LPAR1 antagonist and use thereof

Abstract

The present invention relates to an LPAR1 antagonist and the use thereof. Disclosed in the present invention are a compound as represented by formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and the use thereof in the preparation of a drug for treating / preventing LPAR1-mediated diseases. Each group in formula (I) is as defined in the description.

Description

An LPAR1 antagonist and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a small-molecule compound with LPAR1 antagonistic activity, a stereoisomer or a pharmaceutically acceptable salt thereof, and a use thereof in the preparation of a drug for treating related diseases. BACKGROUND

[0002] Lysophosphatidic acid (LPA) is a small molecule glycerophosphoric acid with a molecular weight of 430-480D. LPA widely exists in the human body and can activate multiple cell signaling pathways after binding to receptors, participate in the regulation of cell proliferation, differentiation, apoptosis, neurotransmitter release and other life activities, and plays an important role in diseases such as cancer, fibrosis, neuronal dysfunction, and bone metabolism disorder. LPA is mainly generated by hydrolysis of lysophospholipids (mainly lysophosphatidylcholine) by autocrine motility factor. In the bleomycin-induced pulmonary fibrosis model, the LPA level of bronchoalveolar lavage fluid is significantly increased, and it leads to increased vascular permeability and pulmonary fibrosis; LPA can also mediate the production of various paracrine mediators by fibroblasts, and act on epithelial cells, leukocytes and endothelial cells to regulate tissue remodeling, angiogenesis, inflammation, wound healing and tumor progression; LPA can even induce the extracellular shedding of epidermal growth factor (EGF) family ligands of fibroblasts, activate soluble factor release, and partially act through EGFR to stimulate lung epithelial cells and expand local fibroblast response. Recent studies have also found that the LPA-LPA1 signaling pathway can promote lung tissue epithelial cell apoptosis 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 related to organ fibrosis, mainly mediated by lysophosphatidic acid receptor (LPAR) 1. Six LPARs have been found, namely LPAR1-LPAR6, and the function of LPAR1 has been a research hotspot in recent years. Clinical studies have confirmed that LPAR antagonists have a therapeutic effect on idiopathic pulmonary fibrosis; it has also been found that LPAR1 antagonist BMS-986020 can effectively improve the lung function of patients with idiopathic pulmonary fibrosis. SUMMARY

[0003] The present application provides a compound shown in general formula (I), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, which has antagonistic effect on LPAR1, has good physical and chemical properties, such as high solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, small side effects, and has the advantages of oral administration, fast absorption, high clearance rate and the like.

[0004] The present application relates to a compound represented by general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-4), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0005] Ring A is selected from a 3-12 membered carbocyclyl, a 4-12 membered heterocyclyl, or is absent, said carbocyclyl or heterocyclyl being optionally substituted with 1-5 groups selected from R A ;

[0006] In some embodiments, ring A is selected from a C 3-6 monocyclic cycloalkyl, a C 5-12 bicyclic cycloalkyl, a 4-8 membered monocyclic heterocycloalkyl, a 6-12 membered bicyclic heterocycloalkyl, a 5-6 membered heteroaryl, a 6-8 membered aryl, or is absent, said cycloalkyl, heterocycloalkyl, heteroaryl, or aryl being optionally substituted with 1-5 groups selected from R A ;

[0007] In some embodiments, ring A is selected from a C 3-6 monocyclic cycloalkyl, a C 6-10 bicyclic cycloalkyl, a 5-6 membered heteroaryl, or is absent, said cycloalkyl, heteroaryl being optionally substituted with 1-5 groups selected from R A ;

[0008] In some embodiments, ring A is selected from a C 3-6 monocyclic cycloalkyl, a 5-6 membered heteroaryl, or is absent, said cycloalkyl, heteroaryl being optionally substituted with 1-5 groups selected from R A ;

[0009] In some embodiments, ring A is selected from a cyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl, a 5 membered heteroaryl, a 6 membered heteroaryl, or is absent, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 membered heteroaryl, or 6 membered heteroaryl being optionally substituted with 1-5 groups selected from R A ;

[0010] In some embodiments, ring A is selected from or is absent;

[0011] In some embodiments, ring A is selected from or is absent, optionally substituted with 1-3 groups selected from R A ;

[0012] Ring B is selected from the “*” end is connected to the pyridine ring, the end is connected to L3;

[0013] In some embodiments, Ring B is selected from

[0014] R A , R B each independently is selected from H, deuterium, halogen, =0, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-4 alkyl, or C 1-4 alkoxy;

[0015] In some embodiments, R A each independently is selected from H, deuterium, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, C 1-4 alkyl, or C 1-4 alkoxy;

[0016] In some embodiments, R B each independently is selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-4 alkyl, or C 1-4 alkoxy;

[0017] In some embodiments, R A each independently is selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, C 1-4 alkyl, or C 1-4 alkoxy;

[0018] In some embodiments, R A each independently is selected from deuterium, halogen, C 1-6 alkyl, said alkyl optionally substituted with 1-3 groups selected from deuterium, halogen;

[0019] In some embodiments, R A each independently is selected from H, deuterium, halogen, C 1-4 alkyl, optionally substituted with 1-3 groups selected from deuterium, halogen;

[0020] In some embodiments, R A each independently is selected from H, deuterium, F, Cl, methyl, ethyl or propyl, optionally substituted with 1-3 groups selected from deuterium, F, Cl;

[0021] In some embodiments, R B each independently is selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-4 alkyl or C 1-4 alkoxy;

[0022] In some embodiments, R B each independently is selected from deuterium, F, Cl, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-4 alkyl or C 1-4 alkoxy;

[0023] In some embodiments, R B is selected from C 1-6 alkyl; in some embodiments, R B is selected from C 1-4 alkyl; in some embodiments, R B is selected from methyl;

[0024] L1, L2are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, -O-, -O-C 1-6 alkyl-, -S-, -S-C 1-6 alkyl-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 -, -NR L1 -C 1-6 alkyl-, -(CH2) p -C3-6 Cycloalkylene, wherein the alkylene, alkylene, alkenylene, ynylene, or cycloalkylene may optionally be further surrounded by 1-4 R groups. L1 replace;

[0025] In some implementation schemes, L1 and L2 are each independently selected from key and C. 1-6 Alkylene, -O-, -OC 1-4 Alkyl group -, -(CH2) p -C 3-6 Cycloalkylene, wherein the alkyl, alkylene, or cycloalkylene group is optionally further surrounded by 1-4 R groups. L1 replace;

[0026] In some implementations, L1 is selected from key, C 1-6 Alkylene, -(CH2) p -C 3-6 Cycloalkylene, wherein the alkylene or cycloalkylene group is optionally further surrounded by 1-4 R groups. L1 replace;

[0027] In some implementations, L2 is independently selected from key, -O-, -OC. 1-4 Alkyl group -, -(CH2) p -C 3-6 Cycloalkylene, wherein the alkylene or cycloalkylene group is optionally further surrounded by 1-4 R groups. L1 replace;

[0028] In some implementations, L1 is selected from C 1-4 Alkylene, -(CH2) p -C 3-6 Cycloalkylene; in some embodiments, L1 is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, and cyclopropyl;

[0029] In some implementations, L2 is selected from -O-, -OC 1-6 Alkyl group; in some embodiments, L2 is selected from -O-, -OC. 1-4 Alkyl-; in some embodiments, L2 is selected from -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CHCH3-, -O-CH2CH2CH(CH3)-, -O-CH2C(CH3)2-;

[0030] In some implementations, when L2 is -O-, ring A is selected from C. 6-10 Bicyclic cycloalkyl, optionally selected from 1-3 R A The group substitution; in some embodiments, when L2 is -O-, ring A is selected from... Choose 1-3 from R Asubstituted with 1-4 groups independently selected from H, deuterium, F, Cl, Br, I, C

[0031] In some embodiments, when L2is -O-C 1-6 alkyl-, ring A is selected from the group consisting of absent; in some embodiments, when L2is -O-C 1-4 alkyl-, ring A is selected from the group consisting of absent; in some embodiments, when L2is -O-CH2CH2-, -O-CH2CHCH3-, -O-CH2CH2CH(CH3)-, -O-CH2C(CH3)2-, ring A is selected from the group consisting of absent;

[0032] R1is selected from -(CH2) p -C(O)OH;

[0033] In some embodiments, R1is selected from -C(O)OH;

[0034] In some embodiments, R1is selected from -CH2-C(O)OH;

[0035] R L1 each is independently selected from H, deuterium, halogen, OH, C 1-4 alkyl, haloC 1-4 alkyl, 3-6 membered cycloalkyl, -COOH, said alkyl, cycloalkyl optionally further substituted with 1-4 groups independently selected from halogen, deuterium, OH, NH2;

[0036] In some embodiments, R L1 each is independently selected from H, deuterium, halogen, C 1-4 alkyl, haloC 1-4 alkyl, -COOH, said alkyl optionally further substituted with 1-4 groups independently selected from halogen, deuterium, OH, NH2;

[0037] In some embodiments, R L1 each is independently selected from H, deuterium, halogen, C 1-4 alkyl, haloC 1-4 alkyl, said alkyl optionally further substituted with 1-4 groups independently selected from halogen, deuterium;

[0038] In some embodiments, R L1 each is independently selected from H, deuterium, F, Cl, CH3, CH2CH3, CH2CH2CH3, CF3, CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CH2CH2CF3, CH2CH2CHF2, CH2CH2CH2F;

[0039] L3is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23)-, -(CR L21 R L22 ) p -N(R L23 )C(O)O-;

[0040] In some embodiments, L3is selected from -(CH2) p -OC(O)-N(C 1-4 alkyl)-, -(CH2) p -OC(O)-NH-, p -N(C 1-4 alkyl)C(O)O-, -(CH2) p -NHC(O)O-;

[0041] In some embodiments, L3is selected from -CH2OC(O)-N(C 1-2 alkyl)-, -CH2-NHC(O)O-;

[0042] In some embodiments, is selected from:

[0043] R L21 , R L22 , R L23 each independently is selected from H, deuterium, halogen, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl optionally further substituted with 1-4 selected from deuterium, halogen, OH, NH2;

[0044] In some embodiments, R L21 , R L22 , R L23 each independently is selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl optionally further substituted with 1-4 selected from deuterium, halogen, OH, NH2;

[0045] In some embodiments, R L21 , R L22 , R L23 each independently is selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4alkyl, alkyl, alkoxy, said alkyl, alkoxy optionally further substituted with 1-4 groups selected from deuterium, halogen, OH, NH2;

[0046] In some embodiments, R L21 , R L22 , R L23 are each independently selected from H, deuterium, F, CI, CH3, CH2CH3, CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, said CH3, CH2CH3, CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3 optionally further substituted with 1-4 groups selected from deuterium, halogen, OH, NH2;

[0047] Y is selected from C 3-6 cycloalkyl, 4-12 membered heterocycloalkyl, said cycloalkyl, heterocycloalkyl further substituted with 1-4 groups selected from =CH2, =CF2, =CH-CH3, =C-(CH3)2, halogenated C 1-4 alkyl, =C 3-6 alkenyl, =C

[0048] In some embodiments, Y is selected from C 3-6 cycloalkyl, said cycloalkyl further substituted with 1-4 groups selected from =CH2, =CF2, halogenated C 1-4 alkyl, =C 3-6 alkenyl, =C

[0049] In some embodiments, Y is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl further substituted with 1-4 groups selected from =CH2, =CF2, halogenated C 1-4 alkyl, =C 3-6 alkenyl, =C

[0050] In some embodiments, Y is selected from cyclobutyl, said cyclobutyl further substituted with 1-4 groups selected from =CH2, =CF2, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCH2CH2CF3, -OCH2CH2CHF2, -OCH2CH2CH2F, =cyclopropyl, =cyclobutyl, =cyclopentyl, =cyclohexyl;

[0051] each p is independently selected from 0, 1, 2, 3, 4;

[0052] In some embodiments, each p is independently selected from 0, 1, 2, or 3;

[0053] In some embodiments, each p is independently selected from 0, 1, or 2;

[0054] In some embodiments, each p is independently selected from 0 or 1.

[0055] In particular, the first technical solution of the present application, the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

[0056] Ring A is selected from 3-12 membered carbocyclyl, 4-12 membered heterocyclyl, or is absent, said carbocyclyl or heterocyclyl being optionally substituted with 1-5 groups selected from R A ;

[0057] Ring B is selected from the “*” end is attached to the pyridine ring, the “*” end is attached to L3;

[0058] R A , R B are each independently selected from H, deuterium, halogen, =O, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl being optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-4 alkyl, or C 1-4 alkoxy;

[0059] L1, L2 are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, -O-, -O-C 1-6 alkyl-, -S-, -S-C 1-6 alkyl-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 -, -NR L1 -C 1-6 alkyl-, -(CH2) p -C 3-6 cycloalkylene, said alkyl, alkylene, alkenylene, alkynylene, cycloalkylene being optionally further substituted with 1-4 R L1 ;

[0060] R1is selected from -(CH2) p -C(O)OH;

[0061] R L1 are each independently selected from H, deuterium, halogen, OH, C1-4 alkyl, haloC 1-4 alkyl, 3-6 membered cycloalkyl, -COOH, said alkyl, cycloalkyl being optionally further substituted with 1-4 groups selected from halo, deuterium, OH, NH2;

[0062] L3is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )-, -(CR L21 R L22 ) p -N(R L23 )C(O)O-;

[0063] R L21 , R L22 , R L23 are each independently selected from H, deuterium, halo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally further substituted with 1-4 groups selected from deuterium, halo, OH, NH2;

[0064] Y is selected from C 3-6 cycloalkyl, 4-12 membered heterocycloalkyl, said cycloalkyl, heterocycloalkyl being further substituted with 1-4 groups selected from =CH2, =CF2, =CH-CH3, =C-(CH3)2, haloC 1-4 alkoxy, =C 3-6 cycloalkyl;

[0065] each p is independently selected from 0, 1, 2, 3, 4.

[0066] In a second aspect of the present application, the compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof, wherein,

[0067] Ring A is selected from C 3-6 monocyclic cycloalkyl, C 5-12 bicyclic cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 6-8 membered aryl, or is absent, said cycloalkyl, heterocycloalkyl, heteroaryl or aryl being optionally substituted with 1-5 groups selected from R A ;

[0068] In a preferred embodiment, Ring A is selected from C 3-6 monocyclic cycloalkyl, C 6-10bicyclic cycloalkyl, 5-6 membered heteroaryl, or absent, said cycloalkyl, heteroaryl being optionally substituted with 1-5 groups selected from R A In another preferred embodiment, ring A is selected from C 3-6 monocyclic cycloalkyl, 5-6 membered heteroaryl, or absent, said cycloalkyl, heteroaryl being optionally substituted with 1-5 groups selected from R A In another preferred embodiment, ring A is selected from C

[0069] R A each independently selected from H, deuterium, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl being optionally substituted with 1-3 groups selected from deuterium, halogen, C 1-4 alkyl, or C 1-4 alkoxy;

[0070] R B each independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl being optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-4 alkyl, or C 1-4 alkoxy;

[0071] L1, L2are each independently selected from a bond, C 1-6 alkylene, -O-, -O-C 1-4 alkyl-, -(CH2) p -C 3-6 cycloalkylene, said alkyl, alkylene, cycloalkylene being optionally further substituted with 1-4 R L1 ;

[0072] The other group definitions are in accordance with the first technical solution.

[0073] In a third aspect of the present application, the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,

[0074] L3is selected from -(CH2) p -OC(O)-N(C 1-4 alkyl)-, -(CH2) p -NHC(O)O-;

[0075] Y is selected from C 3-6 cycloalkyl, said cycloalkyl being further substituted with 1-4 groups selected from =CH2, =CF2, halogenated C 1-4 alkoxy, =C3-6 cycloalkyl groups;

[0076] Other groups are defined in accordance with the second technical solution.

[0077] In a fourth technical solution of the present application, the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,

[0078] is selected from: In some embodiments, is selected from:

[0079] Other groups are defined in accordance with the first, second or third technical solution.

[0080] In a fifth technical solution of the present application, the compound of formula (I-1), (I-2), (I-3), (I-4), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,

[0081] In a sixth technical solution of the present application, the compound of formula (I-1), (I-2), (I-3), (I-4), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,

[0082] Ring A is selected from or is absent, optionally substituted with 1-3 groups selected from R A ;

[0083] R A each independently selected from H, deuterium, halogen, C 1-4 alkyl, said alkyl optionally substituted with 1-3 groups selected from deuterium, halogen;

[0084] L1, L2are each independently selected from a bond, C 1-4 alkylene, -O-, -O-C 1-4 alkyl-, -(CH2) p -C 3-6 cycloalkylene;

[0085] R B each independently selected from deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl or 4-5 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-3 alkyl, C 1-3 alkoxy, preferably deuterium, fluorine, chlorine, methyl, ethyl, cyclopropyl;

[0086] Other groups are defined in accordance with the first, second, third or fourth technical solution.

[0087] In a seventh aspect of the present application, the compound represented by the aforementioned formula (I-1), (I-2), (I-3), (I-4), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,

[0088] Ring A is selected from C 3-6 monocyclic cycloalkyl, C 6-10 bicyclic cycloalkyl, 5-6 membered heteroaryl or absent, optionally substituted with 1-3 groups selected from R A ; preferably or absent, optionally substituted with 1-3 groups selected from R A ;

[0089] R A is selected from deuterium, halogen, C 1-6 alkyl, said alkyl optionally substituted with 1-3 groups selected from deuterium, halogen; in a preferred embodiment, R A is selected from deuterium, halogen, C 1-4 alkyl, said alkyl optionally substituted with 1-3 groups selected from deuterium, halogen;

[0090] L1is selected from C 1-4 alkylene, -(CH2) p -C 3-6 cycloalkylene, in a preferred embodiment, L1is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, cyclopropyl;

[0091] L2is selected from -O-, -O-C 1-6 alkyl-; in a preferred embodiment, L2is selected from -O-, -O-C 1-4 alkyl-; in a more preferred embodiment, L2is selected from -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CHCH3-, -O-CH2CH2CH(CH3)-, -O-CH2C(CH3)2-;

[0092] R B is selected from C 1-6 alkyl; in a preferred embodiment, R B is selected from C 1-4 alkyl; in a more preferred embodiment, R B is selected from methyl;

[0093] R1is selected from -(CH2) p -C(O)OH;

[0094] p is selected from 0 or 1;

[0095] L3and Y are defined in accordance with the first, second, third, or fourth technical solution.

[0096] In an eighth technical solution, the compound represented by formula (I-1) in the aforementioned seventh technical solution, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,

[0097] when L2is -O-, ring A is selected from C 6-10 bicyclic cycloalkyl, optionally substituted with 1-3 groups selected from R A in a preferred embodiment, when L2is -O-, ring A is selected from optionally substituted with 1-3 groups selected from R A in a preferred embodiment, when L2is -O-, ring A is selected from

[0098] when L2is -O-CH2-, ring A is selected from C 1-6 in a preferred embodiment, when L2is -O-CH2-, ring A is selected from C 1-4 in a more preferred embodiment, when L2is -O-CH2CH2-, -O-CH2CHCH3-, -O-CH2CH2CH(CH3)-, -O-CH2C(CH3)2-, ring A is selected from C

[0099] R A is selected from deuterium, halogen, C 1-6 alkyl optionally substituted with 1-3 groups selected from deuterium, halogen; in a preferred embodiment, R A is selected from deuterium, halogen, C 1-4 alkyl optionally substituted with 1-3 groups selected from deuterium, halogen;

[0100] R B is selected from C 1-6 alkyl; in a preferred embodiment, R B is selected from C 1-4 alkyl; in a more preferred embodiment, R B is selected from methyl;

[0101] R1is selected from -(CH2) p -C(O)OH;

[0102] p is selected from 0 or 1;

[0103] is selected from:

[0104] The ninth aspect of the present application, the compound represented by the aforementioned formula (I-1), (I-2), (I-3), (I-4), a stereoisomer or a pharmaceutically acceptable salt thereof, which satisfies the following conditions: (1) when R B is selected from methyl, is selected from , is not selected from (2) when R B is selected from methyl, is selected from , is not selected from (3) when R B is selected from methyl, is selected from , is not selected from

[0105] More specifically, the compound of formula (I) according to the present application, a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from, but not limited to, the structures in Table 1 and Table 2 as follows:

[0106] Table 1

[0107] Table 2

[0108] Secondly, the present application further provides a pharmaceutical composition comprising the compound according to any one of the aforementioned aspects, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or adjuvant.

[0109] Further, the present application provides a pharmaceutical composition or a pharmaceutical preparation comprising 1-1500 mg of the compound according to any one of the aforementioned aspects, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or adjuvant.

[0110] Further, the present application further provides the use of the compound according to any one of the aforementioned aspects, a stereoisomer or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating / preventing a LPAR1-mediated disease. Further, the LPAR1-mediated disease is idiopathic pulmonary fibrosis, etc.

[0111] The present application also provides a method for treating a disease in a mammal or human, said method comprising administering to the subject a therapeutically effective amount of a compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, preferably the disease is idiopathic pulmonary fibrosis or the like, preferably the therapeutically effective amount is 1-1500 mg. In some embodiments, the mammal in the present application does not include human.

[0112] An "effective amount" or "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound comprising a compound disclosed herein that is required to provide a clinically significant decrease in disease symptoms. Examples of a therapeutically effective amount include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg;50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg.

[0113] The present application relates to a pharmaceutical composition or a pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof and a carrier and / or adjuvant. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "the preparation specification"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0114] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound of the present application, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or adjuvant, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0115] A method for treating a disease in a mammal or human, the method comprising administering to the subject a pharmaceutical compound of the present application, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or adjuvant, in a daily dose of 1-1500 mg per day, which can be in a single dose or in divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg per day, 20-1500 mg per day, 25-1500 mg per day, 50-1500 mg per day, 75-1500 mg per day, 100-1500 mg per day, 200-1500 mg per day, 10-1000 mg per day, 20-1000 mg per day, 25-1000 mg per day, 50-1000 mg per day, 75-1000 mg per day, 100-1000 mg per day, 200-1000 mg per day, 25-800 mg per day, 50-800 mg per day, 100-800 mg per day, 200-800 mg per day, 25-400 mg per day, 50-400 mg per day, 100-400 mg per day, 200-400 mg per day, in some embodiments, the daily dose includes but is not limited to 1 mg per day, 5 mg per day, 10 mg per day, 20 mg per day, 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 200 mg per day, 400 mg per day, 600 mg per day, 800 mg per day, 1000 mg per day, 1200 mg per day, 1400 mg per day, 1500 mg per day.

[0116] The present application relates to a kit which can include a composition in single or multiple dose form, the kit comprising a compound of the present application, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the same amount as in the above pharmaceutical composition. The amount of the compound of the present application, or a stereoisomer or a pharmaceutically acceptable salt thereof, is in each case calculated as the free base. The "dosage form" refers to the weight of the main drug contained in each bottle, tablet or other unit of preparation.

[0117] Synthetic route

[0118] The compounds of the present application can be prepared by those skilled in the art with reference to this document and to known techniques of organic synthesis, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, including suppliers such as Titan Scientific, Acros Organics, Shanghai Detong, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yushi, Drugmaker and Bailingwei Technology, etc.

[0119] The specific and analogous reactants can be identified selectively by the Index of Known Chemical Substances prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and on-line. Chemicals that are known but not commercially available in the catalog can be prepared alternatively by custom chemical synthesis houses, many of which standard chemical supply houses (such as those listed above) offer custom synthesis services.

[0120] The specific and analogous reactants can be identified selectively by the Index of Known Chemical Substances prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and on-line. Chemicals that are known but not commercially available in the catalog can be prepared alternatively by custom chemical synthesis houses, many of which standard chemical supply houses (such as those listed above) offer custom synthesis services.

[0121] The term

[0122] The terms of the present application have the following meanings, unless specifically stated otherwise in the present application:

[0123] "Halogen" refers herein to F, Cl, Br, I, or isotopes thereof.

[0124] "Halo" or "halogen substitution" refers to replacement of a hydrogen atom by one or more halogen atoms selected from F, Cl, Br, I, or isotopes thereof, the upper limit of the number of halogen atoms is equal to the sum of the number of hydrogens that the substituted group can be substituted, and the number of halogen atoms is any integer between 1 and the upper limit, unless specifically limited, and when the number of halogen atoms is greater than 1, the halogen atoms can be the same or different.

[0125] "Deuterated" or "deuterated compound" refers to the replacement of a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl, etc. group by at least one isotope of deuterium, the upper limit of the number of deuterium atoms is equal to the sum of the number of hydrogens that the substituted group can be substituted, and the number of deuterium atoms is any integer between 1 and the upper limit, unless specifically limited, and preferably 1-20 deuterium atoms, more preferably 1-10 deuterium atoms, more preferably 1-6 deuterium atoms, more preferably 1-3 deuterium atoms.

[0126] "Alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of one to twenty carbon atoms, unless otherwise specified, preferably one to eight carbon atoms, more preferably one to six carbon atoms, even more preferably one to four carbon atoms, and still more preferably one to two carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, neopentyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and various branched isomers thereof.

[0127] "Alkylene" means a divalent straight or branched chain saturated alkyl group. Non-limiting examples of alkylene groups include methylene, ethylene, propylene, and butylene, and the like.

[0128] "Cycloalkylene" means a divalent group of "cycloalkyl". Non-limiting examples include cyclopropylene, cyclobutylene, and the like.

[0129] "Carbocyclic" or "carbocyclic group" means a substituted or unsubstituted, saturated or unsaturated, aromatic or nonaromatic carbocyclic ring group, including monocyclic carbocyclic rings, bicyclic bridged rings, bicyclic fused rings, and bicyclic spiro rings, and the like, having from three to twelve carbon atoms, unless otherwise specified, preferably having three to ten carbon atoms, more preferably having three to six carbon atoms. The definition includes cycloalkyl and aryl groups. Non-limiting examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, and the like, bicyclic bridged rings include and the like, bicyclic fused rings include and the like, bicyclic spiro rings include and the like.

[0130] "Cycloalkyl" means a monovalent nonaromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group, unless otherwise specified, typically having three to twelve carbon atoms, preferably having three to ten carbon atoms, more preferably having three to six carbon atoms, and still more preferably having three to four carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and the like.

[0131] "Aryl" means a carbocyclic ring having aromaticity. Non-limiting examples include phenyl, naphthyl, and the like.

[0132] "Akynyl" means a straight chain or branched chain monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, akynyl groups contain two to six carbon atoms, preferably two to four carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, and the like.

[0133] "Alkenyl" means a straight or branched chain, monovalent unsaturated hydrocarbon group containing one or more carbon-to-carbon double bonds, unless otherwise specified. The alkenyl group preferably contains 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, isopropenyl, 2-butenyl, 1-butenyl, and the like.

[0134] "Alkoxy" or "alkyloxy" means -O-alkyl, unless otherwise specified. When not specifically stated, alkoxy groups preferably contain 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy, and the like. 1-8 alkyl, preferably -O-C 1-6 alkyl, more preferably -O-C 1-4 alkyl, further preferably -O-C 1-2 alkyl. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy, and the like.

[0135] "Haloalkoxy" means -O-haloalkyl, unless otherwise specified. When not specifically stated, haloalkoxy groups preferably contain 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like. 1-8 haloalkyl, preferably -O-haloC 1-6 haloalkyl, more preferably -O-haloC 1-4 haloalkyl, further preferably -O-haloC 1-2 alkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0136] "C 1-4 alkyl, preferably -C(O)-C 1-4 alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0137] "Heterocycle" or "heterocyclyl" means a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, containing, if not specified, from 1 to 3 heteroatoms selected from N, O or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles and bicyclic spiro heterocycles, and the like, and, if not specified, 3- to 12-membered heterocycles, more preferably 4- to 12-membered heterocycles, more preferably 4- to 10-membered heterocycles, and further more preferably 4- to 7-membered heterocycles. The definition includes heterocycloalkyl and heteroaryl groups. The N, S in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclyl group can be attached to a heteroatom or a carbon atom, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dihydropyrrolinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantanyl and oxaspiro[3.3]heptanyl, and the like.

[0138] "Heteroarylene" is the divalent group corresponding to "heteroaryl", non-limiting examples include imidazolylene, piperidinylene, aziridinylene and the like.

[0139] "Heteroaromatic" or "heteroaryl" means a heterocycle with aromaticity. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridyl, furanyl and the like.

[0140] "Heteroalkyl" refers to a saturated or partially unsaturated non-aromatic carbon ring containing 1, 2, 3, 4, 5 heteroatoms selected from N, S, O, P, Si. The heteroalkyl group can be monocyclic, bicyclic or polycyclic, the bicyclic or polycyclic can be bridged, annulated, spirocyclic or a combination thereof, and can include one or more aromatic or heteroaromatic rings in the bicyclic or polycyclic ring system, but the overall ring system is not aromatic, and the point of attachment is on the non-aromatic ring. Typically, the heteroalkyl group is a 3- to 20-membered ring, when monocyclic, typically a 3- to 15-membered ring, or a 3- to 10-membered ring, or a 3- to 8-membered ring, or a 3- to 6-membered ring; when bicyclic or polycyclic, typically a 5- to 12-membered ring, or a 5- to 11-membered ring, or a 6- to 9-membered ring. The heteroatoms N, S, P therein include their oxidized forms C=O, N-O, S=O, S(=O)2, P=O, P(=O)2. When the heteroalkyl group is bicyclic or polycyclic, at least one of the rings contains at least one heteroatom, which can be a heteroatom-containing ring and a non-heteroatom-containing ring, or a heteroatom-containing ring and a heteroatom-containing ring; when attached to other groups, it can be a heteroatom or a carbon atom as the point of attachment. Non-limiting examples of heteroalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azacyclopentenyl, azacyclohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc., which can be optionally substituted.

[0141] "Spirocycle" refers to a polycyclic group in which a ring shares a carbon atom (referred to as a spiro atom) with another ring, which can contain 0 or 1 or more double or triple bonds, and can contain 0 to 5 heteroatoms selected from N, O, S and their oxidized forms. Typically, the spirocycle is a 5- to 14-membered ring, or a 5- to 12-membered ring, or a 5- to 10-membered ring. Typically, the spirocycle is a trispiro three (indicating a three-membered ring spiro three), trispiro four, trispiro five, trispiro six, tetracyclo four, tetracyclo five, tetracyclo six, pentacyclo five, or pentacyclo six. Non-limiting examples of spirocycles include

[0142] , which can be optionally substituted by substituents.

[0143] "Fused" refers to a polycyclic group in which rings share adjacent ring atoms and a bond, can contain one or more double or triple bonds, and can contain 0 to 5 heteroatoms selected from N, S, O, and oxidation states thereof. Typically, fused rings are 5 to 20 membered, or 5 to 14 membered, or 5 to 12 membered, or 5 to 10 membered. Non-limiting examples of fused rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene,

[0144] ; said fused ring can be optionally substituted with substituents.

[0145] "Bridge" refers to a polycyclic group in which rings share two non-adjacent ring atoms, can contain one or more double or triple bonds. Bridges can contain 0 to 5 heteroatoms selected from N, S, O, and oxidation states thereof. Typically, bridges have 5 to 20 ring atoms, or 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms. Non-limiting examples of bridges include adamantane,

[0146] "Carbocyclo", "cycloalkyl", "carbocyclyl", or "carbocyclyl" refers to a "fused ring" in which the ring system consists only of carbon atoms. As used herein, "carbocyclo", "cycloalkyl", "carbocyclyl", or "carbocyclyl" are defined as fused rings.

[0147] "Heterocyclo", "heterocyclyl", "heterocycloalkyl", "heterocyclyl", or "heterocyclyl" refers to a "fused ring" containing heteroatoms. As used herein, "heterocyclo", "heterocyclyl", "heterocycloalkyl", "heterocyclyl", or "heterocyclyl" are defined as fused rings.

[0148] "Heterospiro", "heterospiro", "spiroheterocyclyl", or "heterospiro" refers to a "spiro ring" containing heteroatoms. As used herein, "heterospiro", "heterospiro", "spiroheterocyclyl", or "heterospiro" are defined as spiro rings.

[0149] "Heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group" means a "bridged ring" containing heteroatoms. As used herein, "heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group" are defined as bridged ring. "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "alkyl optionally substituted with F" means that the alkyl group can or can not be substituted with F, and the description includes instances in which the alkyl group is substituted with F and instances in which the alkyl group is not substituted with F.

[0150] When the linking group is not specified as to its direction of attachment, it is intended that the linking group can be attached in either direction of reading, e.g., A-L-B, where L is selected from -M-W-, includes A-M-W-B and A-W-M-B, as illustrated by A-C(O)NR L1 -B, includes A-C(O)NR L1 -B and A-NR L1 C(O)-B.

[0151] "Pharmaceutically acceptable salt" means a salt of a compound of the present application which retains the biological effectiveness and properties of the free acids or free bases and which is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0152] "Pharmaceutical composition" means a mixture of one or more compounds described herein or stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals thereof, with other ingredients, wherein the other ingredients contain physiologically / pharmaceutically acceptable carriers and / or excipients.

[0153] "Carrier" means a system that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of an administered compound, and can alter the way a drug enters the body and its distribution in the body, control the rate of drug release, and deliver the drug to a targeted organ, non-limiting examples of which include microcapsules and microspheres, nanoparticles, liposomes, and the like.

[0154] "Excipient" refers to a substance, not itself a therapeutic agent, used as a diluent, adjuvant, binder or vehicle, added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate formation of a compound or pharmaceutical composition into a unit dosage form for administration. As is known to those skilled in the art, pharmaceutical excipients can serve various functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose; (4) powdered 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 glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0155] "Isomers" include "stereoisomers" and "tautomers". "Stereoisomers" refer to isomers having the same sequence of atoms but different spatial configurations. Stereoisomers include enantiomers, optical isomers. "Tautomers" refer to one functional group that can be converted into another functional group by a reversible chemical reaction known as tautomerization, usually caused by the migration of a hydrogen atom and a π-bond (double or triple bond). Examples of pairs of tautomers are: aldehyde / keto-enol, imine-enamine.

[0156] "Solvate" refers to a compound formed by the union of solvent molecules with the compound of the present application or its salts, in stoichiometric or non-stoichiometric proportions, by intermolecular non-covalent forces. When the solvent is water, then the solvate is a hydrate.

[0157] "Cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of the API and the CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystal is a multi-component crystal, which includes binary cocrystal formed between two neutral solids, and also includes multi-component cocrystal formed by neutral solid and salt or solvate. DETAILED DESCRIPTION

[0158] The content of the present application will be described in detail below by way of examples. The specific conditions not specified in the examples are carried out according to the conventional experimental method. The examples are given to better illustrate the content of the present application, but should not be understood as limiting the content of the present application to the examples. The person skilled in the art can make non-essential improvements and adjustments to the embodiments according to the above content of the present application, which still belong to the protection scope of the present application.

[0159] Test method

[0160] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0161] The MS is measured by (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0162] The HPLC is measured by using Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C 18 100×4.6mm, 3.5μM);

[0163] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography is 0.15mm-0.20mm, and the specification of the product used in thin layer chromatography separation and purification is 0.4mm-0.5mm;

[0164] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0165] Intermediate 1

[0166] First Step: Potassium tert-butoxide (9.53 g, 85.13 mmol) was taken in a three necked flask, dissolved in DMF (100 ml), purged with nitrogen gas for three times, cooled to -45 °C, a solution of la (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) was added drop wise slowly and the reaction was allowed to proceed for one hour at this temperature. Then saturated solution of ammonium chloride (30 mL) and hydrochloric acid in water (1 N, 50 mL) was added and the reaction was allowed to proceed for 16 hours at room temperature. After completion of the reaction as monitored by TLC, then diluted with water (100 ml) and extracted with methyl tert-butyl ether twice (100 ml x 2), combined the organic layer and dried, concentrated under reduced pressure at 30 °C, the residue obtained was purified by silica gel column chromatography to get compound lb (4 g, yield: 33.53 %).

[0167] 1 H NMR (400 MHz, CDC13-d) δ 7.29 - 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).

[0168] Second Step: Compound lb (4 g, 19.05 mmol) was taken in a reaction flask, dissolved in dichloromethane (100 ml), purged with nitrogen gas for three times, cooled to -78 °C, then boron tribromide (9.52 g, 38.10 mmol) was added drop wise and the reaction was allowed to proceed for one hour at this temperature. After completion of the reaction as monitored by TLC, the reaction was added drop wise slowly to saturated sodium carbonate solution (200 ml) at 0 °C, adjusted to pH more than 7, extracted with dichloromethane twice (50 ml x 2), combined the organic layer and dried, concentrated at 20 °C, the residue obtained was purified by silica gel column chromatography to get compound lc (1.63 g, yield: 71.33 %).

[0169] Third Step: Compound lc (1.63 g, 13.58 mmol) was taken in a reaction flask, dissolved in tetrahydrofuran (20 ml), then pyridine (5.37 g, 67.90 mmol) and p-nitrophenyl chloroformate (8.2 g, 40.74 mmol) was added and the reaction was allowed to proceed for one hour at room temperature. After completion of the reaction as monitored by TLC, concentrated under reduced pressure, the residue obtained was purified by silica gel column chromatography to get compound intermediate 1 (2.4 g, yield: 62.02 %).

[0170] 1H NMR (400 MHz, CDC13-d) δ 8.32-8.26 (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).

[0171] Intermediate 2

[0172] First Step: Compound 2a (500 mg, 2.73 mmol) was taken in a reaction flask, dissolved in DMF (10 ml), NaH (160 mg, 4.10 mmol) was added at 0°C, the temperature was maintained for 30 min, then iodomethane (775 mg, 5.46 mmol) was added, the temperature was raised to room temperature and the reaction was carried out for 3 h. After completion of the reaction as monitored by TLC, it was diluted with water (50 ml), then extracted with ethyl acetate twice (50 ml x 2), the organic layers were combined and dried, concentrated under reduced pressure, the residue obtained was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to obtain compound 2b (475 mg, yield: 88.29%).

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 4.84-4.80 (m, 2H), 4.50-4.24 (m, 1H), 2.90-2.80 (m, 2H), 2.78-2.70 (m, 5H), 1.39 (s, 9H).

[0174] Second Step: Compound 2b (470 mg, 2.38 mmol) was taken in a reaction flask, dissolved in dichloromethane (10 ml), then trifluoroacetic acid (0.5 ml) was added, the reaction was carried out at room temperature for 1 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure to obtain crude intermediate 2 (250 mg, TFA salt) which was used directly in the next step.

[0175] Example 1

[0176] First Step: Compound 1A (2.0 g, 29.37 mmol), methyl 3,3-dimethylacrylate (10.0 g, 88.11 mmol) and cesium carbonate (18.9 g, 58.74 mmol) were taken in a reaction flask, dissolved in DMF (50 ml), the reaction was carried out at 60°C for 16 h. After completion of the reaction as monitored by TLC, it was cooled to room temperature, diluted with water (200 ml), then extracted with ethyl acetate twice (100 ml x 2), the organic layers were combined and dried, concentrated under reduced pressure, the residue obtained was purified by column chromatography on silica gel (PE: EA = 5: 1) to obtain compound 1B (4.0 g, yield: 74.76%).

[0177] LC-MS (ESI): m / z = 183.1 [M+H] + .

[0178] Second step: Compound 1B (500 mg, 2.74 mmol) was dissolved in methyl tert-butyl ether (15 ml), FeBr3(163 mg, 0.55 mmol) and Br2(878 mg, 5.48 mmol) were added at 0 °C and the reaction was allowed to warm to room temperature for 4 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (PE:EA = 7:1) to obtain compound 1C (390 mg, yield: 54.54%).

[0179] LC-MS (ESI): m / z = 262.0 [M+H] + .

[0180] Third step: Compound 1C (390 mg, 1.49 mmol), compound 1D (1.24 g, 2.98 mmol, synthesized as per patent WO2019126093A1), Pd(PPh3)4(170 mg, 0.15 mmol) and potassium carbonate (620 mg, 4.47 mmol) were taken in a reaction flask, dissolved in 1,4-dioxane: water = 5:1 (30 ml), purged with nitrogen three times and the reaction was allowed to proceed at 80 °C for 16 h. After completion of the reaction as monitored by TLC, it was cooled to room temperature, concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 1E (650 mg, yield: 93.12%).

[0181] LC-MS (ESI): m / z = 469.4 [M+H] + .

[0182] Fourth step: Compound 1E (650 mg, 1.38 mmol) was dissolved in methanol (20 ml) followed by the addition of PPTS (350 mg, 1.38 mmol) and the reaction was allowed to proceed at 60 °C for 3 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 1F (380 mg, yield: 71.70%).

[0183] LC-MS (ESI): m / z = 385.2 [M+H] + .

[0184] Fifth step: Compound 1F (380 mg, 0.99 mmol) was taken in a reaction flask, dissolved in THF (20 ml), then DPPA (550 mg, 1.98 mmol) and DBU (300 mg, 1.98 mmol) were added and allowed to react for 3 h at room temperature. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 1G (340 mg, yield: 83.95%).

[0185] LC-MS (ESI): m / z = 410.2 [M+H] + .

[0186] Sixth step: Compound 1G (340 mg, 0.83 mmol) was taken in a reaction flask, dissolved in THF:H2O = 5:1 (24 ml), then triphenylphosphine (435 mg, 1.66 mmol) was added and allowed to react for 1 h at room temperature. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 1H (170 mg, yield: 53.46%).

[0187] LC-MS (ESI): m / z = 384.3 [M+H] + .

[0188] Seventh step: Compound 1H (170 mg, 0.44 mmol), intermediate 1 (126 mg, 0.44 mmol) and DIPEA (0.23 ml, 1.32 mmol) were taken in a reaction flask, dissolved in DCM (10 ml) and allowed to react for 16 h at room temperature. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 1I (210 mg, yield: 90.12%).

[0189] LC-MS (ESI): m / z = 530.3 [M+H] + .

[0190] Eighth step: Compound 1I (210 mg, 0.39 mmol) was taken in a reaction flask, dissolved in THF:MeOH:H2O = 3:1:1 (15 ml), then lithium hydroxide (38 mg, 1.56 mmol) was added and allowed to react for 4 h at room temperature. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by reverse phase column to obtain compound 1 (120 mg, yield: 59.70%).

[0191] 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.93-7.87 (m, 2H), 7.82-7.73 (m, 2H), 4.98-4.90 (m, 1H), 4.87-4.78 (m, 2H), 4.07 (s, 3H), 3.06-2.98 (m, 2H), 2.87 (s, 2H), 2.72-2.62 (m, 5H), 1.68 (s, 6H).

[0192] LC-MS (ESI): m / z = 516.3 [M+H] + .

[0193] Example 2

[0194] First Step: Compound 1A (1.3 g, 19.10 mmol), ethyl 2-cyclopropylmethyl acetoacetate (4.82 g, 38.20 mmol) and cesium carbonate (12.4 g, 38.20 mmol) were taken in a reaction flask, dissolved in DMF (50 ml) and allowed to react at 60 °C for 16 hours. After monitoring the completion of the reaction by TLC, it was cooled to room temperature, diluted with water (200 ml) and then extracted with ethyl acetate twice (100 ml x 2), the organic layers were combined and dried, concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 2A (2.8 g, yield: 75.49%).

[0195] LC-MS (ESI): m / z = 195.1 [M+H] + .

[0196] Second Step: Compound 2A (1.2 g, 6.18 mmol) was dissolved in methyl tert-butyl ether (15 ml), FeBr3(365 mg, 1.23 mmol) and Br2(1.98 g, 12.36 mmol) were added at 0 °C and allowed to react at room temperature for 4 hours. After monitoring the completion of the reaction by TLC, it was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (PE:EA = 7:1) to obtain compound 2B (940 mg, yield: 55.70%).

[0197] LC-MS (ESI): m / z = 275.0 [M+H] + .

[0198] Step 3: Compound 2B (500 mg, 1.83 mmol), compound 1D (1.14 g, 2.75 mmol), Pd(PPh3)4 (210 mg, 0.18 mmol) and potassium carbonate (760 mg, 5.49 mmol) were taken in a reaction flask, dissolved in 1,4-dioxane: water = 5:1 (30 ml), purged with nitrogen gas for three times and stirred at 80 °C for 16 h. After completion of reaction monitored by TLC, cooled to room temperature, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 2C (860 mg, yield: 97.72%).

[0199] LC-MS (ESI): m / z = 481.3 [M+H] + .

[0200] Step 4: Compound 2C (860 mg, 1.79 mmol) was dissolved in methanol (20 ml), then PPTS (450 mg, 1.79 mmol) was added and stirred at 60 °C for 3 h. After completion of reaction monitored by TLC, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford compound 2D (510 mg, yield: 71.87%).

[0201] LC-MS (ESI): m / z = 397.2 [M+H] + .

[0202] Step 5: Compound 2D (510 mg, 1.29 mmol) was taken in a reaction flask, dissolved in THF (20 ml), then DPPA (650 mg, 2.58 mmol) and DBU (393 mg, 2.58 mmol) were added and stirred at room temperature for 3 h. After completion of reaction monitored by TLC, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 2E (460 mg, yield: 84.71%).

[0203] LC-MS (ESI): m / z = 422.2 [M+H] + .

[0204] Step 6: Compound 2E (460 mg, 1.09 mmol) was taken in a reaction flask, dissolved in THF:H2O = 5:1 (24 ml), then triphenylphosphine (570 mg, 2.18 mmol) was added and stirred at room temperature for 1 h. After completion of reaction monitored by TLC, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford compound 2F (350 mg, yield: 81.09%).

[0205] LC-MS (ESI): m / z = 396.3 [M+H]+ .

[0206] Step 7: Compound 2F (350 mg, 0.89 mmol), intermediate 1 (250 mg, 0.89 mmol) and DIPEA (0.5 ml, 2.67 mmol) were added to a reaction flask, dissolved with DCM (10 ml), and reacted at room temperature for 16 hours. After TLC monitoring of the completion of the reaction, concentration under reduced pressure, and purification of the obtained residue by silica gel column chromatography (PE:EA = 1:1), compound 2G (400 mg, yield: 83.46%) was obtained.

[0207] LC-MS (ESI): m / z = 542.3 [M+H] + .

[0208] Step 8: Compound 2G (400 mg, 0.74 mmol) was added to a reaction flask, dissolved with THF:MeOH:H2O = 3:1:1 (20 ml), and then lithium hydroxide (54 mg, 2.22 mmol) was added, and reacted at room temperature for 6 hours. After TLC monitoring of the completion of the reaction, concentration under reduced pressure, and purification of the obtained residue by reverse phase column, compound 2 (150 mg, yield: 39.55%) was obtained.

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.91-7.85 (m, 2H), 7.82-7.73 (m, 2H), 4.99-4.89 (m, 1H), 4.87-4.78 (m, 2H), 4.07 (s, 3H), 3.08-2.96 (m, 2H), 2.78 (s, 2H), 2.73-2.59 (m, 5H), 1.32-1.25 (m, 2H), 1.14-1.07 (m, 2H).

[0210] LC-MS (ESI): m / z = 514.2 [M+H] + .

[0211] Example 3

[0212] Step 1: 1a (1.76 g, 10 mmol) was added to a three-necked flask, dissolved with anhydrous tetrahydrofuran (100 ml), and after nitrogen replacement, cooled to -78°C, pyridine (1.58 g, 20 mmol) and TEBBE reagent (0.5 M, 24 mL) were added, and slowly warmed to room temperature. Saturated sodium bicarbonate solution (100 mL) was added, the organic phase was separated, and the aqueous phase was further extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 3B (853 mg, yield: 49.02%).

[0213] 1 H NMR (400 MHz, Chloroform-d) δ 7.52 - 7.10 (m, 5H), 4.91 - 4.64 (m, 2H), 4.44 (s, 2H), 4.15 - 4.05 (m, 1H), 2.93 - 2.83 (m, 2H), 2.79 - 2.69 (m, 2H).

[0214] Second Step: Compound 3B (0.853 g, 4.9 mmol) was dissolved in dichloromethane (20 ml), after nitrogen replacement, cooled to -78 °C, and boron trichloride (1.17 g, 10 mmol) was added. The reaction was carried out at this temperature for 1 h. After monitoring the completion of the reaction by TLC, the reaction solution was poured into a saturated sodium carbonate solution (40 ml) at 0 °C, adjusted to pH greater than 7, extracted twice with dichloromethane (20 ml x 2), and the organic phase was combined and dried to obtain a dichloromethane solution of compound 3C, which was directly subjected to the next step.

[0215] Third Step: Excess pyridine was added to the solution obtained in the previous step, and p-nitrophenyl chloroformate was added in batches until the starting material disappeared. The residue obtained after concentration under reduced pressure was purified by silica gel column chromatography to obtain compound 3D (225 mg, two-step yield: 18.4%).

[0216] LC-MS (ESI): m / z = 250.1 [M+H] + .

[0217] Fourth Step: Compound 1H (345 mg, 0.9 mmol), compound 3D (225 mg, 0.9 mmol), and DIPEA (1 mL) were added to a reaction bottle, dissolved with DCM (10 ml), and reacted at room temperature for 16 hours. After monitoring the completion of the reaction by TLC, it was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to obtain compound 3E (375 mg, yield: 84.4%).

[0218] LC-MS (ESI): m / z = 494.2 [M+H] + .

[0219] Fifth Step: Compound 3E (246 mg, 0.5 mmol) was dissolved in THF (5 mL), and then 0.5 M aqueous lithium hydroxide solution (1.2 mL) was added, and the reaction was carried out at room temperature for 4 hours. After monitoring the completion of the reaction by TLC, it was concentrated, and the residue obtained was purified by column chromatography to obtain compound 3 (146 mg, yield: 60.9%).

[0220] 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.17 (s, 1H), 7.94-7.86 (m, 2H), 7.80 (s, 1H), 7.70 (s, 1H), 4.95-4.73 (m, 5H), 4.07 (s, 3H), 3.01-2.85 (m, 4H), 2.72-2.59 (m, 5H), 1.69 (s, 6H).

[0221] LC-MS (ESI): m / z = 480.3 [M+H] + .

[0222] Example 4

[0223] First step: Dissolve 4A (22.00 g, 116.40 mmol) in tetrahydrofuran (100 mL), then cool to 0 °C, then add sodium borohydride (6.61 g, 174.60 mmol) in batches, then react at room temperature for 3 hours. After the reaction is completed, quench the reaction with water, then extract with ethyl acetate for 3 times, combine the organic phase and purify by normal phase to obtain product 4B (16.50 g, 74%).

[0224] LC-MS (ESI): m / z = 191.0 [M+H] + .

[0225] Second step: Dissolve 4B (16.50 g, 86.37 mmol) in DCM (100 mL), then add DMF (2 mL), add oxalyl chloride (21.93 g, 172.74 mmol) in batches under ice water bath, react at room temperature for 3 hours. After the reaction is completed, slowly pour the reaction liquid into saturated sodium bicarbonate solution, then extract with ethyl acetate for 3 times, combine the organic phase and dry to obtain crude product 4C (14.00 g, 77%).

[0226] LC-MS (ESI): m / z = 209.1 [M+H] + .

[0227] Third step: Dissolve 4C (14.00 g, 66.84 mmol), tert-butyl carbamate (15.66 g, 133.68 mmol), cesium carbonate (54.44 g, 167.10 mmol) in N,N-dimethylformamide (100 mL), then react at 100 °C for 4 hours. After the reaction is completed, add water, then extract with ethyl acetate for 3 times, combine the organic phase and purify by normal phase to obtain product 4D (11.50 g, 59%).

[0228] LC-MS (ESI): m / z = 290.1 [M+H] + .

[0229] Fourth step: 4D (6.40 g, 22.06 mmol), bis(pinacolato)diboron (8.96 g, 35.30 mmol), potassium acetate (4.33 g, 44.12 mmol) and Xphos Pd G2 (1.74 g, 2.21 mmol) were dissolved in 1,4-dioxane (60 mL). After three times of nitrogen replacement, the reaction was carried out at 90 °C for 5 hours. After the reaction was completed, it was spin-dried and purified by column chromatography to obtain the product 4E (6.00 g, 81%).

[0230] LC-MS (ESI): m / z = 338.3 [M+H] + .

[0231] Fifth step: 4E (2.00 g, 5.93 mmol), 2,5-dibromo-6-methylpyridine (1.64 g, 6.52 mmol), potassium carbonate (1.64 g, 11.86 mmol) and Pd(dppf)Cl2 (0.43 g, 0.59 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), then after three times of nitrogen replacement, the reaction was carried out at 90 °C for 4 hours. After the reaction was completed, it was spin-dried and purified by normal phase to obtain the product 4F (1.5 g, 66%).

[0232] LC-MS (ESI): m / z = 381.1 [M+H] + .

[0233] Sixth step: Compound 4F (0.50 g, 1.31 mmol), bis(pinacolato)diboron (0.50 g, 1.97 mmol), potassium acetate (0.39 g, 3.93 mmol) were added to tetrahydrofuran solvent in turn, Pd(dppf)Cl2 (96 mg, 0.13 mmol) was added after nitrogen replacement, and the reaction was carried out at 80 °C for 4 hours after the temperature was raised. After the reaction was completed, ethyl acetate and saturated brine were added, and the liquid was separated and washed. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 4G (0.55 g, 97.91%).

[0234] LC-MS (ESI): m / z = 429.30 [M+H] + .

[0235] Seventh step: Compound 4G (0.50 g, 1.17 mmol), compound 1C (0.31 g, 1.17 mmol), potassium carbonate (0.40 g, 2.92 mmol) were added into 1,4-dioxane (25 mL) solvent, after nitrogen replacement, tetraphenylphosphonium palladium (0.14 g, 0.12 mmol) and water (5 mL) were added, after nitrogen replacement again, the temperature was raised to 80°C for 12 hours. After the reaction was completed, the temperature was lowered and filtered, the filtrate was added into ethyl acetate and saturated brine, separated and washed. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 4H (0.10 g, 17.75%).

[0236] LC-MS (ESI): m / z = 483.30 [M+H] + .

[0237] Eighth step: Compound 4H (0.10 g, 0.21 mmol) was added into 4 mol / L hydrochloric acid 1,4-dioxane solution (20 mL) solvent, stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure to obtain compound 4I (79 mg, crude product).

[0238] LC-MS (ESI): m / z = 383.2 [M+H] + .

[0239] Ninth step: Compound 4I (79.00 mg, 0.21 mmol, DIPEA (54.28 mg, 0.42 mmol) was added into DCM (20 mL) solvent, and intermediate 1 (71.87 mg, 0.25 mmol) was added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, DCM and distilled water were added, separated, and washed. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was separated and purified by silica gel column to obtain compound 4J (50.00 mg, 45.80%).

[0240] LC-MS (ESI): m / z = 529.30 [M+H] + .

[0241] Tenth step: Compound 4J (40 mg, 0.0076 mmol) was added into tetrahydrofuran (10 mL) solvent, lithium hydroxide monohydrate (4.78 mg, 0.11 mmol), methanol (0.5 mL), distilled water (1 mL), stirred at room temperature for 2 hours, and the reaction solution was directly concentrated to dryness after the reaction was completed. Methanol was added and the pH value was adjusted to 4-5 with 1 mol / L hydrochloric acid water. The obtained solution was directly purified by reversed-phase silica gel column to obtain compound 4 (7 mg, 17.98%).

[0242] 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.92 (s, 1H), 7.82-7.74 (m, 2H), 7.73-7.66 (m, 1H), 7.52 (d, 1H), 5.02-4.86 (m, 1H), 4.83-4.61 (m, 2H), 3.88 (s, 3H), 3.10-2.97 (m, 2H), 2.85 (s, 2H), 2.74-2.58 (m, 5H), 1.75-1.59 (s, 6H).

[0243] LC-MS (ESI): m / z = 515.30 [M+H] +

[0244] Example 5

[0245] First Step: Compound 1F (0.28 g, 0.73 mmol) was weighed in dichloromethane (10 mL), then pyridine (0.4 g, 5.06 mmol) and p-nitrochloroformic acid phenyl ester (0.44 g, 2.18 mmol) were added in turn, and after the addition was completed, the reaction was carried out at room temperature for 1 h. TLC monitoring showed that the reaction was complete. The reaction liquid was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target compound 5D (0.144 g, yield: 35.91%).

[0246] LC-MS (ESI): m / z = 550.3 [M+1] + .

[0247] Second Step: Compound 5D (0.144 g, 0.263 mmol) was dissolved in dichloromethane (10 mL), then DIPEA (0.169 g, 1.31 mmol) and crude trifluoroacetate salt of intermediate 2 (0.174 g, 0.789 mmol) were added in turn, and after the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target compound 5E (0.11 g, yield: 82.40%).

[0248] LC-MS (ESI): m / z = 508.3 [M+1] + .

[0249] Third Step: Compound 5E (0.11 g, 0.215 mmol) was dissolved in a mixed solvent of THF:MeOH:H2O = 3:1:1 (15 ml), then lithium hydroxide (0.011 g, 0.43 mmol) was added, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column to obtain compound 5 (60 mg, yield: 56.07%).

[0250] 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.92-7.88(m,2H),7.80(s,1H),5.71(s,2H) ),4.79(s,2H),4.12(s,3H),2.85-2.78(m,8H),2.67-2.62(m,5H),1.69(s,6H).

[0251] LC-MS (ESI): m / z = 494.3 [M+H] + .

[0252] Example 6

[0253] Step 1: Compound 6A (8.00 g, 63.4 mmol) was dissolved in methanol (120 mL) and heated to reflux. After about 16 hours, the solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 100:0 to 90:10) to give cis compound 6B (9.00 g, 89.7%).

[0254] LC-MS (ESI): m / z = 157.1 [MH] - .

[0255] Step 2: Compound 6B (8.00 g, 50.6 mmol) was dissolved in dry THF (200 mL), cooled to -78 °C under nitrogen protection, and LDA (75.9 mL, 152 mmol, 2 N in THF) was slowly added dropwise. After reacting for 2 hours, saturated ammonium chloride aqueous solution (200 mL) was added to separate the organic and aqueous phases. The aqueous phase was extracted with dichloromethane (100 mL × 5). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 100:0 to 90:10) to obtain a mixture of cis and trans 6C (4.70 g, 58.8%).

[0256] LC-MS (ESI): m / z = 157.1 [MH] - .

[0257] Third step: Compound 6C (3.70 g, 23.4 mmol) was dissolved in dry THF (150 mL), cooled to 0 °C, and borane dimethyl sulfide complex (4.68 mL, 46.8 mmol, 10 N in DMS) was added dropwise slowly, keeping the temperature at 0 °C. After TLC monitoring of the disappearance of the starting material, saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 5). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v:v) = 100:0 ~ 50:50) to give compound 6D (2.70 g, 80.0%).

[0258] LC-MS (ESI): m / z = 145.1 [M+H] + .

[0259] Fourth step: Compound 6F (2.10 g, 6.90 mmol, synthesized according to patent WO2019126093A1), compound 6D (1.49 g, 10.3 mmol), tri-n-butylphosphine (4.21 g, 20.7 mmol), and azobisdimethylvaleronitrile (2.10 g, 6.90 mmol) were all dissolved in dry toluene (200 mL) and heated to 60 °C overnight. After TLC monitoring of the disappearance of the starting material, saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 5). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v:v) = 100:0 ~ 70:30) to give compound 6G (1.90 g, 64.0%).

[0260] LC-MS (ESI): m / z = 431.2 [M+H] + .

[0261] Fifth step: Compound 6G (1.90 g, 4.41 mmol) was dissolved in methanol (60 mL), and p-toluenesulfonic acid pyridine salt (2.22 g, 8.83 mmol) was added, and the mixture was heated to 60 °C overnight. After TLC monitoring of the disappearance of the starting material, saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 5). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v:v) = 100:0 ~ 35:65) to give compound 6H (839 mg, 54.9%).

[0262] LC-MS (ESI): m / z = 347.2 [M+H] + .

[0263] Step 6: Compound 6H (839 mg, 2.42 mmol), DPPA (2.00 g, 7.27 mmol) and DBU (1.11 g, 7.27 mmol) were dissolved in dry THF (100 mL) and reacted at room temperature overnight. After TLC monitoring of the disappearance of the starting material, saturated aqueous ammonium chloride solution (100 mL) was added, and the organic phase was extracted with ethyl acetate (100 mL x 5), combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v:v) = 100:0 ~ 50:50) to obtain compound 6I (810 mg, 90.0%).

[0264] LC-MS (ESI): m / z = 372.2 [M+H] + .

[0265] Step 7: Compound 6I (810 mg, 2.18 mmol) was dissolved in THF (30 mL) and water (10 mL), and triphenylphosphine (857 mg, 3.27 mmol) was added and reacted at room temperature. After TLC monitoring of the disappearance of the starting material, saturated aqueous ammonium chloride solution (50 mL) was added, and the organic phase was extracted with ethyl acetate (100 mL x 5), combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 100:0 ~ 90:10) to obtain compound 6J (700 mg, 92.9%).

[0266] LC-MS (ESI): m / z = 346.2 [M+H] + .

[0267] Step 8: Compound 6J (700 mg, 2.03 mmol), intermediate 1 (693 mg, 2.43 mmol) and triethylamine (615 mg, 6.08 mmol) were dissolved in dry THF (50 mL) and reacted at room temperature. After TLC monitoring of the disappearance of the starting material, saturated aqueous ammonium chloride solution (100 mL) was added, and the organic phase was extracted with ethyl acetate (50 mL x 5), combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v:v) = 100:0 ~ 35:65) to obtain compound 6O (960 mg, 96.4%).

[0268] LC-MS (ESI): m / z = 492.2 [M+H] + .

[0269] Ninth step: Compound 60 (550 mg, 1.12 mmol) was dissolved in a mixture solvent of THF (6 mL), methanol (6 mL) and water (3 mL), and lithium hydroxide monohydrate (234 mg, 5.60 mmol) was added, and the reaction was carried out at room temperature. After the disappearance of the raw material was monitored by TLC, dilute hydrochloric acid was added to adjust the pH to about 4, extracted with ethyl acetate and methanol (20 mL x 5), the organic phase was combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by hand to give compound 6-1 (21.4 mg, 4.01%, 1.580 min), compound 6-2 (23.2 mg, 4.34%, 1.733 min), compound 6-3 (115.3 mg, 21.6%, 1.782 min) and compound 6-4 (82.7 mg, 15.5%, 1.935 min).

[0270] Preparative chromatography method: instrument: SHIMADZU LC-30AD SFC; column: Chiral IK column; mobile phase: A for CO2; B for 0.05% DEA in-methanol; gradient: B for 5-40%; flow rate: 3 mL / min; column temperature: 35 °C; wavelength: 220 nm

[0271] Compound 6-1

[0272] 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (d, 1H), 7.27-7.23 (m, 1H), 5.03-4.91 (m, 1H), 4.57 (s, 2H), 4.24-4.06 (m, 5H), 3.47-3.38 (m, 1H), 3.21-3.13 (m, 1H), 3.07-2.97 (m, 2H), 2.76-2.66 (m, 2H), 2.57-2.44 (m, 4H), 2.29-2.14 (m, 2H), 2.05-1.94 (m, 1H).

[0273] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0274] Compound 6-2

[0275] 1H NMR (400 MHz, Chloroform-d) δ 7.97 (d, 1H), 7.19 (d, 1H), 5.03-4.94 (m, 1H), 4.59-4.50 (m, 2H), 4.24-4.10 (m, 5H), 3.46-3.37 (m, 1H), 3.20-3.10 (m, 1H), 3.08-2.95 (m, 2H), 2.76-2.65 (m, 2H), 2.55-2.44 (m, 4H), 2.31-2.11 (m, 2H), 2.07-1.91 (m, 1H).

[0276] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0277] Compound 6-3

[0278] 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (d, 1H), 7.35 (d, 1H), 5.04-4.91 (m, 1H), 4.60 (s, 2H), 4.23-3.98 (m, 5H), 3.23-2.94 (m, 4H), 2.80-2.67 (m, 2H), 2.60 (s, 3H), 2.36-2.17 (m, 2H), 2.16-1.92 (m, 2H).

[0279] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0280] Compound 6-4

[0281] 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (d, 1H), 7.22 (d, 1H), 5.04-4.94 (m, 1H),, 4.60 (s, 2H), 4.18 (s, 3H), 4.10-3.93 (m, 2H), 3.25-2.95 (m, 4H), 2.77-2.67 (m, 2H),, 2.56 (s, 3H), 2.35-2.19 (m, 2H),, 2.14-1.94 (m, 2H).

[0282] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0283] Example 7

[0284] First Step: Dissolve 7A (1 g, 5.98 mmol) in DMF (20 mL), add sodium hydride (0.54 g, 8.97 mmol, 40% in oil) under ice bath, stir for 10 minutes, then slowly add iodocyclobutane (1.09 g, 5.98 mmol), after adding, stir at room temperature for 2 hours, TLC monitor the complete reaction of raw materials, then dilute with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to obtain the target compound 7B (800 mg, 60%).

[0285] LC-MS (ESI): m / z = 222.0 [M+H] + .

[0286] Second Step: Add 7B (0.83 g, 3.75 mmol) and sodium tungstate (1.1 g, 3.75 mmol) to methanol (20 mL), slowly add hydrogen peroxide (2.98 g, 2.68 mL, 30% content) under ice bath, after adding, stir at room temperature overnight, TLC monitor the complete reaction of raw materials, dilute with water, extract with ethyl acetate, wash with saturated sulfurous acid solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to obtain the target compound 7C (890 mg, 89%).

[0287] LC-MS (ESI): m / z = 254.0 [M+H] + .

[0288] Third Step: Add 7C (0.65 g, 2.57 mmol) and 3-((tert-butyldimethylsilyl)oxy)cyclobutanone (0.77 g, 3.85 mmol) to dry THF (20 mL), slowly add LiHMDS (4.30 g, 5.14 mmol) under ice bath, after adding, continue to stir for 2 hours, then slowly rise to room temperature and stir for 3 hours, add saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to obtain the target compound 7D (200 mg, 33%).

[0289] 1 H NMR (400 MHz, CDCl3) δ 4.31-4.23 (m, 1H), 2.81-2.71 (m, 2H), 2.60-2.44 (m, 6H), 1.96-1.86 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).

[0290] Fourth step: 7D (0.24 g, 1.01 mmol) was added to THF (5 mL), then TBAF (1.47 g, 1.52 mmol) was added, stirred at room temperature for 3 hours, TLC monitoring of the reaction was complete, then diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure at 30°C to obtain the target compound 7E, which was directly used in the next step reaction.

[0291] Fifth step: 7E (120 mg, 0.97 mmol) was dissolved in THF (10 mL), then pyridine (230 mg, 2.91 mmol) was added, followed by the addition of p-nitrophenyl chloroformate (390 mg, 1.94 mmol), and the reaction was carried out at 25°C for 2 hours. After the reaction was completed by TLC monitoring, it was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 7F (130 mg, 46%).

[0292] LC-MS (ESI): m / z = 290.1 [M+H] + .

[0293] Sixth step: 7F (130 mg, 0.45 mmol) and DIPEA (170 mg, 1.35 mmol) were dissolved in THF (10 mL), then intermediate 7G (210 mg, 0.50 mmol) (synthesized according to patent WO2019126093) was added, and the reaction was carried out at 25°C for 3 hours. After the reaction was completed by LCMS monitoring, the reaction was concentrated, and compound 7H (200 mg, 83%) was obtained by column chromatography purification.

[0294] LC-MS (ESI): m / z = 538.3 [M+H] + .

[0295] Seventh step: Compound 7H (200 mg, 0.37 mmol) was added to a reaction bottle, dissolved in THF:MeOH:H2O = 5:1:1 (10 ml), then lithium hydroxide monohydrate (78 mg, 1.85 mmol) was added, and the reaction was carried out at 20°C for 16 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to about 7 with 1M HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified and separated by HPLC to obtain compound 7 (60 mg, 33%).

[0296] LC-MS (ESI): m / z = 496.5 [M+H] + .

[0297] 1H NMR (400 MHz, CDC13) δ 8.05 (d, 1H), 7.27 (d, 1H), 7.07-6.95 (m, 1H), 4.99-4.86 (m, 1H), 4.76-4.69 (m, 1H), 4.61 (d, 2H), 4.19 (s, 3H), 2.95-2.81 (m, 3H), 2.64-2.51 (m, 9H), 2.19-2.11 (m, 1H), 2.03-1.88 (m, 5H), 1.79-1.62 (m, 4H).

[0298] Example 8

[0299] First Step: Compound 8A (1.5 g, 4.95 mmol, synthesized according to patent CN111699180A), methyl 2-(1-(methylsulfonyl)oxy) methyl) cyclopropyl) acetate (2.2 g, 9.9 mmol, synthesized according to patent WO2008141462) and cesium carbonate (4.84 g, 14.85 mmol) were added into DMF (30 mL), after adding, it was reacted at 50 °C for 16 hours, TLC was used to monitor the complete reaction of raw materials, then water was added for dilution, ethyl acetate was used for extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated and then purified by silica gel column chromatography to obtain the target compound 8B (2.5 g, yield: 99%).

[0300] LC-MS (ESI): m / z = 430.2 [M+H] + .

[0301] Second Step: Compound 8B (2.5 g, 5.83 mmol) was dissolved in methanol (30 ml), then PPTS (4.5 g, 17.49 mmol) was added, and it was reacted at 60 °C for 16 hours. TLC was used to monitor the complete reaction of raw materials, then sodium bicarbonate aqueous solution was added for quenching, ethyl acetate was used for extraction, the organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the target compound 8C (2.28 g, yield: 99%).

[0302] LC-MS (ESI): m / z = 346.2 [M+H] + .

[0303] Third Step: Compound 8C (2.28 g, 6.61 mmol) was added into a reaction bottle, dissolved in THF (30 ml), then DPPA (3.63 g, 13.22 mmol) and DBU (2 g, 13.66 mmol) were added, and it was reacted at room temperature for 3 hours. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain compound 8D (1.5 g, yield: 61%).

[0304] LC-MS (ESI): m / z = 371.2 [M+H] + .

[0305] Fourth Step: Compound 8D (1.5 g, 4.05 mmol) was taken in a reaction flask, dissolved in THF:H2O = 5:1 (24 ml), then triphenylphosphine (2.8 g, 8.10 mmol) was added and allowed to react for 1 h at room temperature. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to get compound 8E (1.24 g, yield: 89%).

[0306] LC-MS (ESI): m / z = 345.2 [M+H] + .

[0307] Fifth Step: Compound (1r, 3r)-3-(trifluoromethoxy)cyclobutan-1-ol (200 mg, 1.28 mmol, synthesized as per patent WO2020 / 223538), N,N'-carbonyldiimidazole (125 mg, 0.768 mmol) and N,N-diisopropylethylamine (992 mg, 3.84 mmol) were taken in tetrahydrofuran and allowed to react for 3 h at room temperature. Then compound 8E (175 mg, 0.768 mmol) was added and allowed to react for 16 h at 70 °C. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to get compound 8F (33 mg, yield: 12.4%).

[0308] LC-MS (ESI): m / z = 527.3 [M+H] + .

[0309] Sixth Step: Compound 8F (33 mg, 0.06 mmol) was taken in a reaction flask, dissolved in THF:MeOH:H2O = 3:1:1 (5 ml), then lithium hydroxide monohydrate (8 mg, 0.18 mmol) was added and allowed to react for 16 h at room temperature. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by HPLC to get compound 8 (3.1 mg, yield: 9.34%).

[0310] 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.29 (d, 1H), 7.19 (s, 1H), 7.07 (d, 1H), 5.14-5.06 (m, 1H), 4.90-4.81 (m, 1H), 4.55-4.46 (m, 2H), 4.02 (s, 3H), 3.91 (s, 2H), 2.66-2.57 (m, 2H), 2.56 (s, 2H), 2.53 (s, 3H), 2.52-2.43 (m, 2H), 0.76-0.65 (m, 4H).

[0311] LC-MS (ESI): m / z = 513.5 [M+H] + .

[0312] Example 9

[0313] First Step: Compound 9A (1.00 g, 3.29 mmol), 6F (1.02 g, 4.94 mmol) and cesium carbonate (2.14 g, 6.58 mmol) were added to a reaction flask, dissolved with DMF (10 ml), and reacted at 60°C for 16 hours. After monitoring the completion of the reaction by TLC, it was cooled to room temperature, diluted with water (100 ml), then extracted with ethyl acetate twice (100 ml x 2), the organic phase was combined and dried, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 9B (1.10 g, yield: 77.76%).

[0314] LC-MS (ESI): m / z = 513.5 [M+H] + .

[0315] Second Step: Compound 9B (1.80 g, 4.18 mmol) was dissolved with methanol (15 ml), and 4-methylbenzenesulfonic acid pyridine (2.10 g, 8.36 mmol) was added at room temperature, and stirred at 60°C for 16 hours. After monitoring the completion of the reaction by TLC, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 9C (1.2 g, yield: 82.86%).

[0316] LC-MS (ESI): m / z = 513.5 [M+H] + .

[0317] Step 3: Compound 9C (272.00 mg, 0.79 mmol), p-nitrophenyl chloroformate (318.46 mg, 1.58 mmol), pyridine (187.47 mg, 2.37 mmol) were added to dichloromethane (5 mL) and reacted at 25 °C for 1 h. After the completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 9D (101.00 mg, yield: 25.15%).

[0318] LC-MS (ESI): m / z = 512.2 [M+H] + .

[0319] Step 4: Compound 9D (101.00 mg, 0.20 mmol) was dissolved in N,N- dimethylformamide (3 ml), then intermediate 2 (126.7 mg, 0.60 mmol) and N,N- diisopropylethylamine (80.17 mg, 0.60 mmol) were added and reacted at 25 °C for 3 h. After the completion of the reaction as monitored by TLC, it was diluted with water (10 ml) and extracted with ethyl acetate twice (10 ml x 2), the organic layers were combined and dried, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 9F (43.00 mg, yield: 46.38%).

[0320] LC-MS (ESI): m / z = 470.2 [M+H] + .

[0321] Step 5: Compound 9F (43.00 mg, 0.092 mmol) was taken in a reaction flask and dissolved in THF:MeOH:H2O = 5:1:1 (5 ml), then lithium hydroxide monohydrate (11.02 mg, 0.46 mmol) was added and reacted at 20 °C for 16 h. After the completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the residue was purified by reverse phase column to obtain compound 9 (17.00 mg, yield: 40.75%).

[0322] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, 1H), 7.52 (d, 1H), 5.64 (s, 2H), 4.79 (s, 2H), 4.22 (t, 2H), 4.09 (s, 3H), 3.62 (s, 1H), 2.72 (d, 7H), 2.36 (s, 3H), 1.93 (t, 2H), 0.97 (dd, 2H), 0.64 (dd, 2H).

[0323] LC-MS (ESI): m / z = 456.2 [M+H] + .

[0324] Example 10

[0325] First Step: Take 6F (5.12 g, 16.83 mmol), 2-(1-(methylsulfonyl)oxy) methyl) cyclopropyl) acetate (3.4 g, 15.30 mmol) and cesium carbonate (14.96 g, 45.90 mmol) in DMF (50 mL), after adding, react at 50 °C for 16 hours, monitor the reaction completion by TLC, then dilute with water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to obtain the target compound 10A (5.8 g, yield: 88.07%).

[0326] LC-MS (ESI): m / z = 431.3 [M+H] + .

[0327] Second Step: Dissolve compound 10A (5.8 g, 13.47 mmol) in methanol (30 mL), then add PPTS (6.77 g, 26.94 mmol) and react at 60 °C for 16 hours. Monitor the reaction completion by TLC, then quench with sodium bicarbonate aqueous solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain the target compound 10B (4.1 g, yield: 87.86%).

[0328] LC-MS (ESI): m / z = 347.2 [M+H] + .

[0329] Third Step: Add compound 10B (4.1 g, 11.84 mmol) to the reaction bottle, dissolve with THF (30 mL), then add DPPA (6.52 g, 23.68 mmol) and DBU (3.54 g, 23.68 mmol) and react at room temperature for 3 hours. After the reaction is completed, monitor by TLC, concentrate under reduced pressure, and purify the obtained residue by silica gel column chromatography to obtain compound 10C (3.8 g, yield: 86.44%).

[0330] LC-MS (ESI): m / z = 372.2 [M+H] + .

[0331] Fourth Step: Add compound 10C (3.8 g, 10.23 mmol) to the reaction bottle, dissolve with THF:H2O = 5:1 (48 mL), then add triphenylphosphine (5.37 g, 20.46 mmol) and react at room temperature for 1 hour. After the reaction is completed, monitor by TLC, concentrate under reduced pressure, and purify the obtained residue by silica gel column chromatography to obtain compound 10D (3.2 g, yield: 90.55%).

[0332] LC-MS (ESI): m / z = 346.2 [M+H] + .

[0333] Step 5: Compound (1r, 3r)-3-(trifluoromethoxy)cyclobutane-1-ol (312 mg, 2.0 mmol), N, N'- carbonyldiimidazole (320 mg, 2.0 mmol) and triethylamine (300 mg, 3.0 mmol) were added to tetrahydrofuran and allowed to react at room temperature for 0.5 hours. Then, compound 10D (345 mg, 1.0 mmol) was added and allowed to react at 80°C for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by TLC, it was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to obtain compound 10E (240 mg, yield: 45.50%).

[0334] LC-MS (ESI): m / z = 528.2 [M+H] + .

[0335] Step 6: Compound 10E (240 mg, 0.45 mmol) was added to a reaction flask and dissolved with THF:MeOH:H2O = 3:1:1 (10 ml), then lithium hydroxide monohydrate (57 mg, 1.35 mmol) was added and allowed to react at room temperature for 16 hours. After completion of the reaction was confirmed by TLC, the pH was adjusted to neutral with 1M hydrochloric acid and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound 10 (72 mg, yield: 31.16%).

[0336] LC-MS (ESI): m / z = 514.1 [M+H] + .

[0337] 1 H NMR (400 MHz, CDC13) δ 8.01 - 7.99 (d, 1H), 7.16 - 7.11 (m, 2H), 5.11 - 5.06 (m, 1H), 4.87 - 4.81 (m, 1H), 4.59 - 4.57 (d, 2H), 4.18 (s, 3H), 3.95 (s, 2H), 2.64 - 2.57 (m, 2H), 2.54 (s, 4H), 2.50 - 2.46 (m, 2H), 1.35 - 1.26 (m, 2H), 0.72 - 0.69 (d, 4H).

[0338] Example 11

[0339] First Step: Compound 11A (1.00 g, 6.66 mmol) was dissolved in toluene (20 mL) and ethoxycarbonyl ethylene triphenyl phosphonium (2.90 g, 7.99 mmol) was added to it at room temperature. The mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound 11B (1.22 g, 78.20 %).

[0340] LC-MS (ESI): m / z = 235.2 [M+H] + .

[0341] Second Step: Compound 11B (1.22 g, 5.21 mmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (200.00 mg) was added to it at 25 °C for 16 hours. After completion of the reaction, which was monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 11C (0.71 g, yield: 94.58 %).

[0342] LC-MS (ESI): m / z = 145.2 [M+H] + .

[0343] Third Step: Compound 11C (700.00 mg, 4.86 mmol) was dissolved in dichloromethane (7 mL) and triethylamine (1475.35 mg, 14.58 mmol) and methanesulfonic anhydride (1015.93 mg, 5.83 mmol) were added to it at 25 °C for 1 hour. After completion of the reaction, which was monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 11D (877.00 mg, yield: 80.54 %).

[0344] LC-MS (ESI): m / z = 225.2 [M+H] + .

[0345] Fourth Step: Compound 11D (0.88 g, 3.97 mmol), 6F (1.31 g, 4.31 mmol) and cesium carbonate (2.55 g, 7.84 mmol) were taken in a reaction flask and dissolved in DMF (10 ml) and stirred at 60 °C for 16 hours. After completion of the reaction, which was monitored by TLC, it was cooled to room temperature, diluted with water (50 ml) and then extracted with ethyl acetate twice (50 ml x 2), the organic phases were combined and dried, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 11E (0.98 g, yield: 57.75 %).

[0346] LC-MS (ESI): m / z = 433.2 [M+H]+ .

[0347] Step 5: Compound 11E (0.98 g, 2.27 mmol) was dissolved in methanol (15 ml) and 4-methylbenzenesulfonic acid pyridine (1.14 g, 4.54 mmol) was added at room temperature and stirred at 60 °C for 16 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 11F (0.65 g, yield: 82.34 %).

[0348] LC-MS (ESI): m / z = 349.2 [M+H] + .

[0349] Step 6: Compound 11F (500.00 mg, 1.44 mmol), p-nitrophenyl chloroformate (580.49 mg, 2.88 mmol), pyridine (341.71 mg, 4.32 mmol) were taken in dichloromethane (10 mL) and stirred at 25 °C for 1 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to afford compound 11G (430.00 mg, yield: 58.35 %).

[0350] LC-MS (ESI): m / z = 514.2 [M+H] + .

[0351] Step 7: Compound 11G (430.00 mg, 0.84 mmol) was dissolved in N,N- dimethylformamide (5 ml) and then intermediate 2 (354.78 mg, 1.68 mmol) and N,N- diisopropylethylamine (325.68 mg, 2.52 mmol) were added and stirred at 25 °C for 3 h. After completion of the reaction as monitored by TLC, it was diluted with water (50 ml) and then extracted with ethyl acetate twice (50 ml x 2), the organic layers were combined and dried, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford compound 11H (338.00 mg, yield: 85.60 %).

[0352] LC-MS (ESI): m / z = 472.3 [M+H] + .

[0353] Eighth step: Compound 11H (338.00 mg, 0.72 mmol) was added to the reaction bottle, dissolved with THF:MeOH:H2O = 5:1:1 (10 ml), then lithium hydroxide monohydrate (86.22 mg, 3.60 mmol) was added, and reacted at 20 °C for 16 hours. After monitoring the completion of the reaction by TLC, it was concentrated under reduced pressure, and the residue was separated by hand to obtain compound 11-1 (40.60 mg, 12.77%, 1.577 min) and compound 11-2 (100.20 mg, 31.5%, 1.677 min).

[0354] Preparative chromatography method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral IK column; Mobile phase: A for CO2; B for 0.05% DEA in-methanol; Gradient: B for 10-50%; Flow rate: 3 mL / min; Column temperature: 35 °C; Wavelength: 220 nm

[0355] Compound 11-1

[0356] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, 1H), 7.43 (d, 1H), 5.64 (s, 2H), 4.79 (s, 2H), 4.12-4.04 (m, 5H), 2.93-2.53 (m, 9H), 2.37 (s, 3H), 2.14-2.01 (m, 1H), 1.83 (dq, 1H), 1.15 (d, 3H).

[0357] LC-MS (ESI): m / z = 444.3 [M+H] + .

[0358] Compound 11-2

[0359] 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, 1H), 7.44 (d, 1H), 5.65 (s, 2H), 4.79 (s, 2H), 4.14-4.04 (m, 5H), 2.92-2.54 (m, 9H), 2.38 (s, 3H), 2.09 (dt, 1H), 1.90-1.77 (m, 1H), 1.16 (d, 3H).

[0360] LC-MS (ESI): m / z = 444.3 [M+H] + .

[0361] Example 12

[0362] First Step: Compound 12A (2.8 g, 19.15 mmol, Refer US5565473, 1996, A synthesis) was dissolved in dry DCM (30 mL) at room temperature, triethylamine (6.0 g, 59.41 mmol) was added, then methylsulfonic anhydride (5.0 g, 28.72 mmol) was added portion wise in an ice bath, the reaction was allowed to proceed at room temperature for 16 h, the reaction was monitored by TLC, the reaction was stopped when the starting material was consumed. The reaction was quenched by the addition of sodium bicarbonate, the organic layer was washed with water twice, dried and concentrated, the compound 12B (4.1 g, yield: 98.45%) was obtained without further purification.

[0363] Second Step: Compound 6F (6.12 g, 20.11 mmol), 12B (4.1 g, 18.28 mmol) and cesium carbonate (17.87 g, 54.84 mmol) were taken in DMF (50 mL), the reaction was allowed to proceed at 50 °C for 16 h, the reaction was monitored by TLC, then diluted with water, the organic layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and purified by silica gel column chromatography to obtain the desired compound 12C (1.0 g, yield: 12.65%).

[0364] LC-MS (ESI): m / z = 433.1 [M+H] + .

[0365] Third Step: Compound 12C (1.0 g, 2.31 mmol) was dissolved in methanol (10 mL), then PPTS (1.16 g, 4.62 mmol) was added, the reaction was allowed to proceed at 60 °C for 16 h. The reaction was monitored by TLC, then quenched by the addition of aqueous sodium bicarbonate solution, the organic layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the desired compound 12D (620 mg, yield: 76.97%).

[0366] LC-MS (ESI): m / z = 349.2 [M+H] + .

[0367] Fourth Step: Compound 12D (620 mg, 1.78 mmol) was taken in a reaction flask, dissolved in THF (10 mL), then DPPA (0.98 g, 3.56 mmol) and DBU (0.54 g, 3.56 mmol) were added, the reaction was allowed to proceed at room temperature for 3 h. The reaction was monitored by TLC, then concentrated under reduced pressure, the residue was purified by silica gel column chromatography to obtain compound 12E (600 mg, yield: 90.29%).

[0368] LC-MS (ESI): m / z = 374.2 [M+H] + .

[0369] Step 4: Compound 12E (600 mg, 1.61 mmol) was taken in a reaction flask, dissolved in THF:H2O = 5:1 (6 mL) and then triphenylphosphine (840 mg, 3.22 mmol) was added and allowed to react for 1 h at room temperature. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to get compound 12F (430 mg, yield: 77.03%).

[0370] LC-MS (ESI): m / z = 348.2 [M+H] + .

[0371] Step 5: Compound (1r, 3r)-3-(trifluoromethoxy)cyclobutane-1-ol (187 mg, 1.2 mmol), N,N'-carbonyldiimidazole (190 mg, 1.2 mmol) and triethylamine (120 mg, 1.2 mmol) were taken in tetrahydrofuran and allowed to react for 0.5 h at room temperature. Then compound 12F (210 mg, 0.6 mmol) was added and allowed to react for 16 h at 80 °C under nitrogen atmosphere. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to get compound 12G (140 mg, yield: 43.74%).

[0372] LC-MS (ESI): m / z = 530.2 [M+H] + .

[0373] Step 6: Compound 12G (137 mg, 0.26 mmol) was taken in a reaction flask, dissolved in THF:MeOH:H2O = 3:1:1 (5 ml) and then lithium hydroxide monohydrate (33 mg, 0.78 mmol) was added and allowed to react for 16 h at room temperature. After completion of the reaction as monitored by TLC, it was neutralized with 1 M hydrochloric acid and concentrated under reduced pressure. The resulting residue was purified by column chromatography to get compound 12 (20 mg, yield: 14.92%).

[0374] LC-MS (ESI): m / z = 516.2 [M+H] + .

[0375] 1 H NMR (400 MHz, CDC13) δ 8.03-8.01 (d, 1H), 7.35-7.33 (d, 1H), 5.11-5.06 (m, 1H), 4.87-4.81 (m, 1H), 4.60 (s, 2H), 4.18-4.15 (t, 5H), 2.64-2.57 (m, 5H), 2.50-2.44 (m, 2H), 2.20-2.16 (t, 2H), 1.35 (s, 6H).

[0376] Example 13:

[0377] First step: Compound (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-ol (187 mg, 1.2 mmol), N, N'-carbonyldiimidazole (190 mg, 1.2 mmol) and triethylamine (120 mg, 1.2 mmol) were added to tetrahydrofuran and allowed to react at room temperature for 0.5 hours. Then, compound 12F (210 mg, 0.6 mmol) was added and allowed to react at 80°C for 16 hours under a nitrogen atmosphere. After completion of the reaction was confirmed by TLC, the resulting residue was purified by column chromatography on silica gel to obtain compound 13A (230 mg, yield: 71.86%).

[0378] LC-MS (ESI): m / z = 530.2 [M+H] + .

[0379] Second step: Compound 13A (230 mg, 0.43 mmol) was added to a reaction bottle and dissolved with THF:MeOH:H2O = 3:1:1 (5 ml), then lithium hydroxide monohydrate (54 mg, 1.29 mmol) was added and allowed to react at room temperature for 16 hours. After completion of the reaction was confirmed by TLC, the pH was adjusted to neutral with 1M hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 13 (23 mg, yield: 10.27%).

[0380] LC-MS (ESI): m / z = 516.2 [M+H] + .

[0381] 1 H NMR (400 MHz, CDCl3) δ 8.02-8.00 (d, 1H), 7.48-7.43 (d, 1H), 4.63-4.57 (m, 3H), 4.36-4.28 (m, 1H), 4.21 (s, 1H), 4.17 (s, 3H), 3.95 (s, 1H), 2.89-2.82 (m, 2H), 2.71-2.68 (d, 3H), 2.52 (s, 1H), 2.36-2.28 (m, 3H), 2.20-2.17 (t, 2H), 1.35 (s, 6H).

[0382] Example 14

[0383] First Step: Take 14A (2.0 g, 13.88 mmol, synthesized as per patent WO2017036978) and DIPEA (3.58 g, 27.76 mmol) in dichloromethane (20 mL), add methyl sulfonic anhydride (4.83 g, 27.76 mmol) portion wise under ice bath condition, allow to warm to room temperature after addition is complete, allow to react for 2 hours, monitor the reaction completion by TLC, then dilute with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to isolate the target compound 14B (2.2 g, yield: 71.43%).

[0384] 1 HNMR (400 MHz, CDC13) δ 4.39 (m, 2H), 3.64 (s, 3H), 2.97 (s, 3H), 1.98 (m, 2H), 1.31-1.13 (m, 2H), 0.83-0.78 (m, 2H).

[0385] Second Step: Take 8A (810 mg, 2.67 mmol), 14B (890 mg, 4.01 mmol) and cesium carbonate (2.03 g, 5.34 mmol) in DMF (30 mL), allow to react at 50 °C for 16 hours after addition is complete, monitor the reaction completion by TLC, then dilute with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography to isolate the target compound 14C (712 mg, yield: 62.13%).

[0386] LC-MS (ESI): m / z = 430.3 [M+H] + .

[0387] Third Step: Dissolve compound 14C (712 mg, 1.66 mmol) in methanol (10 ml), then add PPTS (833 mg, 3.32 mmol) and allow to react at 60 °C for 16 hours. Monitor the reaction completion by TLC, then quench with aqueous sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure to obtain the target compound 14D (480 mg, yield: 83.92%).

[0388] LC-MS (ESI): m / z = 346.2 [M+H] + .

[0389] Step 4: Compound 14D (480 mg, 1.39 mmol) was taken in a reaction flask, dissolved in THF (10 ml), then DPPA (765 mg, 2.78 mmol) and DBU (423 mg, 2.78 mmol) were added and allowed to react at room temperature for 3 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain compound 14E (440 mg, yield: 85.61 %).

[0390] LC-MS (ESI): m / z = 371.2 [M+H] + .

[0391] Step 5: Compound 14E (440 mg, 1.19 mmol) was taken in a reaction flask, dissolved in THF:H20 = 5:1 (24 ml), then triphenylphosphine (821 mg, 2.38 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain compound 14F (400 mg, yield: 97.79 %).

[0392] LC-MS (ESI): m / z = 345.2 [M+H] + .

[0393] Step 6: Compound (lr, 3r)-3-(trifluoromethoxy)cyclobutan-l-ol (200 mg, 1.28 mmol, synthesized as per patent WO 2020 / 223538, 2020, Al), N,N'- carbonyldiimidazole (125 mg, 0.768 mmol) and N,N-diisopropylethylamine (992 mg, 3.84 mmol) were taken in tetrahydrofuran and allowed to react at room temperature for 3 h. Then compound 14F (175 mg, 0.768 mmol) was added and allowed to react at 70 °C for 16 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain compound 14G (33 mg, yield: 12.4 %).

[0394] LC-MS (ESI): m / z = 527.3 [M+H] + .

[0395] Step 7: Compound 14G (33 mg, 0.06 mmol) was taken in a reaction flask, dissolved in THF:MeOH:H20 = 3:1:1 (5 ml), then lithium hydroxide monohydrate (8 mg, 0.18 mmol) was added and allowed to react at room temperature for 16 h. After completion of the reaction as monitored by TLC, it was concentrated under reduced pressure and the resulting residue was purified by reverse phase column to obtain compound 14 (22 mg, yield: 68.75 %).

[0396] 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.64-7.52 (m, 1H), 7.47-7.41 (m, 1H), 7.40-7.32 (m, 1H), 5.15-4.80 (m, 2H), 4.75-4.50 (m, 2H), 4.17-4.14 (m, 2H), 3.85 (s, 3H), 2.62-2.59 (m, 4H), 2.38 (s, 3H), 2.00-1.96 (m, 2H), 1.14-1.03 (tm, 2H), 0.92-0.81 (m, 2H).

[0397] 1 LC-MS (ESI): m / z = 513.1 [M+H] + .

[0398] Example 15

[0399] First Step: Compound cis 3-(trifluoromethoxy)cyclobutan-1-ol (123 mg, 0.79 mmol, synthesized according to patent WO2020 / 223538), N,N'-carbonyldiimidazole (64 mg, 0.39 mmol) and N,N-diisopropylethylamine (254.2 mg, 1.97 mmol) were added to tetrahydrofuran and reacted at room temperature for 3 hours. Then compound 8E (150 mg, HCl salt, 0.39 mmol) was added and reacted at 80 °C for 16 hours. After the completion of the reaction was monitored by TLC, it was concentrated under reduced pressure and the residue obtained was purified by column chromatography on silica gel to obtain compound 15A (110 mg, yield: 53.0%).

[0400] LC-MS (ESI): m / z = 513.1 [M+H] + .

[0401] Second Step: Compound 15A (110 mg, 0.21 mmol) was taken in a reaction flask and dissolved in THF:MeOH:H2O = 3:1:1 (5 ml), then lithium hydroxide monohydrate (42 mg, 1.04 mmol) was added and reacted at room temperature for 16 hours. After the completion of the reaction was monitored by TLC, it was concentrated under reduced pressure and the residue obtained was purified by HPLC to obtain compound 15 (15.2 mg, yield: 14.2%).

[0402] 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.60 (s, 1H), 7.44-7.38 (m, 1H), 7.30-7.24 (m, 1H), 4.63-4.49 (m, 4H), 3.92 (s, 2H), 3.84 (s, 3H), 2.87-2.75 (m, 2H), 2.41 (s, 3H), 2.37 (s, 2H), 2.22-2.10 (m, 2H), 0.64-0.53 (m, 4H).

[0403] LC-MS (ESI): m / z = 513.3 [M+H] + .

[0404] Example 16

[0405] First step: compound 16A (100 mg, 0.31 mmol, from Nanjing Wiker), 16B (57 mg, 0.31 mmol, synthesis method reference: WO2023001177 A1) was dissolved in toluene (10 mL), then CMBP (90 mg, 0.37 mmol) was added, stirred at 100°C for 16 hours, TLC monitored the completion of the reaction, then diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 16C (80 mg, yield: 52.6%).

[0406] LC-MS (ESI): m / z = 486.3 [M+H] + .

[0407] Second step: compound 16C (80 mg, 0.16 mmol) was added to a mixture of dichloromethane (6 mL) and trifluoroacetic acid (2 mL), stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, it was concentrated under reduced pressure. The obtained crude compound 16D (80 mg, crude) was directly used in the next step.

[0408] LC-MS (ESI): m / z = 386.2 [M+H] + .

[0409] Third step: compound 16D (80 mg, 0.21 mmol) and intermediate 1 (90 mg, 0.32 mmol) were added to a reaction bottle, dissolved in tetrahydrofuran (10 mL), then triethylamine (64 mg, 0.63 mmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 16E (70 mg, yield: 63.5%).

[0410] LC-MS (ESI): m / z = 532.2 [M+H] + .

[0411] Fourth step: Compound 16E (70 mg, 0.13 mmol) was dissolved in methanol (10 mL), then lithium hydroxide monohydrate (16 mg, 0.39 mmol) and water (5 mL) were added, and the reaction was carried out at room temperature for 16 hours. After TLC monitoring of the completion of the reaction, the pH was adjusted to about 5 with 1M HC1, concentrated under reduced pressure, and the obtained residue was purified and separated by column chromatography, and then chiral resolution to obtain compound 16-1 (SFC analysis retention time: 1.333 min, 7 mg), 16-2 (SFC analysis retention time: 1.578 min, 7 mg).

[0412] SFC analysis method: instrument: CAS-05-ANA-SFC-D; column: AS column; mobile phase: A carbon dioxide; B for 0.05% ammonia water ethanol; flow rate: 3 mL / min; column temperature: 35°C; wavelength: 220 nm.

[0413] SFC preparation method: instrument: CAS-05-Prep-SFC-E, column: AS column; mobile phase: A: CO2, B: 0.1% NH3.H2O in EtOH; column temperature: 25°C wavelength: 254 nm cycle time: 6 min; sample preparation: sample concentration 2 mg / mL, ethanol solution sample: 2 mL each time.

[0414] Compound 16-1 (SFC analysis retention time: 1.333 min): 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, 1H), 7.73-7.61 (m, 1H), 7.43 (d, 1H), 4.99-4.88 (m, 2H), 4.78-4.72 (m, 2H), 4.04 (s, 3H), 3.05-2.86 (m, 2H), 2.74-2.62 (m, 4H), 2.37 (s, 3H), 2.15-2.10 (m, 1H), 2.03-1.81 (m, 2H), 1.72-1.37 (m, 6H); LC-MS (ESI): m / z = 518.2 [M+H] + .

[0415] Compound 16-2 (SFC analysis retention time: 1.578 min): 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, 1H), 7.73-7.61 (m, 1H), 7.43 (d, 1H), 5.00-4.88 (m, 2H), 4.80-4.72 (m, 2H), 4.04 (s, 3H), 3.06-2.86 (m, 2H), 2.77-2.62 (m, 4H), 2.38 (s, 3H), 2.16-1.84 (m, 3H), 1.73-1.59 (m, 2H), 1.52-1.38 (m, 4H); LC-MS (ESI): m / z = 518.2 [M+H] + .

[0416] Example 17

[0417] First step: Compound 16D (250 mg, 0.65 mmol) and compound 3D (190 mg, 0.78 mmol) were added to the reaction bottle, dissolved in tetrahydrofuran (10 mL), then triethylamine (200 mg, 1.95 mmol) was added, and the reaction was carried out at room temperature for 16 hours. After monitoring the completion of the reaction by TLC, it was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 17A (150 mg, yield: 46.7%).

[0418] LC-MS (ESI): m / z = 496.2 [M+H] + .

[0419] Second step: Compound 17A (150 mg, 0.30 mmol) was dissolved in methanol (10 mL), then lithium hydroxide monohydrate (38 mg, 0.90 mmol) and water (5 mL) were added, and the reaction was carried out at room temperature for 16 hours. After monitoring the completion of the reaction by TLC, the pH was adjusted to about 5 with 1M HC1, concentrated under reduced pressure, and the residue was purified by column chromatography and then separated by chiral resolution to obtain compound 17-1 (SFC analysis retention time: 2.101 min, 11 mg), 17-2 (SFC analysis retention time: 2.151 min, 5 mg), 17-3 (SFC analysis retention time: 2.263 min, 10 mg), 17-4 (SFC analysis retention time: 2.298 min, 3 mg).

[0420] SFC analysis method: instrument: CAS-05-ANA-SFC-D; column: AS column; mobile phase: A carbon dioxide; B 0.05% ammonia water ethanol; flow rate: 3 mL / min; column temperature: 35°C; wavelength: 220 nm.

[0421] SFC preparation method: Instrument: CAS-05-Prep-SFC-G, Column: AY column; Mobile phase: A: C02, B: 0.1% NH3.H20 in EtOH; Column temperature: 25 °C Wavelength: 254 nm Cycle time: 8.1 min; Sample preparation: Sample concentration 2 mg / mL, EtOH solution Injection: 2 mL each time.

[0422] Compound 17-1 (SFC analytical retention time: 2.101 min): 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.82 (d, 1H), 7.66-7.54 (m, 1H), 7.43 (d, 1H), 4.98-4.75 (m, 6H), 4.04 (s, 3H), 2.99-2.87 (m, 3H), 2.78-2.61 (m, 4H), 2.38 (s, 3H), 2.15-2.10 (m, 1H), 1.91-1.85 (m, 1H), 1.74-1.58 (m, 3H), 1.52-1.39 (m, 3H); LC-MS (ESI): m / z = 482.2 [M+H] + .

[0423] Compound 17-2 (SFC analytical retention time: 2.151 min): 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.82 (d, 1H), 7.66-7.54 (m, 1H), 7.46 (d, 1H), 4.98-4.75 (m, 6H), 4.04 (s, 3H), 2.99-2.89 (m, 2H), 2.84-2.60 (m, 4H), 2.49-2.45 (m, 1H), 2.39 (s, 3H), 2.06-1.84 (m, 4H), 1.78-1.61 (m, 3H), 1.39-1.31 (m, 1H); LC-MS (ESI): m / z = 482.2 [M+H] + .

[0424] Compound 17-3 (SFC analytical retention time: 2.263 min): 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.82 (d, 1H), 7.65-7.54 (m, 1H), 7.43 (d, 1H), 4.98-4.73 (m, 6H), 4.04 (s, 3H), 3.00-2.87 (m, 3H), 2.78-2.61 (m, 4H), 2.38 (s, 3H), 2.15-2.10 (m, 1H), 1.91-1.85 (m, 1H), 1.75-1.58 (m, 3H), 1.52-1.39 (m, 3H); LC-MS (ESI): m / z = 482.2 [M+H] + .

[0425] Compound 17-4 (SFC analytical retention time: 2.298 min): 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.82 (d, 1H), 7.65-7.54 (m, 1H), 7.43 (d, 1H), 4.98-4.73 (m, 6H), 4.04 (s, 3H), 3.00-2.87 (m, 3H), 2.78-2.61 (m, 4H), 2.38 (s, 3H), 2.15-2.10 (m, 1H), 1.91-1.85 (m, 1H), 1.75-1.58 (m, 3H), 1.52-1.39 (m, 3H); LC-MS (ESI): m / z = 482.2 [M+H] + .

[0426] Example 18

[0427] First step: Compound 18A (620 mg, 1.61 mmol, synthesis method reference: WO2024153219) was dissolved in tetrahydrofuran (20 ml), then pyridine (635 mg, 8.05 mmol) and p-nitrophenyl chloroformate (646 mg, 3.22 mmol) were added, stirred at room temperature for 1 hour, TLC monitored the completion of the reaction, diluted with water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain compound 18B (650 mg, yield: 73.4%).

[0428] LC-MS (ESI): m / z = 552.3 [M+H] + .

[0429] Second step: Compound 18B (200 mg, 0.36 mmol) and intermediate 2 (80 mg, 0.54 mmol) were added to the reaction bottle, dissolved in tetrahydrofuran (10 ml), then DIPEA (250 mg, 1.80 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, water was added for dilution, and ethyl acetate was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 18C (180 mg, yield: 97.3%).

[0430] LC-MS (ESI): m / z = 510.3 [M+H] + .

[0431] Third step: Compound 18C (180 mg, 0.35 mmol) was dissolved in tetrahydrofuran (15 mL) and methanol (5 mL), then lithium hydroxide monohydrate (45 mg, 1.05 mmol) and water (5 ml) were added, and the reaction was carried out at room temperature for 16 hours. After monitoring the completion of the reaction by TLC, the pH was adjusted to about 5 with 1M HCl, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain compound 18 crude product, which was subjected to first chiral resolution to obtain a mixture and compound 18-4 (SFC analysis retention time: 2.109 min, 66 mg). The mixture was subjected to second chiral resolution to obtain 18-1 (SFC analysis retention time: 1.734 min, 52 mg), 18-2 (SFC analysis retention time: 1.793 min, 9 mg), and 18-3 (SFC analysis retention time: 1.841 min).

[0432] SFC analysis method: instrument: CAS-05-ANA-SFC-D; column: AS column; mobile phase: A carbon dioxide; B 0.05% ammonia water ethanol; flow rate: 3 mL / min; column temperature: 35°C; wavelength: 220 nm.

[0433] First SFC preparation method: instrument: CAS-05-Prep-SFC-C, column: AS column; mobile phase: A: CO2, B: 0.1% NH3.H2O in isopropanol; column temperature: RT wavelength: 220 nm; sample preparation: sample concentration 5 mg / mL, acetonitrile methanol solution sample.

[0434] Second SFC preparation method: instrument: CAS-05-Prep-SFC-F, column: OX column; mobile phase: A: CO2, B: 0.1% NH3.H2O in EtOH; column temperature: RT wavelength: 220 nm; sample preparation: sample concentration 5 mg / mL, acetonitrile methanol solution sample.

[0435] Compound 18-1 (SFC analytical retention time: 1.734 min): LC-MS (ESI): m / z = 496.3 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.83 (d, 1H), 7.42 (d, 1H), 5.64 (s, 2H), 4.98 (s, 1H), 4.79 (s, 2H), 4.65 - 4.15 (m, 1H), 4.09 (s, 3H), 2.98 - 2.57 (m, 10H), 2.34 (s, 3H), 2.19 - 2.05 (m, 1H), 1.94 - 1.82 (m, 1H), 1.16 - 1.56 (m, 3H), 1.55 - 1.30 (m, 3H); LC-MS (ESI): m / z = 496.3 [M+H] + .

[0436] Compound 18-2 (SFC analytical retention time: 1.793 min): LC-MS (ESI): m / z = 496.3 [M+H] + .

[0437] Compound 18-3 (SFC analytical retention time: 1.841 min): LC-MS (ESI): m / z = 496.3 [M+H] + .

[0438] Compound 18-4 (SFC analytical retention time: 2.109 min): 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.83 (d, 1H), 7.42 (d, 1H), 5.64 (s, 2H), 4.98 (s, 1H), 4.79 (s, 2H), 4.65 - 4.15 (m, 1H), 4.09 (s, 3H), 2.98 - 2.57 (m, 10H), 2.34 (s, 3H), 2.19 - 2.05 (m, 1H), 1.94 - 1.82 (m, 1H), 1.16 - 1.56 (m, 3H), 1.55 - 1.30 (m, 3H); LC-MS (ESI): m / z = 496.3 [M+H] + .

[0439] Example 19

[0440] First Step: Compound 19A (360 mg, 1.64 mmol, synthesized as per patent WO2023025324) was taken in a reaction flask, dissolved in DMF (10 ml), cooled to 0 °C, NaH (100 mg, 2.46 mmol) was added, maintained the temperature for 20 min, iodomethane (450 mg, 3.28 mmol) was added, raised to room temperature and reacted for two hours. After completion of reaction monitored by TLC, quenched by adding saturated ammonium chloride solution (50 ml), extracted with ethyl acetate twice (50 ml x 2), combined the organic layers and dried, concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (PE:EA = 20:1) to get compound 19B (340 mg, yield: 88.89 %).

[0441] 1 H NMR (400 MHz, DMSO-d6) δ 4.65-4.40 (m, 1H), 2.95-2.79 (m, 4H), 2.77 (s, 3H), 1.40 (s, 9H).

[0442] Second Step: Compound 19B (340 mg, 1.45 mmol) was taken in a reaction flask, dissolved in DCM (5 ml), then TFA (1 ml) was added, reacted for 3 hours at room temperature. After completion of reaction monitored by TLC, concentrated under reduced pressure to get compound 19C (200 mg, TFA salt), taken for next step directly.

[0443] LC-MS (ESI): m / z = 134.1 [M+H] + .

[0444] Third Step: Compound 18B (350 mg, 0.64 mmol) and 19C (190 mg, 0.78 mmol) were taken in a reaction flask, dissolved in tetrahydrofuran (10 ml), then DIPEA (300 mg, 1.95 mmol) was added, reacted for 1 hour at room temperature. After completion of reaction monitored by TLC, diluted with water, extracted with ethyl acetate, dried the organic layer over anhydrous sodium sulphate, filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography to get compound 19D (380 mg, yield: 100 %).

[0445] LC-MS (ESI): m / z = 546.3 [M+H] + .

[0446] Fourth step: Compound 19D (380 mg, 0.70 mmol) was dissolved in tetrahydrofuran (15 mL) and methanol (5 mL), then lithium hydroxide monohydrate (135 mg, 3.50 mmol) and water (5 ml) were added, and the reaction was carried out at room temperature for 16 hours. After monitoring the completion of the reaction by TLC, the pH was adjusted to about 5 with 1M HC1, and concentrated under reduced pressure. The obtained residue was purified and separated by column chromatography to obtain compound 19 crude product, which was subjected to first chiral resolution to obtain compound 19-3 (SFC analysis retention time: 1.989 min, 64 mg), 19-4 (SFC analysis retention time: 2.093 min, 7 mg) and a mixture. The mixture was subjected to second chiral resolution to obtain compound 19-1 (SFC analysis retention time: 1.817 min, 64 mg), 19-2 (SFC analysis retention time: 1.873 min, 9 mg).

[0447] SFC analysis method: instrument: CAS-05-ANA-SFC-D; column: AD column; mobile phase: A carbon dioxide; B for 0.05% ammonia isopropyl alcohol; flow rate: 3 mL / min; column temperature: 35 °C; wavelength: 220 nm.

[0448] First SFC preparation method: instrument: CAS-05-Prep-SFC-F, column: AD column; mobile phase: A: CO2, B: 0.1% NH3.H2O in isopropanol; column temperature: RT wavelength: 220 nm; sample preparation: sample concentration 5 mg / mL, acetonitrile methanol solution sample.

[0449] Second SFC preparation method: instrument: CAS-05-Prep-SFC-E, column: OD column; mobile phase: A: CO2, B: 0.1% NH3.H2O in MeOH; column temperature: RT wavelength: 220 nm; sample preparation: sample concentration 5 mg / mL, acetonitrile methanol solution sample.

[0450] Compound 19-1 (SFC analysis retention time: 1.817 min): 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.86-7.78 (m, 1H), 7.46-7.38 (m, 1H), 5.65 (s, 2H), 4.98 (s, 1H), 4.70-4.30 (m, 1H), 4.09 (s, 3H), 2.99-2.63 (m, 10H), 2.34 (s, 3H), 2.16-2.06 (m, 1H), 1.95-1.81 (m, 1H), 1.79-1.56 (m, 3H), 1.55-1.33 (m, 3H).

[0451] LC-MS (ESI): m / z = 532.5 [M+H] + .

[0452] Compound 19-2 (SFC analytical retention time: 1.873 min): LC-MS (ESI): m / z = 532.5 [M+H] + .

[0453] Compound 19-3 (SFC analytical retention time: 1.989 min): 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.86 - 7.78 (m, 1H), 7.46 - 7.38 (m, 1H), 5.65 (s, 2H), 4.98 (s, 1H), 4.70 - 4.30 (m, 1H), 4.09 (s, 3H), 2.99 - 2.63 (m, 10H), 2.34 (s, 3H), 2.16 - 2.06 (m, 1H), 1.95 - 1.81 (m, 1H), 1.79 - 1.56 (m, 3H), 1.55 - 1.33 (m, 3H).

[0454] LC-MS (ESI): m / z = 532.5 [M+H] + .

[0455] Compound 19-4 (SFC analytical retention time: 2.093 min): LC-MS (ESI): m / z = 532.5 [M+H] + .

[0456] Biological test evaluation

[0457] The following Comparative Example 1 according to the present invention was prepared according to the method described in the reference patent WO2017223016,

[0458] 1. Cell calcium flux assay

[0459] 1) Test compounds were diluted to 400X stock solutions in DMSO in 384 well plates.

[0460] 2) 1 μΐ of compound solution from Step 1 was transferred to 39 ul assay buffer to make 10X working solutions in 384 well plates using a Bravo automated liquid handling platform.

[0461] 3) CHO-LPA1 cells were incubated with F12 media (10% FBS).

[0462] 4) When cells reached 80% confluency, cells were dissociated with 0.25% trypsin-EDTA.

[0463] 5) Measure cell density and dilute cells to 4x10e5 / ml with F12 (10% FBS).

[0464] 6) Dispense 30 μΐ of cells into 384 well plates (corning 3764#) with 12K cells per well using a multidrop automatic dispenser. Incubate at 37°C, 5% CO2for 18-20 hours.

[0465] 7) Replace with 25uL serum free media overnight.

[0466] 8) Add 10ul of 3.5X loading dye to each well of the cell plate. Incubate at 37°C, 5% CO2for 0.5-1 hour in the dark.

[0467] 9) After incubation, transfer 5 μΐ of the 10X working solution from step 2 to the cell plate.

[0468] 10) Incubate the cell plate at 25°C in the dark for 15 minutes and then read the calcium signal.

[0469] 11) Prepare at least 20 μΐ / well of 5X agonist (LPA) working solution in 384 well assay plates (greiner 784075#), LPA is added in IX HBSS + 20mM HEPES + 0.1% BSA. The agonist concentration used in this assay is determined from the dose response in the previous agonist mode. EC 80 is used as the final agonist concentration in the assay.

[0470] 12) Read and save data using FLIPR using the specified settings at room temperature.

[0471] 13) Curve fitting and IC 50 calculation is performed by plotting signal values versus compound concentration using non-linear regression method of GraphPad Prism software.

[0472] Experimental results: The compounds of the present application have significant antagonistic effect on LPAR 1 enzyme activity in vitro, the IC 50 values of the example compounds on LPAR 1 enzyme activity are less than 100 μΜ. IC 50 values are represented by A, B, C, D grades, A represents 0 < IC 50 ≤ 10 nM, B represents 10 nM < IC 50 ≤ 50 nM, C represents 50 nM < IC 50 ≤ 100 nM, D represents IC 50 > 100 nM. The test results of some examples are shown in Table 1.

[0473] Table 1. Antagonistic activity of the compounds of the present application on LPAR 1

[0474] Experimental conclusion: the compounds of the present application, such as the example compounds, show high antagonistic activity on LPAR 1 receptor; the IC 50 of compound 19-1 is 1 nM, and the IC 50 of comparative example 1 is 8 nM.

[0475] 2. Pharmacokinetic test in mice

[0476] 2.1 Test animals: male C57 mice, 20-25 g, 6 per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0477] 2.2 Test design: on the test day, the C57 mice were randomly divided by weight. Fasting for 12-14 h without water restriction 1 day before administration, and feeding 4 h after administration.

[0478] Table 2. Dosing information

[0479] Note: Intravenous administration vehicle: 5% DMA + 5% HS-15 + 90% Saline; Intragastric administration vehicle: 10% Cremophor-EL + 40% PEG400 + 50% 1X PBS (pH = 7.4).

[0480] 0.06 mL of blood was taken from the orbit under isoflurane anesthesia before and after administration, and placed in an EDTA K2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and the plasma was collected. The blood sampling time points for the intravenous and intragastric groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0481] Table 3. Pharmacokinetic parameters of the test compounds in mouse plasma

[0482] Conclusion: the compounds of the present application, such as the example compounds, have good pharmacokinetic characteristics in mice.

[0483] 3. Pharmacokinetic test in rats

[0484] 3.1 Test animals: male SD rats, 220 g or so, 6-8 weeks old, 6-8 per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0485] 3.2 Test design: on the test day, the SD rats were randomly divided by weight. Fasting for 12-14 h without water restriction 1 day before administration, and feeding 4 h after administration.

[0486] Table 4. Dosing information

[0487] Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; oral administration vehicle: 10% Cremophor-EL + 40% PEG400 + 50% 1X PBS (pH = 7.4).

[0488] Before and after administration, 0.15 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTA K2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and the plasma was collected. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0489] Table 5. Pharmacokinetic parameters of test compounds in rat plasma

[0490] Conclusion: The compounds of the present application, such as the example compounds, have good pharmacokinetic characteristics in rats.

[0491] 4. Pharmacokinetic test of beagle dogs

[0492] 4.1. Test animals: male beagle dogs, 8-11 kg, 6 per compound, purchased from Beijing Mass Biotechnology Co., Ltd.

[0493] 4.2. Test method: On the test day, the beagle dogs were randomly divided according to body weight. Fasting for 12-14 h without water 1 day before administration, and feeding 4 h after administration.

[0494] Table 6. Dosing information

[0495] Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; oral administration vehicle: 10% Cremophor-EL + 40% PEG400 + 50% 1X PBS (pH = 7.4).

[0496] Before and after administration, 1 mL of blood was taken from the jugular vein or limb vein, placed in an EDTA K2 centrifuge tube. Centrifuged at 5000 rpm at 4°C for 10 min, and the plasma was collected. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0497] Table 7. Pharmacokinetic parameters of test compounds in dog plasma

[0498] Conclusion: The compounds of the present application, such as the example compounds, have good pharmacokinetic characteristics in beagle dogs.

[0499] 5. Monkey pharmacokinetic test

[0500] 5.1. Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0501] 5.2. Test method: On the test day, the monkeys were randomly divided into groups according to body weight. Fasting without water for 14-18 h before administration, and feeding 4 h after administration.

[0502] 1.0 mL of blood was taken from the limbs before and after administration, and placed in EDTAK2 centrifuge tubes. Centrifugation at 5000 rpm, 4°C for 10 min, and collection of plasma. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0503] Conclusion: The compounds of the present application, such as the compounds of the examples, have good pharmacokinetic characteristics in monkeys.

[0504] 6. hERG potassium ion channel effect test

[0505] Experimental platform: electrophysiological manual patch clamp system

[0506] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel

[0507] Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, hERG potassium channel current was recorded by whole-cell patch clamp technique at room temperature. Glass microelectrode was drawn by glass electrode embryo (BF150-86-10, Sutter) through a draw instrument, and the tip resistance after perfusion of the electrode internal solution was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe and connected to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by computer through pClamp 10 software, the sampling frequency was 10 kHz, and the filter frequency was 2 kHz. After obtaining the whole-cell recording, the cells were clamped at -80 mV, and the step voltage to induce hERG potassium current (I hERG) was given from -80 mV to +20 mV for 2 s, and then repolarized to -50 mV for 1 s, and then returned to -80 mV. This voltage stimulation was given every 10 s, and after the hERG potassium current was determined to be stable (at least 1 minute), the drug administration process was started. Each test concentration of the compound was given for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[0508] Data processing: Data analysis was processed by pClamp 10, GraphPad Prism 5 and Excel software. The inhibition of hERG potassium current (-50 mV induced hERG tail current peak) by different concentrations of compounds was calculated by the following formula:

[0509] Inhibition% = [1-(I / Io)]x100%

[0510] Wherein, Inhibition% represents the inhibition percentage of hERG potassium current by the compound, I and Io represent the amplitude of hERG potassium current after and before adding the drug, respectively.

[0511] Compound IC 50 The following equation was used to fit the calculated results by using GraphPad Prism 5 software:

[0512] Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0513] Wherein, X is the Log value of the test concentration of the sample, Y is the inhibition percentage at the corresponding concentration, Bottom

[0514] And Top are the minimum and maximum inhibition percentages, respectively.

[0515] Conclusion: The compound of the application, for example, the compound of the examples, has no inhibition on hERG.

[0516] 7. CYP enzyme inhibition test

[0517] The purpose of this study is to evaluate the effect of the test substance on the activity of five isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) by using in vitro test system. The specific probe substrates of CYP450 isozymes are incubated with human liver microsomes and different concentrations of test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is added to start the reaction. After the reaction is completed, the sample is treated and the specific substrate metabolites are quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) method to measure the change of CYP enzyme activity, calculate the IC50 value, and evaluate the inhibition potential of the test substance on each CYP enzyme subtype. Under the test conditions, the incubation concentration is 0-30 μM.

[0518] Conclusion: The compound of the application, for example, the compound of the examples, has no inhibition on CYP enzyme.

[0519] 8. Liver microsomal stability test

[0520] The experiment uses five species of liver microsomes of human, dog, monkey, rat and mouse as in vitro models to evaluate the metabolic stability of the test substance.

[0521] Incubate 1 μM of the test substance with microsomal protein and coenzyme NADPH at 37°C, add ice-cold acetonitrile containing an internal standard to terminate the reaction at a certain time (5, 10, 20, 30, 60 min), and detect the concentration of the test substance in the sample by using LC-MS / MS method, to obtain the T 1 / 2 , and further calculate the liver microsomal intrinsic clearance CL int(mic) and the liver intrinsic clearance CL int(Liver) .

[0522] Conclusion: The compound of the present application, such as the compound of the examples, has good liver microsomal stability.

[0523] 9. Caco2 permeability test

[0524] The test uses single-layer Caco-2 cells, and three parallel incubations are used in 96-well Transwell plates. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing the compound of the present application (2 μM) or control compounds digoxin (10 μM), nadolol (2 μM) and metoprolol (2 μM) is added to the dosing end hole of the top side or the bottom side. The receiving end hole is added with DMSO-containing transport buffer solution. After incubation at 37±1°C for 2 hours, the cell plate is taken out and an appropriate amount of sample is taken from the top and bottom of each new 96-well plate. Then add acetonitrile containing an internal standard to precipitate the protein. Use LC MS / MS to analyze the sample and determine the concentration of the compound of the present application and the control compound. The concentration data is used to calculate the apparent permeability coefficient of the transport from the top side to the bottom side of the single-layer cells, and the bottom side to the top, and to calculate the efflux rate. The integrity of the single-layer cells after 2 hours of incubation is evaluated by the leakage of fluorescein.

[0525] Conclusion: The compound of the present application, such as the compound of the examples, has good permeability.

[0526] 10. Bleomycin (BLM) induced idiopathic pulmonary fibrosis (IPF) mouse model

[0527] 1) Screening and grouping: A total of 9-week-old male C57BL / 6j mice were used in this project. Before the experiment, according to the body weight of the animals, they were divided into sham operation group and model group. One week after modeling, according to the body weight of the animals, the model group was randomly divided into groups.

[0528] 2) Animal modeling: On day 1 of the experiment, the animals were anesthetized with Xylazine (50 mg / kg) and Rumpun (10 mg / kg). Model group mice were injected intratracheally (i.t.) with bleomycin on day 1 at a dose of 0.66 mg / kg (1 U / kg) in a volume of 50 μL. The sham group 1 (n=10) was injected i.t. with normal saline in a volume of 50 μL.

[0529] 3) Test method: Starting on day 7 of the experiment, the mice in each experimental group were given the test compound, administered by gavage, twice daily; the control group was given nintedanib at a dose of 60 mg / kg in a volume of 10 mL / kg body weight, administered by gavage, once daily. The sham group 1 and model group 2 were given vehicle in a volume of 10 mL / kg body weight, administered by gavage, twice daily.

[0530] 4) Detection index: At the end of the study, lung tissue was collected for pathological examination.

[0531] Results: After 21 days of bleomycin (0.66 mg / kg, i.t.) injection, the compounds of the present application, such as the example compounds, significantly increased the Modified Ashcroft score and the area of pulmonary fibrosis in the lung tissue of the model mice. Compared with the model group given vehicle, the example compounds administered by gavage, twice daily, for 14 consecutive days, significantly reduced the Modified Ashcroft score and the area of pulmonary fibrosis in the lung tissue of the model mice at the end of the study.

Claims

1. A compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, ###0001### (I) Ring A is selected from a 3-12 membered carbocyclyl, 4-12 membered heterocyclyl, or is absent, said carbocyclyl or heterocyclyl optionally substituted with 1-5 groups selected from R A ; Ring B is selected from * the end connected to the pyridine ring, the end is connected to L3; R A R B Each is independently selected from H, deuterium, halogens, =O, CN, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocyclic alkyl group is optionally selected from 1-3 elements selected from deuterium, halogen, NH2, CN, C. 1-4 Alkyl or C 1-4 Alkoxy group substitution; L1, L2are each independently selected from the group consisting of a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, -O-, -O-C 1-6 alkyl-, -S-, -S-C 1-6 alkyl-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 -, -NR L1 -C 1-6 alkyl-, -(CH2) p -C 3-6 cycloalkylene, which alkyl, alkylene, alkenylene, alkynylene, cycloalkylene are optionally further substituted by 1-4 R L1 substituents; R1is selected from -(CH2) p -C(O)OH; R L1 each independently selected from H, deuterium, halogen, OH, NH2, C 1-4 alkyl, haloC 1-4 alkyl, 3-6 membered cycloalkyl, -COOH, said alkyl, cycloalkyl optionally further substituted with 1-4 selected from halogen, deuterium, OH, NH2; L3is selected from -(CR L21 R L22 ) p -OC(O)-N(R L23 )-, -(CR L21 R L22 ) p -N(R L23 )C(O)O-; R L21 , R L22 , R L23 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl optionally further substituted with 1-4 selected from deuterium, halogen, OH, NH2; Y is selected from C 3-6 cycloalkyl, 4-12 membered heterocycloalkyl, said cycloalkyl, heterocycloalkyl being further substituted with 1-4 groups selected from =CH2, =CF2, =CH-CH3, =C-(CH3)2, haloC 1-4 alkoxy, =C 3-6 cycloalkyl; each p is independently selected from 0, 1, 2, 3, 4.

2. The compound of formula (I) according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C 3-6 monocyclic cycloalkyl, C 5-12 bicyclic cycloalkyl, 4-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-6 membered heteroaryl, 6-8 membered aryl, or absent, said cycloalkyl, heterocycloalkyl, heteroaryl, or aryl optionally substituted with 1-5 groups selected from R A ; Preferably ring A is selected from C 3-6 monocyclic cycloalkyl, C 6-10 bicyclic cycloalkyl, 5-6 membered heteroaryl or absent, said cycloalkyl, heteroaryl being optionally substituted with 1-5 groups selected from R A ; and R A each independently selected from H, deuterium, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, C 1-4 alkyl or C 1-4 alkoxy; R B each independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with 1-3 groups selected from deuterium, halogen, NH2, CN, C 1-4 alkyl, or C 1-4 alkoxy; L1, L2are each independently selected from the group consisting of a bond, C 1-6 alkylene, -O-, -O-C 1-4 alkyl-, -(CH2) p -C 3-6 cycloalkylene, said alkyl, alkylene, cycloalkylene are optionally further substituted with 1-4 R L1 substituents.

3. The compound of formula (I) according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L3is selected from -(CH2) p -OC(O)-N(C 1-4 alkyl)-, -(CH2) p -NHC(O)O-; Y is selected from C 3-6 cycloalkyl, said cycloalkyl being further substituted with 1 to 4 groups selected from =CH2, 1-4 alkoxy, =C 3-6 cycloalkyl.

4. The compound according to claim 1 or 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ###0002### (I) selected from the group consisting of:

5. The compound according to claim 1 represented by formula (I-1), (I-2), (I-3), (I-4), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, 6. The compound of formula (I-1), (I-2), (I-3), (I-4) according to claim 5, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C 3-6 monocyclic cycloalkyl, C 6-10 bicyclic cycloalkyl, 5-6 membered heteroaryl or absent, optionally substituted with 1-3 groups selected from R A preferably or is absent, optionally substituted with 1-3 groups selected from R A ; and the like. R A selected from deuterium, halogen, C 1-6 alkyl, said alkyl being optionally substituted with 1-3 groups selected from deuterium, halogen; preferably deuterium, halogen, C 1-4 alkyl, said alkyl being optionally substituted with 1-3 groups selected from deuterium, halogen; L1is selected from C 1-4 alkylene, -(CH2) p -C 3-6 cycloalkylene, preferably -CH2-, -CH(CH3)-, -C(CH3)2-, cyclopropyl; L2is selected from -O-, -O-C 1-6 alkyl-, preferably -O-, -O-C 1-4 alkyl-, more preferably -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CHCH3-, -O-CH2CH2CH(CH3)-, -O-CH2C(CH3)2-; R B selected from C 1-6 alkyl, preferably C 1-4 alkyl, more preferably methyl; R1is selected from -(CH2) p -C(O)OH; p is selected from 0 or 1.

7. The compound according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, selected from one of the structures in Table 1, Table 2.

8. A pharmaceutical composition or a pharmaceutical preparation comprising a compound according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

9. The pharmaceutical composition or the pharmaceutical preparation according to claim 8, comprising 1-1500 mg of a compound according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a carrier and / or excipient.

10. Use of a compound according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a composition according to claims 8 to 9, for the manufacture of a medicament for the treatment / prevention of a LPAR1 mediated disease.

11. The use according to claim 10, wherein the LPAR1 mediated disease is selected from idiopathic pulmonary fibrosis.

12. A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount, preferably 1-1500 mg, of a compound according to any one of claims 1 to 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, to the subject, the disease preferably being idiopathic pulmonary fibrosis.

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