Lpar1 antagonists and uses thereof

Abstract

The present application relates to a kind of LPAR 1 antagonist and its use.The present application discloses a kind of compound shown in formula (IA), or its stereoisomer or pharmaceutically acceptable salt and their pharmaceutical compositions, and its use in the preparation of treating / preventing LPAR 1 mediated disease drug, each group in formula (IA) as defined in the specification.

Description

LPAR1 antagonists and uses thereof 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 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. Summary of the Invention

[0003] The present invention provides a compound of formula (IA), formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VIA), formula (VII), formula (VIII), formula (II-1), formula (II-2), or formula (II-3), and a stereoisomer or pharmaceutically acceptable salt thereof. The compound has the excellent effects of good activity, excellent physicochemical properties, ease of formulation, excellent pharmacokinetic properties, high bioavailability, and low toxic and side effects.

[0004] The compounds of formula (IA), formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VIA), formula (VII), formula (VIII), formula (II-1), formula (II-2), and formula (II-3), their stereoisomers or pharmaceutically acceptable salts,

[0005] in,

[0006] Ring A is selected from 3-8 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 4-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R A replace;

[0007] In some embodiments, ring A is selected from 4-8 membered monocyclic carbocyclyl, 6-12 membered bicyclic carbocyclyl, 6-12 membered monocyclic heterocyclyl, 6-12 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; wherein the carbocyclyl and heterocyclyl are optionally substituted by 1-4 R A replace;

[0008] In some embodiments, ring A is selected from 4-7 membered monocyclic carbocyclyl, 6-10 membered bicyclic carbocyclyl, 6-10 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; the carbocyclyl and heterocyclyl are optionally substituted by 1-4 R A replace;

[0009] In some embodiments, ring A is selected from 4-7 membered monocyclic carbocyclyl, 6-9 membered bicyclic carbocyclyl, 6-7 membered monocyclic heterocyclyl, 6-9 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; wherein the carbocyclyl and heterocyclyl are optionally substituted by 1-4 R A replace;

[0010] In some embodiments, ring A is selected from 3-7 membered monocyclic carbocyclyl, 6-10 membered bicyclic carbocyclyl, 4-10 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S, and the carbocyclyl and heterocyclyl are optionally substituted by 1-4 R A replace;

[0011] In some embodiments, ring A is selected from 3-7 membered monocyclic carbocyclic groups, 4-6 membered monocyclic heterocyclic groups, 6-10 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S, and the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R A replace;

[0012] In some embodiments, ring A is selected from 3-7 membered monocyclic carbocyclic groups, 4-6 membered monocyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S, and the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R A replace;

[0013] In some embodiments, Ring A is selected from a 4-7 membered monocyclic carbocyclyl, wherein the carbocyclyl is optionally substituted with 1-4 R A replace;

[0014] In some embodiments, Ring A is selected from C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1-4 R A replace;

[0015] In some embodiments, Ring A is selected from C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-4 COOH groups;

[0016] In some embodiments, Ring A is selected from The ring A is optionally substituted with 1-4 R A replace;

[0017] In some embodiments, Ring A is selected from The ring A is substituted with 1 COOH;

[0018] In some embodiments, Ring A is selected from The ring A is substituted with 1 COOH;

[0019] In some embodiments, Ring A is selected from The ring A is substituted with 1 COOH;

[0020] In some embodiments, Ring A is selected from: In some embodiments, Ring A is selected from:

[0021] Ring B is selected from 6-12 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 5-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R B replace;

[0022] In some embodiments, ring B is selected from 6-12 membered monocyclic carbocyclyl, 6-12 membered bicyclic carbocyclyl, 4-12 membered monocyclic heterocyclyl, 6-12 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; wherein the carbocyclyl and heterocyclyl are optionally substituted by 1-4 R B replace;

[0023] In some embodiments, ring B is selected from 6-10 membered monocyclic carbocyclyl, 6-10 membered bicyclic carbocyclyl, 6-8 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S, and the carbocyclyl and heterocyclyl are optionally substituted by 1-4 R B replace;

[0024] In some embodiments, ring B is selected from 8-10 membered bicyclic carbocyclyl, 6 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, said heterocycloalkyl, heteroaryl containing 1-3 heteroatoms selected from N, O, S, said carbocyclyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-4 R B replace;

[0025] In some embodiments, ring B is selected from 8-10 membered bicyclic carbocyclyl, 6 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, said heterocycloalkyl, heteroaryl containing 1-3 heteroatoms selected from N, O, S, said carbocyclyl, heterocycloalkyl, heteroaryl are optionally substituted by 1-4 R B replace;

[0026] In some embodiments, Ring B is selected from The ring B is optionally substituted with 1-4 R B replace;

[0027] In some embodiments, Ring B is selected from The ring B is optionally substituted with 1-4 R B replace;

[0028] In some embodiments, Selected from in indicates the connection site of loop B with L1 on the left, and indicates the connection site of loop B with L3 or loop C on the right;

[0029] Ring C is selected from a 5-12 membered monocyclic heterocyclic group, a 6-12 membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally substituted by 1-4 R C replace;

[0030] In some embodiments, ring C is selected from 6-8 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; wherein the heterocycloalkyl and heteroaryl groups are optionally substituted by 1-4 R C replace;

[0031] In some embodiments, ring C is selected from 5-6 membered monocyclic heteroaryl, 6-9 membered bicyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; wherein the heterocycloalkyl and heteroaryl groups are optionally substituted by 1-4 R C replace;

[0032] In some embodiments, Ring C is selected from 5-6 membered monocyclic heteroaryl;

[0033] In some embodiments, Ring C is selected from The ring C is optionally substituted with 1-4 R C Substituted; in some embodiments, Ring C is selected from The ring C is optionally substituted with 1-4 R C replace;

[0034] R A Each independently selected from H, halogen, CN, OH, -(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)Ra1 、-(CH2) p -P(O)(OH)2、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -5-10 membered heterocyclic group, 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 1-4 Alkyl radical substitution;

[0035] In some embodiments, R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or -OC 1-4 Alkyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0036] In some embodiments, R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOH, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or -OC 1-2 Alkyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0037] In some embodiments, R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOH, C 1-3 Alkyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0038] In some embodiments, R A Each independently selected from H, F, Cl, CN, OH, -CH2COOH, COOH, CH3, CH2CH3, CH2CH2CH3;

[0039] In some embodiments, RA Each independently selected from COOH;

[0040] R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, -SO2C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-10 membered heteroaryl, -SCF3, -S(=O)(=NH)-C 1-4 Alkyl, the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 heteroatoms selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0041] In some embodiments, R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, -SO2C 1-2 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-10 membered heteroaryl, -SCF3, -S(=O)(=NH)-C 1-2 Alkyl, the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 heteroatoms selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0042] In some embodiments, R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, -SO2C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 4-12 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally further substituted by 1-4 heteroatoms selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0043] In some embodiments, R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or 5-12 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally further substituted by 1-4 heteroatoms selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0044] In some embodiments, R B Each independently selected from H, halogen, CN, ═O, OH, C 1-2 Alkyl, NH2, -OC 1-2 Alkyl, -SO2C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SCF3, -S(=O)(=NH)-C 1- 2 alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0045] In some embodiments, R B Each independently selected from H, halogen, CN, ═O, OH, C 1-2 Alkyl, NH2, -OC 1-2 Alkyl, -SO2C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0046] In some embodiments, R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0047] In some embodiments, R B Each independently selected from H, halogen, CN, ═O, OH, C 1-2 Alkyl, NH2, -OC 1-2 Alkyl, C 2- 4-alkenyl or C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1- 4 alkyl group substitution;

[0048] In some embodiments, R B Each independently selected from H, halogen, =O, C 1-2 Alkyl, -SO2C 1-2 Alkyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrazolyl, imidazolyl, wherein the alkyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrazolyl, imidazolyl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0049] In some embodiments, R B Each independently selected from H, halogen, =O, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0050] In some embodiments, R B Each independently selected from H, F, Cl, ═O, CH 3 , CH 2 CH 3 ;

[0051] In some embodiments, R B Each independently selected from H, Cl, =O, CH3;

[0052] In some embodiments, R B Each independently selected from H, F, Cl, =O, CHF2, CF3, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3;

[0053] In some embodiments, R B Each independently selected from H, F, Cl, =O, CF3, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3;

[0054] In some embodiments, R B Each independently selected from H, F, Cl, =O, CF3, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2;

[0055] In some embodiments, R B Each independently selected from H, F, Cl, =O, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2;

[0056] In some embodiments, R B Each independently selected from H, F, Cl, =O, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH,

[0057] In some embodiments, R B Selected from F, Cl, CHF2, CF3, CH3, CH2CH3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3; in some embodiments, R B Selected from F, CHF2, CF3, CH3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3; in some embodiments, R B is selected from F, CF3, CH3; in some embodiments, RB’ Selected from F, Cl, CHF2, CF3, CH2CH3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3;

[0058] R C Each independently selected from H, halogen, CN, OH, NO2, NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0059] In some embodiments, R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, -OC 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0060] In some embodiments, R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0061] In some embodiments, R C Each independently selected from H, F, Cl, CH3, CH2CH3;

[0062] In some embodiments, R C Each independently selected from H, Cl, CH3;

[0063] In some embodiments, R C is selected from CH3, CH2CH3; in some embodiments, R C selected from CH3;

[0064] L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NR L1 -, -C(=O)NR L1 -、C 1-4Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0065] In some embodiments, L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -C(=O)NR L1 -、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0066] In some embodiments, L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -、-C(=O)-、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0067] In some embodiments, L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -、-C(=O)-、C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0068] In some embodiments, L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -、-C(=O)-、C 1-2 Alkyl, the alkyl group is optionally further substituted by 1-4 R L1 replace;

[0069] In some embodiments, L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NH-, -C(=O)NH-, C 1-2 Alkyl, C 2- 4-alkenyl, C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0070] In some embodiments, L1 is selected from a bond, -O-, -S-, -NH-, -C(=O)NH-, -CH2-, -O-CH2-, -S-CH2-; In some embodiments, L1 is selected from a bond, O, S, -O-CH2-, -S-CH2-, -C(=O)-, -CH2-, -CH2CH2-; In some embodiments, L1 is selected from a bond, -O-, -S-, -O-CH2-, -S-CH2-; In some embodiments, L1 is selected from a bond, -O-, -NH-, -C(=O)NH-, -CH2-, -O-CH2-; In some embodiments, L1 is selected from a bond, -O-; In some embodiments, L1 is selected from a bond; In some embodiments, L1 is selected from a bond; In some embodiments, L1 is selected from -O-; In some embodiments, L1 is selected from a bond, -O- or -NH-CO-;

[0071] L3 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NR L1 -, -C(=O)NR L1 -、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0072] In some embodiments, L3 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NH-, -C(=O)NH-,C 1-2 Alkyl, C 2- 4-alkenyl, C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0073] In some embodiments, L3 is selected from a bond, -O-, -S-, -C(=O)-, -NH-, -C(=O)NH-, -CH2-, -O-CH2-, -S-CH2-;

[0074] In some embodiments, L3 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NR L1 -、-C 1-4 Alkyl, the alkyl group is optionally further substituted by 1-4 R L1 replace;

[0075] In some embodiments, L3 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NH-, -C 1-2 Alkyl, the alkyl group is optionally further substituted by 1-4 R L1 Substitution; in some embodiments, L3 is selected from a bond, -O-, -S-, -C(=O)-, -NH-, -CH2-; in some embodiments, L3 is selected from a bond, -O-; in some embodiments, L3 is selected from a bond; in some embodiments, L3 is selected from -O-;

[0076] L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2、-(CR L21 R L22 ) p -OC(=O)-NR L2 (CR L21 R L22 ) p R L2 、-C(=O)N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )S(O)2N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-(CR L21 R L22 ) p NR L2 -C(=O)O(CR L21 R L22 ) p R L2 In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2)2、-C(=O)N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )S(O)2N(R L2 )2、(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-NR L2 -C(=O)O(CR L21 R L22 ) p R L2 In some embodiments, L2 is selected from -CH2-OC(=O)-N(R L2 )2, -CH2-OC(=O)-N(CH3)CR L21 R L22 R L2 、-NH-C(=O)OCR L21 R L22 R L2 、-CH2-N(CH3)-C(=O)OCR L21 R L22 R L2 、-CH2-NH-C(=O)OR L2 、-CH2-NH-C(=O)OCR L21 R L22 R L2 In some embodiments, L2 is selected from -CH2-OC(=O)-N(R L2 )2, -CH2-OC(=O)-N(CH3)CR L21 R L22 R L2 、-NH-C(=O)OCR L21 R L22 R L2 、-CH2-N(CH3)-C(=O)OCR L21 R L22 R L2 、-CH2-NH-C(=O)OCR L21 R L22 R L2 In some embodiments, L2 is selected from -(CR L21 RL22 ) p -OC(=O)-N(R L2 )2、-(CR L21 R L22 ) p -OC(=O)-NR L2 (CR L21 R L22 ) p R L2 、-C(=O)N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-(CR L21 R L22 ) p NR L2 -C(=O)O(CR L21 R L22 ) p R L2 In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2、-C(=O)N(R L2 )2; In some embodiments, L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2、-(CR L21 R L22 ) p -OC(=O)-NR L2 (CR L21 R L22 ) p R L2 In some embodiments, L2 is selected from -CH2-OC(=O)-N(R L2 )2; In some embodiments, L2 is selected from -CH2-OC(=O)-N(R L2 )2, -CH2-OC(=O)-N(CH3)CR L21 R L22 R L2 、-NH-C(=O)OCRL21 R L22 R L2 、-CH2-N(CH3)-C(=O)OCR L21 R L22 R L2 ; In some embodiments, L2 is selected from -CH2-OC(=O)-N(CH3)CH2CH2CH3, -CH2-OC(=O)-NHCH2CH2CH3; In some embodiments, L2 is selected from -CH2-OC(=O)-N(CH3)CH2CH2CH3;

[0077] In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, L2 is selected from In some embodiments, when Selected from When L2 is selected

[0078] In some embodiments, when Selected from When L3 is selected from -O-, -S-, -C(=O)-, -NH-, -C(=O)NR L1 -, -CH2-;

[0079] Each R a1 、R a2 、R L1 、R L2 、R L21 、R L22 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, C 6-10Aryl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl 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 Alkoxy group substitution;

[0080] In some embodiments, R L1 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 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 In some embodiments, R L1 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally 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 In some embodiments, R L1 Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally 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 In some embodiments, R L1 Each independently selected from H, C 1-3 Alkyl, wherein the alkyl is optionally 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 In some embodiments, R L1Each is independently selected from H, CH3, CH2CH3, CH2CH2CH3; in some embodiments, R L1 are each independently selected from H; in some embodiments, R L2 Each independently selected from H, C 1-4 Alkyl, C 3-10 Cycloalkyl, 5-14 membered heterocyclic group, C 6-10 Aryl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl 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 In some embodiments, R L2 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 5-14 membered heterocyclic group, C 6-10 Aryl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl 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 In some embodiments, R L2 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 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 In some embodiments, R L2 Each independently selected from H, C 1-4 Alkyl, C 3-6Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally 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 In some embodiments, R L2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 6-8 Aryl, the heterocycloalkyl, heteroaryl contains 1-3 heteroatoms selected from N, O, S; the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl 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 In some embodiments, R L2 Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally 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 In some embodiments, R L2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally 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 In some embodiments, R L2 Each independently selected from H, C 1-3 Alkyl, wherein the alkyl is optionally 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 In some embodiments, R L2 Each independently selected from H, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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 In some embodiments, R L2 Each is independently selected from H, CH3, CH2CH3, CH2CH2CH3; in some embodiments, R L2 Each independently selected from H, CH3, CH2CH3, CH2CH2CH3,

[0081] R L21 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 5-14 membered heterocyclic group, C 6-10 Aryl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl 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 In some embodiments, R L21 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, acetyl, C 1- 4 alkyl, C 1-4 Alkoxy, halogenated C 1-4 In some embodiments, R L21 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally 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 In some embodiments, RL21 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 6-8 Aryl, the heterocycloalkyl, heteroaryl contains 1-3 heteroatoms selected from N, O, S; the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl 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 alkoxy groups; in some embodiments, R L21 Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally 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 In some embodiments, R L21 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-8 Aryl, the alkyl, cycloalkyl, aryl 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 In some embodiments, R L21 Each independently selected from H, C 1-3 Alkyl, wherein the alkyl is optionally 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 Alkoxy group substitution;

[0082] In some embodiments, R L21 Each independently selected from H, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, wherein the alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl is optionally 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 Alkoxy group substitution;

[0083] In some embodiments, R L21 Each is independently selected from H, CH3, CH2CH3, CH2CH2CH3; in some embodiments, R L21 Each independently selected from H, CH3, CH2CH3, CH2CH2CH3, 2-chlorophenyl;

[0084] R L22 Each independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 5-14 membered heterocyclic group, C 6-10 Aryl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl 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 Alkoxy group substitution;

[0085] In some embodiments, 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, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0086] In some embodiments, R L22 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally 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 Alkoxy group substitution;

[0087] In some embodiments, R L22 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 6-8 Aryl, the heterocycloalkyl, heteroaryl contains 1-3 heteroatoms selected from N, O, S; the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl 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 Alkoxy group substitution;

[0088] In some embodiments, R L22 Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally 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 Alkoxy group substitution;

[0089] In some embodiments, R L22 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-8 Aryl, the alkyl, cycloalkyl, aryl 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 Alkoxy group substitution;

[0090] In some embodiments, R L22 Each independently selected from H, C 1-3 Alkyl, wherein the alkyl is optionally 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 Alkoxy group substitution;

[0091] In some embodiments, R L22 Each independently selected from H, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, wherein the alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl is optionally 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 Alkoxy group substitution;

[0092] In some embodiments, R L22 Each independently selected from H, CH3, CH2CH3, CH2CH2CH3;

[0093] In some embodiments, R L22 Each independently selected from H, CH3, CH2CH3, CH2CH2CH3, 2-chlorophenyl;

[0094] R a1 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, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0095] In some embodiments, R a1 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally 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 Alkoxy group substitution;

[0096] In some embodiments, R a1 Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally 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 Alkoxy group substitution;

[0097] In some embodiments, R a1Each independently selected from H, C 1-3 Alkyl, wherein the alkyl is optionally 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 Alkoxy group substitution;

[0098] In some embodiments, R a1 Each independently selected from H, CH3, CH2CH3, CH2CH2CH3;

[0099] R a2 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, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0100] In some embodiments, R a2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally 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 Alkoxy group substitution;

[0101] In some embodiments, R a2 Each independently selected from H, C 1-4 Alkyl, wherein the alkyl is optionally 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 Alkoxy group substitution;

[0102] In some embodiments, R a2 Each independently selected from H, C 1-3 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, =O, OH, NH2, CN, acetyl, C1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0103] In some embodiments, R a2 Each independently selected from H, CH3, CH2CH3, CH2CH2CH3;

[0104] p is selected from 0, 1, 2, 3, 4; in some embodiments, p is selected from 0, 1, 2, or 3; in some embodiments, p is selected from 0, 1, or 2; in some embodiments, p is selected from 0; in some embodiments, p is selected from 1; in some embodiments, p is selected from 2;

[0105] Provided that, (1) Ring B is not optionally replaced by 1-4 R B Replace the following structure:

[0106] (2) Ring B is selected from 1-4 R B Replaced or halogen-substituted When at least one R L2 Selected from C 3-10 Cycloalkyl or 5-14 membered heterocyclic group, and R L2 Further selected substituted by a group.

[0107] Specifically, in the first technical solution, the present invention provides a compound represented by formula (IA) or formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

[0108] in,

[0109] Ring A is selected from 3-8 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 4-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R A replace;

[0110] Ring B is selected from 6-12 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 4-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R B replace;

[0111] Ring C is selected from a 5-12 membered monocyclic heterocyclic group, a 6-12 membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally substituted by 1-4 R Creplace;

[0112] L1, L3 are selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NR L1 -, -C(=O)NR L1 -、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0113] L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2、-(CR L21 R L22 ) p -OC(=O)-NR L2 (CR L21 R L22 ) p R L2 、-C(=O)N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )S(O)2N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-(CR L21 R L22 ) p NR L2 -C(=O)O(CR L21 R L22 ) p R L2 ;

[0114] R A Each independently selected from H, halogen, CN, OH, -(CH2) p -COOR a1 、-(CH2) p -C(=O)NRa1 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、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -5-10 membered heterocyclic group, 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 1-4 Alkyl radical substitution;

[0115] R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, -SO2C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-10 membered heteroaryl or -SCF3, -S(=O)(=NH)-C 1-4 Alkyl, the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 heteroatoms selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0116] R C Each independently selected from H, halogen, CN, OH, NO2, NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0117] Each R a1 、R a2 、R L1 、R L2 、R L21 、R L22 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, C 6-10 Aryl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl 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 Alkoxy group substitution;

[0118] p is selected from 0, 1, 2, 3, 4;

[0119] Provided that, (1) Ring B is not optionally replaced by 1-4 R B Replace the following structure:

[0120] (2) Ring B is selected from 1-4 R B Replaced or halogen-substituted When at least one R L2 Selected from C 3-10 Cycloalkyl or 5-14 membered heterocyclic group, and R L2 Further selected The group is substituted.

[0121] Specifically, in the second technical solution, the present invention provides a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, which is further represented by formula (I):

[0122] in,

[0123] Ring A is selected from 4-8 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 6-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R A replace;

[0124] Ring B is selected from 6-12 membered monocyclic carbocyclic group, 6-12 membered bicyclic carbocyclic group, 6-12 membered monocyclic heterocyclic group, 6-12 membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the carbocyclic group and heterocyclic group are optionally substituted by 1-4 R B replace;

[0125] Ring C is selected from a 5-12 membered monocyclic heterocyclic group, a 6-12 membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally substituted by 1-4 R C replace;

[0126] L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -C(=O)NR L1 -、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0127] L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2、-C(=O)N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )S(O)2N(R L2 )2、(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-NR L2 -C(=O)O(CR L21 R L22 ) pR L2 ;

[0128] R A Each independently selected from H, halogen, CN, OH, -(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、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -5-10 membered heterocyclic group, 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 1-4 Alkyl radical substitution;

[0129] R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or 5-12 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0130] R C Each independently selected from H, halogen, CN, OH, NO2, NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0131] R a1 、R a2 、R L1 、R L2 、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, acetyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy group substitution;

[0132] p is selected from 0, 1, 2, 3, 4;

[0133] Provided that Ring B is not optionally replaced by 1-4 R B Replace the following structure:

[0134] The third technical solution of the present invention provides a compound described in formula (IA) or formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0135] Ring A is selected from a 3-7 membered monocyclic carbocyclyl, a 6-10 membered bicyclic carbocyclyl, a 4-10 membered monocyclic heterocyclyl, a 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S;

[0136] In some embodiments, Ring A is selected from a 3-7 membered monocyclic carbocyclyl, a 4-6 membered monocyclic heterocyclyl, a 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S;

[0137] In some embodiments, Ring A is selected from The ring A is substituted with 1 COOH;

[0138] In some embodiments, Ring A is selected from The ring A is substituted with 1 COOH;

[0139] In some embodiments, Ring A is selected from a 3-7 membered monocyclic carbocyclyl, a 4-6 membered monocyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S;

[0140] In some embodiments, Ring A is selected from The ring A is substituted with 1 COOH;

[0141] In some embodiments, Ring A is selected from a 4-7 membered monocyclic carbocyclyl, a 6-10 membered bicyclic carbocyclyl, a 6-10 membered monocyclic heterocyclyl, a 6-10 membered bicyclic heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S;

[0142] In some embodiments, Ring A is selected from 4-7 membered monocyclic carbocyclyl;

[0143] In some embodiments, Ring A is selected from The ring A is substituted with 1 COOH;

[0144] The definitions of other groups are consistent with those of any of the above technical solutions.

[0145] The fourth technical solution of the present invention provides a compound described in formula (IA) or formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0146] Ring B is selected from 8-10 membered bicyclic carbocyclyl, 6 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O and S;

[0147] In some embodiments, Ring B is selected from The ring B is optionally substituted with 1-4 R B replace;

[0148] R B Each independently selected from H, halogen, CN, ═O, OH, C 1-2 Alkyl, NH2, -OC 1-2 Alkyl, -SO2C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -SCF3, -S(=O)(=NH)-C 1-4 Alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0149] In some embodiments, R B Each independently selected from H, halogen, =O, C1-2 Alkyl, -SO2C 1-2 Alkyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrazolyl, imidazolyl or -SCF3, -S(=O)(=NH)-C 1-2 Alkyl, the alkyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrazolyl, imidazolyl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0150] In some embodiments, R B Each independently selected from H, F, Cl, =O, CHF2, CF3, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3;

[0151] In some embodiments, R B Each independently selected from H, F, Cl, =O, CF3, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2 or -SCF3, -S(=O)(=NH)-CH3;

[0152] In some embodiments, R B Each independently selected from H, F, Cl, =O, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2;

[0153] In some embodiments, R B Each independently selected from H, F, Cl, =O, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH,

[0154] In some embodiments, ring B is selected from 8-10 membered bicyclic carbocyclyl, 6 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S;

[0155] In some embodiments, Ring B is selected from The ring B is optionally substituted with 1-4 R B replace;

[0156] R B Each independently selected from H, halogen, CN, ═O, OH, C 1-2 Alkyl, NH2, -OC 1-2 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0157] In some embodiments, R B Each independently selected from H, halogen, =O, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0158] In some embodiments, R B Each independently selected from H, F, Cl, ═O, CH 3 , CH 2 CH 3 ;

[0159] The definitions of other groups are consistent with those of any of the above technical solutions.

[0160] The fifth technical solution of the present invention provides a compound described in formula (IA) or formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0161] Ring C is selected from 6-8 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the heterocycloalkyl and heteroaryl groups are optionally substituted by 1-4 R C replace;

[0162] In some embodiments, Ring C is selected from 5-6 membered monocyclic heteroaryl;

[0163] In some embodiments, Ring C is selected from The ring C is optionally substituted with 1-4 R C replace;

[0164] In some embodiments, Ring C is selected from The ring C is optionally substituted with 1-4 R C replace;

[0165] R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, -OC1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0166] In some embodiments, R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0167] In some embodiments, R C Each independently selected from H, F, Cl, CH3, CH2CH3;

[0168] The definitions of other groups are consistent with those of any of the above technical solutions.

[0169] The sixth technical solution of the present invention provides a compound described in formula (IA) or formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0170] L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NH-, -C(=O)NH-,C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0171] In some embodiments, L1 is selected from a bond, -O-, -S-, -NH-, -C(=O)NH-, -CH2-, -O-CH2-, -S-CH2-;

[0172] L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2、-(CR L21 R L22 ) p -OC(=O)-NR L2 (CR L21 R L22 ) p R L2 、-C(=O)N(R L2 )2、-(CR L21 R L22 ) pN(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-(CR L21 R L22 ) p NR L2 -C(=O)O(CR L21 R L22 ) p R L2 ;

[0173] In some embodiments, L2 is selected from -CH2-OC(=O)-N(R L2 )2, -CH2-OC(=O)-N(CH3)CR L21 R L22 R L2 、-NH-C(=O)OCR L21 R L22 R L2 、-CH2-N(CH3)-C(=O)OCR L21 R L22 R L2 、-CH2-NH-C(=O)OR L2 、-CH2-NH-C(=O)OCR L21 R L22 R L2 ;

[0174] In some embodiments, L2 is selected from -CH2-OC(=O)-N(R L2 )2, -CH2-OC(=O)-N(CH3)CR L21 R L22 R L2 、-NH-C(=O)OCR L21 R L22 R L2 、-CH2-N(CH3)-C(=O)OCR L21 R L22 R L2 、-CH2-NH-C(=O)OCR L21 R L22 R L2 ;

[0175] In some embodiments, L2 is selected from -CH2-OC(=O)-N(R L2 )2, -CH2-OC(=O)-N(CH3)CRL21 R L22 R L2 、-NH-C(=O)OCR L21 R L22 R L2 、-CH2-N(CH3)-C(=O)OCR L21 R L22 R L2 ;

[0176] In some embodiments, L2 is selected from Or selected from

[0177] In some embodiments, L2 is selected from

[0178] In some embodiments, L2 is selected from

[0179] Each R L1 、R L2 、R L21 、R L22 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 6-8 Aryl, the heterocycloalkyl, heteroaryl contains 1-3 heteroatoms selected from N, O, S; the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl 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 Alkoxy group substitution;

[0180] In some embodiments, L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -、-C(=O), C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace;

[0181] In some embodiments, L1 is selected from a bond, -O-, -S-, -O-CH2-, -S-CH2-;

[0182] L2 is selected from -(CR L21 RL22 ) p -OC(=O)-N(R L2 )2、-C(=O)N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )S(O)2N(R L2 )2、(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-NR L2 -C(=O)O(CR L21 R L22 ) p R L2 ;

[0183] In some embodiments, L2 is selected from CH2-OC(=O)-N(R L2 )2;

[0184] R L1 、R L2 、R L21 、R L22 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally 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 Alkoxy group substitution;

[0185] p is selected from 0, 1 or 2;

[0186] The definitions of other groups are consistent with those of any of the above technical solutions.

[0187] The seventh technical solution of the present invention provides a compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), or formula (VIII), or a stereoisomer or pharmaceutically acceptable salt thereof,

[0188] The definitions of other groups are consistent with those of any of the above technical solutions.

[0189] Another alternative to the seventh technical solution of the present invention provides a compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), or formula (VII), or a stereoisomer or pharmaceutically acceptable salt thereof,

[0190] The definitions of other groups are consistent with those of any of the above technical solutions.

[0191] Another alternative to the seventh technical solution of the present invention provides a compound of formula (II-1), a stereoisomer or a pharmaceutically acceptable salt thereof,

[0192] Ring B, L2, and R c The definition of is consistent with any of the previous technical solutions.

[0193] The eighth technical solution of the present invention provides a compound of formula (I), formula (IA), formula (II), formula (III), formula (IV), formula (V), formula (VI), or formula (VII), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0194] Selected from

[0195] L2 is selected from

[0196] The definitions of other groups are consistent with those of any of the above technical solutions.

[0197] The ninth technical solution of the present invention provides a compound of formula (II-2) or formula (II-3), or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0198] in,

[0199] Ring A is selected from:

[0200] L1 is selected from a bond, -O- or -NH-CO-;

[0201] R B’ Selected from F, Cl, CHF2, CF3, CH2CH3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3;

[0202] R B Selected from F, Cl, CHF2, CF3, CH3, CH2CH3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3;

[0203] R C Selected from CH3, CH2CH3;

[0204] L2 is selected from

[0205] The definitions of other groups are consistent with those of any of the above technical solutions.

[0206] The tenth technical solution of the present invention, the compounds of formula (IA), formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (II-1), formula (II-2), and formula (II-3), their stereoisomers or pharmaceutically acceptable salts, are selected from but not limited to the structures in the following Tables 1 and 2:

[0207] Table 1:

[0208] Table 2:

[0209] Secondly, the present invention also provides a pharmaceutical composition, which contains the compound described in any one of the aforementioned schemes, its stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0210] 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 or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0211] Furthermore, the present invention also provides the use of the compound of any one of the aforementioned embodiments, its stereoisomers or pharmaceutically acceptable salts in the preparation of a medicament for treating / preventing LPAR1-mediated diseases. Furthermore, the LPAR1-mediated disease is idiopathic pulmonary fibrosis, etc.

[0212] 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, or a pharmaceutically acceptable salt thereof, as described in any of the foregoing schemes, wherein the disease is preferably idiopathic pulmonary fibrosis, and the therapeutically effective amount is preferably 1-1500 mg. In some embodiments, the mammal described in the present invention does not include humans.

[0213] 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- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 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, 5-60mg, 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, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 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. ;

[0214] 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 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 g, 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 or a pharmaceutically acceptable salt thereof.

[0215] 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 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg. The disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0216] A method for treating a disease in a mammal or a human comprises administering a compound of the present invention, a stereoisomer 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.

[0217] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof is the same as that in the above-mentioned pharmaceutical composition.

[0218] The amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0219] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0220] Synthesis route

[0221] 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.

[0222] Specific and similar reactants can be selectively identified by indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, 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 standard chemical supply facilities (e.g., those listed above) offer custom synthesis services.

[0223] the term

[0224] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0225] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0226] "Halo" or "halogen substitution" 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.

[0227] "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.

[0228] "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.

[0229] "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.

[0230] "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.

[0231] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", non-limiting examples of which include cyclopropylene, cyclobutylene, and the like.

[0232] "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.

[0233] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolyl, piperidinyl, aziridinyl, and the like.

[0234] "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.

[0235] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0236] "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. "Alkynylene" refers to a divalent radical of "alkynyl".

[0237] "Alkenyl" refers to a linear or branched, monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, alkynyl contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc. "Alkenylene" refers to a divalent radical of "alkenyl".

[0238] "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.

[0239] "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.

[0240] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0241] “C 1-4 "Alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

[0242] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furyl, and the like.

[0243] "Heterocycloalkyl" refers to a non-aromatic, partially unsaturated or fully saturated heterocycle, generally having 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to carbon atoms, heterocycloalkyl also contains 1-3 heteroatoms selected from N, S, O, Si, and P as ring members. Non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, and the like.

[0244] "Alkylamino" or "alkylamino" refers to an amino group substituted with a single or double alkyl group, also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0245] When a linking group is listed without specifying its connection direction, its connection direction includes connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes the cases of AMWB and AWMB. In addition, if a structure contains a linking group, the Markush variable listed for the linking group is understood to be the linking group, wherein if the Markush variable lists "alkyl", "alkenyl", or "alkynyl", it is understood that "alkyl" represents an alkylene linking group, "alkenyl" represents an alkenylene linking group, and "alkynyl" represents an alkynylene linking group.

[0246] "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 instances 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.

[0247] "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.

[0248] 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.

[0249] "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.

[0250] "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.

[0251] "Isomers" include "stereoisomers" and "tautomers." "Stereoisomers" refer to isomers in which the atoms or groups of atoms in a molecule have the same order of attachment but different spatial arrangements. Stereoisomers include cis-trans isomers, optical isomers, and conformational 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). Examples include the following pairs of compounds: aldehyde / ketone-enol, imine-enamine.

[0252] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0253] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION

[0254] 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.

[0255] Test Method

[0256] 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).

[0257] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0258] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C 18 100 × 4.6 mm, 3.5 μM);

[0259] 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.

[0260] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0261] Intermediate 1

[0262] Step 1: Compound 1a (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 1b (475 mg, yield: 88.29%).

[0263] 1 H 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).

[0264] Step 2: Compound 1b (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 intermediate 1 (250 mg, TFA salt), which was used directly in the next step.

[0265] Intermediate 2

[0266] Step 1: Dissolve lithium aluminum hydride (815 mg, 21.48 mmol) in tetrahydrofuran (10 ml), then dissolve compound 2a (1.0 g, 10.74 mmol) in THF (10 ml). Add the mixture to the above system at room temperature and react at 70°C for 3 hours. Monitor the reaction by TLC. Cool to room temperature, quench with water (1 ml), stir at room temperature for 30 minutes, filter, collect the filtrate, and concentrate under reduced pressure to obtain compound 2b (0.9 g, 86.54% yield).

[0267] LC-MS (ESI): m / z = 98.2 [M+H] + .

[0268] Step 2: Compound 2b (900 mg, 9.26 mmol) was added to a reaction flask and dissolved in THF (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 2c (1.36 g, 95.10% yield).

[0269] 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).

[0270] Step 3: Compound 2c (1.36 g, 6.89 mmol) was added to a reaction flask and dissolved in DMF (15 ml). NaH (410 mg, 10.33 mmol) was added at 0°C and maintained at this temperature for 30 min. Iodomethane (1.96 g, 13.78 mmol) was added and the mixture was allowed to warm to room temperature for 1 hour. The reaction was monitored for completion by TLC. Water (50 ml) was added and the mixture was 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 = 15:1) to afford compound 2d (1.13 g, yield: 77.93%).

[0271] 1 H NMR (400MHz, DMSO-d6) δ4.76–4.72(m,2H),3.28–2.24(m,2H),2.76(s,3H),2.73–2.64(m,2H),2.55–2.45(m,1H)2.38–2.30(m,2H),1.39(s,9H).

[0272] Step 4: Compound 2d (530 mg, 2.51 mmol) was added to a reaction flask, dissolved in dichloromethane (10 ml), and trifluoroacetic acid (0.5 ml) was added. The mixture was allowed to react at room temperature for 1 h. The reaction was monitored for completion by TLC and concentrated under reduced pressure to afford Intermediate 2 (300 mg, TFA salt), which was used directly in the next step.

[0273] LC-MS (ESI): m / z = 112.2 [M+H] + .

[0274] Intermediate 3:

[0275] 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 3a (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 added, and the temperature was slowly warmed to room temperature and allowed to react for 16 hours. The reaction was monitored for completion by TLC. 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 to yield compound 3b (4 g, yield: 33.53%).

[0276] 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).

[0277] Step 2: Compound 3b (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, cooled to -78°C, and boron tribromide (9.52 g, 38.10 mmol) was added dropwise. The reaction was maintained at this temperature for one hour. TLC monitored the reaction completion. The reaction solution was slowly added dropwise to a saturated sodium carbonate solution (200 ml) at 0°C and adjusted to a pH greater than 7. The product was extracted twice with dichloromethane (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 to afford compound 3c (1.63 g, 71.33% yield).

[0278] Step 3: Compound 3c (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, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford compound intermediate 3 (2.4 g, 62.02% yield).

[0279] 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).

[0280] Intermediate 4:

[0281] Step 1: Compound 4a (1.0 g, 10.19 mmol) was added to 20 ml of tetrahydrofuran, followed by the addition of pyridine (4.03 g, 50.95 mmol) and phenylmethyl p-nitrochloroformate (6.16 g, 30.57 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored to be complete by TLC. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain intermediate 4 (870 mg, yield: 32%).

[0282] LC-MS (ESI): m / z = 264.1 [M+H] + .

[0283] Intermediate 5:

[0284] Step 1: Potassium tert-butoxide (5.0 g, 44.56 mmol) was dissolved in DMF (50 ml) in a three-necked flask. The atmosphere was replaced with nitrogen three times and cooled to -45°C. A solution of 5a (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. TLC monitored the reaction completion. Saturated ammonium chloride solution (50 ml) and 3M aqueous hydrochloric acid (15 ml) were added to the reaction mixture and stirred at room temperature for 1 hour. The mixture was 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 5b (360 mg, yield: 6.08%).

[0285] 1H 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).

[0286] Step 2: Compound 5b (360 mg, 1.64 mmol) was added to a reaction flask, dissolved in DMF (10 ml), cooled to 0°C, and NaH (100 mg, 2.46 mmol) was added. The reaction was maintained at this temperature for 20 min. Iodomethane (450 mg, 3.28 mmol) was added, and the mixture was allowed to react at room temperature for two hours. The reaction was monitored for completion by TLC, and quenched by the addition of saturated ammonium chloride solution (50 ml). The product was 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 (PE:EA = 20:1) to obtain compound 5c (340 mg, yield: 88.89%).

[0287] 1 H NMR (400MHz, DMSO-d6) δ4.65–4.40(m,1H),2.95–2.79(m,4H),2.77(s,3H),1.40(s,9H).

[0288] Step 3: Compound 5c (340 mg, 1.45 mmol) was added to a reaction flask, dissolved in dichloromethane (5 ml), and trifluoroacetic acid (1 ml) was added. The reaction was allowed to react at room temperature for 3 hours. The reaction was monitored for completion by TLC and concentrated under reduced pressure to afford compound intermediate 5 (200 mg, TFA salt), which was directly used in the next step.

[0289] LC-MS (ESI): m / z = 134.1 [M+H] + .

[0290] Example 1

[0291] Step 1: Compound 1A (1.0 g, 7.45 mmol) and N-bromosuccinimide (1.33 g, 7.45 mmol) were dissolved in acetonitrile (10 mL), reacted at room temperature overnight, concentrated, added with water, and extracted with dichloromethane (20 mL × 2). The organic phases were combined, concentrated, and purified by column chromatography (tetrahydrofuran: petroleum ether = 3% to 50%) to give compound 1B (1.3 g, yield: 81.90%).

[0292] LC-MS (ESI): m / z = 213.1 [M+H] + .

[0293] Step 2: Compound 1B (0.1 g, 0.47 mmol) and copper bromide (0.11 g, 0.51 mmol) were dissolved in acetonitrile (10 mL), cooled to -20°C, and tert-butyl nitrite (0.058 g, 0.56 mmol) was slowly added. The mixture was naturally warmed to room temperature and reacted for 2 hours. The mixture was concentrated and purified by column chromatography (tetrahydrofuran: petroleum ether = 1% to 10%) to obtain compound 1C (0.11 g, yield: 84.50%).

[0294] Step 3: Dissolve compound 1C (0.1 g, 0.36 mmol), 2-(2-propargyloxy)tetrahydropyran (65.60 mg, 0.47 mmol), bis(triphenylphosphine)palladium dichloride (25.27 mg, 0.036 mmol), cuprous iodide (13.71 mg, 0.072 mmol), and triethylamine (109.29 mg, 1.08 mmol) in acetonitrile (10 mL) and react overnight at room temperature under a nitrogen atmosphere. Add 25 mL of water, extract with ethyl acetate (15 mL x 3), combine the organic layers, backwash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and chromatograph on a silica gel column (tetrahydrofuran:petroleum ether = 1% to 10%) to afford compound 1D (0.11 g, yield: 90.88%).

[0295] LC-MS (ESI): m / z = 336.1 [M+H] + .

[0296] Step 4: Compound 1D (1 g, 2.97 mmol) was dissolved in anhydrous methanol (10 mL), and p-toluenesulfonic acid (0.051 g, 0.30 mmol) was added. The mixture was reacted at 40°C for 5 hours, concentrated, and purified by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to obtain compound 1E (0.7 g, yield: 93.49%).

[0297] LC-MS (ESI): m / z = 252.0 [M+H] + .

[0298] Step 5: Compound 1E (2 g, 7.93 mmol), trimethylsilylmethyl azide (2.05 g, 15.86 mmol), bis(triphenylphosphino)cyclopentadienylruthenium(II) chloride (0.58 g, 0.79 mmol), cuprous iodide (0.30 g, 1.59 mmol), and tetrabutylammonium iodide (0.59 g, 1.59 mmol) were dissolved in tetrahydrofuran (20 mL), replaced with nitrogen three times, and reacted at 40°C for 16 hours. The mixture was purified by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 1F (2.7 g, yield: 89.28%).

[0299] LC-MS (ESI): m / z = 381.1 [M+H] + .

[0300] Step 6: Dissolve compound 1F (2 g, 5.24 mmol) and tetrabutylammonium fluoride (2.74 g, 10.48 mmol) in tetrahydrofuran (20 mL), replace the atmosphere with nitrogen three times, and react at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 1G (1.5 g, yield: 92.59%).

[0301] LC-MS (ESI): m / z = 309.1 [M+H] + .

[0302] Step 7: Dissolve compound 1G (0.5 g, 1.62 mmol) and p-toluenesulfonic acid monohydrate (0.092 g, 0.49 mmol) in dichloromethane (5 mL). Add 3,4-dihydro-2H-pyran (0.27 g, 3.24 mmol) and react at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 1H (0.5 g, yield: 78.61%).

[0303] LC-MS (ESI): m / z = 309.1 [M+H] + .

[0304] Step 8: Dissolve compound 1H (0.1 g, 0.25 mmol), bis(pinacolato)diboron (0.095 g, 0.38 mmol), potassium acetate (0.098 g, 1 mmol), and 1,1-bis(diphenylphosphino)diboronium palladium chloride (0.018 g, 0.025 mmol) in tetrahydrofuran (5 mL) under nitrogen at 70°C for 16 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 1I (0.08 g, yield: 71.45%).

[0305] LC-MS (ESI): m / z = 441.8 [M+H] + .

[0306] Step 9: Dissolve compound 1I (0.1 g, 0.22 mmol) in ethyl acetate (5 mL), then add 30% hydrogen peroxide (0.26 g, 2.30 mmol). React at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to obtain compound 1J (0.06 g, yield: 79.97%).

[0307] LC-MS (ESI): m / z = 331.2 [M+H] + .

[0308] Step 10: Compound 1J (0.1 g, 0.30 mmol), isopropyl (1S,3S)-3-hydroxycyclohexane-1-carboxylate (0.11 g, 0.60 mmol, synthesis reference: Tetrahedron Asymmetry, 2002, vol. 13, #6, pp. 579-585), and tributylphosphine (0.18 g, 0.90 mmol) were dissolved in toluene (5 mL). Azodicarbonyldipiperidine (0.23 g, 0.90 mmol) was added and reacted at 50°C for 6 hours. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 1K (0.11 g, yield: 72.89%).

[0309] LC-MS (ESI): m / z = 499.2 [M+H] + .

[0310] Step 11: Dissolve compound 1K (0.1 g, 0.20 mmol) and p-toluenesulfonic acid (0.0069 g, 0.04 mmol) in methanol (5 mL). React at 50°C for 6 hours. Cool to room temperature, concentrate, and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to obtain compound 1L (0.08 g, yield: 96.23%).

[0311] LC-MS (ESI): m / z = 415.1 [M+H] + .

[0312] Step 12: Dissolve compound 1L (0.1 g, 0.24 mmol) and pyridine (0.076 g, 0.96 mmol) in dichloromethane (5 mL). Add p-nitrophenyl chloroformate (0.15 g, 0.72 mmol) in portions and react at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to obtain compound 1M (0.12 g, yield: 93.03%).

[0313] LC-MS (ESI): m / z = 580.2 [M+H] + .

[0314] Step 13: Dissolve compound 1M (0.2 g, 0.35 mmol) and triethylamine (0.14 g, 1.4 mmol) in dichloromethane (5 mL), then add intermediate 1 (0.11 g, 0.52 mmol). React at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 1N (0.15 g, yield: 80.85%).

[0315] LC-MS (ESI): m / z = 538.3 [M+H] + .

[0316] Step 14: Dissolve compound 1N (0.15 g, 0.28 mmol) in tetrahydrofuran (3 L) and water (1 mL), then add lithium hydroxide monohydrate (0.047 g, 1.12 mmol) and react at room temperature for 2 hours. Add formic acid to adjust the pH to 4, concentrate, and purify by reverse phase column chromatography (acetonitrile:water = 3% to 60%) to obtain compound 1 (0.05 g, yield: 36.16%).

[0317] LC-MS (ESI): m / z = 496.3 [M+H] + .

[0318] 1 H NMR(400MHz,DMSO-d6)δ7.76(d,1H),7.47(d,1H),5.56(s,2H),4.79(s,3H),4.09(s,3H),3.88–3.81( m,4H),2.78–2.67(m,6H),2.06–2.02(m,1H),1.92–1.75(m,3H),1.69–1.50(m,4H),0.97–0.94(m,4H).

[0319] Example 2

[0320] Step 1: Dissolve compound 1G (1.5 g, 4.85 mmol) and pyridine (1.15 g, 14.55 mmol) in dichloromethane (15 mL). Add p-nitrophenyl chloroformate (1.47 g, 7.27 mmol) in portions and react at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 2A (1.5 g, yield: 65.21%).

[0321] LC-MS (ESI): m / z = 474.0 [M+H] + .

[0322] Step 2: Dissolve compound 2A (1.4 g, 2.95 mmol) and triethylamine (0.90 g, 8.85 mmol) in dichloromethane (10 mL). Add N-methylpropylamine (0.43 g, 5.9 mmol) and react at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to obtain compound 2B (1.0 g, yield: 83.03%).

[0323] LC-MS (ESI): m / z = 408.1 [M+H] + .

[0324] Step 3: Compound 2B (1 g, 2.45 mmol), tert-butyl carbamate (0.57 g, 4.9 mmol), cesium carbonate (2.39 g, 7.35 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.28 g, 0.49 mmol), and tris(dibenzylideneacetone)dipalladium (0.14 g, 0.25 mmol) were dissolved in 1,4-dioxane (10 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 2C (1.0 g, yield: 91.82%).

[0325] LC-MS (ESI): m / z = 445.3 [M+H] + .

[0326] Step 4: Dissolve compound 2C (0.275 g, 0.62 mmol) in 1,4-dioxane (2 mL), add 4 M hydrogen chloride in dioxane (3 mL), and react at room temperature for 2 hours. Concentrate directly for the next step.

[0327] LC-MS (ESI): m / z = 345.3 [M+H] + .

[0328] Step 5: Compound 2D (0.21 g, 0.61 mmol), trans-2,2-difluoro-3-(methoxycarbonyl)cyclopropanecarboxylic acid (0.22 g, 1.22 mmol) (Helvetica Chimica Acta, 1992, vol. 75, #3, pp. 766-772), and N-methylimidazole (0.20 g, 2.44 mmol) were dissolved in acetonitrile (10 mL). Tetramethylchlorouronium hexafluorophosphate (0.51 g, 1.83 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 2E (0.2 g, yield: 64.74%).

[0329] LC-MS (ESI): m / z = 507.2 [M+H] + .

[0330] Step 12: Dissolve compound 2E (0.2 g, 0.39 mmol) in tetrahydrofuran (5 mL) and water (1 mL), then add lithium hydroxide monohydrate (0.033 g, 0.79 mmol). React at room temperature for 2 hours. Add formic acid to adjust the pH to 4. Concentrate and purify by reverse-phase column chromatography (acetonitrile:water = 3% to 60%) to obtain compound 2 (0.1 g, yield: 52.07%).

[0331] LC-MS (ESI): m / z = 493.2 [M+H] + .

[0332] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),7.94–7.90(m,1H),7.84–7.82(m,1H),5.57(s,2H),4.11(s,3H),3.60–3.56( m,1H),3.19–3.00(m,3H),2.77–2.75(m,3H),2.33(s,1H),1.45–1.30(m,2H),1.11–0.94(m,4H),0.81–0.65(m,3H).

[0333] Example 3

[0334] Step 1: Chiral analysis of compound 2 (49 mg) revealed four isomers: P1 (retention time: 1.622 min, designated as compound 3-1), P2 (retention time: 1.816 min, designated as compound 3-2), P3 (retention time: 2.347 min, designated as compound 3-3), and P4 (retention time: 3.480 min, designated as compound 3-4). 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 isopropanol (0.05% DEA); Gradient: 40% B gradient elution; Flow rate: 2.5 mL / min; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 4 min.

[0335] 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: 35% B gradient elution; Flow rate: 120mL / min; Column temperature: 38°C; Wavelength: 220nm; Cycle time: 5min; Sample preparation: The compound was dissolved in approximately 20ml of methanol / DCM and injected 2.2mL each time. After separation, the mixture was dried and concentrated by rotary evaporation at a bath temperature of 35°C, and the solvent was then dried in a lyophilizer at -80°C to obtain compound 3-1 (5mg), compound 3-2 (4mg), compound 3-3 (9mg), and compound 3-4 (9mg).

[0336] Compound 3-1: 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),7.94–7.90(m,1H),7.84–7.82(m,1H),5.57(s,2H),4.11(s,3H),3.60–3.55( m,1H),3.19–3.02(m,3H),2.77–2.74(m,3H),2.33(s,1H),1.45–1.31(m,2H),1.11–0.93(m,4H),0.81–0.65(m,3H).

[0337] LC-MS (ESI): m / z = 493.2 [M+H] + .

[0338] Compound 3-2: 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),7.94–7.90(m,1H),7.84–7.82(m,1H),5.57(s,2H),4.11(s,3H),3.60–3.55( m,1H),3.19–3.00(m,3H),2.77–2.74(m,3H),2.33(s,1H),1.45–1.31(m,2H),1.11–0.94(m,4H),0.81–0.65(m,3H).

[0339] LC-MS (ESI): m / z = 493.2 [M+H] + .

[0340] Compound 3-3: 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),7.94–7.90(m,1H),7.84–7.82(m,1H),5.57(s,2H),4.11(s,3H),3.60–3.55( m,1H),3.19–3.00(m,3H),2.77–2.75(m,3H),2.33(s,1H),1.46–1.31(m,2H),1.11–0.92(m,4H),0.81–0.65(m,3H).

[0341] LC-MS (ESI): m / z = 493.2 [M+H] + .

[0342] Compound 3-4: 1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),7.94–7.90(m,1H),7.84–7.82(m,1H),5.57(s,2H),4.11(s,3H),3.60–3.53( m,1H),3.19–3.00(m,3H),2.77–2.75(m,3H),2.33(s,1H),1.46–1.31(m,2H),1.11–0.92(m,4H),0.81–0.65(m,3H).

[0343] LC-MS (ESI): m / z = 493.2 [M+H] + .

[0344] Example 4

[0345] Step 1: Dissolve compound 1M (0.2 g, 0.35 mmol) and triethylamine (0.14 g, 1.4 mmol) in dichloromethane (5 mL). Add intermediate 2 (0.078 g, 0.70 mmol) and react at 25°C for 2 hours. Concentrate and purify by column chromatography (tetrahydrofuran:petroleum ether = 1% to 50%) to afford compound 4A (0.15 g, yield: 78.80%).

[0346] LC-MS (ESI): m / z = 552.3 [M+H] + .

[0347] Step 2: Dissolve compound 4A (0.15 g, 0.27 mmol) in tetrahydrofuran (3 L) and water (1 mL), then add lithium hydroxide monohydrate (0.045 g, 1.08 mmol) and react at room temperature for 2 hours. Add formic acid to adjust the pH to 4, concentrate, and purify by reverse phase column chromatography (acetonitrile:water = 3% to 60%) to obtain compound 4 (0.08 g, yield: 57.74%).

[0348] LC-MS (ESI): m / z = 510.3 [M+H] + .

[0349] 1H NMR (400MHz, DMSO-d6) δ7.76(d,1H),7.46(d,1H),5.55(s,2H),4.78–4.74(m,2H),4.57(s,1H),4.09(s,3H),3.86–3.62(m,2H),3.31–3.20( m,2H),2.79–2.75(m,3H),2.73–2.61(m,2H),2.39–2.27(m,2H),2.22– 1.96(m,2H),1.91–1.73(m,3H),1.69–1.50(m,4H),1.01–0.90(m,4H).

[0350] Example 5

[0351] Step 1: Compound 5A (5 g, 28.56 mmol) and platinum dioxide (0.5 g, 2.20 mmol) were dissolved in acetic acid (50 mL). The atmosphere was replaced with hydrogen three times under a nitrogen atmosphere. The reaction was continued at 50°C in a hydrogen atmosphere (3 MPa) for 48 h. After completion of the reaction, the mixture was filtered through celite, washed with methanol, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to obtain compound 5B (3.88 g, yield: 74.19%).

[0352] Step 2: Dissolve compound 1H (2.0 g, 5.09 mmol), compound 5B (1.12 g, 6.11 mmol), cesium carbonate (3.32 g, 10.18 mmol), and Brettphos Pd G3 (100 mg, 0.51 mmol) in 1,4-dioxane (30 mL). Replace the atmosphere with nitrogen three times and react at 100°C for 16 hours. Cool to room temperature, concentrate, and purify by column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to afford compound 5C (800 mg, yield: 31.62%).

[0353] LC-MS (ESI): m / z = 496.2 [M+H] + .

[0354] Step 3: Dissolve compound 5C (0.8 g, 1.61 mmol) and p-toluenesulfonic acid (0.84 g, 3.22 mmol) in methanol (5 mL) and react at 50°C for 6 hours. Cool to room temperature, concentrate, and purify by column chromatography (ethyl acetate:petroleum ether = 0% to 70%) to obtain compound 5D (500 mg, yield: 75.30%).

[0355] Step 4: Dissolve compound 5D (0.5 g, 1.22 mmol) and pyridine (0.59 g, 7.32 mmol) in dichloromethane (10 mL). Then add p-nitrophenyl chloroformate (0.75 g, 3.66 mmol) in portions and react at 25°C for 2 hours. Concentrate and purify by column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to obtain compound 5E (0.59 g, yield: 83.57%).

[0356] Step 5: Compound 5E (0.3 g, 0.52 mmol) and N,N-diisopropylethylamine (0.21 g, 1.56 mmol) were dissolved in tetrahydrofuran (15 mL), and intermediate 1 (0.11 g, 0.78 mmol) was added. The mixture was reacted at 25°C for 2 hours, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 5F (0.30 g, yield: 98.12%).

[0357] LC-MS (ESI): m / z = 535.9 [M+H] + .

[0358] Step 6: Compound 5F (0.30 g, 0.56 mmol) was dissolved in tetrahydrofuran (12 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide monohydrate (0.071 g, 1.68 mmol) was added and allowed to react at room temperature for 16 hours. 1N aqueous hydrochloric acid was added to adjust the pH to 3. The mixture was concentrated to give a crude product (0.25 g). Purification by HPLC (acetonitrile:water = 28% to 58%) afforded compound 5G (0.15 g).

[0359] Preparation Method: Instrument: SHIMADZU LC-20AP; Column: C18 column; Mobile phase: A for 0.1% TFA in water; B for acetonitrile; Gradient: B from 28% to 58% in 10 minutes; Flow rate: 25 mL / min; Column temperature: room temperature; Wavelength: 220 nm; Cycle time: 15 minutes; Injection method: The compound was dissolved in acetonitrile at a concentration of 20 mg / mL. After separation, the solution was concentrated by rotary evaporation at 35°C, and the solvent was then dried in a lyophilizer at -80°C to obtain the racemate.

[0360] LC-MS (ESI): m / z = 521.3 [M+H] + .

[0361] Step 7: Compound 5G (0.2 g) was subjected to chiral separation to obtain two isomers: P1 (retention time: 0.875 min, designated as compound 5-1) and P2 (retention time: 1.100 min, designated as compound 5-2).

[0362] Chiral separation method: Instrument: Waters 150Prep-SFC; Column: Chiral OX column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol and acetonitrile; Gradient: B from 30%; Flow rate: 100 mL / min; Pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nm; Cycle time: 3 min; Injection method: Compound concentration was 3 mg / ml, dissolved in acetonitrile and ethanol; Injection volume: 3.0 ml per injection. After separation, the product was concentrated by rotary evaporation at 35°C, and the solvent was then dried in a lyophilizer at -80°C to obtain compound 5-1 (58.6 mg) and compound 5-2 (47.8 mg).

[0363] Compound 5-1: 1 H NMR(400MHz,DMSO-d6)δ7.71(d,1H),7.37(d,1H),5.57(m,2H),4.79(s,2H),4.41(s,1H ),4.08(s,3H),3.98–3.93(m,1H),3.73–3.67(m,1H),3.05–2.99(m,1H),2.97–2.65(m,7 H),2.50–2.38(m,1H),2.29–2.12(m,2H),2.03–1.87(m,1H),1.85–1.70(m,2H),1.70–1 .49(m,4H),1.46–1.35(m,1H),1.32–1.23(m,1H),1.11–1.07(m,1H),0.87–0.72(m,2H).

[0364] LC-MS (ESI): m / z = 521.3 [M+H] + .

[0365] Compound 5-2: 1H NMR(400MHz,DMSO-d6)δ7.71(d,1H),7.37(d,1H),5.57(m,2H),4.79(s,2H),4.41(s,1H ),4.08(s,3H),3.98-3.93(m,1H),3.73–3.67(m,1H),3.05–2.99(m,1H),2.97–2.65(m,7 H),2.50–2.38(m,1H),2.29–2.12(m,2H),2.03–1.87(m,1H),1.85–1.70(m,2H),1.70–1 .49(m,4H),1.46–1.35(m,1H),1.32–1.23(m,1H),1.11–1.07(m,1H),0.87–0.72(m,2H).

[0366] LC-MS (ESI): m / z = 521.4 [M+H] + .

[0367] Example 6

[0368] Step 1: Dissolve compound 6A (120 g, 0.40 mol), 2-(2-propargyloxy)tetrahydropyran (65.6 g, 0.47 mol), bis(triphenylphosphine)palladium dichloride (2.53 g, 3.6 mmol), cuprous iodide (1.37 g, 7.2 mmol), and triethylamine (109.29 g, 1.08 mol) in acetonitrile (1 L). React at room temperature overnight under a nitrogen atmosphere. Concentrate to 500 mL, add 1 L of water, and extract with ethyl acetate (1 L x 3). Combine the organic layers, backwash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and chromatograph on a silica gel column (petroleum ether:ethyl acetate = 1% to 30%) to afford compound 6B (71 g, yield: 47%).

[0369] 1 H NMR(400MHz,DMSO-d6)δ11.27(s,1H),7.49–7.40(m,1H),7.30–7.24(m,1H),4.83–4.78(m,1H), 4.51–4.29(m,2H),3.80–3.70(m,1H),3.53–3.45(m,1H),1.79–1.60(m,2H),1.60–1.41(m,4H).

[0370] Step 2: Compound 6B (10 g, 32.05 mmol) and acetic anhydride (4.91 g, 48.1 mmol) were dissolved in dichloromethane (100 mL). Triethylamine (9.73 g, 96.2 mmol) was added and the mixture was allowed to warm to room temperature for 2 hours. 20 mL of saturated sodium bicarbonate was added, the layers were separated, and the mixture was extracted once with 100 mL of dichloromethane. The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 10%) to obtain compound 6C (11 g, yield: 97%).

[0371] LC-MS (ESI): m / z = 354.1 [M+H] + .

[0372] Step 3: Compound 6C (11 g, 31.07 mmol), trimethylsilylmethyl azide (10.3 g, 79.3 mmol), bis(triphenylphosphino)cyclopentadienylruthenium(II) chloride (3.0 g, 0.40 mmol), cuprous iodide (1.5 g, 7.9 mmol), and tetrabutylammonium iodide (0.30 g, 0.4 mmol) were dissolved in dioxane (100 mL), replaced with nitrogen three times, and reacted at 50°C for 16 hours. The mixture was purified by column chromatography (petroleum ether:ethyl acetate = 1% to 20%) to afford compound 6D (6.8 g, 45% yield).

[0373] LC-MS(ESI):m / z=399.3[M-THP+H] + .

[0374] Step 4: Compound 6D (6.8 g, 14.07 mmol) was dissolved in anhydrous methanol (100 mL), and potassium carbonate (3.89 g, 28.14 mmol) was added. The mixture was reacted at room temperature for 16 hours, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 50%) to give compound 6E (5.6 g, yield: 90%).

[0375] LC-MS(ESI):m / z=357.2[M-THP+H] + .

[0376] Step 5: Dissolve compound 6E (2.9 g, 6.57 mmol), isopropyl (1S,3S)-3-hydroxycyclohexane-1-carboxylate (1.21 g, 6.57 mmol), and tributylphosphine (3.6 g, 18.02 mmol) in toluene (50 mL). Add azodicarbonyldipiperidine (4.6 g, 18.02 mmol) and react at 50°C for 16 hours. Cool to room temperature, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate = 1% to 50%) to afford compound 6F (1.7 g, 40% yield).

[0377] LC-MS(ESI):m / z=525.2[M-THP+H] + .

[0378] Step 6: Compound 6F (0.6 g, 0.98 mmol) and tetrabutylammonium fluoride (0.51 g, 1.96 mmol) were dissolved in tetrahydrofuran (10 mL), replaced with nitrogen three times, and reacted at 25°C for 2 hours. After adding 20 mL of purified water, the mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 50%) to afford compound 6G (0.5 g, yield: 94.53%).

[0379] LC-MS(ESI):m / z=453.2[M-THP+H] + .

[0380] Step 7: Compound 6G (0.5 g, 0.93 mmol) and potassium vinyl trifluoroborate (0.25 g, 1.86 mmol) were dissolved in dioxane (20 mL). Potassium carbonate (0.39 g, 2.79 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.14 g, 0.19 mmol) were added and reacted at 90°C for 16 hours. Water (20 mL) was added, the mixture was extracted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 50%) to obtain compound 6H (0.35 g, yield: 77.64%).

[0381] LC-MS (ESI): m / z = 485.1 [M+H] + .

[0382] Step 8: Dissolve compound 6H (0.35 g, 0.72 mmol) and pyridinium p-toluenesulfonate (0.36 g, 1.44 mmol) in methanol (10 mL). React at 50°C for 16 hours. Cool to room temperature, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to obtain compound 6I (0.25 g, yield: 86.43%).

[0383] LC-MS (ESI): m / z = 401.2 [M+H] + .

[0384] Step 9: Dissolve compound 6I (0.2 g, 0.50 mmol) and pyridine (0.12 g, 1.50 mmol) in dichloromethane (5 mL). Then add p-nitrophenyl chloroformate (0.20 g, 1.00 mmol) in portions and react at 15°C for 2 hours. Concentrate and purify by column chromatography (petroleum ether:ethyl acetate = 1% to 40%) to afford compound 6J (0.25 g, yield: 88.51%).

[0385] LC-MS (ESI): m / z = 566.2 [M+H] + .

[0386] Step 10: Dissolve compound 6J (0.2 g, 0.35 mmol) and triethylamine (0.11 g, 1.05 mmol) in dichloromethane (10 mL), then add intermediate 1 (68 mg, 0.70 mmol). React at 25°C for 2 hours. Concentrate and purify by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to afford compound 6K (0.15 g, yield: 81.01%).

[0387] LC-MS (ESI): m / z = 524.2 [M+H] + .

[0388] Step 11: Dissolve compound 6K (0.10 g, 0.19 mmol) in methanol (5 mL) and water (2 mL), then add lithium hydroxide monohydrate (0.024 g, 0.57 mmol). Allow to react at room temperature for 16 hours. Adjust the pH to 4 with 2N hydrochloric acid. Concentrate the mixture, and purify the crude product by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the crude title compound. Preparative HPLC yields compound 6 (25 mg, 27%).

[0389] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Samples were dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM ammonium bicarbonate); b. Gradient elution, mobile phase A content ranging from 30% to 60%; c. Flow rate: 15 mL / min; d. Elution time: 20 min.

[0390] LC-MS (ESI): m / z = 482.3 [M+H] + .

[0391] 1 H NMR(400MHz,DMSO-d6)δ7.96(d,1H),7.62(d,1H),7.15–7.22(m,1H),6.33–6.39(m,1H),5.69(s,2H),5.48–5.51(m,1H),4.9 6–5.40(m,3H),4.74–4.86(m,3H),4.12(s,3H),2.59–2.86(m,7H),2.01–2.05(m,1H),1.77–1.89(m,3H),1.43–1.67(m,3H).

[0392] Example 7

[0393] Step 1: Potassium tert-butoxide (5.9 g, 52.63 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 7A (10 g, 52.63 mmol) in DMF (25 ml) and a solution of 2-(difluoromethanesulfonyl)pyridine (9.14 g, 47.37 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 7B (4.5 g, yield: 38.17%).

[0394] Step 2: Compound 7B (1 g, 4.46 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 (2.23 g, 8.92 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 twice with dichloromethane (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 7C (550 mg, 91.97% yield).

[0395] Step 3: Compound 7C (200 mg, 1.49 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (10 ml). Pyridine (590 mg, 7.45 mmol) and p-nitrophenyl chloroformate (902 mg, 4.47 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 and the resulting residue was purified by silica gel column chromatography (PE:EA = 4:1) to afford compound 7D (386 mg, 86.55% yield).

[0396] 1 H NMR (400MHz, CDCl3-d) δ8.31–8.27(m,2H),7.41–7.38(m,2H),4.34(d,2H),3.02–2.74(m,3H),2.65–2.28(m,2H).

[0397] Step 4: Compound 1L (270 mg, 0.65 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and diphenylphosphoryl azide (359 mg, 1.30 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (200 mg, 1.30 mmol) were slowly added. The mixture was naturally warmed to room temperature and reacted for 2 hours. The mixture was concentrated and purified by column chromatography (ethyl acetate) to give compound 7E (250 mg, yield: 87.41%).

[0398] LC-MS (ESI): m / z = 440.5 [M+H] + .

[0399] Step 5: Compound 7E (250 mg, 0.57 mmol) was dissolved in tetrahydrofuran (12 mL) and water (4 mL), and triphenylphosphine (298 mg, 1.14 mmol) was added. The mixture was reacted for 6 hours, concentrated, and purified by column chromatography (ethyl acetate) to give compound 7F (175 mg, yield: 74.47%).

[0400] LC-MS (ESI): m / z = 414.5 [M+H] + .

[0401] Step 6: Compound 7F (120 mg, 0.29 mmol) and compound 7D (130 mg, 0.43 mmol) were added to a reaction flask, dissolved in tetrahydrofuran (20 ml), and DIPEA (110 mg, 0.87 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, monitored by TLC, the mixture 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 7G (40 mg, 24% yield).

[0402] LC-MS (ESI): m / z = 574.3 [M+H] + .

[0403] Step 7: Compound 7G (40 mg, 0.07 mmol) was added to a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (10 ml). Lithium hydroxide monohydrate (15 mg, 0.35 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 by reverse-phase column chromatography to afford compound 7 (7 mg, 19% yield).

[0404] Preparation method: Instrument: SHIMADZU LC-20AP; Column: C18 column; Mobile phase: A for 0.0375% TFA in water; B for acetonitrile; Gradient: B from 15% to 45% in 16 minutes; Flow rate: 25 mL / min; Column temperature: room temperature; Wavelength: 210 nm & 254 nm. After separation, the product was concentrated by rotary evaporation at 35°C, and the solvent was then dried in a lyophilizer at -80°C to obtain the compound.

[0405] LC-MS (ESI): m / z = 532.4 [M+H] + .

[0406] 1 H NMR(400MHz,CD3OD)δ7.77(d,1H),7.43(d,1H),4.74–4.82(s,3H),4.12(s,3H),4.09(d,2H),2.65–2.86(m,4H),2 .57–2.63(m,1H),2.37–2.48(m,2H),2.09–2.17(m,1H),1.89–2.00(m,3H),1.60–1.84(m,4H),0.98–1.08(m,4H).

[0407] Example 8

[0408] Step 1: Dissolve compound 6G (1.80 g, 3.35 mmol) and pyridinium p-toluenesulfonate (1.26 g, 5.02 mmol) in methanol (30 mL) and react at 50°C for 16 hours. After completion of the reaction, monitor by LCMS and TLC. Cool the reaction mixture to room temperature, concentrate it, and purify it by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to afford compound 8A (1.20 g, 79%).

[0409] LC-MS (ESI): m / z = 453.2 [M+H] + .

[0410] Step 2: Compound 8A (1 g, 2.21 mmol) and pyridine (0.56 g, 6.62 mmol) were dissolved in dichloromethane (10 mL). p-Nitrophenyl chloroformate (0.89 g, 4.42 mmol) was added portionwise and allowed to react at 25°C for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 40%) to afford compound 8B (0.69 g, 50%).

[0411] LC-MS (ESI): m / z = 618.2 [M+H] + .

[0412] Step 3: Compound 8B (0.69 g, 1.11 mmol) and triethylamine (0.34 g, 3.33 mmol) were dissolved in dichloromethane (10 mL). Intermediate 1 (298 mg, 2.22 mmol) was then added and reacted at 25°C for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to obtain compound 8C (0.47 g, 73%).

[0413] LC-MS (ESI): m / z = 576.3 [M+H] + .

[0414] Step 4: Dissolve 8C (200 mg, 0.35 mmol) and triisopropylsilyl acetylene (191 mg, 1.05 mmol) in tetrahydrofuran (5 mL). Add Pd(PPh3)2Cl2 (25 mg, 0.035 mmol), cuprous iodide (7 mg, 0.035 mmol), and triethylamine (177 mg, 1.75 mmol) sequentially. After nitrogen replacement three times, the mixture was reacted at 50°C under nitrogen for 3 hours. After completion of the reaction, saturated aqueous ammonium chloride (20 mL) was added and the mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 50%) to yield compound 8D (110 mg, 47%).

[0415] LC-MS (ESI): m / z = 678.5 [M+H] + .

[0416] Step 5: Dissolve compound 8D (110 mg, 0.16 mmol) in tetrahydrofuran (5 mL) and add tetrabutylammonium fluoride (0.5 mL, 0.48 mmol, 1 M in THF). Stir the mixture at room temperature for 3 hours. After completion of the reaction, monitor the reaction mixture by LCMS and TLC. The reaction mixture was concentrated and purified by silica gel column chromatography to yield compound 8E (75 mg, 89%).

[0417] LC-MS (ESI): m / z = 522.3 [M+H] + .

[0418] Step 6: Dissolve compound 8E (75 mg, 0.14 mmol) in 8 mL of tetrahydrofuran, add methanol (2 mL) and water (2 mL), then add lithium hydroxide monohydrate (24 mg, 0.56 mmol). React at room temperature for 16 hours. Adjust the pH to 4 with 2N hydrochloric acid. Concentrate, and purify the crude product by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the crude title compound. Purify by preparative HPLC to yield compound 8 (15 mg, 28%).

[0419] Preparation method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Gradient: B from 25% to 55% in 17 min; Flow rate: 25 mL / min; Column temperature: 25°C; Detection wavelengths: 210 & 254 nm; Samples were dissolved in DMF and filtered through a 0.45 μm filter.

[0420] LC-MS (ESI): m / z = 480.2 [M+H] + .

[0421] 1 H NMR(400MHz,DMSO-d6)δ8.02(d,1H),7.72(d,1H),5.60(s,2H),4.92–4.72(m,3H), 4.48(s,1H),4.10(s,3H),2.88–2.60(s,9H),2.05–1.97(m,1H),1.87–1.38(m,7H).

[0422] Example 9

[0423] Step 1: Compound 6G (1.8 g, 3.35 mmol) and potassium 1-methylvinyl trifluoroborate (1.14 g, 7.70 mmol) were dissolved in dioxane (20 mL). Potassium carbonate (1.39 g, 10.05 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.25 g, 0.34 mmol) were added and reacted at 90°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to 10 mL, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 50%) to obtain compound 9A (1.1 g, 66%).

[0424] LC-MS(ESI):m / z=415.3[M-THP+H] + .

[0425] Step 2: Dissolve compound 9A (1.1 g, 2.21 mmol) and pyridinium p-toluenesulfonate (1.66 g, 6.62 mmol) in methanol (25 mL). React at 50°C for 16 hours. After completion of the reaction, monitor by TLC and LCMS. Cool to room temperature, concentrate the reaction solution, and purify by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to afford compound 9B (0.71 g, 75%).

[0426] LC-MS (ESI): m / z = 415.3 [M+H] + .

[0427] Step 3: Compound 9B (0.71 g, 1.71 mmol) and pyridine (0.43 g, 5.14 mmol) were dissolved in dichloromethane (5 mL). p-Nitrophenyl chloroformate (0.69 g, 3.43 mmol) was then added portionwise and reacted at 25°C for 2 hours. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 40%) to obtain compound 9C (0.70 g, 72%).

[0428] LC-MS (ESI): m / z = 580.4 [M+H] + .

[0429] Step 4: Dissolve compound 9C (0.70 g, 1.21 mmol) and triethylamine (0.37 g, 3.62 mmol) in dichloromethane (10 mL), then add intermediate 1 (323 mg, 2.42 mmol). React at 25°C for 2 hours. The reaction solution is concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to obtain compound 9D (0.42 g, 64%).

[0430] LC-MS (ESI): m / z = 538.4 [M+H] + .

[0431] Step 5: Dissolve compound 9D (0.42 g, 0.78 mmol) in tetrahydrofuran (8 mL), methanol (2 mL), and water (2 mL). Add lithium hydroxide monohydrate (0.16 g, 3.9 mmol) and react at room temperature for 16 hours. Adjust the pH to 4 with 2N hydrochloric acid. Concentrate the mixture, and purify the crude product by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the crude title compound. Purify the mixture by HPLC to obtain compound 9 (62 mg, 16%).

[0432] Preparation method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Gradient: B from 15% to 45% in 17 min; Flow rate: 25 mL / min; Column temperature: 25°C; Detection wavelengths: 210 & 254 nm; Samples were dissolved in DMF and filtered through a 0.45 μm filter.

[0433] LC-MS (ESI): m / z = 496.3 [M+H] + .

[0434] 1 H NMR(400MHz,DMSO-d6)δ7.93(d,1H)7.63(d,1H),5.92–5.86(m,1H),5.64(s,2H),5.55–5.50(m,1H),4.86–4.76 (m,3H),4.11(s,3H),2.90–2.60(m,9H),2.17(s,3H),2.03–1.92(m,1H),1.87–1.74(m,3H),1.69–1.46(m,4H).

[0435] Example 10

[0436] Step 1: Compound 5a (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. The reaction was monitored for completion by TLC. 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 10B (5.4 g, 59%).

[0437] 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).

[0438] Step 2: Compound 10B (2.0 g, 5.90 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (50 ml). The mixture was cooled to 0°C and NaH (0.35 g, 8.85 mmol) was added. The reaction was maintained at this temperature for 30 min. Iodomethane (1.7 g, 11.80 mmol) was added and the mixture was allowed to warm to room temperature for 2 hours. The reaction was monitored for completion by TLC. Saturated ammonium chloride solution (100 ml) was added to the reaction system for quenching. The mixture was 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 10C (2.02 g, 97%).

[0439] 1 H NMR (400MHz, DMSO-d6) δ4.39(s,1H),2.86–2.71(m,7H),1.40(s,9H).

[0440] 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 10C (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 as monitored by TLC. The mixture was 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 (PE:EA = 20:1) to obtain compound 10D (800 mg, 62%).

[0441] 1 H NMR (400MHz, DMSO-d6) δ4.36(s,1H),2.77–2.64(m,7H),1.50(s,6H),1.39(s,9H).

[0442] Step 4: Compound 10D (800 mg, 2.54 mmol) was added to a reaction flask, dissolved in dichloromethane (18 ml), and trifluoroacetic acid (6 ml) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction was monitored for completion by TLC and concentrated under reduced pressure to afford compound 10E (453 mg, TFA salt), which was directly used in the next step.

[0443] Step 5: Dissolve compound 9C (0.28 g, 0.49 mmol) and triethylamine (0.15 g, 1.48 mmol) in dichloromethane (10 mL), then add 10E (237 mg, 2.42 mmol). React at 25°C for 2 hours. The reaction solution is concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to afford compound 10F (0.21 g, 83%).

[0444] LC-MS (ESI): m / z = 566.2 [M+H] + .

[0445] Step 6: Compound 10F (0.21 g, 0.37 mmol) was dissolved in 8 mL of tetrahydrofuran, methanol (2 mL), and water (2 mL). Lithium hydroxide monohydrate (78 mg, 1.86 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 (dichloromethane:methanol = 10:1) to obtain the crude title compound. This was then purified by C18 column chromatography to obtain compound 10 (75 mg, 38%).

[0446] LC-MS (ESI): m / z = 524.3 [M+H] + .

[0447] 1 H NMR(400MHz,DMSO-d6)δ7.92(d,1H),7.63(d,1H),5.89-5.87(m,1H),5.64(s,2H),5.53(s,1H),4.83(s ,1H),4.11(s,3H),2.85–2.52(m,9H),2.17(s,3H),2.00(d,1H),1.88–1.75(m,3H),1.64–1.32(m,10H).

[0448] Example 11

[0449] Step 1: Compound 6I (530 mg, 1.32 mmol) and NIS (327 mg, 1.45 mmol) were dissolved in anhydrous dichloromethane (10 mL) and stirred at -10°C under nitrogen for 10 min. HF-Py (151 mg, 1.45 mmol) was then slowly added dropwise at -10°C. The mixture was slowly warmed from -10°C to room temperature and the reaction was continued for 1 h. After completion of the reaction as monitored by LCMS, saturated aqueous sodium bicarbonate (10 mL) was slowly added dropwise under an ice bath. The layers were separated, and the aqueous phase was extracted once with dichloromethane (10 mL). The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to afford the target compound 11A (390 mg, 56%).

[0450] LC-MS (ESI): m / z = 547.2 [M+H] + .

[0451] Step 2: Compound 11A (200 mg, 0.37 mmol) was dissolved in dichloromethane (10 mL), and DBU (112 mg, 73 mmol) was added. The mixture was allowed to react at room temperature overnight. After completion of the reaction as monitored by LCMS, saturated aqueous sodium bicarbonate (10 mL) was slowly added dropwise under an ice bath. The layers were separated, and the aqueous phase was extracted once with dichloromethane (10 mL). The organic phases were combined, dried, concentrated, and isolated by silica gel column chromatography (PE:EA = 10:1 to 1:1) to afford the target compound 11B (105 mg, 69%).

[0452] LC-MS (ESI): m / z = 419.3 [M+H] + .

[0453] Step 3: Compound 11B (105 mg, 0.24 mmol) and pyridine (61 mg, 73 mmol) were dissolved in dichloromethane (5 mL). p-Nitrophenyl chloroformate (98 mg, 0.49 mmol) was then added portionwise. The mixture was reacted at 15°C for 2 hours. The mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 40%) to afford compound 11C (110 mg, 68%).

[0454] LC-MS (ESI): m / z = 584.3 [M+H] + .

[0455] Step 4: Dissolve compound 11C (110 mg, 0.19 mmol) and triethylamine (57 mg, 0.57 mmol) in dichloromethane (10 mL), then add intermediate 1 (50 mg, 0.38 mmol). React at 25°C for 2 hours. Concentrate and purify by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to afford compound 11D (90 mg, 88%).

[0456] LC-MS (ESI): m / z = 542.1 [M+H] + .

[0457] Step 5: Dissolve compound 11D (90 mg, 0.17 mmol) in a mixture of methanol (5 mL) and water (1 mL). Add lithium hydroxide monohydrate (36 mg, 0.85 mmol) and react at room temperature for 16 hours. Adjust the pH to 4 with 2N hydrochloric acid. Concentrate the mixture, and purify the crude product by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the crude title compound. Preparative HPLC yields compound 11 (35 mg, 41%).

[0458] LC-MS (ESI): m / z = 500.1 [M+H] + .

[0459] 1 H NMR(400MHz, DMSO-d6))δ8.05(d,1H),7.78(d,1H),5.66–5.50(m,3H),5.32–5.28(m,1H),4.92(s,1H), 4.78(s,2H),4.11(s,3H),2.85–2.58(m,9H),2.05–1.96(d,1H),1.90–1.79(m,3H),1.70–1.46(m,4H).

[0460] Example 12

[0461] Step 1: Compound 1L (165 mg, 0.40 mmol) was dissolved in tetrahydrofuran (10 mL). Diphenylphosphoryl azide (223 mg, 0.8 mmol) and 1,8-diazabicycloundec-7-ene (123 mg, 0.8 mmol) were added dropwise in an ice bath. The mixture was reacted at room temperature for one hour. The mixture was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 3% to 50%) to give compound 12B (65 mg, yield: 43.95%).

[0462] LC-MS (ESI): m / z = 440.1 [M+H] + .

[0463] Step 2: Compound 12B (65 mg, 0.15 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Triphenylphosphine (78 mg, 0.30 mmol) was added and allowed to react at room temperature for 1 hour. The mixture was concentrated and purified by column chromatography (dichloromethane:methanol = 0% to 10%) to afford compound 12C (60 mg, yield: 98.36%).

[0464] LC-MS (ESI): m / z = 414.1 [M+H] + .

[0465] Step 3: Compound 12C (60 mg, 0.15 mmol) and N,N-diisopropylethylamine (57 mg, 0.45 mmol) were dissolved in tetrahydrofuran (5 mL). Intermediate 3 (83 mg, 0.30 mmol) was then added portionwise and reacted at 25°C for 2 hours. The mixture was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 30%-60%) to afford compound 12D (45 mg, yield: 55.56%).

[0466] LC-MS (ESI): m / z = 560.1 [M+H] + .

[0467] Step 4: Dissolve compound 12D (45 mg, 0.08 mmol) in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL), then add lithium hydroxide monohydrate (11 mg, 0.24 mmol) and react at room temperature for 16 hours. Add formic acid to adjust the pH to 4, concentrate, and purify by reverse phase column chromatography to obtain compound 12 (10 mg, yield: 24.39%).

[0468] LC-MS (ESI): m / z = 518.4 [M+H] + .

[0469] 1 H NMR(400MHz,DMSO-d6)δ7.75–7.73(d,1H),7.56(s,1H),7.47–7.45(d,1H),4.95(s,1H),4.77–4.75(m,3H),4.00(s,3 H),3.08–2.98(m,2H),2.72–2.62(m,3H),2.07–1.97(m,1H),1.86–1.76(m,3H),1.72–1.43(m,5H),1.02–0.90(m,4H).

[0470] Example 13

[0471] Step 1: Compound 8A (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (10 mL). Diphenylphosphoryl azide (101 mg, 0.44 mmol) and 1,8-diazabicycloundec-7-ene (69 mg, 0.44 mmol) were added dropwise in an ice bath. The mixture was reacted at room temperature for one hour. The mixture was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 3% to 50%) to give compound 13B (95 mg, yield: 90.48%).

[0472] LC-MS (ESI): m / z = 478.1 [M+H] + .

[0473] Step 2: Compound 13B (95 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Triphenylphosphine (104 mg, 0.40 mmol) was added and allowed to react at room temperature for 1 hour. The mixture was concentrated and purified by column chromatography (dichloromethane:methanol = 0% to 10%) to afford compound 13C (76 mg, yield: 84.44%).

[0474] LC-MS (ESI): m / z = 452.1 [M+H]+ .

[0475] Step 3: Compound 13C (76 mg, 0.17 mmol) and N,N-diisopropylethylamine (66 mg, 0.51 mmol) were dissolved in tetrahydrofuran (5 mL). Intermediate 3 (96 mg, 0.34 mmol) was then added portionwise and reacted at 25°C for 2 hours. The mixture was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 30%-60%) to afford compound 13D (100 mg, yield: 98%).

[0476] LC-MS (ESI): m / z = 598.1 [M+H] + .

[0477] Step 4: Compound 13D (100 mg, 0.17 mmol), potassium ethylene trifluoroborate (45 mg, 0.34 mmol), cesium carbonate (164 mg, 0.51 mmol), and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) were dissolved in dioxane (10 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 80°C for 16 hours. The product was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 3% to 50%) to provide compound 13E (84 mg, yield: 92.31%).

[0478] LC-MS (ESI): m / z = 546.3 [M+H] + .

[0479] Step 5: Dissolve compound 13E (84 mg, 0.15 mmol) in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL), then add lithium hydroxide monohydrate (19.42 mg, 0.45 mmol) and react at room temperature for 16 hours. Add formic acid to adjust the pH to 4, concentrate, and purify by reverse phase column chromatography to obtain compound 13 (9.5 mg, yield: 12.26%).

[0480] LC-MS (ESI): m / z = 504.4 [M+H] + .

[0481] 1 H NMR(400MHz,DMSO-d6)δ7.94–7.92(d,1H),7.63–7.40(m,2H),7.23–7.16(m,1H),6.34–6.29(m,1H ),5.52–5.48(m,1H),5.05–4.73(m,4H),4.04(s,3H),3.05–2.95(m,2H),2.68–2.56(m,3H),2.00–

[0482] 1.97(m,1H),1.85–1.79(m,3H),1.71–1.44(m,4H).

[0483] Example 14

[0484] Step 1: Compound 14A (0.15 g, 0.26 mmol, synthesized according to patent WO2024022314) and triethylamine (0.079 g, 0.78 mmol) were dissolved in dichloromethane (10 mL). Intermediate 1 (38 mg, 0.39 mmol) was then added and reacted at 25°C for 2 hours. The reaction was confirmed by TLC. Water (10 mL) was added and extracted with dichloromethane (10 mL). The organic phase was separated, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to afford compound 14B (0.13 g, yield: 93.44%).

[0485] LC-MS (ESI): m / z = 537.2 [M+H] + .

[0486] Step 2: Dissolve compound 14B (0.13 g, 0.24 mmol) in methanol (5 mL) and water (5 mL), then add lithium hydroxide monohydrate (0.03 g, 0.72 mmol). React at room temperature for 16 hours. Adjust the pH to 4 with 2N hydrochloric acid. Concentrate, and purify the crude product by column chromatography to obtain the crude target compound. Purify the crude product by preparative HPLC to yield compound 14 (60 mg, 47%).

[0487] LC-MS (ESI): m / z = 523.2 [M+H] + .

[0488] 1 H NMR(400MHz,DMSO-d6)δ8.26(d,1H),8.04(d,1H),5.59(s,2H),4.77(s,2H),4.13(s,3H),3.11–2.98(m,2H),2. 83–2.54(m,9H),2.28–2.17(m,2H),2.13–2.02(m,1H),1.84–1.71(m,2H),1.66–1.57(m,1H),1.27–1.13(m,2H).

[0489] Example 15

[0490] Step 1: Compound 14A (0.15 g, 0.26 mmol) and triethylamine (0.079 g, 0.78 mmol) were dissolved in dichloromethane (10 mL). Intermediate 5 (52 mg, 0.39 mmol) was added and reacted at 25°C for 2 hours. The reaction was confirmed by TLC. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL). The organic phase was separated, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to afford compound 15A (0.13 g, yield: 93.44%).

[0491] LC-MS (ESI): m / z = 573.2 [M+H] + .

[0492] Step 2: Dissolve compound 15A (0.14 g, 0.24 mmol) in methanol (5 mL) and water (5 mL), then add lithium hydroxide monohydrate (0.03 g, 0.72 mmol). React at room temperature for 16 hours. Adjust the pH to 4 with 2N hydrochloric acid. Concentrate, and purify the crude product by column chromatography to obtain the crude target compound. Purify the crude product by preparative HPLC to yield compound 15 (60 mg, 47%).

[0493] LC-MS (ESI): m / z = 559.2 [M+H] + .

[0494] 1 H NMR(400MHz,DMSO-d6)δ8.27(d,1H),8.03(d,1H),5.60(s,2H),4.13(s,3H),3.11–2.98(m,2H),2.91–2.66(m,8H), 2.60–2.55(m,1H),2.29–2.17(m,2H),2.14–2.03(m,1H),1.83–1.72(m,2H),1.65–1.56(m,1H),1.24–1.12(m,2H).

[0495] Example 16

[0496] Step 1: Compound 6G (1.0 g, 1.86 mmol) and (2,2'-bipyridine) trifluoromethylsulfonate copper (1.20 g, 3.72 mmol) were dissolved in dioxane (20 mL) and reacted at 100°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to 10 mL, added with water (20 mL), and extracted twice with ethyl acetate (30 mL). The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 50%) to obtain compound 16A (0.8 g, 77%).

[0497] LC-MS(ESI):m / z=475.3[M-THP+H] + .

[0498] Step 2: Dissolve compound 16A (0.75 g, 1.34 mmol) and pyridinium p-toluenesulfonate (0.83 g, 3.31 mmol) in methanol (25 mL). React at 50°C for 16 hours. After completion of the reaction, monitor by TLC and LCMS. Cool to room temperature, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to afford compound 16B (0.40 g, 63%).

[0499] LC-MS (ESI): m / z = 475.3 [M+H] + .

[0500] Step 3: Compound 16B (0.35 g, 0.74 mmol) and pyridine (0.18 g, 2.22 mmol) were dissolved in dichloromethane (10 mL). p-Nitrophenyl chloroformate (0.30 g, 1.48 mmol) was then added portionwise. The mixture was reacted at 25°C for 2 hours. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 40%) to afford compound 16C (0.25 g, 53%).

[0501] LC-MS (ESI): m / z = 640.2 [M+H] + .

[0502] Step 4: Compound 16C (0.25 g, 0.39 mmol) and triethylamine (0.12 g, 1.17 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of intermediate 1 (76 mg, 0.78 mmol). The mixture was allowed to react at 25°C for 2 hours. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1% to 60%) to afford compound 16D (0.15 g, 64%).

[0503] LC-MS (ESI): m / z = 598.2 [M+H] + .

[0504] Step 5: Compound 16D (0.10 g, 0.17 mmol) was dissolved in methanol (5 mL) and water (2 mL). Lithium hydroxide monohydrate (21 mg, 0.51 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 extracted with ethyl acetate (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain the crude target compound, which was then purified by HPLC to afford compound 16 (50 mg, 53%).

[0505] LC-MS (ESI): m / z = 556.1 [M+H]+ .

[0506] 1 H NMR(400MHz,DMSO-d6)δ8.04(d,1H),7.75(d,1H),5.55(s,2H),4.94(s,1H),4.78(s,2H),4.52–4.2 2(m,1H),4.10(s,3H),2.99–2.54(m,8H),2.05–1.96(m,1H),1.90–1.76(m,3H),1.70–1.43(m,4H).

[0507] Example 17

[0508] Step 1: Compound 17A (643 mg, 1.56 mmol, synthesized by referring to patent WO2024022314) was dissolved in tetrahydrofuran (10 mL). Diphenylphosphoryl azide (856 mg, 3.12 mmol) and 1,8-diazabicycloundec-7-ene (473 mg, 3.12 mmol) were added dropwise in an ice bath. The mixture was allowed to react at room temperature for one hour. The reaction was quenched by adding water (10 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford compound 17B (660 mg, 96.92% yield).

[0509] LC-MS (ESI): m / z = 439.2 [M+H] + .

[0510] Step 2: Compound 17B (660 mg, 1.50 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Triphenylphosphine (790 mg, 3.00 mmol) was added and allowed to react at room temperature for 1 hour. Water (10 mL) was added and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford compound 17C (550 mg, yield: 88.71%).

[0511] LC-MS (ESI): m / z = 413.2 [M+H] + .

[0512] Step 3: Compound 17C (200 mg, 0.49 mmol) and N,N-diisopropylethylamine (191 mg, 1.47 mmol) were dissolved in tetrahydrofuran (5 mL), followed by the addition of intermediate 4 (255 mg, 0.98 mmol) in portions. The mixture was allowed to react at 25°C for 1 hour. The reaction was quenched with water (10 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford compound 17D (241 mg, 92.69% yield).

[0513] LC-MS (ESI): m / z = 537.2 [M+H] + .

[0514] Step 4: Dissolve compound 17D (241 mg, 0.45 mmol) in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Add lithium hydroxide monohydrate (57 mg, 1.35 mmol) and react at room temperature for 16 hours. Adjust the pH to 4 with 6 mol / L aqueous hydrochloric acid. Concentrate and purify by reverse-phase column chromatography to obtain compound 17 (162.1 mg, yield: 69.07%).

[0515] LC-MS (ESI): m / z = 523.3 [M+H] + .

[0516] 1 H NMR(400MHz,DMSO-d6)(400MHz,DMSO)δ8.24(d,1H),8.04(d,1H),7.37(s,1 H),4.86–4.62(m,4H),4.06(s,3H),3.97(d,2H),3.09(d,1H),2.99(d,1H),2 .81–2.53(m,4H),2.50–2.40(m,1H),2.41–2.26(m,2H),2.21–2.18(m,2H), 2.15–2.00(m,1H),1.87–1.70(m,2H),1.68-1.53(m,1H),1.22–1.07(m,1H).

[0517] Example 18

[0518] Step 1: Compound 17C (100 mg, 0.24 mmol) and N,N-diisopropylethylamine (95 mg, 0.72 mmol) were dissolved in tetrahydrofuran (5 mL). 7D (120 mg, 0.48 mmol) was then added portionwise and allowed to react at 25°C for 1 hour. The reaction was quenched with water (10 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford compound 18A (150 mg, 100% yield).

[0519] LC-MS (ESI): m / z = 573.3 [M+H] + .

[0520] Step 2: Dissolve compound 18A (150 mg, 0.26 mmol) in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Add lithium hydroxide monohydrate (33 mg, 0.78 mmol) and react at room temperature for 16 hours. Adjust the pH to 4 with 6 mol / L aqueous hydrochloric acid. Concentrate and purify by reverse-phase column chromatography to obtain compound 18 (112.8 mg, yield: 77.10%).

[0521] LC-MS (ESI): m / z = 559.1 [M+H] + .

[0522] 1 H NMR(400MHz,DMSO-d6)δ8.25(d,1H),8.05(d,1H),7.42(s,1H),4.79(d,2H),4.07(s,3H),3.99(d,2H),3.09(d,1H),2.99(d,1H),2. 84–2.52(m,5H),2.42–2.32(m,2H),2.30–2.17(m,2H),2.14–2.03(m,1H),1.87–1.70(m,2H),1.69–1.55(m,1H),1.23–1.13(m,1H).

[0523] Example 19

[0524] Step 1: Compound 17C (200 mg, 0.49 mmol) and N,N-diisopropylethylamine (191 mg, 1.47 mmol) were dissolved in tetrahydrofuran (5 mL). Intermediate 3 (277 mg, 0.98 mmol) was then added portionwise and allowed to react at 25°C for 1 hour. The reaction was quenched with water (10 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford compound 19A (251 mg, 92.66% yield).

[0525] LC-MS (ESI): m / z = 559.3 [M+H] + .

[0526] Step 2: Dissolve compound 19A (251 mg, 0.45 mmol) in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Add lithium hydroxide monohydrate (57 mg, 1.35 mmol) and react at room temperature for 16 hours. Add 6 mol / L aqueous hydrochloric acid to adjust the pH to 4. Concentrate and purify by reverse phase column chromatography to obtain compound 19 (130.3 mg, yield: 53.13%).

[0527] LC-MS (ESI): m / z = 545.2 [M+H] + .

[0528] 1 H NMR(400MHz,DMSO-d6)δ8.25(d,1H),8.04(d,1H),7.52(s,1H),5.03–4.70(m,3H),4.06(s,3H),3.10–2.98(m,4H), 2.79–2.53(m,4H),2.21–2.19(m,2H),2.14–2.04(m,1H),1.87–1.69(m,2H),1.67–1.54(m,1H),1.22–1.06(m,1H).

[0529] Example 20

[0530] Step 1: Dissolve 20A (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 20B (290 mg, 54%).

[0531] LC-MS(ESI):m / z=214.0[M+H-56] + .

[0532] Step 2: Dissolve 20B (290 mg, 1.08 mmol) in dichloromethane (5 mL) and add 4M hydrogen chloride in dioxane (2 mL). Allow to react at room temperature for 1 hour. After the reaction is complete, the solution is concentrated by rotary evaporation to afford compound 20C (208 mg, 94%), which is used directly in the next step without further purification.

[0533] LC-MS (ESI): m / z = 170.1 [M+H] + .

[0534] Step 3: Dissolve 8B (340 mg, 0.55 mmol) in tetrahydrofuran (10 mL). Add diisopropylethylamine (210 mg, 1.65 mmol). Slowly add a solution of 20C (200 mg, 0.99 mmol) in tetrahydrofuran (2 mL) dropwise under an ice bath. React at room temperature for 4 h. After completion of the reaction, add water (25 mL) to the reaction solution, 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 to afford 20D (300 mg, 84%).

[0535] LC-MS (ESI): m / z = 648.2 [M+H] + .

[0536] Step 4: Compound 20D (100 mg, 0.15 mmol) and potassium vinyl trifluoroborate (40 mg, 0.30 mmol) were dissolved in dioxane (10 mL). Potassium carbonate (41 mg, 0.30 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (12 mg, 0.015 mmol) were added and reacted at 90°C for 16 hours. Water (10 mL) was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 20E (90 mg, yield: 98%).

[0537] LC-MS (ESI): m / z = 596.3 [M+H] + .

[0538] Step 5: Compound 20E (90 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 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 and isolated by reverse-phase HPLC to afford compound 20 (30 mg, 36% yield).

[0539] LC-MS (ESI): m / z = 554.2 [M+H] + .

[0540] 1 H NMR(400MHz, DMSO-d6)δ7.96(d,1H),7.62(d,1H),7.24–7.13(m,1H),6.40–6.31(m,1H),5.68(s,2H),5.52–5.46(m,1H),4.85–4.80(m,1 H),4.17–4.08(m,4H),2.83–2.72(m,4H),2.64–2.54(m,3H),2.37–2.24(m,2H),2.05–1.97(m,1H),1.86–1.75(m,3H),1.66–1.48(m,4H).

[0541] Example 21

[0542] Step 1: Compound 8A (200 mg, 0.44 mmol), methyl thiocarbamide (79 mg, 0.88 mmol), and cesium carbonate (430 mg, 1.32 mmol) were added to DMF (15 mL) and heated to 100°C for 2 h. After completion of the reaction, monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to afford compound 21A (150 mg, 81%).

[0543] LC-MS (ESI): m / z = 421.2 [M+H] + .

[0544] Step 2: Compound 21A (150 mg, 0.36 mmol) and pyridine (140 mg, 1.80 mmol) were dissolved in tetrahydrofuran (10 mL), followed by the addition of p-nitrophenyl chloroformate (220 mg, 1.08 mmol). The mixture was allowed to react at 25°C for 2 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to afford compound 21B (170 mg, 81%).

[0545] LC-MS (ESI): m / z = 586.2 [M+H] + .

[0546] Step 3: Compound 21B (170 mg, 0.29 mmol) and DIPEA (110 mg, 0.87 mmol) were dissolved in tetrahydrofuran (10 mL), followed by the addition of Intermediate 1 (58 mg, 0.43 mmol). The mixture was reacted at 25°C for 3 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography to afford Compound 21C (150 mg, 100%).

[0547] LC-MS (ESI): m / z = 544.3 [M+H] + .

[0548] Step 4: Compound 21C (150 mg, 0.28 mmol) and iodophenyldiacetic acid (180 mg, 0.56 mmol) were added to anhydrous methanol (10 mL), followed by ammonium acetate (43 mg, 0.56 mmol). The mixture was reacted at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography to afford compound 21D (80 mg, 50%).

[0549] LC-MS (ESI): m / z = 575.3 [M+H] + .

[0550] Step 5: Compound 21D (80 mg, 0.14 mmol) was added to a 5:1:1 THF:MeOH:H₂O (7 ml) mixture, followed by the addition of lithium hydroxide monohydrate (29 mg, 0.70 mmol). The mixture was 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 HPLC to afford compound 21 (50 mg, 67% yield).

[0551] LC-MS (ESI): m / z = 533.3 [M+H] + .

[0552] 1 H NMR(400MHz,DMSO-d6)δ8.25–8.18(m,1H),8.01–7.91(m,1H),5.74–5.66(m,1H) ,5.59–5.52(m,1H),5.05–4.94(m,1H),4.83–4.73(m,2H),4.71–4.59(m,1H),4.1 4(s,3H),4.04–3.97(m,1H),2.83–2.75(m,4H),2.74–2.55(m,3H),2.39–2.25(m, 1H),2.15–1.99(m,1H),1.93–1.78(m,7H),1.73–1.65(m,1H),1.57–1.39(m,2H).

[0553] Example 22

[0554] Step 1: Dissolve 20D (200 mg, 0.31 mmol) and triisopropylsilyl acetylene (230 mg, 1.24 mmol) in tetrahydrofuran (15 mL). Add Pd(PPh3)2Cl2 (22 mg, 0.031 mmol), cuprous iodide (6 mg, 0.031 mmol), and triethylamine (160 mg, 1.55 mmol) sequentially. After nitrogen replacement three times, the mixture was reacted at 50°C under nitrogen for 3 hours. After completion of the reaction, monitored by LCMS and TLC, saturated aqueous ammonium chloride (20 mL) was added and the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography to yield compound 22A (200 mg, 86%).

[0555] LC-MS (ESI): m / z = 750.4 [M+H] + .

[0556] Step 2: Dissolve compound 22A (200 mg, 0.27 mmol) in 5 mL of tetrahydrofuran, add tetrabutylammonium fluoride (0.54 mL, 0.54 mmol, 1 M in THF), and stir at room temperature for 3 hours. After completion of the reaction, monitored by LCMS and TLC, the reaction solution was concentrated and purified by silica gel column chromatography to yield compound 22B (150 mg, 95%).

[0557] LC-MS (ESI): m / z = 594.2 [M+H] + .

[0558] Step 3: Dissolve compound 22B (150 mg, 0.25 mmol) in 8 mL of tetrahydrofuran, add methanol (2 mL) and water (2 mL), then add lithium hydroxide monohydrate (52 mg, 1.25 mmol). React at room temperature for 16 hours. Adjust the pH to 4 with 2N hydrochloric acid, concentrate, and purify the crude product by column chromatography to obtain the crude title compound. Purify by preparative HPLC to obtain compound 22 (50 mg, 36%).

[0559] LC-MS (ESI): m / z = 552.3 [M+H] + .

[0560] 1 H NMR(400MHz,DMSO-d6)δ8.02(d,1H),7.71(d,1H),5.60(s,2H),4.92–4.77(m,2H),4.74–4.51(m,1H),4.44(s,1H),4.1 0(s,3H),2.78(s,3H),2.71–2.54(m,3H),2.40–2.25(m,2H),2.04–1.95(m,1H),1.90–1.65(m,4H),1.64–1.41(m,3H).

[0561] Example 23

[0562] Step 1: Compound 11B (200 mg, 0.48 mmol) was dissolved in tetrahydrofuran (10 mL). Diphenylphosphoryl azide (260 mg, 0.96 mmol) and 1,8-diazabicycloundec-7-ene (150 mg, 0.96 mmol) were added under ice-cooling and allowed to react at room temperature for one hour. The reaction was quenched by adding water (10 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound 23A (130 mg, yield: 61.3%).

[0563] LC-MS (ESI): m / z = 444.2 [M+H] + .

[0564] Step 2: Compound 23A (130 mg, 0.29 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Triphenylphosphine (150 mg, 0.58 mmol) was added and allowed to react at room temperature for 1 hour. Water (10 mL) was added and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound 23B (120 mg, yield: 98.05%).

[0565] LC-MS (ESI): m / z = 418.2 [M+H] + .

[0566] Step 3: Compound 23B (120 mg, 0.29 mmol) and N,N-diisopropylethylamine (110 mg, 0.87 mmol) were dissolved in tetrahydrofuran (5 mL), followed by the addition of intermediate 3 (170 mg, 0.58 mmol) in portions. The mixture was allowed to react at 25°C for 1 hour. The reaction was quenched 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 under reduced pressure. The residue was purified by column chromatography to afford compound 23C (110 mg, yield: 67.9%).

[0567] LC-MS (ESI): m / z = 564.2 [M+H] + .

[0568] Step 4: Compound 23C (110 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (25 mg, 0.6 mmol) was added and reacted at room temperature for 16 hours. 2 mol / L aqueous hydrochloric acid was added to adjust the pH to 4. The mixture was extracted with ethyl acetate (20 mL), concentrated under reduced pressure, and purified by HPLC to obtain compound 23 (40 mg, yield: 39.3%).

[0569] LC-MS (ESI): m / z = 522.2 [M+H] + .

[0570] 1H NMR(400MHz,DMSO-d6)δ12.2(s,1H),8.05(d,1H),7.79(d,1H),7.46(s,1H),5.70–5.57(m,1H),5.42–5.36(m,1H),4.97–4.85(m,2 H),4.78–4.69(m,2H),4.07(s,3H),3.06–2.95(m,2H),2.71–2.55(m,2H),2.28–2.01(m,2H),1.91–1.78(m,3H),1.72–1.47(m,4H).

[0571] Example 24

[0572] Step 1: Compound 24A (3 g, 7.14 mmol, synthesized according to patent WO2022034568), bis(pinacol)diboron (2.72 g, 10.71 mmol), potassium acetate (2.1 g, 21.42 mmol), and 1,1-bis(diphenylphosphine)diboron palladium chloride (0.5 g, 0.714 mmol) were dissolved in 1,4-dioxane (60 mL) under nitrogen protection at 80 ° C for 16 hours and concentrated to give the crude product 24B (8 g).

[0573] LC-MS(ESI):m / z=385.2[M-THP+1] + .

[0574] Step 2: Compound 24B (8 g) was dissolved in ethyl acetate (50 mL), and then 30% hydrogen peroxide (6 mL) was added. The mixture was reacted at 25°C for 2 hours. The mixture was quenched with a saturated aqueous sodium thiosulfate solution (10 mL), and 50 mL of water was added. The mixture was separated and extracted twice with 50 mL of ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography to obtain compound 24C (1.7 g, yield: 36.20%).

[0575] LC-MS(ESI):m / z=275.1[M-THP+1] + .

[0576] Step 3: Dissolve compound 24C (1 g, 2.79 mmol), isopropyl (1S, 3S)-3-hydroxycyclohexane-1-carboxylate (1.04 g, 5.58 mmol), and tributylphosphine (1.41 g, 6.98 mmol) in toluene (30 mL). Add azodicarbonyl dipiperidine (1.76 g, 6.98 mmol) and react at 50°C for 6 hours. Cool to room temperature, concentrate, and purify by column chromatography to obtain compound 24D (860 mg, yield: 68%).

[0577] LC-MS (ESI): m / z = 527.2 [M+H] + .

[0578] Step 4: Dissolve compound 24D (860 mg, 1.63 mmol) and p-toluenesulfonic acid (615 mg, 2.45 mmol) in methanol (20 mL) and react at 50°C for 6 hours. Cool to room temperature, concentrate, and purify by column chromatography to obtain compound 24E (600 mg, yield: 83%).

[0579] LC-MS (ESI): m / z = 443.2 [M+H] + .

[0580] Step 5: Compound 24E (600 mg, 1.36 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and diphenylphosphoryl azide (747 mg, 2.72 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (413 mg, 2.72 mmol) were slowly added. The mixture was naturally warmed to room temperature and reacted for 2 hours. The mixture was concentrated and purified by column chromatography to obtain compound 24F (600 mg, yield: 95%).

[0581] LC-MS (ESI): m / z = 468.2 [M+H] + .

[0582] Step 6: Compound 24F (600 mg, 1.28 mmol) was dissolved in tetrahydrofuran (12 mL) and water (4 mL), and triphenylphosphine (533 mg, 2.56 mmol) was added. The mixture was reacted for 1 hour, concentrated, and purified by column chromatography to obtain compound 24G (500 mg, yield: 88%).

[0583] LC-MS (ESI): m / z = 442.3 [M+H] + .

[0584] Step 7: Compound 24G (500 mg, 1.13 mmol) and N,N-diisopropylethylamine (442 mg, 3.39 mmol) were dissolved in tetrahydrofuran (20 mL). Intermediate 3 (487 mg, 1.70 mmol) was then added portionwise. The mixture was reacted at 25°C for 2 hours. The mixture was concentrated and purified by column chromatography to afford compound 24H (690 mg, 100% yield).

[0585] LC-MS (ESI): m / z = 588.2 [M+H] + .

[0586] Step 8: Compound 24H (690 mg, 1.18 mmol) was dissolved in tetrahydrofuran (18 mL), methanol (6 mL), and water (3 mL). Lithium hydroxide monohydrate (148 mg, 3.54 mmol) was added and reacted at room temperature for 16 hours. Hydrogen chloride methanol solution (4 mL, 4 M) was added to adjust the pH to 4. The mixture was concentrated and purified by reverse phase column chromatography to obtain compound 24 (416 mg, yield: 65%).

[0587] LC-MS (ESI): m / z = 546.5 [M+H] + .

[0588] 1 H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.25(d,1H),7.95(d,1H),7.55(s,1H),5.00(s,1H),4.97–4.87(m,1H), 4.78(d,2H),4.06(s,3H),2.92(d,2H),2.74–2.52(m,3H),2.05(d,1H),1.94–1.74(m,3H),1.74–1.39(m,4H).

[0589] Example 25

[0590] Step 1: 13C (450 mg, 0.99 mmol), di-tert-butyl dicarbonate (430 mg, 1.98 mmol), and triethylamine (300 mg, 2.97 mmol) were added to dichloromethane (15 mL), stirred, and allowed to react at room temperature for 2 h. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were 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 to afford 25A (300 mg, 55%).

[0591] LC-MS (ESI): m / z = 552.2 [M+H] + .

[0592] Step 2: 25A (300 mg, 0.54 mmol), XphosPdG2 (42 mg, 0.054 mmol), and (tributyltin)methanol (690 mg, 2.16 mmol) were added to 1,4-dioxane (15 mL) under nitrogen atmosphere and heated to 95°C for 16 hours. After the reaction was complete, the mixture was cooled and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to afford 25B (90 mg, 33%).

[0593] LC-MS (ESI): m / z = 504.3 [M+H]+ .

[0594] Step 3: 25B (90 mg, 0.18 mmol) was added to DCM (15 mL), followed by the addition of Dess-Martin oxidation reagent (190 mg, 0.45 mmol). The reaction was allowed to react at room temperature for 4 h. After the reaction was complete, 10 mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was then extracted with dichloromethane (15 mL x 3). The combined organic layers were 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 to afford 25C (70 mg, 78%).

[0595] LC-MS (ESI): m / z = 502.3 [M+H] + .

[0596] Step 4: 25C (70 mg, 0.14 mmol) was added to dichloromethane (10 mL), followed by DAST (68 mg, 0.42 mmol), and the mixture was allowed to react at room temperature for 4 h. After the reaction was complete, the reaction mixture was poured into 10 mL of saturated aqueous ammonium chloride solution and extracted with dichloromethane (15 mL x 3). The combined organic layers were 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 to afford 25D (60 mg, 82%).

[0597] LC-MS (ESI): m / z = 524.3 [M+H] + .

[0598] Step 5: 25D (60 mg, 0.11 mmol) was added to dichloromethane (1 mL), followed by the addition of dioxane hydrochloride (3 mL, 4 M). The mixture was allowed to react at room temperature for 6 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated to dryness to afford the target compound 25E, which was used directly in the next step.

[0599] LC-MS (ESI): m / z = 424.3 [M+H] + .

[0600] Step 6: Compound 25E (53 mg, 0.12 mmol) and DIPEA (47 mg, 0.36 mmol) were dissolved in tetrahydrofuran (10 mL), followed by the addition of Intermediate 3 (51 mg, 0.18 mmol). The mixture was reacted at 25°C for 3 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography to afford Compound 25F (50 mg, 76%).

[0601] LC-MS (ESI): m / z = 570.2 [M+H] + .

[0602] Step 7: Compound 25F (50 mg, 0.088 mmol) was added to a 5:1:1 THF:MeOH:H2O (7 ml) mixture, followed by the addition of lithium hydroxide monohydrate (18 mg, 0.44 mmol). The reaction was allowed to react at 25°C for 6 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 HPLC to afford compound 25 (10 mg, 22% yield).

[0603] LC-MS (ESI): m / z = 528.2 [M+H] + .

[0604] 1 H NMR(400MHz,CD3OD)δ8.18(d,1H),7.75(d,1H),6.94–7.21(m,1H),4.93–5.00(m,1H),4.88–4.93(m,1H),4.68–4.78(m,2H),4 .19(s,3H),2.95–3.07(m,2H),2.76–2.85(m,1H),2.60–2.75(m,2H),2.07–2.17(m,1H),1.88–2.01(m,3H),1.56–1.84(m,4H).

[0605] Example 26

[0606] Step 1: Compound 26A (3.90 g, 18.53 mmol), 2-(2-propargyloxy)tetrahydropyran (3.90 g, 27.80 mmol), bis(triphenylphosphine)palladium dichloride (0.65 g, 0.93 mmol), cuprous iodide (0.71 g, 3.71 mmol), and triethylamine (5.63 g, 55.59 mmol) were dissolved in N,N-dimethylformamide (50 mL) and reacted at room temperature overnight under a nitrogen atmosphere. 100 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 1:10) to afford compound 26B (4.1 g, 82.02% yield).

[0607] LC-MS(ESI):m / z=186.1[M-THP+H] + .

[0608] Step 2: Compound 26B (4.1 g, 15.20 mmol) was dissolved in anhydrous methanol (60 mL), followed by the addition of p-toluenesulfonic acid (7.64 g, 30.4 mmol). The mixture was reacted at 40°C for 5 hours, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether (v / v) = 1:3) to obtain compound 26C (2.8 g, yield: 99.25%).

[0609] LC-MS (ESI): m / z = 186.1 [M+H] + .

[0610] Step 3: Compound 26C (2.8 g, 15.09 mmol), trimethylsilylmethyl azide (7.8 g, 60.36 mmol), bis(triphenylphosphino)cyclopentadienylruthenium(II) chloride (1.1 g, 1.51 mmol), cuprous iodide (0.57 g, 3.02 mmol), and tetrabutylammonium iodide (1.11 g, 3.02 mmol) were dissolved in tetrahydrofuran (60 mL), replaced with nitrogen three times, and reacted at 40°C for 16 hours. The mixture was cooled to room temperature, and then tetrabutylammonium fluoride (7.89 g, 30.18 mmol) was added and reacted at room temperature for 2 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic layers were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 1:2) to give compound 26D (3.4 g, yield: 92.87%).

[0611] LC-MS (ESI): m / z = 243.2 [M+H] + .

[0612] Step 4: Dissolve 26D (3 g, 12.36 mmol), 3,4-dihydro-2H-pyran (2.08 g, 24.72 mmol), and p-toluenesulfonic acid (0.21 g, 1.24 mmol) in dichloromethane (60 mL) and react at room temperature for 16 hours. Add 50 mL of water, extract with dichloromethane (30 mL x 3), wash, and concentrate. The residue is purified by column chromatography (ethyl acetate:petroleum ether (v / v) = 1:4) to afford compound 26E (4 g, 99.01% yield).

[0613] LC-MS(ESI):m / z=243.2[M-THP+H] + .

[0614] Step 5: Compound 26E (3.8 g, 11.63 mmol), bis(pinacol)diboron (4.43 g, 17.45 mmol), potassium acetate (3.42 g, 34.89 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.55 g, 1.16 mmol), and tris(dibenzylideneacetone)dipalladium (0.53 g, 0.58 mmol) were dissolved in dioxane (40 mL) and reacted at 100°C under nitrogen for 16 hours. The mixture was cooled, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed, and concentrated to give crude compound 26F (4.9 g).

[0615] LC-MS(ESI):m / z=253.1[M-THP+H] + .

[0616] Step 6: Compound 26F (4.9 g, 14.58 mmol) was dissolved in ethyl acetate (50 mL), and 30% hydrogen peroxide (14.89 ml, 145.8 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 1:0) to provide compound 26G (2.4 g, 53.4% ​​yield).

[0617] LC-MS(ESI):m / z=225.2[M-THP+H] + .

[0618] Step 7: Compound 26G (2.2 g, 7.14 mmol) and isopropyl (1S,3S)-3-hydroxycyclohexane-1-carboxylate (2.39 g, 12.85 mmol, synthesis reference: Tetrahedron Asymmetry, 2002, vol. 13, #6, pp. 579-585) were dissolved in 40 ml of toluene. Cyanomethylidenetri-n-butylphosphine (4.31 g, 17.85 mmol) was then added and the mixture was reacted at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford compound 26H (3.2 g, yield: 94.11%).

[0619] LC-MS(ESI):m / z=393.1[M-THP+H] + .

[0620] Step 8: 26H (3.2 g, 6.72 mmol) was dissolved in methanol (60 mL), and pyridinium p-toluenesulfonate (3.38 g, 13.44 mmol) was added. The mixture was reacted at 60°C for 3 hours. The mixture was concentrated, and 50 mL of water was added. The mixture was extracted with ethyl acetate (20 mL × 3), washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain compound 26I (2.2 g, yield: 83.49%).

[0621] LC-MS (ESI): m / z = 393.1 [M+H] + .

[0622] Step 9: Compound 26I (320 mg, 0.82 mmol), diphenylphosphoryl azide (338 mg, 1.23 mmol), and 1,8-diazacyclo[5,4,0]undecene-7 (249 mg, 1.64 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction was allowed to proceed at room temperature for 16 hours. Water (2 mL) and triphenylphosphine (430 mg, 1.64 mmol) were then added, and the reaction was continued at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3), washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:5) to afford compound 26J (250 mg, 78.32% yield).

[0623] LC-MS (ESI): m / z = 392.1 [M+H] + .

[0624] Step 10: Compound 26J (250 mg, 0.64 mmol) and intermediate 3 (365 mg, 1.28 mmol) were dissolved in dichloromethane (10 ml), followed by the addition of N,N-diisopropylethylamine (248 mg, 1.92 mmol). The mixture was allowed to react at room temperature for 16 hours. The mixture was concentrated, and 10 mL of water was added. The mixture was extracted with dichloromethane (20 mL x 3), washed, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to afford compound 26K (150 mg, 43.69% yield).

[0625] LC-MS (ESI): m / z = 538.2 [M+H] + .

[0626] Step 11: Compound 26K (150 mg, 0.28 mmol) was added to a reaction flask, followed by tetrahydrofuran:methanol:water (3 ml:3 ml:1 ml) and lithium hydroxide monohydrate (47 mg, 1.12 mmol). The mixture was allowed to react at room temperature for 16 hours. 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 preparative HPLC to afford compound 26 (9 mg, 6.51% yield).

[0627] LC-MS (ESI): m / z = 496.2 [M+H] + .

[0628] 1 H NMR(400MHz, CDCl3)δ8.09(d,1H),7.53(t,1H),6.25(t,1H),4.99(t,1H),4.73(s,1H ),4.62(d,2H),4.22(s,3H),3.06–2.96(m,3H),2.77–2.70(s,2H),2.10–1.66(m,8H).

[0629] Example 27

[0630] Step 1: Compound 27A (reference patent WO2019126085A1) (200 mg, 0.52 mmol) was dissolved in tetrahydrofuran (5 mL), and intermediate 3 (177 mg, 0.62 mmol) and N,N-diisopropylethylamine (201 mg, 1.56 mmol) were added. The mixture was reacted at room temperature for 1 h, concentrated, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target compound 27B (220 mg, yield: 79.88%).

[0631] LC-MS (ESI): m / z = 534.3 [M + 1] +

[0632] Step 2: Compound 27B (200 mg, 0.374 mmol) was added to a reaction flask and dissolved in THF:MeOH:H₂O = 3:1:1 (15 ml). Anhydrous lithium hydroxide (45 mg, 1.87 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 27 (100 mg, 54.28% yield).

[0633] 1HNMR(400MHz,DMSO-d6)δ12.21(s,1H),8.43(s,1H),7.88(s,1H),7.53–7.50(m,1H),4.99–4.89(m,1H),4.86–4.70(m,3H) ,3.87(s,3H),3.06–2.97(m,2H),2.70–2.61(m,3H),2.42(s,3H),2.05–1.98(m,1H),1.88–1.74(m,3H),1.70–1.47(m,4H).

[0634] LC-MS (ESI): m / z = 492.2 [M+H] + .

[0635] Biological test methods

[0636] 1. Cellular calcium flux experiment

[0637] 1) Dilute test compounds to 400X stock solution with DMSO in a 384-well plate.

[0638] 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.

[0639] 3) CHO-LPA1 cells were cultured using F12 medium (10% FBS).

[0640] 4) When the cells reached 80% confluency, 0.25% trypsin-EDTA was used to dissociate the cells.

[0641] 5) Measure the cell density and dilute the cells to 4 x 10e5 / ml with F12 (10% FBS).

[0642] 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.

[0643] 7) Replace with 25uL serum-free medium overnight.

[0644] 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.

[0645] 9) After incubation, transfer 5 μl of the 10X working solution from step 2 to the cell plate.

[0646] 10) Incubate the cell plate at 25°C in the dark for 15 minutes and then read the calcium signal.

[0647] 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.

[0648] 12) Read and save data using the FLIPR at room temperature using the specified settings.

[0649] 13) The signal value and compound concentration were plotted and the curve fitting and IC were performed using the nonlinear regression method of GraphPad Prism software. 50 Calculation. 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, Table B 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.

[0650] Table 1 Antagonistic activity of the compounds of the present invention against LPAR 1

[0651] Conclusion: The compounds of the present invention, such as the compounds in the examples, showed high antagonistic activity against LPAR1 receptor.

[0652] 2. Pharmacokinetic test in mice

[0653] 2.1. Experimental Animals: Male C57 mice, 22-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0654] 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.

[0655] Table 2. Dosing Information

[0656] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4).

[0657] Before and after drug administration, 0.06 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.

[0658] Table 3. Pharmacokinetic parameters of test compounds in mouse plasma

[0659] The control compound (BMS-986278) was synthesized according to WO2017223016.

[0660] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in mice.

[0661] 3. Pharmacokinetic test in rats

[0662] 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.

[0663] 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.

[0664] Table 4. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 10% Cremophor-EL + 40% PEG400 + 50% 1XPBS (pH = 7.4).

[0665] 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.

[0666] Table 5. Pharmacokinetic parameters of test compounds in rat plasma -:not applicable.

[0667] Conclusion: The compounds of the present invention, such as the compounds in the Examples, have good pharmacokinetic characteristics in rats.

[0668] 4. Beagle dog pharmacokinetic test

[0669] 4.1. Experimental Animals: Male beagle dogs, weighing approximately 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0670] 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.

[0671] 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.

[0672] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.

[0673] 5. Monkey pharmacokinetic test

[0674] 5.1. Experimental Animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0675] 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.

[0676] 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.

[0677] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

[0678] 6. hERG potassium channel effect test

[0679] Experimental platform: electrophysiology manual patch clamp system

[0680] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0681] 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).

[0682] 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:

[0683] Inhibition%=[1–(I / Io)]×100%

[0684] 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.

[0685] The IC50 of the compounds was calculated using GraphPad Prism 5 software by fitting the following equation:

[0686] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0687] Among them, X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom

[0688] and Top are the minimum and maximum inhibition percentages, respectively.

[0689] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit hERG.

[0690] 7. CYP enzyme inhibition test

[0691] 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.

[0692] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no inhibitory effect on CYP enzymes.

[0693] 8. Liver microsome stability test

[0694] 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.

[0695] 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) .

[0696] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0697] 9. Caco2 permeability test

[0698] 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.

[0699] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability and low efflux rate in Caco-2 cells.

[0700] 10. Bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) mouse model

[0701] 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, 8 mice each) based on their body weight.

[0702] 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.

[0703] 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.

[0704] 4) Detection indicators: Lung tissue was collected for pathological examination at the end of the study.

[0705] Conclusion: Compared with the model group administered with vehicle, the compounds of the present invention, especially the example compounds, administered by oral gavage twice a day for 14 consecutive days, significantly reduced the Modified Ashcroft score and pulmonary fibrosis area of ​​the lung tissue of the model mice at the end of the study.

Claims

1. A compound represented by formula (IA) or formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, in, Ring A is selected from 3-8 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 4-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R A replace; Ring B is selected from 6-12 membered monocyclic carbocyclic groups, 6-12 membered bicyclic carbocyclic groups, 4-12 membered monocyclic heterocyclic groups, 6-12 membered bicyclic heterocyclic groups, wherein the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; the carbocyclic groups and heterocyclic groups are optionally substituted by 1-4 R B replace; Ring C is selected from a 5-12 membered monocyclic heterocyclic group, a 6-12 membered bicyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S; the heterocyclic group is optionally substituted by 1-4 R C replace; L1, L3 are selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NR L1 -, -C(=O)NR L1 -、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 replace; L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2, -(CR L21 R L22 ) p -OC(=O)-NR L2 (CR L21 R L22 ) p R L2 、-C(=O)N(R L2 )2, -(CR L21 R L22 ) p N(R L2 )2, -(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )S(O)2N(R L2 )2, -(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2, -(CR L21 R L22 ) p NR L2 -C(=O)O(CR L21 R L22 ) p R L2 ; R A Each independently selected from H, halogen, CN, OH, -(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、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl or -(CH2) p -5-10 membered heterocyclic group, 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 1-4 Alkyl radical substitution; R B Each independently selected from H, halogen, CN, =O, OH, NO2, -SF5, C 1-4 Alkyl, NH2, -OC 1-4 Alkyl, -SO2C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-10 membered heteroaryl, -SCF3, -S(=O)(=NH)-C 1-4 Alkyl, the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 heteroatoms selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution; R C Each independently selected from H, halogen, CN, OH, NO2, NH2, C 1-4 Alkyl, -OC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN; Each R a1 、R a2 、R L1 、R L2 、R L21 、R L22 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, C 6-10 Aryl, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl 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 Alkoxy group substitution; p is selected from 0, 1, 2, 3, 4; Provided that, (1) Ring B is not optionally replaced by 1-4 R B Replace the following structure: (2) Ring B is selected from 1-4 R B Replaced or halogen-substituted When at least one R L2 Selected from C 3-10 Cycloalkyl or 5-14 membered heterocyclic group, and R L2 Further selected The group is substituted.

2. The compound of formula (IA) or formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein: Ring A is selected from 3-7 membered monocyclic carbocyclic groups, 6-10 membered bicyclic carbocyclic groups, 4-10 membered monocyclic heterocyclic groups, 6-10 membered bicyclic heterocyclic groups, and the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; preferably, ring A is selected from 3-7 membered monocyclic carbocyclic groups, 4-6 membered monocyclic heterocyclic groups, and 6-10 membered bicyclic heterocyclic groups, and the heterocyclic groups contain 1-3 heteroatoms selected from N, O, and S; preferably, ring A is selected from The ring A is substituted with 1 COOH.

3. The compound of formula (IA) or formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein: Ring B is selected from 8-10 membered bicyclic carbocyclic group, 6 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O and S; preferably, Ring B is selected from The ring B is optionally substituted with 1-4 R B replace; R B Each independently selected from H, halogen, CN, ═O, OH, C 1-2 Alkyl, NH2, -OC 1-2 Alkyl, -SO2C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SCF3, -S(=O)(=NH)-C 1-4 Alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl group substitution; preferably, R B Each independently selected from H, halogen, =O, C 1-2 Alkyl, -SO2C 1-2 Alkyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrazolyl, imidazolyl, -SCF3, -S(=O)(=NH)-C 1-2 Alkyl, the alkyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrazolyl, imidazolyl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, NH2, CN, -O-halogenated C 1-4 Alkyl group substitution; preferably, R B Each independently selected from H, F, Cl, =O, CHF2, CF3, CH3, CH2CH3, -SO2CH3, -OCF3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3.

4. The compound of formula (IA) or formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein: Ring C is selected from 6-8 membered monocyclic heterocycloalkyl, 6-10 membered bicyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 6-10 membered bicyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; the heterocycloalkyl and heteroaryl groups are optionally substituted by 1-4 R C substituted; preferably, ring C is selected from 5-6 membered monocyclic heteroaryl; preferably, ring C is selected from The ring C is optionally substituted with 1-4 R C replace; R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, -OC 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; preferably, R C Each independently selected from H, halogen, CN, OH, NH2, C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; preferably, R C Each is independently selected from H, F, Cl, CH3, CH2CH3.

5. The compound of formula (IA) or formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein: L1 is selected from a bond, -O-(CH2) p -、-S-(CH2) p -, -C(=O)-, -NH-, -C(=O)NH-,C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, the alkyl, alkenyl, alkynyl optionally further 1-4 R L1 Substituted; preferably, L1 is selected from a bond, -O-, -S-, -NH-, -C(=O)NH-, -CH2-, -O-CH2-, -S-CH2-; L2 is selected from -(CR L21 R L22 ) p -OC(=O)-N(R L2 )2、-(CR L21 R L22 ) p -OC(=O)-NR L2 (CR L21 R L22 ) p R L2 、-C(=O)N(R L2 )2、-(CR L21 R L22 ) p N(R L2 )2、-(CH2) p R L2 、-(CR L21 R L22 ) p N(R L2 )C(=O)N(R L2 )2、-(CR L21 R L22 ) p NR L2 -C(=O)O(CR L21 R L22 ) p R L2 ; Preferably, L2 is selected from -CH2-OC(=O)-N(R L2 )2, -CH2-OC(=O)-N(CH3)CR L21 R L22 R L2 、-NH-C(=O)OCR L21 R L22 R L2 、-CH2-N(CH3)-C(=O)OCR L21 R L22 R L2 、-CH2-NH-C(=O)OR L2 、-CH2-NH-C(=O)OCR L21 R L22 R L2 ; Preferably, L2 is selected from Each R L1 、R L2 、R L21 、R L22 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 6-8 Aryl, the heterocycloalkyl, heteroaryl contains 1-3 heteroatoms selected from N, O, S; the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl 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 Alkoxy group substitution; p is selected from 0, 1 or 2.

6. The compound of formula (IA) or formula (I) according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof having a structure of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), or formula (VIII), 7. The compound of formula (IA) or formula (I) according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (II-2) or formula (II-3), in, Ring A is selected from: L1 is selected from a bond, -O- or -NH-CO-; R B’ Selected from F, Cl, CHF2, CF3, CH2CH3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3; R B Selected from F, Cl, CHF2, CF3, CH3, CH2CH3, CH=CH2, C≡CH, C(CH3)=CH2, C(F)=CH2, -SCF3, -S(=O)(=NH)-CH3; R C Selected from CH3, CH2CH3; L2 is selected from 8. The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures in Table 1 or Table 2.

9. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 8, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

10. The pharmaceutical composition or pharmaceutical preparation according to claim 9, comprising 1-1500 mg of the compound according to any one of claims 1-8 or a stereoisomer or a pharmaceutically acceptable salt thereof and a carrier and / or excipient.

11. Use of the compound according to any one of claims 1 to 8, its stereoisomers or pharmaceutically acceptable salts, or the composition according to claims 9 to 10 in the preparation of a medicament for treating / preventing LPAR1-mediated diseases.

12. The use according to claim 11, wherein the LPAR1-mediated disease is selected from idiopathic pulmonary fibrosis.

13. A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of the compound according to any one of claims 1 to 8, or a stereoisomer or a pharmaceutically acceptable salt thereof, preferably 1 to 1500 mg, wherein the disease is preferably idiopathic pulmonary fibrosis.

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