min) and 35-2 (retention time: 3.449 min). Analytical method: Instrument: Waters UPC2 analytical SFC (SFC-H); Column: ChiralPak IK, 150×4.6 mm ID, 3 μm; Mobile phase: A for CO2 and B for Ethanol (0.05% DEA); Gradient: 40% B gradient elution; Flow rate: 2.5 mL / min; Column pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 4 min.

[0667] Preparation method: Instrument: WATERS150preparative SFC (SFC-26); Column: ChiralPak IH, 250×30mm ID, 10μm; Mobile phase: A for CO2 and B for Ethanol (0.1% NH3H2O); Gradient: 40% B gradient elution; Flow rate: 120mL / min; Column temperature: 38℃; Wavelength: 220nm; Cycle time: 4min; Sample preparation: Compound was dissolved in ~20ml methanol / DCM Injection: 2.2mL each time, to obtain compound 35-1 (17mg), compound 35-2 (13mg).

[0668] Compound 35-1: 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.01-7.87(m,1H),7.89(d,1H),5.65(s,2H),4.66(d,2H),4.11(s,3H),3.49(s,1H),3. 24-3.13(m,2H),2.99-3.90(m,1H),2.80-2.66(m,4H),2.47(s,3H),2.38(s,1H),2.19(s,1H),1.72-1.41(m,1H),1.24(s,1H).

[0669] LC-MS (ESI): m / z = 505.3 [M+H] + .

[0670] Compound 35-2: 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.01-7.87(m,1H),7.89(d,1H),5.65(s,2H),4.66(d,2H),4.11(s,3H),3.49(s,1H),3. 24-3.13(m,2H),2.99-3.90(m,1H),2.80-2.66(m,4H),2.47(s,3H),2.38(s,1H),2.19(s,1H),1.72-1.41(m,1H),1.24(s,1H).

[0671] LC-MS (ESI): m / z = 505.3 [M+H] + .

[0672] Example 36

[0673] Step 1: Compound 36A (0.1 g, 0.45 mmol, synthesized according to the method of patent WO2008 / 141462) was added to DMF (5 mL), followed by the addition of compound 17E (0.14 g, 0.45 mmol) and cesium carbonate (0.44 g, 1.35 mmol). The mixture was reacted at 50°C for 2 hours. After completion of the reaction as monitored by TLC, the reaction was quenched with water and extracted three times with ethyl acetate (20 mL). The combined organic phases were concentrated and the resulting residue was purified by normal phase column chromatography to give compound 36E (120 mg, yield: 62%).

[0674] LC-MS (ESI): m / z = 431.2 [M+H] + .

[0675] According to the fourth step, fifth step, sixth step and seventh step of Example 29, compound 36 (20 mg) was obtained.

[0676] LC-MS (ESI): m / z = 456.2 [M+H] + .

[0677] 1 H NMR(400MHz, CDCl3)δ=7.91(d,1H),7.09(d,1H),5.74(s,2H),5.56(s,2H),4.82(s, 2H),4.12(s,3H),3.92(s,2H),2.83(s,6H),2.53(s,2H),2.48(s,3H),0.69(d,4H).

[0678] Example 37

[0679] Using compound 17E as starting material and referring to steps 1 to 5 of Example 25, compound 37F (574 mg, 91.6%) was obtained.

[0680] Compound 37F was separated by SFC to obtain compound 37-1 (SFC analysis retention time: 2.311 min, 98 mg), compound 37-2 (SFC analysis retention time: 2.173 min, 112 mg), compound 37-3 (SFC analysis retention time: 1.763 min, 42.3 mg) and compound 37-4 (SFC analysis retention time: 1.374 min, 39.1 mg).

[0681] SFC primary analysis method: Instrument: Waters 150Prep-SFC, Column: Chiral WHEIK column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in MeOH; Gradient: 35% B gradient elution, flow rate: 120 mL / min, column temperature: room temperature, wavelength: 220 nm, cycle time: 4.3 min; Sample preparation: Sample concentration: 10 mg / mL, methanol solution injection: 3 mL per injection. After separation, the fractions were dried to yield Compounds 37-1 and 37-2.

[0682] Secondary SFC analysis method: Instrument: Waters 150Prep-SFC, Column: Chiral AD column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in MeOH; Gradient: 30% B gradient elution, flow rate: 120 mL / min, column temperature: room temperature, wavelength: 220 nm, cycle time: 8 min; Sample preparation: Sample concentration: 10 mg / mL, methanol solution injection: 3 mL per injection. After separation, the dried fractions yielded compounds 37-3 and 37-4.

[0683] Compound 37-1 (SFC analysis retention time: 2.311 min): 1 H NMR(400MHz,DMSO-d6)δ7.86-7.79(m,1H),7.44-7.36(m,1H),5.65(s,2H),4.79(s,2H),4.45-4.37(m,1H), 4.15-4.00(m,4H),2.92-2.56(m,8H),2.37(s,3H),1.83-1.68(m,2H),1.16-1.04(m,1H),1.02-0.92(m,1H).

[0684] LC-MS (ESI): m / z = 442.3 [M+H] + .

[0685] Compound 37-2 (SFC analysis retention time: 2.173 min): 1 H NMR(400MHz,DMSO-d6)δ7.86-7.79(m,1H),7.44-7.36(m,1H),5.65(s,2H),4.79(s,2H),4.45-4.37(m,1H), 4.15-4.00(m,4H),2.92-2.56(m,8H),2.37(s,3H),1.83-1.68(m,2H),1.16-1.04(m,1H),1.02-0.92(m,1H).

[0686] LC-MS (ESI): m / z = 442.3 [M+H] + .

[0687] Compound 37-3 (SFC analysis retention time: 1.763 min): 1 H NMR(400MHz,DMSO-d6)δ7.86-7.79(m,1H),7.44-7.36(m,1H),5.65(s,2H),4.79(s,2H),4.45-4.37(m,1H), 4.15-4.00(m,4H),2.92-2.56(m,8H),2.37(s,3H),1.83-1.68(m,2H),1.16-1.04(m,1H),1.02-0.92(m,1H).

[0688] LC-MS (ESI): m / z = 442.3 [M+H] + .

[0689] Compound 37-4 (SFC analysis retention time: 1.374 min): 1 H NMR(400MHz,DMSO-d6)δ7.86-7.79(m,1H),7.44-7.36(m,1H),5.65(s,2H),4.79(s,2H),4.45-4.37(m,1H), 4.15-4.00(m,4H),2.92-2.56(m,8H),2.37(s,3H),1.83-1.68(m,2H),1.16-1.04(m,1H),1.02-0.92(m,1H).

[0690] LC-MS (ESI): m / z = 442.3 [M+H] + .

[0691] Example 38

[0692] Step 1: Compound 24J (360.0 mg, 0.76 mmol) was added to a mixed solvent of dry toluene (10 mL) and N,N-dimethylformamide (3 mL), and then iodine (407.0 mg, 3.04 mmol) was added. After nitrogen replacement three times, (trifluoromethyl)trimethylsilane (540.0 mg, 3.80 mmol) and tri-n-butylphosphine (921.2 mg, 4.56 mmol) were added in sequence. After the addition, the temperature was raised to 45°C and the reaction was carried out for 16 hours. After the completion of the reaction monitored by TLC, the reaction solution was slowly added to 50 mL of ice water and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 3) to obtain compound 38A (90.0 mg, yield: 23%).

[0693] LC-MS (ESI): m / z = 508.2 [M+H] + .

[0694] Step 2: 38A (90.0 mg, 0.18 mmol) was dissolved in a mixed solvent of methanol (3 mL), tetrahydrofuran (3 mL), and water (3 mL). Lithium hydroxide (37 mg, 0.90 mmol) was then added and allowed to react at room temperature for 6 hours. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to a weakly acidic state. A small amount of water was then added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were concentrated and purified by HPLC to afford compound 38 (30.0 mg, 32%).

[0695] LC-MS (ESI): m / z = 494.2 [M+H] + .

[0696] 1 H NMR(400MHz,CD3Cl)δ8.01(d,1H),7.84(d,1H),5.60(s,2H),4.97(s,1H),4.21(s,3H),3.23-3.19(m,2H),2.88-2.84(m ,4H),2.69-2.59(m,5H),2.40-2.36(m,1H),2.28-2.24(m,2H),2.09-2.03(m,1H),1.55-1.45(m,2H),0.88-0.77(m,3H).

[0697] Example 39

[0698] Using compound 30A as starting material and referring to the first to fourth steps of Example 30, compound 39 (54 mg, 46%) was obtained.

[0699] LC-MS (ESI): m / z = 524.4 [M+H] + .

[0700] 1 H NMR (400MHz, CDCl3) δ8.06-8.03(m,1H),7.77-7.74(m,1H),6.33-5.95(m,1H),5.62-5.45(m,2H),4.81(s,1H),4.35-4.27(m,1H),4.22-4. 03(m,4H),2.91-2.79(m,4H),2.68(s,3H),2.64-2.56(m,2H),2.32-2 .21(m,2H),2.12-1.95(m,2H),1.94-1.71(m,5H),1.70-1.57(m,1H).

[0701] Example 40

[0702] Compound 40 (41 mg) was synthesized using 31A (400 mg, 1.99 mmol) as starting material by referring to steps 1 to 4 of Example 30.

[0703] LC-MS (ESI): m / z = 524.3 [M+H] + .

[0704] 1 H NMR (400MHz, CDCl3) δ8.08-8.05(m,1H),7.87-7.84(m,1H),6.37-5.96(m,1H),5.64-5.48(m,2H),4.89-4.61(m,3H),4.19(s,3H) ,2.90-2.81(m,4H),2.75(s,3H),2.54-2.46(m,2H),2.46-2.37(m,2H),2.11-1.96(m,2H),1.95-1.70(m,5H),1.69-1.59(m,1H).

[0705] Example 41

[0706] Step 1: Compound 41B (300 mg, 21.40%) was synthesized using 41A (890 mg, 5.0 mmol) as starting material and referring to the synthesis method of Step 1 in Example 30.

[0707] Step 2: Dissolve 41B (300 mg, 1.22 mmol) in dry tetrahydrofuran (10 mL) at room temperature. Add palladium hydroxide / carbon (856 mg, 1.22 mmol) and hydrochloric acid (5 mg, 0.12 mmol). Under a hydrogen atmosphere, react at room temperature for 16 hours. Stop the reaction by TLC monitoring of the disappearance of the starting material. Filter to obtain compound 41C (180 mg, 94.64%).

[0708] Step 3: 41C (180 mg, 1.15 mmol) was dissolved in dry tetrahydrofuran (5 mL) at room temperature. Under a nitrogen atmosphere, triethylamine (350 mg, 3.45 mmol) and N,N'-carbonyldiimidazole (186 mg, 1.15 mmol) were added. The reaction was continued for 1 hour, and then 11D (534 mg, 1.38 mmol) was added. The reaction was continued at 80°C under a nitrogen atmosphere for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. Ethyl acetate (20 mL) was added to the reaction solution, and the organic phase was washed with water (30 mL × 3) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by column chromatography (PE:EA = 2:1) to obtain compound 41D (70 mg, 10.66%).

[0709] LC-MS (ESI): m / z = 570.3 [M+H] + .

[0710] Step 4: Compound 41 (25 mg, 38.56%) was synthesized using 41D (70 mg, 0.12 mmol) as starting material and referring to the synthesis method of Step 4 of Example 1.

[0711] LC-MS (ESI): m / z = 528.3 [M+H] + .

[0712] 1 H NMR(400MHz,DMSO-d6)δ7.85-7.83(d,1H),7.69(s,1H),7.51-7.49(d,1H),4.78-4.74(t,3H),4.55(s,2H),4.04(s,3H),2.8 3-2.80(m,2H),2.67-2.60(m,1H),2.45(s,3H),2.17-2.14(m,2H),2.05-1.99(m,1H),1.88-1.75(m,3H),1.67-1.46(m,4H).

[0713] Example 42:

[0714] Compound 42 (27 mg, 29.15%) was synthesized using 42A (890 mg, 5.0 mmol) as starting material and referring to the synthetic route of Example 41.

[0715] LC-MS (ESI): m / z = 528.3 [M+H] + .

[0716] 1 H NMR(400MHz,DMSO-d6)δ7.85-7.83(d,1H),7.68(s,1H),7.52-7.50(d,1H),5.00-4.93(d,3H),4.78-4.76(d ,4H),4.05(s,3H),2.66-2.64(m,1H),2.46(s,3H),2.05-1.97(m,2H),1.91-1.73(m,4H),1.69-1.43(d,4H).

[0717] Example 43

[0718] Step 1: Compound 43A (1.5 g, 13.05 mmol) was synthesized into compound 43B (1.5 g) according to the method of patent WO2011046771.

[0719] According to the first and second steps of Example 36, Compound 43D (0.43 g) was obtained.

[0720] Step 4: Compound 43D (0.1 g, 0.29 mmol) was dissolved in dry tetrahydrofuran (5 ml), and diphenylphosphoryl azide (44 mg, 1.16 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (178 mg, 1.16 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After completion of the reaction monitored by TLC, the residue was directly concentrated and purified by normal phase column to give compound 43E (90 mg, yield: 83%).

[0721] LC-MS (ESI): m / z = 374.2 [M+H] + .

[0722] Step 5: Compound 43E (90 mg, 0.24 mmol) was dissolved in tetrahydrofuran / water (3 ml / 1 ml), and triphenylphosphine (94 mg, 0.36 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction monitored by TLC, the residue was directly concentrated and purified by normal phase column to give compound 43F (53 mg, yield: 64%).

[0723] LC-MS (ESI): m / z = 348.2 [M+H] + .

[0724] Using compound 43F and compound 22D as starting materials, compound 43 (20 mg) was obtained according to the fourth and fifth steps of Example 22.

[0725] LC-MS (ESI): m / z = 480.2 [M+H] + .

[0726] 1 H NMR(400MHz, CDCl3)δ8.03(d,1H),7.21(d,1H),7.16(s,1H),5.03-4.95(m,1H),4.57(d,2H),4.18 (s,3H),4.11(t,2H),3.06-3.00(m,2H),2.77-2.66(m,2H),2.48(s,3H),2.17(t,2H),1.35(s,6H).

[0727] Example 44

[0728] Step 1: Compound 29F (85 mg, 0.24 mmol) was added to tetrahydrofuran (5 ml), followed by the addition of DPPA (180 mg, 0.48 mmol) and DBU (73 mg, 0.48 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give compound 44A (75 mg, yield: 82%).

[0729] LC-MS (ESI): m / z = 374.2 [M+H] + .

[0730] Step 2: Compound 44A (75 mg, 0.20 mmol) was added to a mixed solvent of 3 mL of tetrahydrofuran and 1 mL of water, followed by the addition of triphenylphosphine (100 mg, 0.40 mmol). The mixture was stirred at room temperature for 12 hours under nitrogen protection. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 44B (55 mg, yield: 79%).

[0731] LC-MS (ESI): m / z = 348.2 [M+H] + .

[0732] Step 3: Compound 44B (55 mg, 0.16 mmol) and compound 22D (68 mg, 0.24 mmol) were added to a reaction flask and dissolved in tetrahydrofuran (5 ml). DIPEA (41 mg, 0.32 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 44C (60 mg, 77% yield).

[0733] LC-MS (ESI): m / z = 494.2 [M+H] + .

[0734] Step 4: Compound 44C (60 mg, 0.12 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (5 ml). Lithium hydroxide monohydrate (25 mg, 0.60 mmol) was then added and reacted at 35°C for 16 hours. After completion of the reaction, the pH was adjusted to approximately 7 with 1 M HCl, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to afford compound 44 (16 mg, 27% yield).

[0735] LC-MS (ESI): m / z = 480.3 [M+H] + .

[0736] 1 H NMR (400MHz, CD3OD) δ7.90-7.75(m,1H),7.41-7.34(m,1H),5.02-4.94(m,1H),4.75(s,2H),4.15( s,3H),3.91(s,2H),3.08-2.97(m,2H),2.78-2.62(m,2H),2.53(s,3H),2.44(s,2H),1.21(s,6H).

[0737] Example 45

[0738] Step 1: Compound 45A (1.0 g, 5.81 mmol) was dissolved in THF (20 ml). Borane dimethyl sulfide solution (0.8 ml, 10 M in DMS) was added at 0°C and the mixture was allowed to warm to room temperature for 16 hours. After completion of the reaction, the reaction was quenched with methanol and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 45B (0.9 g, 97.82% yield).

[0739] 1H NMR (400MHz, DMSO-d6) δ4.65-4.61(m,1H),3.56(s,3H),3.39-3.36(m,2H),2.43(s,2H),1.84-1.77(m,6H).

[0740] Step 2: Compound 17E (0.95 g, 3.12 mmol), compound 45B (0.89 g, 5.62 mmol), and tributylphosphine (1.9 g, 9.36 mmol) were added to a reaction flask and dissolved in toluene (50 ml). ADDP (2.35 g, 9.36 mmol) was then added and the mixture was reacted at 55°C for 16 hours. After completion of the reaction, as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 45C (1.2 g, 86.48% yield).

[0741] LC-MS (ESI): m / z = 445.3 [M+H] + .

[0742] Step 3: Compound 45C (1.2 g, 2.70 mmol) was added to a reaction flask and dissolved in methanol (15 ml). PPTS (0.68 g, 2.70 mmol) was then added and reacted at 60°C for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford compound 45D (0.56 g, 57.56% yield).

[0743] LC-MS (ESI): m / z = 361.2 [M+H] + .

[0744] Step 4: Compound 45D (0.56 g, 1.55 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (10 ml). DPPA (850 mg, 3.10 mmol) and DBU (470 mg, 3.10 mmol) were then added and allowed to react at room temperature for 2 hours. After completion of the reaction, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford compound 45E (0.55 g, 91.84% yield).

[0745] LC-MS (ESI): m / z = 386.3 [M+H] + .

[0746] Step 5: Compound 45E (0.55 g, 1.43 mmol) was added to a reaction flask and dissolved in THF:H₂O = 5:1 (12 ml). Triphenylphosphine (750 mg, 2.86 mmol) was then added and allowed to react at room temperature for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford compound 45F (0.25 g, 48.74% yield).

[0747] LC-MS (ESI): m / z = 360.3 [M+H] + .

[0748] Step 6: Compound 45F (0.25 g, 0.70 mmol) was added to a reaction flask and dissolved in dichloromethane (10 ml). DIPEA (0.36 ml, 2.1 mmol) and compound 22D (0.24 g, 0.84 mmol) were then added and allowed to react at room temperature for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford compound 45G (0.3 g, 85.32% yield).

[0749] LC-MS (ESI): m / z = 506.2 [M+H] + .

[0750] Step 7: Compound 45G (0.3 g, 0.59 mmol) was added to a reaction flask and dissolved in THF:H2O:MeOH = 3:1:1 (10 ml). Lithium hydroxide (28 mg, 1.18 mmol) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure and the resulting residue was purified by reverse-phase column chromatography to afford compound 45 (0.1 g, 34.28% yield).

[0751] 1 H NMR (400MHz, DMSO-d6) δ7.86-7.81(m,1H),7.74-7.66(m,1H),7.48-7.43(m,1H),4.98-4.88(m,1H),4.80-4.72(m, 2H),4.08(s,2H),4.04(s,3H),3.07-2.96(m,2H),2.72-2.61(m,2H),2.58(s,2H),2.43(s,3H),2.06-1.89(m,6H).

[0752] LC-MS (ESI): m / z = 492.2 [M+H] + .

[0753] Example 46

[0754] Step 1: Compound 25B (600 mg, 1.63 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (496 mg, 3.26 mmol) were dissolved in tetrahydrofuran (15 ml), followed by the addition of diphenylphosphoryl azide (897 mg, 3.26 mmol). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EA = 2:1) to afford compound 46A (430 mg, 67.12% yield).

[0755] LC-MS (ESI): m / z = 394.1 [M+H] + .

[0756] Step 2: Compound 46A (430 mg, 1.09 mmol) was dissolved in a mixture of tetrahydrofuran (10 ml) and water (2 ml). Triphenylphosphine (573 mg, 2.19 mmol) was then added and stirred at room temperature for 4 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford compound 46B (200 mg, 50.0% yield).

[0757] LC-MS (ESI): m / z = 368.2 [M+H] + .

[0758] Step 3: Compound 46B (200 mg, 0.54 mmol) was added to a reaction flask and dissolved in 20 ml of dichloromethane. DIPEA (210 mg, 1.63 mmol) and 22D (230 mg, 0.81 mmol) were then added and reacted at room temperature for 16 hours. After completion of the reaction, as monitored by TLC, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 46C (230 mg, 83.03% yield).

[0759] LC-MS (ESI): m / z = 514.2 [M+H] + .

[0760] Step 4: Compound 46C (230 mg, 0.45 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 1:1:1 (12 ml). Anhydrous lithium hydroxide (43 mg, 1.79 mmol) was then added and stirred at room temperature for 18 hours. After completion of the reaction, the pH was adjusted to a weakly acidic state with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and concentrated under reduced pressure. The resulting residue was separated by preparative HPLC to afford compound 46D (190 mg, 85.20% yield).

[0761] LC-MS (ESI): m / z = 500.3 [M+H] + .

[0762] Step 5: Compound 46D was resolved by SFC to give compound 46-1 (SFC analysis retention time: 2.004 min, 70 mg) and compound 46-2 (SFC analysis retention time: 2.219 min, 80 mg).

[0763] SFC analysis: Instrument: SHIMADZU LC-30AD SFC, Column: Chiral IK column; Mobile phase: A: CO2, B: 0.05% DEA in i-PrOH; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation: Instrument: Waters 150Prep-SFC, Column: Chiral IK column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in i-PrOH; Gradient: 30% B; Flow rate: 100 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 7.0 min. Sample preparation: Sample concentration: 8 mg / mL, 5.0 mL injection per acetonitrile-methanol mixture. After separation, the dried fractions yielded Compounds 46-1 and 46-2.

[0764] Compound 46-1 (SFC analysis retention time: 2.004 min): 1 H NMR(400MHz,DMSO-d6)δ13.18(s,1H),7.86-7.84(m,1H),7.68(s,1H),7.50-7.48(m,1H),4.94-4.91(m,1H),4.77- 4.76(m,2H),4.31-4.29(m,1H),4.24-4.19(m,1H),4.04(s,3H),3.02-3.00(m,2H),2.81-2.64(m,4H),2.42(s,3H).

[0765] LC-MS (ESI): m / z = 500.4 [M+H] + .

[0766] Compound 46-2 (SFC analysis retention time: 2.219 min): 1H NMR(400MHz,DMSO-d6)δ13.18(s,1H),7.86-7.84(m,1H),7.69(s,1H),7.50-7.48(m,1H),4.95-4.91(m,1H),4.77- 4.76(m,2H),4.34-4.29(m,1H),4.24-4.20(m,1H),4.04(s,3H),3.02-3.00(m,2H),2.81-2.65(m,4H),2.43(s,3H).

[0767] LC-MS (ESI): m / z = 500.4 [M+H] + .

[0768] Example 47

[0769] Step 1: Cool a solution of diazomethane (1 mol / L) in diethyl ether (200 mL) to 0°C, add 47A (5 g, 51 mmol) and palladium acetate (0.57 g, 2.5 mmol), and react at room temperature for 3 h after N2 substitution. Filter, and concentrate the filtrate under reduced pressure to yield 47B (5 g, 87.5%).

[0770] 1 HNMR(400MHz,MeOD)δ4.45-4.40(m,2H),2.34(t,2H),1.16-1.12(m,2H),1.07-1.03(m,2H).

[0771] Step 2: 47B (5 g, 44.59 mmol) was added portionwise to a 33% HBr solution in acetic acid (40 ml) and reacted at room temperature for 2 h. Water (200 ml) was added, filtered, and the solid was washed with water to obtain 47C (4 g, 46.47%).

[0772] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),3.62-3.54(m,2H),2.05-1.95(m,2H),1.08-1.06(m,2H),0.86-0.84(m,2H).

[0773] Step 3: 47C (2 g, 10.36 mmol) was added to methanol (20 mL), followed by thionyl chloride (3.70 g, 31.08 mmol). The reaction was allowed to proceed at 70°C for 2 h. The reaction was monitored for completion, cooled to room temperature, and the methanol was directly evaporated under reduced pressure. Ethyl acetate (30 mL) was added, and the mixture was washed with water and then with saturated sodium chloride solution. The organic phase was concentrated under reduced pressure to yield 47D (2 g, 93.22%).

[0774] According to the second step, third step, fourth step, fifth step, sixth step and seventh step of Example 43, compound 47 (0.03 g) was obtained.

[0775] 1 HNMR(400MHz, CDCl3)δ8.03(d,1H),7.35(s,1H),5.04-4.94(m,1H),4.60(s,2H),4.30- 4.26(m,2H),4.18(s,3H),3.06-3.00(m,2H),2.75-2.69(m,2H),2.58(s,3H),2.12-2.10(m,2H),1.45-1.40(m,2H),1.00-0.95(m,2H).

[0776] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0777] Example 48

[0778] Compound 48E (160 mg, yield: 82%) was obtained by referring to steps 4 to 7 of Example 43 using compound 48A (580 mg, 1.55 mmol, synthesis method reference: WO2020060916) as starting material.

[0779] LC-MS (ESI): m / z = 506.2 [M+H] + .

[0780] Step 5: Compound 48E was subjected to chiral resolution to afford compounds 48-1 (SFC retention time: 1.671 min, 8 mg), 48-2 (SFC retention time: 1.791 min, 10 mg), 48-3 (SFC retention time: 1.634 min, 6 mg), and 48-4 (SFC retention time: 1.708 min, 3 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral WHELK column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in MeOH; Gradient: 35% B in A; Flow rate: 110 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150Prep-SFC, Column: Chiral WHELK column; Mobile phase: A: CO2, B: isopropanol; Gradient: 33% B gradient elution, flow rate: 120 mL / min, column temperature: 25°C, wavelength: 254 nm, cycle time: 8.1 min; Sample preparation: Sample concentration: 2 mg / mL, ethanol solution injection: 2 mL per sample. After separation, compounds 48-1, 48-2, 48-3, and 48-4 were lyophilized at -80°C.

[0781] Compound 48-1 (SFC analysis retention time: 1.671 min): 1 H NMR(400MHz,DMSO-d6)δ12.07(s,1H),7.83(d,1H),7.69(s,1H),7.45(d,1H) ,4.98-4.88(m,1H),4.78-4.75(s,2H),4.63-4.54(m,1H),4.04(s,3H),3.08 -2.96(m,2H),2.72-2.62(m,2H),2.57-2.52(m,1H),2.40(s,3H),2.32-2.22 (m,1H),2.04-1.90(m,2H),1.85-1.48(m,7H); LC-MS(ESI):m / z=506.2[M+H] + .

[0782] Compound 48-2 (SFC analysis retention time: 1.791 min): 1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),7.82(d,1H),7.70(s,1H),7.48(d,1H),4.98-4.87(m,1H),4.81-4.72(m,3H),4.04(s,3H),3.07 -2.97(m,2H),2.72-2.60(m,3H),2.42(s,3H),2.19-2.10(m,1H),2.05-1.91(m,3H),1.83-1.41(m,6H); LC-MS(ESI):m / z=506.2[M+H] + .

[0783] Compound 48-3 (SFC analysis retention time: 1.634 min): 1 H NMR(400MHz,DMSO-d6)δ12.07(s,1H),7.83(d,1H),7.69(s,1H),7.45(d,1H) ,4.98-4.87(m,1H),4.79-4.75(m,2H),4.63-4.53(m,1H),4.04(s,3H),3.08 -2.96(m,2H),2.71-2.60(m,2H),2.57-2.51(m,1H),2.40(s,3H),2.33-2.22 (m,1H),2.04-1.91(m,2H),1.85-1.47(m,7H); LC-MS(ESI):m / z=506.2[M+H] + .

[0784] Compound 48-4 (SFC analysis retention time: 1.708 min): 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),7.82(d,1H),7.70(s,1H),7.48(d,1H),4.97-4.88(m,1H),4.78-4.72(m,3H),4.04(s,3H),3.07 -2.97(m,2H),2.72-2.61(m,3H),2.42(s,3H),2.17-2.09(m,1H),2.05-1.91(m,3H),1.83-1.41(m,6H); LC-MS(ESI):m / z=506.2[M+H] + .

[0785] Biological test evaluation

[0786] 1. Cellular calcium flux experiment

[0787] 1) Dilute test compounds to 400X stock solution with DMSO in a 384-well plate.

[0788] 2) Transfer 1 μl of compound solution from step 1 to 39 μl of assay buffer and prepare a 10X working solution in a 384-well plate using the Bravo automated liquid handling platform.

[0789] 3) CHO-LPA1 cells were cultured using F12 medium (10% FBS).

[0790] 4) When the cells reached 80% confluency, 0.25% trypsin-EDTA was used to dissociate the cells.

[0791] 5) Measure the cell density and dilute the cells to 4 x 10e5 / ml with F12 (10% FBS).

[0792] 6) Use a multidrop automatic dispenser to dispense 30 μl of cells into a 384-well plate (Corning 3764#), with 12K cells per well. Incubate at 37°C, 5% CO2 for 18-20 hours.

[0793] 7) Replace with 25uL serum-free medium overnight.

[0794] 8) Add 10 μl of 3.5X loading dye to each well of the cell plate and incubate at 37°C, 5% CO2 in the dark for 0.5-1 hour.

[0795] 9) After incubation, transfer 5 μl of the 10X working solution from step 2 to the cell plate.

[0796] 10) Incubate the cell plate in the dark at 25°C for 15 minutes and then read the calcium signal.

[0797] 11) Prepare at least 20 μl / well of a 5X agonist (LPA) working solution in 1X HBSS + 20 mM HEPES + 0.1% BSA in a 384-well assay plate (Greiner #784075). The agonist concentration used in this assay is determined by the dose-response model previously tested. The EC80 is used as the final agonist concentration in the assay.

[0798] 12) Read and save the data using the FLIPR at room temperature using the specified settings.

[0799] 13) The signal value was plotted against the compound concentration, and the curve fitting and IC were performed using the nonlinear regression method of GraphPad Prism software. 50 calculate.

[0800] Experimental results: The compounds of the present invention have a significant antagonistic effect on LPAR 1 enzyme activity in vitro. The IC values ​​of the compounds of the examples on LPAR 1 enzyme activity are 50 The value is less than 100 μM. IC 50 The value is expressed as A, B, C, D, with A representing 0 <IC 50 ≤10nM, B means 10nM <IC 50 ≤50nM, C represents 50nM <IC 50 ≤100nM, D represents IC 50 The test results of some examples are shown in Table 1.

[0801] Table 1 Antagonistic activity of the compounds of the present invention against LPAR 1

[0802] Experimental conclusion: The compounds of the present invention, such as the example compounds, show high antagonistic activity against LPAR1 receptors, such as the IC values ​​of compounds 4, 5, 7, 12, and 19. 50 is 2nM.

[0803] 2. Pharmacokinetic test in mice

[0804] 2.1 Experimental Animals: Male C57 mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0805] 2.2 Experimental Design: On the day of the experiment, C57 mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0806] Table 2. Dosing Information

[0807] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4).

[0808] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0809] Table 3. Pharmacokinetic parameters of test compounds in mouse plasma

[0810] -:not applicable.

[0811] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic characteristics in mice. For example, compounds 4, 12, 22, 26, and 47 have excellent pharmacokinetic characteristics in mice.

[0812] 3. Pharmacokinetic test in rats

[0813] 3.1. Experimental Animals: Male SD rats, approximately 220 g, 6-8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0814] 3.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0815] Table 4. Dosing Information

[0816] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4).

[0817] Before and after drug administration, 0.15 mL of blood was collected from the eye socket under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0818] Table 5. Pharmacokinetic parameters of test compounds in rat plasma

[0819] -:not applicable.

[0820] Conclusion: The compounds of the present invention, such as Example Compounds 22, 26, and 29, have good pharmacokinetic characteristics in rats.

[0821] 4. Beagle dog pharmacokinetic test

[0822] 4.1. Experimental Animals: Male beagle dogs, weighing approximately 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0823] 4.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0824] Table 6. Dosing Information

[0825] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4).

[0826] Before and after dosing, 1 mL of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. All samples were stored at -80°C prior to analysis and quantitative analysis by LC-MS / MS.

[0827] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.

[0828] 5. Monkey pharmacokinetic test

[0829] 5.1. Experimental Animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0830] 5.2 Experimental Methods: On the day of the experiment, monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0831] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0832] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

[0833] 6. hERG potassium channel effect test

[0834] Experimental platform: electrophysiology manual patch clamp system

[0835] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0836] Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[0837] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0838] Inhibition%=[1-(I / Io)]×100%

[0839] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0840] The IC50 of the compounds was calculated using GraphPad Prism 5 software by fitting the following equation:

[0841] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0842] Among them, X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom

[0843] and Top are the minimum and maximum inhibition percentages, respectively.

[0844] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit hERG.

[0845] 7. CYP enzyme inhibition test

[0846] The purpose of this study was to evaluate the effects of test compounds on the activities of five cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro assay system. Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test compounds. The reaction was initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Following the reaction, the samples were processed and metabolites generated by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and IC50 values ​​were calculated to evaluate the inhibitory potential of the test compounds against each CYP enzyme isoform. Under the assay conditions, the incubation concentration ranged from 0 to 30 μM.

[0847] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no inhibitory effect on CYP enzymes.

[0848] 8. Liver microsome stability test

[0849] In this study, liver microsomes from five species, including humans, dogs, rats, and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0850] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and hepatic intrinsic clearance CL int(Liver) .

[0851] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0852] 9. Caco2 permeability test

[0853] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0854] Table 7

[0855] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0856] 10. Bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) mouse model

[0857] 1) Screening and Grouping: This study used a total of 48 9-week-old male C57BL / 6j mice. Before the experiment, the animals were divided into a sham-operated group (Group 1, 8 mice) and a model group (40 mice) based on their body weight. One week after modeling, the model group was divided into six groups (Groups 2 to 6), each with 8 mice, based on their body weight.

[0858] 2) Animal Modeling: On day 1 of the experiment, animals were anesthetized with Zotadine (50 mg / kg) and Xylazine (10 mg / kg). Mice in the model group received an intratracheal (it) injection of bleomycin at a dose of 0.66 mg / kg (1 U / kg) in a volume of 50 μL. Sham-operated group 1 (n=10) received an intratracheal injection of normal saline in a volume of 50 μL.

[0859] 3) Dosing of the test substances: Starting from day 7 of the experiment, Group 3 was administered with Compound 22 at a dose of 1 mg / kg in a volume of 10 mL / kg body weight, via gavage twice daily; Group 4 was administered with Compound 22 at a dose of 3 mg / kg in a volume of 10 mL / kg body weight, via gavage twice daily; Group 5 was administered with BMS-986278 at a dose of 10 mg / kg in a volume of 10 mL / kg body weight, via gavage twice daily; Group 6 was administered with Nintedanib at a dose of 60 mg / kg in a volume of 10 mL / kg body weight, via gavage once daily. Sham group 1 and model group 2 were administered with vehicle, via gavage twice daily at a volume of 10 mL / kg body weight.

[0860] 4) Detection indicators: Lung tissue was collected for pathological examination at the end of the study.

[0861] Results: Bleomycin (0.66 mg / kg, intravenously) injected for 21 days significantly increased the Modified Ashcroft score and pulmonary fibrosis area in the model mice's lung tissue. Compared with the vehicle-treated group, compound 22, administered orally twice daily for 14 days at doses of 1 mg / kg and 3 mg / kg, significantly reduced the Modified Ashcroft score and pulmonary fibrosis area in the model mice's lung tissue at the study endpoint. The Modified Ashcroft score was less than 4 points, and the pulmonary fibrosis area was less than 20% at the 3 mg / kg dose. At a dose of 1 mg / kg, compound 22 was comparable in efficacy to 10 mg / kg BMS-986278 and 60 mg / kg nintedanib, and was superior to both BMS-986278 and nintedanib at a dose of 3 mg / kg.

Claims

1. A compound represented by formula (I), its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, Ring C is selected from The "*" end is connected to the left pyridine ring, The end is connected to L2; Ring A is selected from a 3-12-membered carbocyclic group, a 4-12-membered heterocyclic group, or Ring A is absent, and the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and heterocyclic group are optionally further substituted by 1-4 R A replace; R A Each is independently selected from H, halogen, =O, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -(5-10 membered heterocyclic group), -(3-6 membered carbocyclic group)-COOR a1 、-(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 、-(CH2) p -P(O)(OH)2, =CH2, =CF2, =CH-CH3 or =C-(CH3)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution; L1 is selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace; R L1 are each independently selected from H, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2; When ring A is absent, L1 is selected from -OC substituted with one COOH 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; L2 is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2, -(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2, -(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 )、-C(=O)N(R L31 )2、-N(R L31 )-C(=O)OR L32 、-(CH2) p R L33 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2, -(CR L21 R L22 ) p -SC(O)-N(R L25 )2, -(CR L21 R L22 ) p N(R L29 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocyclic group substitution; R a1 , R a2 , R L1 , R L2 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L30 , R L31 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, -(CH2) p -OC 3-10 Cycloalkyl, -OC 3-10 The cycloalkyl group, the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally further substituted by 1-4 heteroatoms selected from Halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -SCF3, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 radical substitution of cycloalkyl groups; R L32 Selected from -C 1-4 Alkyl-(5-10 membered heteroaryl), -C 1-4 Alkyl-(6-10 membered aryl), wherein the heteroaryl and aryl are optionally further substituted with 1-3 groups selected from halogen, CN, OH, NO2, NH2, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Substitution of alkynyl groups by substituents; R L33 Selected from C 1-4 Alkyl, halogen, OH, NH2, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)H, -C(=O)OH, C 3-10 Cycloalkyl, C 1-4 Alkoxy, 5-14 membered heterocyclic group, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocyclic group may be further substituted by 1-4 halogen, OH, NH2, CN, N3, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; Alternatively, R L24 With R L25 or R L26 With R L27 or two R L23 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, acetyl group substitution; p is independently selected from 0, 1, 2, 3, and 4.

2. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, having the structure of formula (I-1), wherein: L 2-1 Selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2, -(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2, -(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 ),-(CR L21 R L22 ) p N(R L29 )(R L30 ),-(CR L21 R L22 ) p -C(O)-N(R L29 )-C(O)R L21 、-(CR L21 R L22 ) p -C(O)-N(R L29 )-S(O)2R L21 、-(3-6 membered cycloalkyl)-C(=O)N(R L25 )2, -(4-7 membered heterocyclyl)-C(=O)N(R L25 )2、-(C 2-4 alkenyl)-(4-7 membered heterocyclyl)-N(R L25 )2, -(CR L21 R L22 ) p -SC(O)-N(R L25 )2, -(CR L21 R L22 ) p N(R L26 )C(S)N(R L27 )(R L28 ), -(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -OR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)OR L23 , Cy is selected from 4-7 membered heterocyclic groups, the cycloalkyl and heterocyclic groups are optionally further substituted by 1-4 selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocyclic group substitution; R L21 , R L22 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by 1-4 atoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution; Each R L23 Each independently selected from C 1-4 Alkyl, -(CH2) p -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, S, S(O), S(O)2; wherein the alkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted by 1-4 heteroatoms selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution; And when R L21 , R L22 When both are H and L1 is O, at least one R L23 Selected from -(CH2) p -(4-7 membered heterocycloalkyl), 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -(CH2) p -OC 3-6 Cycloalkyl, 1-4 selected from -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, Substituted C 3-6 Cycloalkyl, the heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from =O, halogen, OH, -OCF3, -OCHF2, -SCF3, NH2, CN, acetyl, -S(O)2CH3, The group substitution; R L24 Each independently selected from H, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkenyl and alkynyl are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group substitution; Each R L25 , R L27 , R L28 Each independently selected from C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1 to 4 groups selected from halogen, OH, NH2, and CN; R L26 Each independently selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, the alkenyl, alkynyl, cycloalkyl may be further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution; R L29 Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1 to 4 groups selected from halogen, OH, NH2, and CN; R L30 is selected from a 6-14 membered bicyclic or tricyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, CN, OH, NH2, C 1-4 Alkyl, halogenated C 1-4 Alkyl radical substitution; p is selected from 0, 1, 2, 3, 4; Alternatively, R L24 With R L25 or R L26 With R L27 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl, acetyl group substitution; Alternatively, two R L23 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 groups selected from =O, OH, NH2, CN, and acetyl; The conditions are: (1) R L30 Not for (2) The compound is not 3. The compound represented by formula (I-1) according to claim 2, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, wherein: L 2-1 Selected from L1 is selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -NHC(O)-, -CH2-, -NH-, -N(CH3)-, -NHCH(CH3)-.

4. The compound represented by formula (I) according to claim 1, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, having the structure of formula (I-2), (I-2a), (I-2b), (I-2c), wherein: Ring A1, A1b, A1c are each independently selected from a 3-12 membered carbocyclic group, a 4-12 membered heterocyclic group or are absent, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and the heterocyclic group are optionally further substituted by 1-4 R A replace; R A Each is independently selected from H, =O, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -5-10 membered heterocyclic group, -(3-6 membered carbocyclic ring)-COOR a1 、-(CH2) p -COOR a1 、-(CH2) p -C(O)NR a1 R a2 、-(CH2) p -C(O)NHC(O)R a1 、-(CH2) p -C(O)NHS(O)2R a1 、-(CH2) p -C(O)NHS(O)R a1 、-(CH2) p -S(O)2OH, -(CH2) p -S(O)2NHC(O)R a1 、-(CH2) p -P(O)(OH)2, =CH2, =CF2, =CH-CH3 or =C-(CH3)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 alkyl radical; and L 1-1 -A1, L 1-1b -A1b, O-A1c are not selected L 1-1 , L 1-1b are each independently selected from a bond, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace; L 1-1a Select from key, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace; R L1 are each independently selected from H, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2; When rings A1 and A1b are each independently selected from 1-1 , L 1-1b Each independently selected from -OC substituted with one COOH 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; L 2-2 and L 2-2c are each independently selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )2, -(CR L21 R L22 ) p N(R L24 )S(O)2N(R L25 )2, -(CR L21 R L22 ) p N(R L26 )C(O)N(R L27 )(R L28 )、-(CR L21 R L22 ) p N(R L29 )(R L30 )、-(CR L21 R L22 ) p -OC(O)-R L23 、-(CR L21 R L22 ) p -O-R L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)O-R L23 ; R a1 , R a2 , R L1 , R L2 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, 5-10 membered heterocycloalkyl, -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, -(CH2) p -OC 3-10 The cycloalkyl group contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl group are optionally further substituted by 1-4 halogen, =O, =CH2, =CF2, =CH-CH3, =C-(CH3)2, OH, NH2, CN, acetyl, -S(O)2CH3, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, -SCF3, C 3-10 Cycloalkyl, 5-12 membered heterocyclic group, -C≡CC 3-10 radical substitution of cycloalkyl groups; R L29 Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted with 1-4 Substituted with a group selected from halogen, OH, NH2, CN; R L30 is selected from a 6-14 membered bicyclic or tricyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, CN, OH, NH2, C 1-4 Alkyl, halogenated C 1-4 Alkyl radical substitution; Alternatively, R L24 With R L25 or R L26 With R L27 Together with the atoms to which it is attached, it forms a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally further substituted by 1-3 heteroatoms selected from halogen, =O, OH, NH2, CN, C 1-4 Alkyl radical substitution; p is each independently selected from 0, 1, 2, 3, 4; The conditions are: (1) For formula (I-2), when L 2-2 Selected from When L 1-1 -A1 is not selected from (2) For formula (I-2), when L 2-2 Selected from When L 1-1 -A1 is not selected from (3) For formula (I-2b), L 1-1b -A1b not selected (4) For formula (I-2c), O-A1c is not selected from 5. The compound represented by formula (I-2), (I-2b), (I-2c) according to claim 4, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, wherein: Ring A1, A1b, A1c is selected from 3-8 membered monocyclic cycloalkyl, 6-12 membered paracycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered heteroparacycloalkyl, 6-10 membered heterospirocyclyl, 6-10 membered heterobridged cyclyl or does not exist, the heterocycloalkyl, heteroparacycloalkyl, heterospirocyclyl, heterobridged cyclyl contains 1-3 heteroatoms selected from N, O, S, the cycloalkyl, heterocycloalkyl, heteroparacycloalkyl, heterospirocyclyl, heterobridged cyclyl is optionally further substituted by 1-4 R A replace; R A Each is independently selected from H, halogen, =O, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-2 Alkyl, -(CH2) p -(5-8 membered heterocyclic group), -(3-6 membered carbocyclic group)-COOR a1 、-(CH2) p -COOR a1 , =CH2, =CF2, =CH-CH3 or =C-(CH3)2, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, heterocyclic group is optionally further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution; L 1-1 , L 1-1b are each independently selected from a bond, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -O-, -OC 1-4 Alkyl-, -S-, -SC 1-4 Alkyl-, -C(O)NR L1 -、-NR L1 C(O)-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace; R L1 are each independently selected from H, halogen, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, 3-6 membered cycloalkyl, -COOH, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, and NH2.

6. The compound represented by formula (I-2), (I-2b), (I-2c) according to claim 5, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, wherein: Rings A1, A1b, and A1c are each independently selected from A One of the groups formed by the following structures: R A Each independently selected from H, C 1-2 Alkyl, halogen, CN, OH, -COOH, -CH2-COOH, -CH2CH2-COOH, =CH2, =CF2, =CH-CH3 or =C-(CH3)2; L 1-1 , L 1-1b are each independently selected from a bond, C 1-2 Alkyl, -OC 1-2 Alkyl-, -S-, -O-, vinyl, propenyl, ethynyl, -C(O)NH-, -NHC(O)-, wherein the alkyl group is optionally further substituted by 1 to 4 R L1 replace; R L1 are each independently selected from H, halogen, OH, C 1-2 Alkyl, 3-6 membered cycloalkyl; L 2-2 , L 2-2c Each independently selected from 7. The compound represented by formula (I-2), (I-2a), (I-2b), (I-2c) according to claim 6, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, wherein: Rings A1, A1b, and A1c are each independently selected from the following structures: L 1-1 , L 1-1b Each independently selected from a bond, -OCH2-, -OCH2CH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -O-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-; L 1-1a Each independently selected from a bond, -OCH2-, -S-, -OCH(CH3)-, -OCH(CF3)-, -C(=O)-, -CH2-, -CH=CH-CH2-, ethynyl, -NHCO-, -NH-, -N(CH3)-, -NHCH(CH3)-.

8. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, having the structure of formula (I-6), wherein: in, L 2-2 Selected from -(CR L21 R L22 ) p -OC(O)-N(CH3)R L23 、-(CR L21 R L22 ) p -OC(O)-NHR L23 、-(CR L21 R L22 ) p -N(R L26 )C(O)O-R L23 ; R L21 , R L22 , R L26 Each independently selected from H, C 1-4 alkyl; R L23 Selected from -(CH2) p -(4-7 membered heterocyclic group), -(CH2) p -C 3-10 Cycloalkyl, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the cycloalkyl and heterocyclic groups are further substituted by 1-4 groups selected from =CH2, =CF2, =CH-CH3, and =C-(CH3)2; Ring A1 is selected from a 3-12-membered carbocyclic group, a 4-12-membered heterocyclic group or is absent, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and the heterocyclic group are optionally further substituted by 1-4 R A replace; When ring A1 is absent, L 1-1 Selected from -OC substituted with one COOH 1-6 alkyl; L 1-1 Select from key, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-, -OC 1-6 Alkyl-, -S-, -SC 1-6 Alkyl-, -C(O)NR L1 -、 -NR L1 -、-NR L1 -C 1-6 Alkyl-, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 R L1 replace; R A , R L1 , pAs described in claim 1.

9. The compound according to claim 1, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table 1 and Table 2.

10. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 9, or a stereoisomer, a deuterated substance, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

11. The pharmaceutical composition or pharmaceutical preparation according to claim 10, comprising 1-1500 mg of the compound according to any one of claims 1-9 or its stereoisomer, deuterated substance, or pharmaceutically acceptable salt and a carrier and / or excipient.

12. Use of the compound according to any one of claims 1 to 9, its stereoisomer, deuterated substance, or pharmaceutically acceptable salt, or the composition according to claims 10 to 11 in the preparation of a medicament for treating / preventing a disease mediated by LPAR1.

13. The use according to claim 12, wherein the LPAR1-mediated disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, and neuralgia.

14. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a stereoisomer, deuterated substance, or a pharmaceutically acceptable salt thereof, or a composition according to claims 10 to 11, the therapeutically effective amount preferably being 1 to 1500 mg, wherein the disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis, benign prostatic hyperplasia, multiple sclerosis, nerve damage, and neuralgia.

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