Oxygen-substituted aminocarbonate thiophene compounds

Abstract

The present invention provides oxygen-substituted aminocarbonate thiophene compounds, specifically relating to a class of new compounds that effectively antagonize LPAR, which are compounds represented by the following formula, or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compounds represented by the following formula: #imgabs0#

Description

[0001] Priority Information

[0002] This application claims the priority and benefits of the patent application with the patent application number 202011249593.7, which was filed with the China National Intellectual Property Administration on November 10, 2020, and the entire text thereof is incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to oxygen-substituted aminocarbonate thiophene compounds. More specifically, the present invention relates to oxygen-substituted aminocarbonate thiophene compounds and their uses in the preparation of drugs. Background Art

[0004] Lysophosphatidic acid (LPA) is a class of key endogenous lipid signaling molecules with a molecular weight of 430 - 480 Da. It exists widely in intracellular and extracellular compartments of various tissues in the human body, such as various body fluids, saliva, urine, cerebrospinal fluid, blood, bronchoalveolar lavage fluid (BALF), etc. (Kaffe E et al., Cancers (Basel). 2019; 11(11): 1626.). LPA is mainly produced from membrane phospholipids through the following two pathways: (1) the phospholipase D (PLD)-phospholipase A2 (PLA2) pathway; (2) the PLA2-lysophospholipase D (LysoPLD) pathway. Autotaxin (ATX) encoded by the Enpp2 gene is a pyrophosphatase / phosphodiesterase, which has lysophospholipase D (LysoPLD) activity and can hydrolyze extracellular lysophosphatidylcholine (LPC) into the corresponding LPA and free choline (Choi JW et al., Annu Rev Pharmacol Toxicol. 2010; 50: 157 - 186.). This reaction is the main source of LPA, and inhibiting ATX activity can inhibit the production of more than 80% of LPA in the whole body (Kaffe E et al., Cancers (Basel). 2019; 11(11): 1626.).

[0005] LPA mediates multiple functions by acting on G protein-coupled receptors, including cell survival, cell proliferation, cell adhesion, cell migration, cytoskeletal changes, calcium mobilization, increased vascular permeability and angiogenesis, immune function, and myelination, etc. LPA can bind to six lysophosphatidic acid receptors (LPARs) and exert its functions, namely: LPAR1-LPAR6. LPA regulates multiple physiological / pathological processes by binding to 6 LPARs, including vascular and neural development, hair follicle development, lymphocyte trafficking, bone development, fibrosis, regulation of fat mass, cholestatic pruritus, neuropathic pain, embryo implantation, obesity and glucose homeostasis, sperm production, chronic inflammation, cell proliferation, cell chemotaxis, wound healing, tumor progression, fetal hydrocephalus, etc. (Fang Yang et al., World journal of gastroenterology, 2018, 24(36):4132.)

[0006] LPAR1 is the earliest identified and most widely distributed LPA receptor. It is a 41 kDa membrane protein composed of 364 amino acids and is widely expressed in various tissues and organs of the human body. The mRNA levels are relatively high in the brain, heart, colon, small intestine, and placenta, while relatively low in other organs and tissues. LPAR1 activates downstream pathways such as Akt, Rho, mitogen-activated protein kinase, and phospholipase C by coupling with GαI / o, GαQ / 11, and Gα12 / 13. Although it has been shown that LPA-LPAR1 signaling plays an important role in the developmental stage of the nervous system, no obvious toxicity was found in the systemic inhibition of adult individuals. However, the inhibition of LPAR3 signaling will produce significant reproductive toxicity. Therefore, compounds need to avoid inhibiting LPAR3 signaling.

[0007] The diseases that have a significant correlation with LPAR1 are mainly fibrosis diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), certain central diseases, etc.

[0008] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology, characterized by diffuse alveolitis and alveolar structural disorder, and mainly manifested as usual interstitial pneumonia in imaging and pathological histology. IPF originates from repeated injuries of alveolar tissue, and such injuries trigger a series of physiological and pathological events, including (I) disrupting homeostasis; (II) causing inflammatory responses; (III) cell proliferation, migration and differentiation; (IV) matrix and tissue remodeling; and (V) wound contracture and scar formation. Many of these events are controlled by the coordinated release of biochemical factors at and around the injury site, and LPA plays an important role among them. Pathologically elevated LPA concentrations may continuously activate the LPAR1 receptor on lung cells, thereby enhancing tissue inflammation and stimulating excessive extracellular matrix (ECM) production. LPA is one of the main mediators of fibroblast migration in the bronchoalveolar lavage fluid (BALF) of damaged lung tissue (Tager AM et al., Proceedings of the American Thoracic Society, 2008.). The LPA level in the BALF (bronchoalveolar lavage fluid) of IPF patients is higher than that of the normal control group, and inhibiting the LPA signal significantly reduces the chemotactic response of fibroblasts to IPF BALF.

[0009] In preclinical studies, bleomycin was used to treat LPAR1 gene-deficient mice, and it was found that LPAR1 gene knockout had a significant protective effect on the mice, and in LPAR1-deficient mice, the fibroblast aggregation after bleomycin treatment was significantly reduced. LPA induces endothelial cell barrier dysfunction and vascular leakage. In the early stage of tissue injury repair, increased vascular permeability can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated vascular permeability promotes fibrosis development. In another preclinical model of bleomycin-induced IPF, bleomycin treatment led to a significant increase in the LPA level in the bronchoalveolar lavage fluid after lung injury, and caused pulmonary fibrosis, vascular leakage and death. These pathological changes were observed in LPAR1 - / -It was significantly alleviated in mice; the LPAR1 antagonist AM966 reduced the total protein content and LDH activity in the bronchoalveolar lavage fluid in the bleomycin model, indicating that AM966 reduced LPA-mediated vascular leakage and epithelial cell death in IPF and other interstitial lung diseases. These findings suggest that LPAR1 is a promising target for the treatment of IPF. In a randomized, double-blind, placebo-controlled clinical trial, the use of the LPAR1 antagonist BMS-986020 significantly slowed the decline in vital capacity and alleviated clinical symptoms in patients with idiopathic pulmonary fibrosis. Its second-generation compound, BMS-986278, is undergoing a phase II clinical trial for the treatment of IPF (Swaney JS et al., Br J Pharmacol. 2010;160(7):1699-1713.).

[0010] Radiation-induced pulmonary fibrosis is a common and severe complication of radiotherapy for lung cancer. The LPAR1 / LPAR3 antagonist VPC12249 can inhibit the expression of profibrotic cytokines transforming growth factor-β1 and connective tissue growth factor in vivo, resulting in reduced fibroblast proliferation in mice and slowing the progression of radiation-induced pulmonary fibrosis, indicating that LPAR1 antagonists also have the potential to treat radiation-induced pulmonary fibrosis (Xiang H et al., J Cancer. 2020;11(12):3519-3535.).

[0011] LPAR1 is closely associated with the development of liver fibrosis. Studies have shown that the ATX-LPA signaling axis activates PI3K and stabilizes the mRNA of hypoxia-inducible factor HIF-1, thereby promoting the replication of hepatitis C virus. Inhibiting the ATX-LPA signal reduces the replication of hepatitis C virus. This process may be related to LPAR1 and LPAR3, and hepatitis is a key factor in the development of liver fibrosis, indicating that antagonizing LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol. 2017;66(5):919-929.); in another study, downregulating LPAR1 signaling reduced the expression of α-SMA, CTGF, and TGF-β1, thereby significantly improving thioacetamide-induced liver fibrosis, further demonstrating that LPAR1 antagonists can be used to treat liver fibrosis.

[0012] LPA promotes the progression of renal fibrosis through LPAR1. In mice with unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis (TIF), the concentrations of ATX and LPA increased, LPAR1 was significantly upregulated, and LPAR3 was significantly downregulated (Sakai N et al., FASEB J. 2013;27(5):1830-1846.). The ATX-LPA-LPAR1 signal can stimulate fibroblast migration and proliferation. In LPAR1 - / -In mice or after pretreatment with the LPAR1 / 3 antagonist Ki16425, UUO-induced renal fibrosis was significantly alleviated, and when LPAR1 signaling was blocked, the expression of profibrotic cytokines (connective tissue growth factor and transforming growth factor-β) was also significantly downregulated. This suggests that LPAR1 antagonists may be useful for the treatment of renal fibrosis.

[0013] Fetal hydrocephalus (FH) is a common neonatal neurological disease, and its occurrence is closely related to LPAR1 signaling. In a preclinical mouse model of intracranial hemorrhage, by exposing the embryonic mouse brain to blood or LPA, LPAR1 expressed by neural progenitor cells (NPCs) was overactivated, resulting in cortical destruction and thinning, and ultimately leading to FH. (Yung YC et al., Sci Transl Med. 2011;3(99):99ra87.). Pretreatment with Ki16425 (LPAR1 / 3 antagonist) in a relevant mouse model could reduce the probability and severity of hemorrhagic hydrocephalus (PHH), suggesting that LPAR1 antagonists may be used to treat fetal hydrocephalus.

[0014] The LPA-LPAR1 signaling has significant pro-tumor effects. LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion, activates vascular endothelial growth factor and activates matrix metalloproteinases in vitro, and promotes tumor cell resistance to cisplatin. LPAR1 signaling downregulates the expression of the tumor suppressor p53 in hepatocellular carcinoma cells; LPA activates the PI3K and P38MPAK signaling pathways through LPAR1, promoting the expression of MMP-9 and the invasion of HCC; LPA-LPAR1 can also promote invasiveness through GTPase RhoA and Rho-associated protein kinase (ROCK); it also induces protein kinase C (PKC) and nuclear factor κB (NF-κB) to promote epithelial-mesenchymal transition (EMT); in addition, the positive effect of LPA-LPAR1 on angiogenesis can also promote cancer development, because new blood vessels are essential for the development of solid tumors. These research results indicate that LPAR1 antagonists have great potential in the treatment of related tumors (Xiang H et al., J Cancer. 2020;11(12):3519-3535.).

[0015] Peripheral nerve injury in humans can lead to a pain state called neuropathic pain, the symptoms of which include persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia. LPAR1 signaling is associated with the occurrence of neuropathic pain. The leakage of serum at the injury site due to nervous system damage, which exposes nerve cells to a large amount of LPA, may be one of the causes of neuropathic pain. Studies by Makoto Inoue et al. have shown that the behavioral abnormalities and pain hypersensitivity in animal models caused by nerve injury can be eliminated by pretreatment with an LPAR1 antagonist or targeted deletion of LPAR1, and can be mimicked by intrathecal injection of LPA. Another study has shown that LPA can cause neuropathic pain by activating LPAR1 and releasing the nociceptive factor substance P, and LPAR1 - / - mice are resistant to neuropathic pain caused by partial sciatic nerve ligation. These results indicate that LPA-LPAR1 signaling plays a key role in the initiation of neuropathic pain, and LPAR1 antagonists may hold promise as analgesics for the treatment of neuropathic pain. (Inoue M et al., ERRATUM:Initiation ofneuropathicpainrequires lysophosphatidic acidreceptorsignaling[J].2004,10(7):755-755.).

[0016] Rheumatoid arthritis (RA) is a chronic autoimmune disease, and LPAR1 signaling is associated with the occurrence of RA. Compared with patients with osteoarthritis, the expression levels of LPAR1 and / or LPAR2 in the synovium of rheumatoid arthritis patients are elevated. Preclinical studies have shown that gene knockout of LPAR1 completely eliminates the symptoms of RA, and pharmacological antagonism of LPAR1 reduces the severity of the disease, alleviates inflammation and bone erosion. (Kaffe E et al., Cancers(Basel).2019;11(11):1626.Published2019 Oct 23.doi:10.3390 / cancers11111626). Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and makes them sensitive to tumor necrosis factor (TNF)-mediated apoptosis. In addition, LPA is also involved in the production of interleukin (IL)-6, IL-8 and cyclooxygenase-2 (COX-2) in RA FLS. These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals oftheRheumaticDiseases,2014,73(1):298-305.). Summary of the Invention

[0017] The present invention aims to solve at least one of the above technical problems to some extent or at least provide a useful commercial option.

[0018] The present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

[0019]

[0020] wherein, R 1 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), -Z-R a , unsubstituted or substituted by R b substituted C 1-6 alkyl {the "C 1-6 alkyl" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of R b is one or more (the number is based on the valence bond theory and stable existence of the substituted group. For example, 1, 2 or 3), when there are multiple R b , the R b are the same or different}, unsubstituted or substituted by R b substituted C 3-6 cycloalkyl (the "C 3-6 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or substituted by R b substituted C 1-6 alkylamino (the "C 1-6 alkylamino" such as wherein m1 and m2 are each independently selected from integers from 0 to 6, the sum of m1 and m2 does not exceed 6, and / or m1 and m2 are not both 0), unsubstituted or substituted by R b substituted C 1-6 alkoxy (the "C 1-6 alkoxy" such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy);

[0021] Z is selected from a single bond or -O-, -S-;

[0022] R a is selected from C 1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1-6 alkyl substituted by halogenAlkyl {the "halogen" is, for example, fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number is determined by the valence bond theory and stable existence of the substituted group. For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different};

[0023] R b Selected from -CN, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1-6 Alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy);

[0024] R 2 Selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), -Y-R d , unsubstituted or substituted by R e Substituted C 1-6 Alkyl {the "C 1-6 Alkyl" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R e is one or more (the number is determined by the valence bond theory and stable existence of the substituted group. For example, 1, 2 or 3), when there are multiple R e s, the R e s are the same or different}, unsubstituted or substituted by R e Substituted C 3-6 Cycloalkyl (the "C 3-6 Cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or substituted by R e Substituted C 1-6 Alkylamino (the "C 1-6 Alkylamino" is, for example wherein n1 and n2 are each independently selected from integers from 0 to 6, and the sum of n1 and n2 does not exceed 6, and / or n1 and n2 are not both 0), unsubstituted or substituted by R e Substituted C 1-6 Alkoxy (the "C 1-6 Alkoxy" is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy);

[0025] Y is selected from a single bond, -O- or -S-;

[0026] R d Selected from C 1-6Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), halogen-substituted C 1-6 alkyl groups {wherein the "halogen" is, for example, fluorine, chlorine, bromine or iodine; the number of halogens is one or more (the number is such that the substituted group conforms to the valence bond theory and exists stably. For example, 1, 2 or 3), and when there are multiple halogens, the halogens are the same or different};

[0027] R e is selected from -CN, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1-6 alkoxy groups (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy);

[0028] X 1 , X 2 , X 3 are each independently selected from C or N, and X 1 , X 2 and X 3 are not simultaneously N;

[0029] is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R 1 , for example

[0030] R 3 is selected from -H, C 1-3 alkyl groups (such as methyl, ethyl, n-propyl, isopropyl), halogen-substituted C 1-3 alkyl groups {wherein the "halogen" is, for example, fluorine, chlorine, bromine or iodine; the number of halogens is one or more (the number is such that the substituted group conforms to the valence bond theory and exists stably. For example, 1, 2 or 3), and when there are multiple halogens, the halogens are the same or different};

[0031] R 4 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), unsubstituted or substituted by R g substituted C 1-6 alkyl groups {wherein the "C 1-6 alkyl groups" are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of R g is one or more (the number is such that the substituted group conforms to the valence bond theory and exists stably. For example, 1, 2 or 3), and when there are multiple R g s, the Rg same or different}, unsubstituted or substituted by R g substituted C 3-8 cycloalkyl (the "C 3-6 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), unsubstituted or substituted by R g substituted 4-8 membered heterocyclic group {in the "4-8 membered heterocyclic group", the heteroatoms are selected from N, O and S; the number of heteroatoms is 1-2 (the number is based on the substituted group conforming to the valence bond theory and existing stably), when there are multiple heteroatoms, the heteroatoms are the same or different}, unsubstituted or substituted by R g substituted 5-8 membered aryl group (such as phenyl, naphthalene ring), unsubstituted or substituted by R g substituted 5-8 membered heteroaryl group (such as thiophene, furan, oxazole, thiazole, triazole, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl);

[0032] R g is selected from -H, halogen (such as fluorine, chlorine, bromine, iodine), C 1-6 alkyl (such as), C 1-6 cycloalkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl), halogen substituted C 1-6 alkyl (such as fluoroalkyl, and for example trifluoromethyl), C 1-6 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy), halogen substituted C 1-6 alkoxy (such as difluoromethoxy);

[0033] L 1 is selected from a single bond, unsubstituted C 1-3 alkylene (such as ) or C 1-3 substituted by alkyl C 1-3 alkylene (such as ).

[0034] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 1 is selected from fluorine, chlorine or bromine.

[0035] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 1Selected from -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -O(CH2)2OCH3, -OCH2F, -OCH2CH2F, -O(CH2)2CH2F, -OCH(CH3)(CH2F).

[0036] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 1 Selected from -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH(CH3)2, -SCH2F, -SCH2CH2F, -S(CH2)2CH2F, -SCH(CH3)(CH2F).

[0037] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 1 Selected from -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3, -NH-(CH2)2CH3, -NH-CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2;

[0038] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 1 Selected from -CH2CN, -CH2CH2CN, -(CH2)2CH2CN, -CH(CH3)(CH2CN), -NH-CH2CN, -N(CH3)(CH2CN), -NH-CH2CH2CH2CN, -NH-(CH2)2CH2CN, -NH-CH(CH3)(CH2CN), -OCH2CN, -OCH2CH2CN, -O(CH2)2CH2CN, -OCH(CH3)(CH2CN), -CH2F, -CHF2, CF3, -CF2CH3, -CH2CF3, -CH2CH2F, -(CH2)2CH2F, -CH(CH3)(CH2F). -NH-CH2F, -N(CH3)(CH2F), -NH-CH2CH2CH2F, -NH-(CH2)2CH2F, -NH-CH(CH3)(CH2F), -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)2CH2F, -OCH(CH3)(CH2F), -CH2CH2Cl, -(CH2)2CH2Cl, -CH(CH3)(CH2Cl), -NH-CH2Cl, -N(CH3)(CH2Cl), -NH-CH2CH2CH2Cl, -NH-(CH2)2CH2Cl, -NH-CH(CH3)(CH2Cl), -OCH2Cl, -OCH2CH2Cl, -O(CH2)2CH2Cl, -OCH(CH3)(CH2Cl),

[0039] In one embodiment, certain groups of the compound of formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: R 2 is selected from fluorine, chlorine or bromine.

[0040] In one embodiment, certain groups of the compound of formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: R 2 is selected from -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -O(CH2)2OCH3, -OCH2F, -OCH2CH2F, -O(CH2)2CH2F, -OCH(CH3)(CH2F).

[0041] In one embodiment, certain groups of the compound of formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: R 2 is selected from -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH(CH3)2, -SCH2F, -SCH2CH2F, -S(CH2)2CH2F, -SCH(CH3)(CH2F).

[0042] In one embodiment, certain groups of the compound of formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: R 2 is selected from -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3, -NH-(CH2)2CH3, -NH-CH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2.

[0043] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 2 Selected from -CH2CN, -CH2CH2CN, -(CH2)2CH2CN, -CH(CH3)(CH2CN), -NH-CH2CN, -N(CH3)(CH2CN), -NH-CH2CH2CH2CN, -NH-(CH2)2CH2CN, -NH-CH(CH3)(CH2CN), -OCH2CN, -OCH2CH2CN, -O(CH2)2CH2CN, -OCH(CH3)(CH2CN), -CH2F, -CHF2, CF3, -CF2CH3, -CH2CF3, -CH2CH2F, -(CH2)2CH2F, -CH(CH3)(CH2F), -NH-CH2F, -N(CH3)(CH2F), -NH-CH2CH2CH2F, -NH-(CH2)2CH2F, -NH-CH(CH3)(CH2F), -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)2CH2F, -OCH(CH3)(CH2F), -CH2CH2Cl, -(CH2)2CH2Cl, -CH(CH3)(CH2Cl), -NH-CH2Cl, -N(CH3)(CH2Cl), -NH-CH2CH2CH2Cl, -NH-(CH2)2CH2Cl, -NH-CH(CH3)(CH2Cl), -OCH2Cl, -OCH2CH2Cl, -O(CH2)2CH2Cl, -OCH(CH3)(CH2Cl),

[0044] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 3 Selected from -H, methyl, ethyl, -CF3, -CH2CH2F.

[0045] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl.

[0046] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from cyclopropyl, cyclobutyl, cyclopentyl.

[0047] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from

[0048] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from phenyl, naphthalene ring.

[0049] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from pyridyl.

[0050] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CF3, -CH2CH2F, -(CH2)2CH2F, -CH(CH3)(CH2F), -CH2CH2Cl, -(CH2)2CH2Cl, -CH(CH3)(CH2Cl).

[0051] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from

[0052] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from

[0053] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows, and the undefined groups are as described in any previous embodiment: R 4 Selected from

[0054] In one embodiment, certain groups of the compound represented by formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: R 4 selected from

[0055] In one embodiment, certain groups of the compound represented by formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: R 1 selected from -H, -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3 -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)2CH2F, -OCH(CH3)(CH2F),

[0056] In one embodiment, certain groups of the compound represented by formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: R 2 selected from -H, -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3 -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)2CH2F, -OCH(CH3)(CH2F),

[0057] In one embodiment, certain groups of the compound represented by formula (I) are defined as follows, and the undefined groups are as described in any previous embodiment: selected from

[0058] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows. For groups not defined, they are as described in any previous embodiment: R 1 is selected from -H, -F, methyl, cyclopropyl.

[0059] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows. For groups not defined, they are as described in any previous embodiment: R 2 is selected from -H, -F, -Cl, -CH3.

[0060] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows. For groups not defined, they are as described in any previous embodiment: R 4 is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, -CH2F, -CH2CH2F, -CF3, -CH2CF3.

[0061] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows. For groups not defined, they are as described in any previous embodiment: is selected from wherein R 1 is selected from -CN, halogen (such as fluorine), C 1-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl); R 2 is selected from -H, -CN, halogen (such as fluorine, chlorine), C 1-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl); R 3 is selected from -H, C 1-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl); R 4 is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, -CH2F, -CH2CH2F, -CF3, -CH2CF3; L 1 is selected from a single bond,

[0062] In one embodiment, the definitions of certain groups of the compound represented by formula (I) are as follows. For groups not defined, they are as described in any previous embodiment: is R 1 is selected from -F, methyl; R 2 is selected from -F, -Cl; R 3 is selected from methyl; R 4 is selected from C 3-8 cycloalkyl; L 1 is selected from a single bond.

[0063] In one embodiment, certain groups of the compound of formula (I) are defined as follows, and the undefined groups are as described in any of the previous embodiments: is R 1 is methyl; R 2 is selected from -F, -Cl; R 3 is selected from -H, methyl; R 4 is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, -CH2F, -CH2CH2F, -CF3, -CH2CF3; L 1 is selected from a single bond,

[0064] In one embodiment, certain groups of the compound of formula (I) are defined as follows, and the undefined groups are as described in any of the previous embodiments: is R 1 is selected from methyl; R 2 is selected from -F, -Cl; R 3 is selected from methyl; R 4 is selected from -H, -F, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, -CH2F, -CH2CH2F; L 1 is selected from a single bond,

[0065] In one embodiment, certain groups of the compound of formula (I) are defined as follows, and the undefined groups are as described in any of the previous embodiments: is R 1 is selected from methyl; R 2 is selected from -F, -Cl; R 3 is selected from -H, methyl; R 4 is selected from methyl, ethyl, cyclobutyl, cyclopentyl; L 1 is selected from a single bond,

[0066] In one embodiment, the compound of formula (I) is further a compound of formula (I-0):

[0067]

[0068] wherein, R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3 - OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)3F, -OCH(CH3)(CH2F),

[0069] R 2 selected from -H, -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3 - OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)3F, -OCH(CH3)(CH2F),

[0070] selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R 1 ;

[0071] R 3 selected from -H, C 1-3 alkyl, C alkyl substituted by halogen 1-3 alkyl;

[0072] R 4 selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, naphthalene ring, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CF3, -CH2CH2F, -(CH2)2CH2F, -CH(CH3)(CH2F), -CH2CH2Cl, -(CH2)2CH2Cl, -CH(CH3)(CH2Cl),

[0073] L 1Selected from a single bond, unsubstituted or substituted by C 1-3 alkyl-substituted C 1-6 alkylene group.

[0074] In one embodiment, the compound represented by formula (I) is further a compound represented by formula (I-0):

[0075]

[0076] wherein, R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3 -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)2CH2F, -OCH(CH3)(CH2F),

[0077] R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -NH2, -NH-CH3, -N(CH3)2, -NH-CH2CH3 -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, -O(CH2)2CH2F, -OCH(CH3)(CH2F),

[0078] is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R 1 ;

[0079] R 3 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;

[0080] R 4 Selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, naphthalene ring, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CF3, -CH2CH2F, -(CH2)2CH2F, -CH(CH3)(CH2F), -CH2CH2Cl, -(CH2)2CH2Cl, -CH(CH3)(CH2Cl),

[0081] Selected from

[0082] In one embodiment, the compound of formula (I) is further a compound of formula (I-1'):

[0083]

[0084] wherein, R 4 is selected from C 1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl), C 1-6 alkyl substituted by halogen {the "halogen" such as fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number is based on the valence theory and stable existence of the substituted group. For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different}; X 1 , X 2 , X 3 are each independently selected from C or N, and X 1 , X 2 and X 3 are not simultaneously N.

[0085] In one embodiment, R 1 is methyl, R 2 is halogen, R 3 is methyl, Selected from

[0086] In one embodiment, the compound of formula (I) can be any of the following compounds:

[0087]

[0088]

[0089]

[0090] The present invention also provides a pharmaceutical composition, which comprises the compound represented by the above formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

[0091] In the pharmaceutical composition described above, the compound represented by the formula (I), or the pharmaceutical composition of the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I) may be a therapeutically effective dose.

[0092] The present invention also provides the use of the compound represented by the above formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I) in the preparation of a drug for treating diseases related to LPAR.

[0093] In the use described above, the diseases related to LPAR are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.

[0094] In the use described above, the diseases related to LPAR are selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.

[0095] In some embodiments, the present invention provides a pharmaceutical composition comprising an effective dose of the aforementioned compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 are the experimental results of the compound according to the embodiment of the present invention reducing bleomycin-induced pulmonary fibrosis in mice by antagonizing LPAR1.

[0097] Term definitions and explanations

[0098] Unless otherwise specified, the definitions of the groups and terms recorded in the specification and claims of this application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The defined groups and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

[0099] Unless otherwise defined, all scientific and technical terms herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and published materials cited throughout this text are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

[0100] Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / Vis spectroscopy and pharmacological methods. Unless otherwise specifically defined, the terms employed in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions of the manufacturer for the kits can be utilized, or the reactions and purifications can be carried out in a manner known in the art or as described in the present application. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, according to the conventional methods well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also equally includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0101] For the numerical ranges recited in the specification and claims of the present application, when the numerical range is understood as "integers", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "integers from 1 to 6" should be understood to have recited each of 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as "numbers", it should be understood that the two endpoints of the range and each integer within the range and each decimal within the range are recited. For example, "numbers from 1 to 10" should be understood to have recited not only each of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.

[0102] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0103] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.

[0104] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. They can serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization, or purification of the compounds of the present invention.

[0105] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers. The stereochemical definitions and conventions used in this invention generally follow those defined in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0106] Depending on the choice of starting materials and methods, the compounds of the invention may exist in the form of one or a mixture of the possible isomers, e.g., as pure enantiomers, or as mixtures of isomers such as racemic and diastereoisomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of said isomers are generally called mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and such racemic mixtures or racemates may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain an alkene double bond, unless otherwise specified, such double bonds include E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituents on the cycloalkyl group may be in the cis- or trans- configuration.

[0107] When the bonds to a chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The graphical representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, the absolute configuration of a stereocenter is represented by wedge and dashed bonds.

[0108] The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral auxiliaries, or resolved using conventional techniques. The compounds of the present invention containing an asymmetrically substituted carbon atom can be isolated in optically active form or in racemic form. The resolution of the racemic mixtures of the compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional crystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for the fractional crystallization method are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of α-methyl-benzylamine (e.g., the S and R forms or diastereomerically pure forms), 2-phenylglycol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl-phenylglycine). High performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be employed. The choice of the specific method, as well as the elution conditions and the choice of the column, can be made by those skilled in the art according to the structure of the compound and the test results. Further, any enantiomer or diastereomer of the compounds described in the present invention can be obtained by stereoselective organic synthesis using optically pure starting materials or reagents of known configuration.

[0109] The term "tautomer" refers to functional group isomers resulting from the rapid migration of an atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomers of a compound can exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium form, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are identical to those of a mixture of the compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0110] The term "pharmaceutical composition" denotes a mixture of one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0111] For a drug or a pharmacological active agent, the terms "effective dose", "effective amount" or "therapeutically effective amount" refer to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art according to conventional tests.

[0112] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or condition.

[0113] The term "solvate" refers to a stoichiometric or non-stoichiometric solvent in which a compound or its salt of the present invention is included and bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0114] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl group or an amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group respectively.

[0115] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic composition transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0116] The term "excipient" refers to a pharmaceutically inert ingredient. Non-limiting examples of the types of "formulating agent" include binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents, etc.

[0117] The term "C 1-6"Alkyl" shall be understood to represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl and the like or their isomers. In particular, the group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

[0118] The term "C 3-6 "Cycloalkyl" shall be understood to represent a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0119] The term "alkylamino" or "alkyamino" means that one or two hydrogen atoms in the amino group are replaced by an alkyl group, including "N-alkylamino" and "N,N-dialkylamino", wherein the amino group is independently replaced by one or two alkyl groups, and the alkyl group has the meaning as described in the present invention. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of such include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), and the like. The alkyamino group is optionally substituted by one or more substituents described in the present invention.

[0120] The term "C 1-6 "Alkylamino" means "alkylamino" or "alkyamino" having 1 to 6 carbon atoms.

[0121] The term "C 1-6 "Alkoxy" shall be understood as -O-(C 1-6 "Alkyl), where "C 1-6 "Alkyl" has the above definition.

[0122] The term "4-8 membered heterocyclic group" shall be understood to represent a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, and unless otherwise specified, it can be linked through carbon or nitrogen, where -CH 2-The group is optionally replaced by -C(O)-; and unless otherwise stated to the contrary, the ring nitrogen atom or ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted by an acetyl group, a formyl group, a methyl group or a methanesulfonyl group; and the ring is optionally substituted by one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclic group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetidinyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5-dioxoimidazolidinyl.

[0123] The term "5-8-membered aryl" should be understood to mean a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent and aromatic or partially aromatic and has 5-8 carbon atoms, especially a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; when the 5-8-membered aryl is substituted, it can be mono-substituted or multi-substituted. And there is no restriction on its substitution site, for example, it can be ortho-substituted, para-substituted or meta-substituted.

[0124] The term "5-8-membered heteroaryl" should be understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring group having 5-8 ring atoms - especially 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S. Preferably 1-3 - a monovalent monocyclic, bicyclic or tricyclic aromatic ring group of heteroatoms independently selected from N, O and S, and, additionally, in each case, can be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0125] The term "halogenated group" or "halogen" is fluorine, chlorine, bromine and iodine.

[0126] "Halogenated alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms and substituted by one or more halogens (such as -CvFw, where v = 1 to 3 and w = 1 to (2v + 1)). Examples of halogenated alkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0127] Beneficial effects

[0128] According to a specific example of the present invention, the compound represented by formula (I) of the present invention, its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs have a good antagonistic effect on LPAR1.

[0129] According to a specific example of the present invention, the compound of the present invention has a good antagonistic effect on LPAR1 and a very weak antagonistic effect on LPAR3, that is, the compound of the present invention shows excellent selectivity; the compound of the present invention has better safety, no risk of cholestatic toxicity and no hepatocyte toxicity; the compound of the present invention has excellent pharmacokinetic properties and good drug-forming properties; the compound of the present invention can significantly inhibit LPA-induced histamine release by antagonizing LPAR1, and at the same time significantly improve the symptoms of bleomycin-induced pulmonary fibrosis in mice.

[0130] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention. Detailed implementation manners

[0131] The solution of the present invention will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples regarding specific techniques or conditions, they shall be carried out according to the techniques or conditions described in the literature in the art or according to the product specifications. For reagents or instruments not indicated with the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0132] The embodiments of the present invention provide a compound represented by formula (I), its pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs, methods and intermediates for preparing the compound represented by formula (I) or its pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs, pharmaceutical compositions, and the use of the compounds and pharmaceutical compositions of the present invention in the preparation of drugs.

[0133] There are no particular restrictions on the reaction solvents used in each reaction step of the present invention. Any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different ratios of solvent combinations equivalent to those described in the present invention are considered to be within the scope of the present invention.

[0134] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0135] Liquid chromatography-mass spectrometry (LC-MS) was determined by a Waters Acquity H-class Uplc-QDA mass spectrometer, and monitored using an ACQUITY UPLC BEH C18, 2.1*50mm, 1.7μm chromatographic column. Gradient elution conditions: at a flow rate of 1.0 mL / min, 95 - 5% solvent A1 and 5 - 95% solvent B1, then 95% B1 and 5% A1 were maintained for 0.5 min. The percentages are the volume percentages of a certain solvent in the total solvent volume. Among them, solvent A1: an aqueous solution of 0.1% formic acid; solvent B1: an acetonitrile solution of 0.1% formic acid. The percentages are the volume percentages of the solute in the solution.

[0136] The abbreviations in the present invention are defined as follows:

[0137] Symbols or units:

[0138] IC 50 : Half inhibitory concentration, referring to the concentration when the maximum inhibitory effect reaches half.

[0139] M: mol / L. For example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) represents an n-hexane solution of n-butyllithium with a molar concentration of 2.5 mol / L.

[0140] N: Normal concentration. For example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0141] RT: Retention time

[0142] Reagents:

[0143] CuI: Copper(I) iodide

[0144] DCM: Dichloromethane

[0145] DIBAL-H: Diisobutylaluminum hydride

[0146] DIPEA: It can also be written as DIEA, diisopropylethylamine, that is, N,N - diisopropylethylamine

[0147] DMF: N,N - dimethylformamide

[0148] DMSO: Dimethyl sulfoxide

[0149] Et3N: Triethylamine

[0150] HATU: 2-(7 - Azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0151] MeOH: Methanol

[0152] NADPH: Reduced nicotinamide adenine dinucleotide phosphate

[0153] NaH: Sodium hydride

[0154] NMM: N - Methylmorpholine

[0155] NMP: N - Methylpyrrolidone

[0156] T3P: Propylphosphonic anhydride, that is, 2,4,6 - tripropyl - 1,3,5,2,4,6 - trioxatriphosphinane - 2,4,6 - trioxide or 1 - propylphosphonic anhydride

[0157] THF: Tetrahydrofuran

[0158] TMSN3: Trimethylsilyl azide

[0159] TsCl: p - Toluenesulfonyl chloride

[0160] Test or detection methods:

[0161] HPLC: High - performance liquid chromatography

[0162] SFC: Supercritical fluid chromatography

[0163] Unless otherwise indicated, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0

[0164] Control Example 1: Control Compound 1 and its preparation

[0165]

[0166] Control Compound 1 was synthesized with reference to Patent Application WO2010141768A2

[0167] Control Example 2: Control Compound 2 and its preparation

[0168]

[0169] The reference compound 2 was synthesized with reference to the patent application WO2017223016A1.

[0170] Comparative Example 3: Reference Compound 3 and Its Preparation

[0171]

[0172] The reference compound 3 was synthesized with reference to the patent application WO2017223016A1.

[0173] Comparative Example 4: Reference Compound 4 and Its Preparation

[0174]

[0175] The reference compound 4 was synthesized with reference to the patent application WO2019126098A1.

[0176] Comparative Example 5: Reference Compound 5 and Its Preparation

[0177]

[0178] The reference compound 5 was synthesized with reference to the patent application WO2019126084A1.

[0179] Preparation Example 1: Preparation of Intermediate A

[0180] (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (Intermediate A)

[0181] methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate (Intermediate A)

[0182]

[0183] The synthetic route of Intermediate A is shown as follows:

[0184]

[0185] The first step: Synthesis of (1S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (A-2)

[0186] (1S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (A-2)

[0187]

[0188] (S)-Cyclohex-3-ene-1-carboxylic acid (8.1 g) was dissolved in DCM (135 mL) and water (270 mL). Sodium bicarbonate (10.79 g, 128.3 mmol), potassium iodide (64.0 g, 385.5 mmol) and iodine (48.9 g, 192.6 mmol) were added to the reaction solution. The reaction was stirred overnight at room temperature in the dark. The reaction was monitored by TLC until completion. The layers were separated, and the aqueous phase was extracted with methyl tert-butyl ether (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the product (1S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (A-2) (13.6 g, yield 84%), which was directly used in the next step of the reaction.

[0189] Step 2: Synthesis of (1S,5R)-6-oxabicyclo[3.2.1]octan-7-one (A-3)

[0190] (1S,5R)-6-oxabicyclo[3.2.1]octan-7-one (A-3)

[0191]

[0192] (1S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (A-2) (13.2 g, 52.4 mmol) was dissolved in MeOH (150 mL). Sodium acetate (4.30 g, 52.4 mmol), lithium chloride (2.22 g, 52.4 mmol) and 10% dry palladium on carbon (1.115 g) were added. The reaction was purged with hydrogen three times and then stirred overnight at room temperature under a hydrogen balloon. The reaction solution was filtered through diatomaceous earth and concentrated. The residue was dissolved in methyl tert-butyl ether (100 mL), washed once with saturated sodium bicarbonate, once with saturated sodium sulfite, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1 - 20:1) to obtain the white solid (1S,5R)-6-oxabicyclo[3.2.1]octan-7-one (A-3) (3.88 g, yield 58.7%).

[0193] Step 3: Synthesis of methyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (Intermediate A)

[0194] methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate (Intermediate A)

[0195]

[0196] (1S,5R)-6-Oxabicyclo[3.2.1]octan-7-one (A-3) (4.2 g, 33.3 mmol) was dissolved in MeOH (150 mL). The reaction solution was cooled to 0 - 5 °C, and acetyl chloride (7.5 mL) was added dropwise to the reaction solution. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 3 h. After monitoring the reaction by TLC until completion, water (150 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain a light yellow oil, methyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (Intermediate A) (4.63 g, yield 88%).

[0197] 1 HNMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.65 - 3.57 (m, 1H), 2.39 - 2.31 (m, 1H), 2.20 - 2.14 (m, 1H), 1.96 - 1.78 (m, 4H), 1.44 - 1.16 (m, 4H).

[0198] Preparation Example 2: Preparation of Intermediate B

[0199] methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate B)

[0200] methyl(1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(Intermediate B)

[0201]

[0202] The synthetic route of Intermediate B is shown as follows:

[0203]

[0204] At 0 °C, azodicarboxyldipiperidine (3.19 g, 10.7 mmol) was added dropwise to a solution of methyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (intermediate A) (1.10 g, 6.95 mmol), 6-bromo-2-methylpyridin-3-ol (1.19 g, 6.31 mmol) and tributylphosphine (2.55 g, 12.6 mmol) in toluene (20.0 mL). Then the mixture was stirred at 80 °C under nitrogen for 10 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:0 - 20:1) to obtain methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (intermediate B) (0.580 g, yield 30.3%).

[0205] Preparation Example 3: Synthesis of Intermediate C

[0206] (1S,3S)-3-((2-Methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate C)

[0207] methyl(1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate C)

[0208]

[0209] The synthetic route of Intermediate C is shown below:

[0210]

[0211] Tetrakis(triphenylphosphine)palladium (88.02 mg, 76.17 μmol) and hexabutylditin (5.30 g, 9.14 mmol, 4.57 mL) were added to a solution of methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (intermediate B) (0.5 g, 1.52 mmol) in xylene (10 mL). Under a nitrogen atmosphere, the mixture was heated to 135 °C and stirred for 2 h. After cooling to room temperature, saturated potassium fluoride solution (10 mL) was added to quench the reaction, and then the mixture was extracted with ethyl acetate (10 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain methyl (1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (intermediate C) (0.82 g, crude product).

[0212] Example 1: Preparation of Target Compound I-1

[0213] (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)pheno xy)cyclohexane-1-carboxylic acid (Target Compound I-1)

[0214] (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)pheno xy)cyclohexane-1-carboxylic acid (Target Compound I-1)

[0215]

[0216] The synthetic route of Target Compound I-1 is as follows:

[0217]

[0218] The first step: Synthesis of (2-bromothiophen-3-yl)methanol (I-1B)

[0219] (2-bromothiophen-3-yl)methanol (I-1B)

[0220]

[0221] At 0 °C, N-bromosuccinimide (15.59 g, 88 mmol) was slowly added to a solution of thiophen-3-ylmethanol (10 g, 88 mmol) in tetrahydrofuran (70 mL) and water (5 mL). Stir at room temperature for 1 h. After the raw materials reacted completely, distilled water (30 mL) was added for dilution, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1) to obtain a yellow oil, (2-bromothiophen-3-yl)methanol (I-1B) (12.3 g, yield 72.7%).

[0222] 1 HNMR(400MHz,DMSO-d6)δ7.54(d,1H),7.05(d,1H),4.38(s,2H).

[0223] The second step: Synthesis of (2-bromothiophen-3-yl)methyl (4-nitrophenyl) carbonate (I-1C)

[0224] (2-bromothiophen-3-yl)methyl(4-nitrophenyl)carbonate(I-1C)

[0225]

[0226] Pyridine (10.89 mL, 135 mmol) and phenyl 4-nitrochloroformate (16.29 g, 81 mmol) were successively added to a solution of (2-bromothiophen-3-yl)methanol (5.2 g, 26.9 mmol) in dichloromethane (50 mL), and the mixture was stirred at room temperature overnight. After the reaction of the starting materials was completed, the reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the yellow solid (2-bromothiophen-3-yl)methyl(4-nitrophenyl)carbonate (I-1C) (5.4 g, yield 56.0%).

[0227] 1 HNMR (400 MHz, DMSO-d6) δ 8.34 - 8.30 (m, 1H), 7.67 (d, 1H), 7.58 (d, 2H), 7.15 (d, 1H), 5.24 (s, 2H).

[0228] Step 3: Synthesis of (2-bromothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1D)

[0229] (2-bromothiophen-3-yl)methyl cyclopentyl(methyl)carbamate(I-1D)

[0230]

[0231] DIEA (4.75 mL, 27.2 mmol) was added dropwise to a solution of (2-bromothiophen-3-yl)methyl(4-nitrophenyl)carbonate (3.9 g, 10.89 mmol) and N-methylcyclopentanamine hydrochloride (1.625 g, 11.98 mmol) in THF (30 mL), and the reaction was carried out at room temperature overnight. After the reaction of the starting materials was completed, distilled water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the yellow oily (2-bromothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1D) (3.04 g, yield 88%).

[0232] 11H NMR (400 MHz, DMSO-d6) δ 7.60 (d, 1H), 7.05 (d, 1H), 4.96 (s, 2H), 2.71 (s, 3H), 1.73 - 1.44 (m, 9H).

[0233] Step 4: Synthesis of (2-bromo-5-chlorothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1E)

[0234] (2-bromo-5-chlorothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1E)

[0235]

[0236] At 0 °C, N-chlorosuccinimide (0.766 g, 5.74 mmol) was slowly added to a solution of (2-bromothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (1.66 g, 5.22 mmol) in DMF (15 mL). The mixture was stirred at 70 °C overnight. After the raw materials were reacted completely, distilled water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain a yellow oil, (2-bromo-5-chlorothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1E) (1.55 g, yield 84%).

[0237] 1 1H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 1H), 4.86 (s, 2H), 2.71 (s, 3H), 1.49 - 1.70 (m, 9H).

[0238] Step 5: Synthesis of (5-chloro-2-(4-hydroxyphenyl)thiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1F)

[0239] (5-chloro-2-(4-hydroxyphenyl)thiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1F)

[0240]

[0241] Bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.322 g, 0.439 mmol) was added to a reaction solution containing (2-bromo-5-chlorothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (1.55 g, 4.39 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.967 g, 4.39 mmol), and cesium carbonate (2.86 g, 8.79 mmol) in 1,4-dioxane (20 mL) and water (1 mL). Under nitrogen protection, the mixture was stirred at 90 °C overnight. After the reaction was completed, the mixture was filtered and the filtrate was concentrated directly. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the yellow solid (5-chloro-2-(4-hydroxyphenyl)thiophen-3-yl)methyl cyclopentyl(methyl)carbamate (I-1F) (910 mg, yield 56.6%).

[0242] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.25 - 7.28 (m, 2H), 7.12 (s, 1H), 6.85 (dd, 2H), 4.86 (s, 2H), 2.68 (s, 3H), 1.44 - 1.66 (m, 9H).

[0243] Step 6: Synthesis of methyl (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (I-1G)

[0244] methyl(1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) phenoxy)cyclohexane-1-carboxylate(I-1G)

[0245]

[0246] Tri-tert-butylphosphine (0.645 g, 2.460 mmol), diisopropyl azodicarboxylate (0.478 mL, 2.460 mmol), and (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (0.259 g, 1.640 mmol) were added sequentially to THF (10 mL) containing (5-chloro-2-(4-hydroxyphenyl)thiophen-3-yl)methylcyclopentyl(methyl)carbamate (0.3 g, 0.820 mmol), and the mixture was stirred at 60° C. overnight under nitrogen protection. After the reaction, distilled water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (10 mL), separated, and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain a yellow oil (1S, 3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester (I-1G) (110 mg, yield 26.5%).

[0247] 1 H NMR(400MHz,DMSO-d6)δ7.34-7.31(m,2H),6.97-6.92(m,3H),4.96(s,2H),3.68 (s,3H),2.83-2.77(m,4H),2.08-1.88(m,3H),1.80-1.76(m,4H),1.66-1.47(m,11H).

[0248] Step 7: Synthesis of (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid (target compound I-1)

[0249] (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)pheno xy)cyclohexane-1-carboxylic acid (target compound I-1)

[0250]

[0251] Lithium hydroxide monohydrate (32.3 mg, 0.771 mmol) was added to a mixed solution of THF (2 mL) and MeOH (2 mL) containing methyl (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (130 mg, 0.257 mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed, distilled water (5 mL) was added for dilution, and the pH was adjusted to 3 - 4 with dilute hydrochloric acid (1N). Then, it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative plate (ethyl acetate) to obtain the white solid (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid (target compound I-1) (40.8 mg, yield 32.3%).

[0252] 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (d, 2H), 7.15 (s, 1H), 7.05 (d, 2H), 4.95 (d, 2H), 4.70 (s, 1H), 2.67 - 2.64 (m, 4H), 1.97 - 1.40 (m, 17H).

[0253] LC-MS, M / Z (ESI): 492.1 [M + H] + 。

[0254] Example 2: Preparation of target compound I-2

[0255] (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)

[0256] (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)

[0257]

[0258] The synthetic route of target compound I-2 is as follows:

[0259]

[0260] Step 1: Synthesis of 6-bromo-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pyridine (I-2B)

[0261] 6-bromo-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pyridine(I-2B)

[0262]

[0263] At room temperature, the raw material 6-bromo-2-methylpyridin-3-ol (5.5 g, 29.3 mmol) was added to 20 mL of anhydrous DCM, pyridine hydrochloride (0.735 g, 2.93 mmol), and 3,4-dihydropyran (3.69 g, 43.9 mmol) were added, and the mixture was stirred at room temperature for 16 h. Water (400 mL) was added, and the mixture was extracted with DCM (100 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain the title compound as a colorless liquid, 6-bromo-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pyridine (I-2B) (6.2 g, yield 77.9%).

[0264] LC-MS, M / Z(ESI): 272.3[M+H] +

[0265] Step 2: Synthesis of 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C)

[0266] 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C)

[0267]

[0268] At room temperature, the raw material 6-bromo-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pyridine (200 mg, 0.74 mmol) was added to 15 mL of DMF. Under nitrogen protection, 3-formyl-2-thiopheneboronic acid (149 mg, 0.96 mmol), bis(tri-tert-butylphosphine)palladium (38 mg, 0.074 mmol), and anhydrous potassium carbonate (304 mg, 2.20 mmol) were added. The mixture was heated to 90 °C and stirred for 16 h. Water (200 mL) was added for dilution, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain the title compound, colorless liquid 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C) (200 mg, yield 89.7%).

[0269] LC-MS, M / Z(ESI): 304.4[M+H] +

[0270] Step 3: Synthesis of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methanol (I-2D)

[0271] (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methanol

[0272]

[0273] At room temperature, 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C) (3.8 g, 12.5 mmol) was added to a methanol (30 mL) solution. Sodium borohydride (709.3 mg, 18.75 mmol) was added at 0 °C, and then the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (20 mL), and then extracted with ethyl acetate (30 mL × 2). The organic layers were combined to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methanol (I-2D) (3.1 g, yield 81.2%).

[0274] Step 4: Synthesis of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (4-nitrophenyl) carbonate (I-2F)

[0275] (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (4-nitrophenyl)carbonate (I-2F)

[0276]

[0277] At room temperature, pyridine (0.78 g, 9.82 mmol) was added to a solution of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methanol (I-2D) (1 g, 3.27 mmol) and phenyl 4-nitrocarbonate (0.99 g, 4.91 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to give a brown liquid compound, (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (4-nitrophenyl)carbonate (I-2F) (1.1 g, yield 71.4%).

[0278] Step 5: Synthesis of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)carbamate (I-2G)

[0279] (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)carbamate (I-2G)

[0280]

[0281] To a solution of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (4-nitrophenyl) carbonate (I-2F) (1.1 g, 2.34 mmol) and N,N-diisopropylethylamine (0.906 mg, 7.01 mmol) in tetrahydrofuran (15 mL) was added cyclobutylmethylamine hydrochloride (0.341 mg, 2.81 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1) to give a black liquid compound (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)carbamate (I-2G) (0.84 g, yield 86%).

[0282] Step 6: Synthesis of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)(methyl)carbamate (I-2H)

[0283] (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)(methyl)carbamate(I-2H)

[0284]

[0285] Under an ice bath, sodium hydride (0.500 g, 12.49 mmol, 60% purity) was added to a solution of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)carbamate (I-2G) (1.9 g, 6.25 mmol) in DMF (20 mL), and then methyl iodide (0.778 mL, 12.49 mmol) was added. The ice bath was removed, and the reaction was carried out overnight at room temperature. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 2). After the organic phase was concentrated, the residue was purified by silica gel column chromatography to give a brown solid (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)(methyl)carbamate (I-2H) (1.5 g, yield 75%).

[0286] Step 7: Synthesis of (5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl (cyclobutylmethyl)(methyl)carbamate (I-2I)

[0287] (5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl)(meth yl)carbamate (I-2I)

[0288]

[0289] At room temperature, N-chlorosuccinimide (0.34 mg, 2.51 mmol) was added to a solution of (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl)(methyl)carbamate (I-2H) (0.54 g, 1.25 mmol) in N,N-dimethylformamide (10 mL), and then the mixture was stirred at 80 °C overnight. After the reaction was complete, the reaction mixture was diluted with water (30 mL), and then extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated aqueous sodium chloride (30 mL × 2). The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography to obtain the yellow solid compound (5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl)(methyl)carbamate (I-2I) (0.22 g, yield 46.1%).

[0290] Step 8: Synthesis of methyl(1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2J)

[0291] methyl(1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiop hen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2J)

[0292]

[0293] At room temperature, (5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl)(methyl)carbamate (I-2I) (0.09 g, 236.29 μmol), methyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (112.14 mg, 708.87 μmol) and triphenylphosphine (185.93 mg, 708.87 μmol) were added to tetrahydrofuran (2 mL). The reaction solution was protected by nitrogen, and diisopropyl azodicarboxylate (143.34 mg, 708.87 μmol) was slowly added. The mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1 - 2:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyloxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2J) (0.3 g, crude product).

[0294] Step 9: Synthesis of (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)aminocarbonyl)oxo)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxo)cyclohexane-1-carboxylic acid (Target Compound I-2)

[0295] (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-2)

[0296]

[0297] At room temperature, methyl (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2J) (0.12 g, 204.73 μmol) was added to tetrahydrofuran (1 mL) and methanol (1 mL), and then 1 M aqueous lithium hydroxide solution (1.02 mL, 1.02 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH = 5 with 1 M hydrochloric acid and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative separation (separation method: column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: A = water + 0.05% (by volume) hydrochloric acid (36.5%), B = acetonitrile; gradient elution: 59%-89% B, 10 minutes)) to obtain the compound (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)aminocarbonyl)oxo)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxo)cyclohexane-1-carboxylic acid (target compound I-2) as a yellow solid (0.024 g, yield 22.63%).

[0298] 1 H NMR(400MHz,CDCl3)δ7.30(br s,1H),7.14(br d,1H),6.95(br s,1H),5.24(s,2H), 4.69(br s,1H),3.38-3.15(m,2H),2.89(br d,4H),2.64-2.42(m,4H),2.17(br d,1H),2.07-1.60(m,13H).

[0299] LC-MS,M / Z(ESI):507.2[M+H] + 。

[0300] Example 3: Preparation of target compound I-3

[0301] (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)

[0302] (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2 -yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-3)

[0303]

[0304] The synthetic route of Target Compound I-3 is as follows:

[0305]

[0306] The First Step: Synthesis of methyl (1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3B)

[0307] methyl(1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3B)

[0308]

[0309] At room temperature, methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (3 g, 9.14 mmol) (Intermediate B), potassium fluoride (3.19 g, 54.84 mmol) and (3-formylthiophen-2-yl)boronic acid (2.85 g, 18.28 mmol) were added to tetrahydrofuran (50 mL), then bis(tri-tert-butylphosphine)palladium (373.71 mg, 731.26 μmol) was added. The reaction solution was protected by nitrogen and stirred at 25 °C for 4 hours. The reaction mixture was diluted with ethyl acetate (30 mL), then extracted with saturated sodium chloride aqueous solution (30 mL). The organic layers were combined and concentrated to obtain the title compound methyl (1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3B) (3.12 g, yield 94.96%).

[0310] The Second Step: Synthesis of methyl (1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3C)

[0311] methyl(1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexa ne-1-carboxylate(I-3C)

[0312]

[0313] At 0°C, sodium borohydride (236.82 mg, 6.26 mmol) was added in batches to a methanol solution (10 mL) of (1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (1.5 g, 4.17 mmol) and stirred at 0°C for 0.5 hours. After the reaction was completed, the reaction mixture was quenched with water (10 mL), then extracted with ethyl acetate (15 mL×2), the organic layers were combined and concentrated to give (1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3C) (1.4 g, yield 92.81%).

[0314] Step 3: Synthesis of (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3D)

[0315] methyl(1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) cyclohexane-1-carboxylate(I-3D)

[0316]

[0317] At room temperature, N-chlorosuccinimide (682.71 mg, 5.11 mmol) was added to a solution of methyl (1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (1.68 g, 4.65 mmol) in N,N-dimethylformamide (8 mL), and then the mixture was stirred at 45 °C for 12 h. After the reaction was complete, the reaction mixture was diluted with water (20 mL), and then extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated aqueous sodium chloride solution (30 mL × 2). The combined organic layers were concentrated to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3D) (2.05 g), and the crude product was directly used in the next step of the reaction.

[0318] Step 4: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E)

[0319] methyl(1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3E)

[0320]

[0321] At room temperature, pyridine (1.05 g, 13.26 mmol) was added to a solution of methyl (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (1.05 g, 2.65 mmol) and phenyl 4-nitrochloroformate (1.60 g, 7.96 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1 - 1:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (0.96 g, yield 64.52%).

[0322] Step 5: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3F)

[0323] methyl(1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)thiophen-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3F)

[0324]

[0325] To a solution of methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.86 g, 1.53 mmol) and N,N-diisopropylethylamine (594.38 mg, 4.60 mmol) in tetrahydrofuran (5 mL) was added 2-cyclopropylethylamine (186.42 mg, 1.53 mmol), and the mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1 - 3:1) to give methyl (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3F) (0.85 g, crude product).

[0326] Step 6: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3G)

[0327] methyl(1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thio phen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3G)

[0328]

[0329] To a solution of methyl (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.75 g, 1.48 mmol) and methyl iodide (524.88 mg, 3.70 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (142 mg, 3.55 mmol, 60% content). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL × 2). The organic phase was concentrated in vacuo to obtain a crude product, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 15:1 - 1:1) to give the title compound, methyl (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3G) (0.55 g, yield 71.36%).

[0330] Step 7: (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-3)

[0331] (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2 -yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid (Target Compound I-3)

[0332]

[0333] At room temperature, lithium hydroxide aqueous solution (1 M, 1.92 mL) was added to methyl (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.2 g, 383.83 umol) in tetrahydrofuran (5 mL), and the mixture was stirred at 20 °C for 5 hours. After the reaction was complete, the reaction solution was adjusted to pH = 6 with saturated citric acid aqueous solution, concentrated under reduced pressure to obtain a crude product, and the residue was purified by silica gel plate to obtain (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3) (0.1 g, yield 51.38%).

[0334] LC-MS, M / Z(ESI): 507.2[M+H] + 。

[0335] 1 H NMR(400 MHz, CDCl3) δ 7.53(br d, 2H), 7.04 - 6.90(m, 1H), 5.32(br d, 1H), 5.14(br d, 1H), 4.82(br s, 1H), 3.34(br t, 2H), 2.92(s, 4H), 2.74(br s, 3H), 2.15(br d, 1H), 1.99 - 1.86(m, 3H), 1.82 - 1.62(m, 4H), 1.49 - 1.35(m, 2H), 0.61(br s, 1H), 0.44(br d, 2H), 0.04(br s, 2H).

[0336] Example 4: Preparation of target compound I-4

[0337] (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)

[0338] (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)

[0339]

[0340] The synthetic route of the target compound I-4 is as follows:

[0341]

[0342] Step 1: Synthesis of (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothien-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-4A)

[0343] methyl(1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-4A)

[0344]

[0345] (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3E) (180 mg, 0.321 mmol) and N-methylbenzylamine (46.7 mg, 0.385 mmol) were dissolved in dichloromethane (6 mL), and N,N-diisopropylethylamine (83 mg, 0.642 mmol) was added and stirred at room temperature for 3 h. The reaction system was concentrated, and the residue was separated and purified by silica gel plate to obtain a yellow solid compound (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-4A) (110 mg, yield 63.1%).

[0346] Step 2: Synthesis of (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothien-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)

[0347] (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-4)

[0348]

[0349] At room temperature, lithium hydroxide monohydrate (23.18 mg, 0.552 mmol) was added to a mixed solution of methyl (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate (100 mg, 0.184 mmol) in tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL). The reaction was carried out at room temperature overnight. Then the pH was adjusted to 3 with 1N HCl solution, and the mixture was concentrated. The residue was separated and purified by silica gel plate to obtain a white solid compound (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (62 mg, yield 63.6%).

[0350] LC-MS, M / Z(ESI): 529.2 [M+H] +

[0351] 1 HNMR(400MHz, DMSO-d6) δ 7.50 - 6.80(m, 8H), 5.21(d, 2H), 4.74(s, 1H), 4.40(s, 2H), 2.79(d, 3H), 2.63 - 2.53(m, 1H), 2.37(s, 3H), 2.02 - 1.92(m, 1H), 1.88 - 1.71(m, 3H), 1.65–1.42 (m, 4H).

[0352] Example 5: Preparation of Target Compound I-5

[0353] (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-5)

[0354] (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-5)

[0355]

[0356] The synthetic route of Target Compound I-5 is as follows:

[0357]

[0358] Step 1: Synthesis of tert-butyl isopentylcarbamate (I-5B)

[0359] tert-butyl isopentylcarbamate (I-5B)

[0360]

[0361] At room temperature, 3-methylbutan-1-amine (I-5A) (1 g, 11.47 mmol) was added to 15 mL of dichloromethane, cooled to 0 °C, and di-tert-butyl dicarbonate (0.7 g, 8.03 mmol) was slowly added. After the addition, the reaction was carried out at room temperature overnight. The mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain tert-butyl isopentylcarbamate (I-5B) as a colorless oily compound (1.4 g, yield 65.2%).

[0362] Step 2: Synthesis of tert-butyl isopentyl(methyl)carbamate (I-5C)

[0363] tert-butyl isopentyl(methyl)carbamate (I-5C)

[0364]

[0365] tert-Butyl isopentylcarbamate (I-5B) (1.4 g, 7.48 mmol) was added to 20 mL of tetrahydrofuran, cooled to 0 °C, and sodium hydride (0.359 g, 8.97 mmol, 60% content) was added. The mixture was stirred for 0.5 h, and then iodomethane (1.592 g, 11.21 mmol) was added. The reaction was stirred at room temperature overnight. 1 mL of methanol was added to quench the reaction, and the mixture was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain tert-butyl isopentyl(methyl)carbamate (I-5C) as a colorless oily compound (1.3 g, yield 86%).

[0366] Step 3: Synthesis of N,3-dimethylbutan-1-amine hydrochloride (I-5D)

[0367] N,3-dimethylbutan-1-amine hydrochloride (I-5D)

[0368]

[0369] tert-Butyl isopentyl(methyl)carbamate (I-5C) (1.3 g, 6.46 mmol) was added to a 4 mL solution of 4 M hydrogen chloride in 1,4-dioxane. The mixture was stirred at room temperature for 3 h and concentrated to obtain the white solid compound N,3-dimethylbutan-1-amine hydrochloride (I-5D) (0.89 g, yield 100%).

[0370] Step 4: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5E)

[0371] methyl(1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5E)

[0372]

[0373] Methyl (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3D) (0.2 g, 0.505 mmol) was dissolved in 3 mL of dichloromethane. Pyridine (0.12 g, 1.516 mmol) and 4-nitrophenyl chloroformate (0.15 g, 0.758 mmol) were added, and the mixture was stirred at room temperature for 3 h.

[0374] The mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the light yellow oily compound methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5E) (0.2 g, yield 70.6%).

[0375] Step 5: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5F)

[0376] methyl (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpy ridin-3-yl)oxy)cyclohexane-1-carboxylate

[0377]

[0378] Dissolve methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5E) (0.14 g, 0.250 mmol) and N,3-dimethylbutan-1-amine hydrochloride (026D) (0.103 g, 0.749 mmol) in 4 mL of tetrahydrofuran, then add diisopropylethylamine (0.194 g, 1.50 mmol). Stir at room temperature for 24 h, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5F) as a colorless oily compound (80 mg, yield 60.3%).

[0379] Step 6: Synthesis of (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-5)

[0380] (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-meth ylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-5)

[0381]

[0382] At room temperature, methyl (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5F) (0.08 g, 0.157 mmol) was added to a 2 mL solution of tetrahydrofuran, and then 0.2 mL of water and lithium hydroxide (0.061 g, 2.54 mmol) were added. The reaction was carried out at room temperature for 4 h. The pH was adjusted to acidic with a 1,4-dioxane solution of 4 M hydrogen chloride, concentrated to dryness, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:2) to obtain the white solid compound (1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5) (20 mg, yield 25.7%).

[0383] LC-MS, M / Z(ESI): 509.1[M+H] +

[0384] 1 1H NMR(400 MHz, DMSO-d6) δ 12.18(s, 1H), 7.45 - 7.43(m, 2H), 7.05(s, 1H), 5.16(s, 2H), 4.76(s, 1H), 3.12 - 3.10(m, 2H), 2.77(s, 3H), 2.62 - 2.57(m, 1H), 2.38(s, 3H), 2.00 - 1.21(m, 11H), 0.86 - 0.72(m, 6H).

[0385] Example 6: Preparation of target compound I-6

[0386] (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6)

[0387] (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6)

[0388]

[0389] The synthetic route of the target compound I-6 is as follows:

[0390]

[0391] Step 1: Synthesis of 2-bromo-4-methylpyrimidin-5-ol (I-6B)

[0392] 2-bromo-4-methylpyrimidin-5-ol (I-6B)

[0393]

[0394] At room temperature, 2-chloro-4-methylpyrimidin-5-ol (7 g, 48.42 mmol) was added to hydrogen bromide (104.30 g, 386.72 mmol, 70.00 mL), and then the mixture was stirred at 100 °C for 1 hour. After the reaction solution was cooled to room temperature, it was poured into ice water (100 mL), and then extracted with ethyl acetate (100 mL × 3). The organic layers were combined and concentrated in vacuo to obtain the title compound 2-bromo-4-methylpyrimidin-5-ol (I-6B) (8.5 g, yield 92.87%). It was directly used for the next step.

[0395] Step 2: Synthesis of methyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6C)

[0396] methyl(1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6C)

[0397]

[0398] Under nitrogen protection at 0 °C, diisopropyl azodicarboxylate (10.70 g, 52.91 mmol) was added to a solution of 2-bromo-4-methylpyrimidin-5-ol (5 g, 26.45 mmol), methyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (8.37 g, 52.91 mmol) and triphenylphosphine (13.88 g, 52.91 mmol) in tetrahydrofuran (50 mL). Then the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. It was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 - 1:1) to obtain the title compound methyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6C) (6 g, 18.23 mmol, yield 68.90%).

[0399] Step 3: Synthesis of methyl (1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6E)

[0400] methyl(1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-ca rboxylate(I-6E)

[0401]

[0402] At room temperature, (3-formylthiophen-2-yl)boronic acid (2.13 g, 13.67 mmol), methyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (3 g, 9.11 mmol), bis(tri-tert-butylphosphine)palladium (400 mg, 782.70 μmol), and potassium fluoride (3.18 g, 54.68 mmol) were added to a solution of tetrahydrofuran (50 mL). Nitrogen was displaced three times, and then the mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1 - 5:1) to obtain the title compound methyl (1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6E) (2.5 g, yield 76.11%).

[0403] Step 4: Synthesis of methyl (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6F)

[0404] methyl(1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohe xane-1-carboxylate(I-6F)

[0405]

[0406] At room temperature, N-chlorosuccinimide (1.12 g, 8.42 mmol) was added to a solution of methyl (1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (2.76 g, 7.66 mmol) in N,N-dimethylformamide (20 mL). Then the reaction mixture was stirred at 40 °C for 1 hour. The reaction mixture was extracted with ethyl acetate (25 mL×3), and the organic layers were combined to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 15:1 - 1:1) to give methyl (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6F) (2.3 g, yield 76.06%).

[0407] LC-MS, M / Z(ESI): 395.0[M+H] + 。

[0408] Step 5: Synthesis of methyl (1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6G)

[0409] methyl(1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)ox y)cyclohexane-1-carboxylate(I-6G)

[0410]

[0411] At 0 °C, sodium borohydride (95.81 mg, 2.53 mmol) was added portionwise to a solution of methyl (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6F) (1 g, 2.53 mmol) in methanol (2 mL). The mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was quenched with 1 M hydrochloric acid (5 mL), extracted with ethyl acetate (10 mL×2), concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 15:1 - 1:1) to give methyl (1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6G) (0.5 g crude product).

[0412] Step 6: Synthesis of methyl (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6H)

[0413] methyl(1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4- methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6H)

[0414]

[0415] At room temperature, pyridine (398.60 mg, 5.04 mmol) was added to a solution of methyl (1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (0.4 g, 1.01 mmol) and phenyl 4-nitrochloroformate (43 mg, 3.02 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with dichloromethane (10 mL × 2), and concentrated under reduced pressure to give methyl (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6H) (0.45 g, yield 44.8%).

[0416] Step 7: Synthesis of methyl (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6I)

[0417] methyl(1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-y l)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6I)

[0418]

[0419] At room temperature, to a solution of methyl (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (0.4 g, 711.76 μmol) and N-methylcyclopentanamine hydrochloride (96.54 mg, 711.76 μmol) in tetrahydrofuran (5 mL), N,N-diisopropylethylamine (275.97 mg, 2.14 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), and concentrated under reduced pressure to obtain the title compound methyl (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6I) (0.3 g, yield 80.7%).

[0420] Step 8: Synthesis of (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-6)

[0421] (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-6)

[0422]

[0423] At room temperature, to a solution of methyl (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (0.3 g, 574.65 μmol) in tetrahydrofuran (2 mL), 1 M aqueous lithium hydroxide solution (2.87 mL, 2.87 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH = 7 with saturated aqueous citric acid, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3) and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative chromatography (separation method: Phenomenex luna C18 150*25mm*10μm column; mobile phase: A = water + 0.225% by volume formic acid (99%), B = acetonitrile; gradient: 75% - 100% B, 10 minutes) to obtain the white solid compound (1S,3S)-3-((2-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6) (0.029 g, yield 9.9%).

[0424] LC-MS, M / Z(ESI): 508.3[M+H] + 。

[0425] 1 H NMR(400MHz,CDCl3)δ8.20(s,1H),6.95(s,1H),5.63(s,2H),4.73(s,1H),4.57(s,1H),2.87(m,1H),2.83(s,3H),2.47(s,3H),2.14(m,1H),1.90 - 2.05(m,3H),1.82(m,2H),1.45 - 1.75(m,10H).

[0426] Example 7: Preparation of Target Compound I-7

[0427] (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-7)

[0428] (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-7)

[0429]

[0430] The synthetic route of Target Compound I-7 is as follows:

[0431]

[0432] The First Step: Synthesis of tert-butyl (cyclobutylmethyl)carbamate (I-7B)

[0433] tert-butyl(cyclobutylmethyl)carbamate(I-7B)

[0434]

[0435] At room temperature, cyclobutylmethylamine hydrochloride (1 g, 8.22 mmol) and triethylamine (2.08 g, 20.56 mmol) were added to 15 mL of dichloromethane, cooled to 0 °C, and di-tert-butyl dicarbonate (1.795 g, 8.22 mmol) was slowly added. After the addition, the reaction was carried out overnight at room temperature, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the colorless oily compound tert-butyl(cyclobutylmethyl)carbamate (I-7B) (1.27 g, yield 83%).

[0436] The Second Step: Synthesis of tert-butyl(cyclobutylmethyl)(methyl)carbamate (I-7C)

[0437] tert-butyl(cyclobutylmethyl)(methyl)carbamate(I-7C)

[0438]

[0439] tert-Butyl (cyclobutylmethyl)carbamate (I-7B) (1.27 g, 6.86 mmol) was added to 20 mL of tetrahydrofuran, cooled to 0 °C, sodium hydride (60% content, 0.329 g, 8.23 mmol) was added, and the mixture was stirred for 0.5 h. Iodomethane (1.46 g, 10.28 mmol) was added, and the reaction was stirred at room temperature overnight. 5 mL of methanol was added to quench the reaction, and the mixture was concentrated. The residue was separated and purified by silica gel column chromatography to obtain colorless oily compound tert-butyl (cyclobutylmethyl)(methyl)carbamate (I-7C) (0.33 g, yield 24.16%).

[0440] Step 3: Synthesis of 1-cyclobutyl-N-methylmethanamine hydrochloride (I-7D)

[0441] 1-cyclobutyl-N-methylmethanamine hydrochloride(I-7D)

[0442]

[0443] tert-Butyl (cyclobutylmethyl)(methyl)carbamate (0.33 g, 1.656 mmol) was added to 4 mL of a 4 mol / L solution of hydrogen chloride in 1,4-dioxane, and the mixture was stirred at room temperature for 3 h and then concentrated to obtain white solid 1-cyclobutyl-N-methylmethanamine hydrochloride (I-7D) (0.2 g, yield 89.5%).

[0444] Step 4: Synthesis of methyl (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-7E)

[0445] methyl(1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-7E)

[0446]

[0447] (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (0.2 g, 0.356 mmol) (I-6H), 1-cyclobutyl-N-methylmethanamine hydrochloride (0.121 g, 0.890 mmol) were dissolved in 10 mL of tetrahydrofuran, then N,N-diisopropylethylamine (0.184 g, 1.424 mmol) was added, and the mixture was stirred at room temperature overnight, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the yellow solid compound (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-7E) (100 mg, yield 53.8%).

[0448] Step 5: Synthesis of (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-7)

[0449] (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-7)

[0450]

[0451] At room temperature, (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (100 mg, 0.192 mmol) was added to a solution of 3 mL of tetrahydrofuran, then 1 mL of water and 1 mL of methanol were added, and then lithium hydroxide monohydrate (16.08 mg, 0.383 mmol) was added. The reaction was carried out at room temperature overnight, and the pH was adjusted to 3 with a 1M hydrochloric acid 1,4-dioxane solution, concentrated to dryness, and the residue was separated and purified by silica gel plate chromatography to obtain the white solid compound (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-7) (10.2 mg, yield 10.48%).

[0452] LC-MS, M / Z (ESI): 508.2 [M+H] +

[0453] 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 6.94 (s, 1H), 5.60 (s, 2H), 4.72 (s, 1H), 3.40–3.25 (m, 2H), 2.91 (s, 3H), 2.89–2.81 (m, 1H), 2.64–2.52 (m, 1H), 2.46 (s, 3H), 2.20–2.10 (m, 1H), 2.05–1.95 (m, 4H), 1.93–1.80 (dd, 3H), 1.77–1.60 (m, 6H).

[0454] Example 8: Preparation of Target Compound I-8

[0455] (1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-8)

[0456] (1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-8)

[0457]

[0458] The synthetic route of the target compound I-8 is as follows:

[0459]

[0460] The first step: Synthesis of methyl (1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-8A)

[0461] methyl(1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4- methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-8A)

[0462]

[0463] Dissolve methyl (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6H) (0.2 g, 0.356 mmol) and N-methyl-1-phenylmethanamine (0.108 g, 0.890 mmol) in 4 mL of tetrahydrofuran, then add N,N-diisopropylethylamine (0.184 g, 1.424 mmol), stir at room temperature for 24 h. TLC (PE:EA = 5:1) shows that the raw materials have reacted completely. Concentrate the solution, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the colorless oily compound methyl (1S,3S)-3-((2-(3-(((benzyl(methyl)aminocarbonyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-8A) (100 mg, yield 51.6%).

[0464] Step 2: Synthesis of (1S,3S)-3-((2-(3-(((benzyl(methyl)aminocarbonyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8)

[0465] (1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylicacid(target compound I-8)

[0466]

[0467] At room temperature, methyl (1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-8A) (0.1 g, 0.184 mmol) was added to a 2 mL solution of tetrahydrofuran, and then 0.2 mL of water and lithium hydroxide monohydrate (0.061 g, 2.54 mmol) were added. The reaction was carried out at room temperature for 4 h. The pH was adjusted to acidic with a 1,4-dioxane solution of 1 M hydrogen chloride, concentrated to dryness, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:2) to obtain the white solid compound (1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8) (50 mg, yield 51.3%).

[0468] LC-MS, M / Z(ESI): 530.2[M+H] +

[0469] 1 H NMR(400 MHz, DMSO-d6) δ 12.20(s, 1H), 8.46(s, 1H), 7.33 - 7.11(m, 5H), 6.81(s, 1H), 5.53 - 5.50(d, 2H), 4.86(s, 1H), 4.43(s, 2H), 2.83(s, 3H), 2.63 - 2.61(m, 1H), 2.39 - 2.38(d, 3H), 2.01 - 1.476(m, 8H).

[0470] Example 9: Preparation of target compound I-9

[0471] (1S,3S)-3-((2-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-9)

[0472] (1S,3S)-3-((2-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2 -yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-9)

[0473]

[0474] The synthetic method refers to the synthesis of compound I-7 in Example 7, with the starting material cyclobutylmethylamine hydrochloride replaced by 2-cyclopropyleth-1-amine hydrochloride.

[0475] LC-MS, M / Z(ESI): 508.2[M+H] +

[0476] 1 H NMR(400 MHz, CDCl3) δ 8.18(s, 1H), 6.97(s, 1H), 5.61(s, 2H), 4.72(s, 1H), 3.45–3.30(m, 2H), 2.96(s, 3H), 2.90–2.81(m, 1H), 2.47(s, 3H), 2.18–2.11(m, 1H), 2.04–1.94(m, 3H), 1.74–1.64(m, 4H), 1.44(d, 2H), 0.70–0.55(m, 1H), 0.48–0.39(m, 2H), 0.10–0.02(m, 2H).

[0477] Example 10: Preparation of the target compound I-10

[0478] (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)

[0479] (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)

[0480]

[0481] The synthetic route of the target compound I-10 is as follows:

[0482]

[0483] The first step: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-10B)

[0484] methyl(1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-10B)

[0485]

[0486] At room temperature, N,N-diisopropylethylamine (195.59 mg, 1.51 mmol) was added to a solution of methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.283 g, 504.45 μmol) and N-methylcyclopentylamine hydrochloride (68.42 mg, 504.45 μmol) in tetrahydrofuran (5 mL), and then the mixture was stirred for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain the title compound methyl (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-10B) (0.262 g, yield 99.7%). It was directly used for the next reaction.

[0487] Step 3: Synthesis of (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-10)

[0488] (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

[0489]

[0490] At room temperature, an aqueous solution of lithium hydroxide (1 M, 2.49 mL) was added to a solution of methyl (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.26 g, 498.98 μmol) in tetrahydrofuran (5 mL), and then the mixture was stirred at room temperature for 2 hours. After adjusting the pH of the reaction solution to neutral with citric acid, it was extracted with ethyl acetate (10 mL × 2). The organic layers were combined to obtain the crude product. Purification using a silica gel plate gave (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10) (0.066 g, yield 26.1%).

[0491] LC-MS, M / Z(ESI): 507.2[M+H] + 。

[0492] 1 H NMR(400 MHz, DMSO-d6) δ 7.49 - 7.45(m, 1H), 7.44 - 7.39(m, 1H), 7.10(s, 1H), 5.18 (s, 2H), 4.79(br s, 1H), 4.48 - 4.15(m, 1H), 2.69(s, 3H), 2.64 - 2.56(m, 1H), 2.39(s, 3H), 2.00(br d, 1H), 1.90 - 1.72(m, 3H), 1.69 - 1.56(m, 6H), 1.55 - 1.37(m, 6H).

[0493] Example 11: Preparation of target compound I-11

[0494] (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic acid (target compound I-11)

[0495] (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-flu orophenoxy)cyclohexane-1-carboxylic acid (target compound I-11)

[0496]

[0497] The synthetic route of the target compound I-11 is as follows:

[0498]

[0499] The first step: Synthesis of 4-nitrophenyl cyclopentyl(methyl)carbamate (I-11A)

[0500] 4-nitrophenyl cyclopentyl(methyl)carbamate (I-11A)

[0501]

[0502] DIEA (4.75 mL, 27.2 mmol) was added dropwise to a solution of 4-nitrophenyl chloroformate (3.9 g, 19.4 mmol) and N-methylcyclopentylamine hydrochloride (3.95 g, 29.1 mmol) in THF (30 mL), and the reaction was carried out overnight at room temperature. After the raw materials were reacted completely, distilled water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain 4-nitrophenyl cyclopentyl(methyl)carbamate (I-11A) as a yellow oil (3.0 g, yield 58.7%).

[0503] The second step: Synthesis of methyl(1S,3S)-3-(4-bromo-2-fluorophenoxy)cyclohexane-1-carboxylate (I-11C)

[0504] methyl(1S,3S)-3-(4-bromo-2-fluorophenoxy)cyclohexane-1-carboxylate (I-11C)

[0505]

[0506] At 0 °C, 4-bromo-2-fluorophenol (5 g, 26.18 mmol) and methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate (8.28 g, 52.36 mmol) were added to tetrahydrofuran (50 mL), and then diisopropyl azodicarboxylate (10.59 g, 52.36 mmol) and triphenylphosphine (13.73 g, 52.36 mmol) were added successively. Then the mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 40:1 - 5:1) to obtain methyl(1S,3S)-3-(4-bromo-2-fluorophenoxy)cyclohexane-1-carboxylate (I-11C) as a yellow oil (4.5 g, yield 51.9%).

[0507] Step 3: Synthesis of (1S,3S)-3-(2-fluoro-4-(3-formylthiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester (I-11D)

[0508] methyl(1S,3S)-3-(2-fluoro-4-(3-formylthiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (I-11D)

[0509]

[0510] Under nitrogen protection, (1S,3S)-3-(4-bromo-2-fluorophenoxy)cyclohexane-1-carboxylic acid methyl ester (500 mg, 1.51 mmol), 3-formyl-2-thiopheneboronic acid (353.21 mg, 2.26 mmol) and potassium fluoride (526.28 mg, 9.06 mmol) were added to tetrahydrofuran (10 mL), and then bis(tri-tert-butylphosphine)palladium(0) (60 mg, 117.40 umol) was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (15 mL×3), and the organic layers were combined to obtain a crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V)=1:0-20:1) to obtain a yellow oily compound (1S,3S)-3-(2-fluoro-4-(3-formylthiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester (I-11D) (420 mg, yield 76.7%).

[0511] Step 4: Synthesis of (1S,3S)-3-(2-fluoro-4-(3-(hydroxymethyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester (I-11E)

[0512] methyl(1S,3S)-3-(2-fluoro-4-(3-(hydroxymethyl)thiophen-2-yl)phenoxy)cyclohexane-1-carb oxylate(I-11E)

[0513]

[0514] At 0 °C, sodium borohydride (65.77 mg, 1.74 mmol) was added to a solution of methyl (1S,3S)-3-(2-fluoro-4-(3-formylthiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (420 mg, 1.16 mmol) in methanol (5 mL), and then the mixture was stirred at 0 °C for half an hour. The reaction mixture was quenched with water (10 mL), and then extracted with ethyl acetate (15 mL × 2). The combined organic layers gave the crude product methyl (1S,3S)-3-(2-fluoro-4-(3-(hydroxymethyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (I-11E) (420 mg, yield 99.5%). It was directly used for the next reaction.

[0515] Step 5: Synthesis of methyl (1S,3S)-3-(4-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylate (I-11F)

[0516] methyl(1S,3S)-3-(4-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexa ne-1-carboxylate(I-11F)

[0517]

[0518] At room temperature, methyl (1S,3S)-3-(2-fluoro-4-(3-(hydroxymethyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (420 mg, 1.15 mmol) was added to N,N-dimethylformamide (5 mL), then N-chlorosuccinimide (169.28 mg, 1.27 mmol) was added, and then the mixture was stirred at 45 °C for 10 hours. The reaction mixture was diluted with water (20 mL), and then extracted with ethyl acetate (15 mL × 3). The combined organic layers gave the crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:0 - 20:1) to obtain the yellow oily compound methyl (1S,3S)-3-(4-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylate (I-11F) (350 mg, yield 76.1%).

[0519] Step 6: Synthesis of methyl (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylate (I-11G)

[0520] methyl(1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) -2-fluorophenoxy)cyclohexane-1-carboxylate(I-11G)

[0521]

[0522] At 0 °C, sodium hydride (22.56 mg, 564.09 μmol, 60% content) was added to a solution of methyl (1S,3S)-3-(4-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylate (150 mg, 376.06 μmol) in tetrahydrofuran (5 mL), and the mixture was stirred at 0 °C for half an hour. Then 4-nitrophenyl cyclopentyl(methyl)carbamate (99.38 mg, 376.06 μmol) was added, and the reaction was stirred at 15 °C for 10 hours. The reaction mixture was quenched with aqueous ammonium chloride solution (2 mL) and water (20 mL), and then extracted with ethyl acetate (15 mL × 3). The combined organic layers gave crude methyl (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylate (I-11G) (197 mg, crude). It was used directly for the next reaction.

[0523] Step 7: Synthesis of (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic acid (target compound I-11)

[0524] (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-flu orophenoxy)cyclohexane-1-carboxylic acid (target compound I-11)

[0525]

[0526] At room temperature, methyl (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylate (197 mg, 375.92 μmol) and lithium hydroxide monohydrate (200 mg, 4.77 mmol) were added to tetrahydrofuran (2 mL), and then stirred at room temperature for 10 hours. The reaction mixture was diluted with water (20 mL), then adjusted to pH = 3 with saturated aqueous citric acid, and then extracted with ethyl acetate (15 mL × 3). The combined organic layers were obtained as a crude product, which was separated and purified by silica gel plate to obtain a grayish-white solid (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic acid (target compound I-11) (69.01 mg, yield 35.7%).

[0527] 1 H NMR(400MHz,CDCl3)δ7.20(dd,1H),7.15-7.08(m,1H),7.07-7.01(m,1H),6.99(s, 1H),5.00(s,2H),4.69(br s,1H),4.61-4.16(m,1H),3.04-2.88(m,1H),2.79(s,3H),2.19(br d,1H),2.06-1.78(m,4H),1.70-1.45(m,11H).

[0528] LC-MS,M / Z(ESI):532.1[M+Na] + 。

[0529] Example 12: Preparation of target compound I-12

[0530] (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-12)

[0531] (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-12)

[0532]

[0533] The synthetic route of the target compound I-12 is as follows:

[0534]

[0535] The first step: Synthesis of methyl (1S,3S)-3-((5-bromo-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12B)

[0536] methyl(1S,3S)-3-((5-bromo-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-12B)

[0537]

[0538] Under nitrogen protection, a mixture of 5-bromo-3-methylpyrazin-2-ol (1.5 g, 7.94 mmol), methyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (2.51 g, 15.87 mmol) and triphenylphosphine (4.16 g, 15.87 mmol) in tetrahydrofuran (30 mL) was cooled to 0 °C, and diisopropyl azodicarboxylate (3.21 g, 15.87 mmol) was slowly added. Then it was slowly warmed to room temperature and stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:1 - 10:1) to obtain the title compound methyl (1S,3S)-3-((5-bromo-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12B) (2.5 g, yield 95.7%).

[0539] The second step: Synthesis of methyl (1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12C)

[0540] methyl(1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carb oxylate(I-12C)

[0541]

[0542] Under nitrogen protection, a mixed solution of (1S,3S)-3-((5-bromo-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (2.2 g, 6.68 mmol), (3-formylthiophen-2-yl)boric acid (1.56 g, 10.02 mmol), potassium fluoride (2.33 g, 40.10 mmol), bis(tri-tert-butylphosphine)palladium (273.23 mg, 534.65 μmol) and tetrahydrofuran (50 mL) was stirred at room temperature for 10 hours. After cooling to room temperature, the reaction mixture was concentrated to give a crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 100:1-50:1) to give the title compound (1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-12C) (2 g, yield 83.0%).

[0543] Step 3: Synthesis of (1S,3S)-3-((5-(3-(hydroxymethyl)thiophene-2-yl)-3-methylpyrazine-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-12D)

[0544] methyl(1S,3S)-3-((5-(3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohex ane-1-carboxylate(I-12D)

[0545]

[0546] At 0°C, sodium borohydride (209.93 mg, 5.55 mmol) was added in portions to a solution of (1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (2 g, 5.55 mmol) in methanol (10 mL), and the mixture was stirred at 0°C for 0.5 hours. After the reaction was completed, the reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phases were combined and concentrated to obtain the title compound (1S,3S)-3-((5-(3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-12D) (2.5 g, crude product).

[0547] Step 4: Synthesis of (1S,3S)-3-((5-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-12E)

[0548] methyl(1S,3S)-3-((5-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy) cyclohexane-1-carboxylate(I-12E)

[0549]

[0550] At room temperature, N-chlorosuccinimide (1.11 g, 8.28 mmol) was added to a solution of methyl (1S,3S)-3-((5-(3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (2 g, 5.52 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at 45 °C for 10 hours. After the reaction was complete, the reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL × 2). The crude product was obtained by distillation under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:0 - 1:1) to give methyl (1S,3S)-3-((5-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12E) (1.8 g, yield 82.2%).

[0551] Step 5: Synthesis of methyl (1S,3S)-3-((5-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12F)

[0552] methyl(1S,3S)-3-((5-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-3- methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-12F)

[0553]

[0554] At room temperature, to a solution of methyl (1S,3S)-3-((5-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (0.2 g, 503.92 μmol) and triethylamine (152.97 mg, 1.51 mmol) in dichloromethane (10 mL), phenyl 4-nitrochloroformate (111.73 mg, 554.31 μmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined and concentrated under reduced pressure to obtain methyl (1S,3S)-3-((5-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12F) (0.28 g, yield 98.9%).

[0555] Step 6: Synthesis of methyl (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12G)

[0556] methyl(1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) -3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-12G)

[0557]

[0558] At room temperature, to a solution of methyl (1S,3S)-3-((5-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (0.2 g, 355.88 μmol) in tetrahydrofuran (10 mL), N,N-diisopropylethylamine (137.98 mg, 1.07 mmol) and cyclopentylmethylamine hydrochloride (48.27 mg, 358.6 μmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to dryness to obtain methyl (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12G) (0.2 g, crude product).

[0559] Step 7: Synthesis of (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-12)

[0560] (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-met hylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-12)

[0561]

[0562] At room temperature, to a solution of methyl (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (0.2 g, 383.10 μmol) in tetrahydrofuran (5 mL) was added 1 M lithium hydroxide solution (536.34 μL), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the pH of the reaction mixture was adjusted to 6 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a crude product, which was separated by silica gel plate chromatography to give (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-12) (0.058 g, yield 29.6%).

[0563] LC-MS, M / Z (ESI): 508.2 [M+H] +

[0564] 1 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H) 7.15 (s, 1H) 5.36 (s, 1H) 5.18 (s, 2H), 4.04 - 4.60 (m, 1H) 2.67 (s, 3H) 2.42 (s, 4H) 1.71 - 1.86 (m, 2H) 1.52 - 1.69 (m, 8H) 1.35 - 1.51 (m, 6H).

[0565] Example 13: Preparation of Target Compound I-13

[0566] (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-13)

[0567] (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-13)

[0568]

[0569] The synthetic route of Target Compound I-13 is as follows:

[0570]

[0571] The first step: Synthesis of tert-butyl dimethyl(thiophen-3-ylmethoxy)silane (I-13A)

[0572] tert-butyl dimethyl(thiophen-3-ylmethoxy)silane (I-13A)

[0573]

[0574] At room temperature, thiophene-3-ylmethanol (10 g, 87.59 mmol) and tert-butyl dimethylchlorosilane (15.84 g, 105.11 mmol, 12.88 mL) were dissolved in N,N-dimethylformamide (200 mL), then triethylamine (17.73 g, 175.18 mmol, 24.38 mL) was added, and then the mixture was stirred at 60 °C for 3 hours. After the reaction solution was cooled to room temperature, it was poured into ice water (400 mL), then extracted with ethyl acetate (200 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1 - 5:1) to obtain the title compound tert-butyl dimethyl(thiophen-3-ylmethoxy)silane (I-13A) (16 g, yield 79.9%).

[0575] The second step: Synthesis of (5-fluorothiophen-3-yl)methanol (I-13B)

[0576] (5-fluorothiophen-3-yl)methanol (I-13B)

[0577]

[0578] Dissolve tert-butyl dimethyl(thiophen-3-ylmethoxy)silane(16 g, 70.04 mmol) in tetrahydrofuran(200 mL), cool to -78 °C, and slowly add sec-butyllithium(1.3 M, 70.72 mL) under nitrogen protection. After the addition, continue stirring for 30 minutes. Then add N-fluorobenzenesulfonimide(21.26 g, 67.42 mmol), continue stirring at -78 °C for 1 hour, then raise the temperature to room temperature and stir for 1 hour. Quench the reaction with water(100 mL), extract twice with ethyl acetate(100 mL), combine the organic phases, and concentrate to obtain the crude product. Dissolve the crude product in tetrahydrofuran(200 mL), add 1 M tetrabutylammonium fluoride in tetrahydrofuran solution(70 mL), and stir overnight at room temperature. Concentrate the reaction solution to obtain the crude product, and purify by silica gel column chromatography(petroleum ether:ethyl acetate(V / V)=10:1 - 2:1) to obtain the title compound(5-fluorothiophen-3-yl)methanol(I-13B)(3.5 g, yield 37.8%).

[0579] Step 3: Synthesis of (2-bromo-5-fluorothiophen-3-yl)methanol(I-13C)

[0580] (2-bromo-5-fluorothiophen-3-yl)methanol(I-13C)

[0581]

[0582] Dissolve (5-fluorothiophen-3-yl)methanol(3 g, 22.70 mmol) in N,N-dimethylformamide(30 mL), cool to 0 °C, add N-bromosuccinimide(4.04 g, 22.70 mmol), and stir at room temperature for 10 hours. Pour the reaction solution into water(50 mL), then extract with ethyl acetate(50 mL×2), combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Concentrate under reduced pressure to obtain the crude product. Purify by silica gel column chromatography(petroleum ether:ethyl acetate(V / V)=20:1 - 1:1) to obtain the title compound(2-bromo-5-fluorothiophen-3-yl)methanol(I-13C)(4 g, yield 83.5%).

[0583] Step 4: Synthesis of (2-bromo-5-fluorothiophen-3-yl)methyl cyclopentyl(methyl)carbamate(I-13D)

[0584] (2-bromo-5-fluorothiophen-3-yl)methyl cyclopentyl(methyl)carbamate(I-13D)

[0585]

[0586] (2-Bromo-5-fluorothiophen-3-yl)methanol (0.5 g, 2.37 mmol) and 4-nitrophenylcyclopentyl (methyl) carbamate (I-11A) (626.09 mg, 2.37 mmol) were dissolved in N,N-dimethylformamide (10 mL). Potassium bis(trimethylsilyl)amide (1 M, 2.40 mL) was added dropwise at 15°C, and the reaction solution was stirred at 15°C for 1 hour. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic layers were combined to obtain a crude product. The product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 50:1-10:1) to obtain (2-bromo-5-fluorothiophen-3-yl) methylcyclopentyl (methyl) carbamate (I-13D) (0.5 g, yield 62.8%).

[0587] Step 5: Synthesis of (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-13E)

[0588] methyl(1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-13E)

[0589]

[0590] Under a nitrogen atmosphere, (2-bromo-5-fluorothiophen-3-yl)methyl cyclopentyl(methyl)carbamate (320 mg, 951.76 μmol), methyl (1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (768.57 mg, 1.43 mmol) and palladium tetrakis(triphenylphosphine) (109.98 mg, 95.18 μmol) were added to a flask, and 1,4-dioxane (10 mL) was added thereto. The mixture was heated to 100 °C and stirred for 4 hours, then cooled and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1 - 5:1) to obtain methyl (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-13E) (200 mg, yield 41.6%).

[0591] Step 6: Synthesis of (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-13)

[0592] (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-13)

[0593]

[0594] At room temperature, lithium hydroxide monohydrate (83.16 mg, 1.98 mmol) was added to a mixture of methyl (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (6) (200 mg, 396.34 μmol) in methanol (5 mL) and water (1 mL). The mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated, adjusted to pH = 3 - 4 with 1 M hydrochloric acid solution, extracted with ethyl acetate (10 mL × 2), and the organic layers were combined to obtain a crude product. The crude product was purified by preparative separation (column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: A = water + 0.225 vol% formic acid (99%), B = acetonitrile; gradient elution: 60% - 80% B, 7 minutes) to obtain (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-13) (35.83 mg, yield 18.4%).

[0595] LC-MS, M / Z(ESI): 491.2[M+H] + 。

[0596] 1 H NMR(400MHz,CDCl3)δ7.24 - 7.52(m,2H),6.42 - 6.57(m,1H),5.15 - 5.30(m,1H),4.97 - 5.12(m,1H),4.60 - 4.82(m,1H),4.28 - 4.54(m,1H),2.83 - 2.95(m,1H),2.68 - 2.78(m,3H),2.54 - 2.67(m,3H),2.07 - 2.18(m,1H),1.81 - 1.96(m,3H),1.43 - 1.79(m,12H).

[0597] Example 14: Preparation of Target Compound I-14

[0598] (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-14)

[0599] (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thioph en-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-14)

[0600]

[0601] The synthetic route of Target Compound I-14 is as follows:

[0602]

[0603] Step 1: Synthesis of tert-butyl (R)-(1-cyclopropylethyl)carbamate (I-14B)

[0604] tert-butyl (R)-(1-cyclopropylethyl)carbamate (I-14B)

[0605]

[0606] At room temperature, di-tert-butyl dicarbonate (718 mg, 3.28 mmol) was added to a solution of (R)-1-cyclopropylethylamine hydrochloride (400 mg, 3.28 mmol) and triethylamine (732 mg, 7.24 mmol) in dichloromethane (8 mL), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10.0 mL), and the organic phase was washed with water (10.0 mL) and saturated sodium chloride aqueous solution (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain tert-butyl (R)-(1-cyclopropylethyl)carbamate (I-14B) (500 mg, crude product). The crude product was directly used in the next step.

[0607] Step 2: Synthesis of tert-butyl (R)-(1-cyclopropylethyl)(methyl)carbamate (I-14C)

[0608] tert-butyl (R)-(1-cyclopropylethyl)(methyl)carbamate (I-14C)

[0609]

[0610] At 0 °C, to a solution of sodium hydride (172 mg, 4.32 mmol, 60% content) in tetrahydrofuran (3.00 mL), (R)-(tert-butyl (1-cyclopropylethyl)carbamate) (400 mg, 2.16 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. Then, at 0 °C, a solution of methyl iodide (459 mg, 3.24 mmol) in tetrahydrofuran (3.00 mL) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was warmed to 25 °C and stirred for 1 hour. After the reaction was completed, ice water was added dropwise to quench the reaction. After quenching was complete, the mixture was extracted with ethyl acetate (5.00 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-(tert-butyl (1-cyclopropylethyl)(methyl)carbamate) (I-14C) (400 mg, crude product). The crude product was directly used in the next step.

[0611] Step 3: Synthesis of (R)-1-cyclopropyl-N-methylethanamine hydrochloride (I-14D)

[0612] (R)-1-cyclopropyl-N-methylethanamine hydrochloride (I-14D)

[0613]

[0614] At 0 °C, a solution of hydrogen chloride in 1,4-dioxane (4 M, 2.00 mL) was slowly added dropwise to a solution of (R)-(tert-butyl (1-cyclopropylethyl)(methyl)carbamate) (400 mg, 2.01 mmol) in dichloromethane (4.00 mL). After the addition was complete, the reaction mixture was warmed to 25 °C and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated to obtain (R)-1-cyclopropyl-N-methylethanamine hydrochloride (I-14D) (300 mg, crude product). The crude product was directly used in the next step.

[0615] Step 4: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-14E)

[0616] methyl(1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-14E)

[0617]

[0618] At room temperature, DIEA (201.58 mg, 1.56 mmol) was added to a solution of methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (350 mg, 623 μmol) and (R)-1-cyclopropyl-N-methylethanamine hydrochloride (169 mg, 1.25 mmol) in tetrahydrofuran (5.00 mL), and the mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate (V:V) = 20:1 - 3:1) to give the target product methyl (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (7) (300 mg, yield 84.4%).

[0619] Step 5: Synthesis of (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-14)

[0620] (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-14)

[0621]

[0622] At room temperature, lithium hydroxide monohydrate (201 mg, 4.80 mmol) was added to a mixture of methyl (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (250 mg, 479 μmol) in methanol (3.00 mL) and water (1.00 mL), and the mixture was stirred at 25 °C for 12 hours. After completion of the reaction, the reaction mixture was concentrated to obtain a crude product. The crude product was separated by preparative separation (separation method: column: Phenomenex Luna C 18 150*25mm*10μm; mobile phase: solvent: A = water + 0.225% by volume formic acid (99%), B = acetonitrile; gradient elution: 63% - 93% B, 10 minutes) to obtain the target product (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-14) (73.6 mg, yield 29.7%).

[0623] LC-MS, M / Z (ESI): 507.3 [M+H] +

[0624] 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (br s, 1H), 7.50 - 7.45 (m, 1H), 7.43 - 7.37 (m, 1H), 7.07 (m, 1H), 5.23 - 5.11 (m, 2H), 4.79 (s, 1H), 3.17 (m, 1H), 2.78 (s, 3H), 2.69 - 2.60 (m, 1H), 2.40 (s, 3H), 2.00 (m, 1H), 1.92 - 1.71 (m, 3H), 1.67 - 1.42 (m, 4H), 1.10 (m, 3H), 0.94 (br s, 1H), 0.52 - 0.05 (m, 4H).

[0625] Example 15: Preparation of target compound I-15

[0626] (1S,3S)-3-((6-(5-chloro-3-(((((S)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-15)

[0627] (1S,3S)-3-((6-(5-chloro-3-(((((S)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thioph en-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-15)

[0628]

[0629] For the synthetic method of Target Compound I-15, refer to Compound I-14 and replace (R)-1-cyclopropylethylamine hydrochloride with (S)-1-cyclopropylethylamine hydrochloride.

[0630] LC-MS, M / Z(ESI): 507.3 [M+H] +

[0631] 1 H NMR(400MHz, DMSO-d6) δ12.21(br s, 1H), 7.49 - 7.44(m, 1H), 7.43 - 7.36(m, 1H), 7.07(m, 1H), 5.23 - 5.10(m, 2H), 4.79(br s, 1H), 3.17(m, 1H), 2.78(s, 3H), 2.66 - 2.57(m, 1H), 2.40(s, 3H), 2.08 - 1.95(m, 1H), 1.92 - 1.71(m, 3H), 1.68 - 1.42(m, 4H), 1.09(m, 3H), 0.94(br s, 1H), 0.52 - 0.05(m, 4H).

[0632] Example 16: Preparation of Target Compound I-16

[0633] (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-16)

[0634] (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyri din-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-16)

[0635]

[0636] The synthetic route of the target compound I-16 is as follows:

[0637]

[0638] Step 1: Synthesis of methyl(1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-met hylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-16A)

[0639] methyl(1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-met hylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-16A)

[0640]

[0641] At room temperature, to a solution of methyl(1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (0.283 g, 504.45 μmol, crude product) and cyclopentylamine (42.95 mg, 504.45 μmol) in tetrahydrofuran (5 mL), N,N-diisopropylethylamine (195.59 mg, 1.51 mmol) was added. The mixture was stirred at room temperature for 8 hours, and the reaction was concentrated under reduced pressure to obtain methyl(1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-16A) (0.26 g, crude product). The crude product was directly used in the next step.

[0642] Step 2: Synthesis of (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-16)

[0643] (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-16)

[0644]

[0645] At room temperature, to a mixed solution of methyl (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (3) (0.26 g, 512.78 μmol, crude) in water (5 mL) and tetrahydrofuran (5 mL), lithium hydroxide monohydrate (107.59 mg, 2.56 mmol) was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was adjusted to pH = 3 - 4 with 1 M hydrochloric acid solution, and then concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative separation (separation method: column: Phenomenex luna C18 150*25 mm*10 μm; solvent: A = water + 0.225 vol% formic acid (99%), B = acetonitrile; gradient: 55% - 85% B, 10 minutes) to obtain the white solid compound (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-16) (88.41 mg, yield 34.97%).

[0646] LC-MS, M / Z(ESI): 493.3 [M+H] + 。

[0647] 1 H NMR(400 MHz, CDCl3) δ 7.19 - 7.23(m, 1H), 7.02 - 7.08(m, 1H), 6.86 - 6.90(m, 1H), 5.13(s, 2H), 4.54 - 4.72(m, 2H), 3.94(m, 1H), 2.74 - 2.87(m, 1H), 2.42(s, 3H), 2.07(m, 1H), 1.81 - 1.97(m, 5H), 1.47 - 1.73(m, 8H), 1.33(m, 2H).

[0648] Example 17: Preparation of Target Compound I-17

[0649] (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-17)

[0650] (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-17)

[0651]

[0652] The synthetic route of Target Compound I-17 is as follows:

[0653]

[0654] The first step: Synthesis of methyl (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-17A)

[0655] methyl(1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4- methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-17A)

[0656]

[0657] Methyl (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6H) (230 mg, 0.409 mmol) and N-methyl-n-propylamine (150 mg, 2.04 mmol) were added to 5 mL of tetrahydrofuran. N,N-Diisopropylethylamine (0.21 mL, 1.228 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain the title compound, methyl (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-17A) (150 mg, yield 73.9%).

[0658] LC-MS, M / Z (ESI): 496.2 [M+H] +

[0659] Step 2: Synthesis of (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)

[0660] (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)

[0661]

[0662] Methyl (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (150 mg, 0.302 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water. Lithium hydroxide (72.4 mg, 3.02 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Water (10 mL) was added to dissolve the residue, and the pH was adjusted to 2 with 2 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V:V) = 1:1) to give the title compound as a white solid, (1S,3S)-3-((2-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-17) (40 mg, yield 27.4%).

[0663] LC-MS, M / Z (ESI): 482.1 [M+H] +

[0664] 1 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 6.93 (d, 1H), 5.60 (s, 2H), 4.71 (s, 1H), 3.24 - 3.26 (m, 2H), 2.93 (s, 3H), 2.85 - 2.86 (m, 1H), 2.46 (s, 3H), 2.00 - 2.11 (m, 1H), 1.97 - 1.98 (m, 3H), 1.67 - 1.70 (m, 4H), 1.56 - 1.58 (m, 2H), 0.88 - 0.89 (m, 3H).

[0665] Example 18: Preparation of Target Compound I-18

[0666] (1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-18)

[0667] (1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-18)

[0668]

[0669] The synthetic route of the target compound I-18 is shown as follows:

[0670]

[0671] Step 1: Synthesis of methyl (1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-18A)

[0672] methyl(1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-18A)

[0673]

[0674] Methyl (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (250 mg, 0.445 mmol) (I-6H) and N-methylbutan-1-amine (194 mg, 2.224 mmol) were added to 5 mL of tetrahydrofuran, and N,N-diisopropylethylamine (0.23 mL, 1.335 mmol) was added. The mixture was stirred at room temperature for 12 hours. After evaporation to dryness, the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain methyl (1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-18A) (150 mg, yield 66.1%).

[0675] LC-MS, M / Z (ESI): 510.2 [M+H] +

[0676] Step 2: (054)(1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-18)

[0677] (054)(1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-18)

[0678]

[0679] Methyl (1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (150 mg, 0.294 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water, and lithium hydroxide (35.2 mg, 1.47 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in water (10 mL), and the pH was adjusted to 2 with 2 M hydrochloric acid. The solution was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V:V) = 1:1) to give the white solid (1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-18) (60 mg, yield 41.1%).

[0680] LC-MS, M / Z (ESI): 4962.2 [M+H] +

[0681] 1 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 6.94 (d, 1H), 5.61 (s, 2H), 4.71 (s, 1H), 3.28 - 3.29 (m, 2H), 2.93 (s, 3H), 2.83 - 2.88 (m, 1H), 2.47 (s, 3H), 2.00 - 2.01 (m, 1H), 1.97 - 1.98 (m, 3H), 1.65 - 1.70 (m, 4H), 1.51 - 1.53 (m, 2H), 1.30 - 1.32 (m, 2H), 0.90 - 0.93 (m, 3H).

[0682] Example 19: Preparation of Target Compound I-19

[0683] (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-19)

[0684] (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-19)

[0685]

[0686] The synthetic route of Target Compound I-19 is as follows:

[0687]

[0688] The first step: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-19A)

[0689] methyl(1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-19A)

[0690]

[0691] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (381 mg, 0.679 mmol) (the product of the fourth step on 081010) and N-methyl-n-propylamine (149 mg, 2.037 mmol) were added to 5 mL of tetrahydrofuran. N,N-Diisopropylethylamine (0.59 mL, 3.4 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After evaporation to dryness, the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain the title compound methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-19A) (255 mg, yield 76%).

[0692] LC-MS, M / Z (ESI): 495.2 [M+H] +

[0693] Step 2: Synthesis of (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-19)

[0694] (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-19)

[0695]

[0696] Methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (056B) (255 mg, 0.516 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water, and lithium hydroxide (61.8 mg, 2.58 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in water (10 mL). The pH was adjusted to 2 with 2 M hydrochloric acid, and the solution was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V:V) = 1:1) to give the title compound as a white solid, (1S,3S)-3-((6-(5-chloro-3-((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-19) (60 mg, yield 24.2%).

[0697] LC-MS, M / Z (ESI): 481.1 [M+H] +

[0698] 1 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 5.23 (s, 2H), 4.66 (s, 1H), 3.19 - 3.25 (m, 2H), 2.83 - 2.91 (m, 4H), 2.49 (s, 3H), 2.13 - 2.16 (m, 1H), 1.89 - 2.02 (m, 3H), 1.74 - 1.78 (m, 1H), 1.45 - 1.72 (m, 5H), 1.51 - 1.57 (m, 3H)

[0699] Example 20: Preparation of Target Compound I-20

[0700] (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-20)

[0701] (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-20)

[0702]

[0703] The synthetic route of the target compound I-20 is as follows:

[0704]

[0705] Step 1: Synthesis of methyl (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-20A)

[0706] methyl(1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-20A)

[0707]

[0708] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (286 mg, 0.509 mmol) (the product of the fourth step on 081010) and N-methylbutan-1-amine (133 mg, 1.528 mmol) were added to 5 mL of tetrahydrofuran, and N,N-diisopropylethylamine (0.45 mL, 2.55 mmol) was added. The mixture was stirred at room temperature for 12 hours. After evaporation to dryness, the compound was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain methyl (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-20A) (217 mg, yield 84%).

[0709] LC-MS, M / Z (ESI): 509.2 [M+H] +

[0710] Step 2: Synthesis of (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)

[0711] (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-20)

[0712]

[0713] Methyl (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (217 mg, 0.428 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water. Lithium hydroxide (51.3 mg, 2.14 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Water (10 mL) was added to dissolve the residue, and the pH was adjusted to 2 with 2 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative TLC (petroleum ether:ethyl acetate (V:V) = 1:1) to obtain the white solid (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-20) (80 mg, yield 37.7%).

[0714] LC-MS, M / Z (ESI): 495.2 [M+H] +

[0715] 1 H NMR (400 MHz, CDCl3) δ 7.28 (d, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 5.23 (s, 2H), 4.66 (s, 1H), 3.23 - 3.28 (m, 2H), 2.84 - 2.91 (m, 4H), 2.49 (s, 3H), 2.03 - 2.13 (m, 1H), 1.89 - 2.00 (m, 3H), 1.65 - 1.78 (m, 4H), 1.47 - 1.50 (m, 2H), 1.25 - 1.30 (m, 2H), 0.88 - 0.93 (m, 3H)

[0716] Example 21: Preparation of Target Compound I-21

[0717] (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-21)

[0718] (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-21)

[0719]

[0720] The synthetic route of Target Compound I-21 is as follows:

[0721]

[0722] The first step: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-((((4-hydroxybutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21A)

[0723] methyl(1S,3S)-3-((6-(5-chloro-3-((((4-hydroxybutyl)(methyl)carbamoyl)oxy)methyl)thiophe n-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21A)

[0724]

[0725] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (476 mg, 0.849 mmol) (I-3E) and 4-(methylamino)butanol (263 mg, 2.55 mmol) were added to 5 mL of tetrahydrofuran. N,N-Diisopropylethylamine (0.74 mL, 4.24 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 1:1) to obtain the title compound, methyl (1S,3S)-3-((6-(5-chloro-3-((((4-hydroxybutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21A) (409 mg, yield 92%).

[0726] LC-MS, M / Z (ESI): 525.2 [M+H] +

[0727] Step 2: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(4-(tosyloxy)butyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21B)

[0728] methyl(1S,3S)-3-((6-(5-chloro-3-(((methyl(4-(tosyloxy)butyl)carbamoyl)oxy)methyl)thioph en-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-21B)

[0729]

[0730] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-hydroxybutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (409 mg, 0.777 mmol) and p-toluenesulfonyl chloride (178 mg, 0.933 mmol) were added to 5 mL of dichloromethane. 4-Dimethylaminopyridine (9.5 mg, 0.078 mmol) and triethylamine (0.22 mL, 1.55 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 12 h. The solvent was evaporated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 2:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(4-(tosyloxy)butyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21B) (307 mg, yield 58.2%).

[0731] LC-MS, M / Z (ESI): 679.2 [M+H] +

[0732] Step 3: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21C)

[0733] methyl(1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen- 2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-21C)

[0734]

[0735] (1S,3S)-3-((6-(5-chloro-3-(((methyl(4-(toluenesulfonyloxy)butyl)amino)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (307 mg, 0.452 mmol) was added to a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 2:1) to afford the title compound (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-21C) (219 mg, yield 92%).

[0736] LC-MS, M / Z (ESI): 527.2 [M+H] +

[0737] Step 4: Synthesis of (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-21)

[0738] (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-21)

[0739]

[0740] (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (219 mg, 0.414 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water, and lithium hydroxide (99 mg, 4.14 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in water (10 mL). The pH was adjusted to 2 with 2 M hydrochloric acid, and the solution was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V:V) = 1:1) to give the title compound as a white solid, (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-21) (80 mg, yield 37.7%).

[0741] LC-MS, M / Z (ESI): 513.2 [M+H] +

[0742] 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 5.24 (s, 2H), 4.66 (s, 1H), 4.34 - 4.53 (m, 2H), 3.28 - 3.34 (m, 2H), 2.83 - 2.92 (m, 4H), 2.49 (s, 3H), 2.12 - 2.16 (m, 1H), 1.92 - 2.04 (m, 3H), 1.65 - 1.89 (m, 8H)

[0743] Example 22: Preparation of Target Compound I-22

[0744] (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-22)

[0745] (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-22)

[0746]

[0747] The synthetic route of the target compound, target compound I-22, is as follows:

[0748]

[0749] Step 1: Synthesis of methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-22A)

[0750] methyl(1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-22A)

[0751]

[0752] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (371 mg, 0.662 mmol) (the product of the fourth step of 081010) and N-methylpentan-1-amine (201 mg, 1.986 mmol) were added to 5 mL of tetrahydrofuran, and N,N-diisopropylethylamine (0.58 mL, 3.31 mmol) was added. The mixture was stirred at room temperature for 12 hours. After evaporation to dryness, the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-22A) (218 mg, yield 63%).

[0753] LC-MS, M / Z (ESI): 523.2 [M+H] +

[0754] Step 2: Synthesis of (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-22)

[0755] (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-22)

[0756]

[0757] Methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate (218 mg, 0.417 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water. Lithium hydroxide (100 mg, 4.17 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in water (10 mL), and the pH was adjusted to 2 with 2 M hydrochloric acid. The solution was extracted with ethyl acetate (10 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative TLC (petroleum ether:ethyl acetate (V:V) = 1:1) to give the white solid (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-22) (60 mg, yield 28.2%).

[0758] LC-MS, M / Z (ESI): 509.2 [M+H] +

[0759] 1 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 5.23 (s, 2H), 4.66 (s, 1H), 3.22 - 3.27 (m, 2H), 2.83 - 2.91 (m, 4H), 2.49 (s, 3H), 2.00 - 2.12 (m, 1H), 1.94 - 1.99 (m, 1H), 1.89 - 1.91 (m, 2H), 1.73 - 1.75 (m, 1H), 1.64 - 1.67 (m, 3H), 1.49 - 1.51 (m, 2H), 1.25 - 1.32 (m, 4H), 0.85 - 0.89 (m, 3H).

[0760] Example 23: Preparation of Target Compound I-23

[0761] (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-23)

[0762] (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-23)

[0763]

[0764] The synthetic route of the target compound I-23 is as follows:

[0765]

[0766] Step 1: Synthesis of 2-bromo-5-fluorothiophene-3-carboxaldehyde (I-23A)

[0767] 2-bromo-5-fluorothiophene-3-carbaldehyde(I-23A)

[0768]

[0769] To a solution of (2-bromo-5-fluorothiophene-3-yl)methanol (I-13C) (2.50 g, 11.85 mmol) in dichloromethane (30.0 mL) was added Dess-Martin periodinane (10.05 g, 23.69 mmol, 7.33 mL) at 0°C, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain a yellow oily substance 2-bromo-5-fluorothiophene-3-carboxaldehyde (I-23A) (2.20 g, yield 88.8%).

[0770] Step 2: Synthesis of (1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-23B)

[0771] methyl(1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexa ne-1-carboxylate(I-23B)

[0772]

[0773] Under nitrogen atmosphere, tetrakistriphenylphosphine palladium (221.12 mg, 191.35 umol) was added to a solution of 2-bromo-5-fluorothiophene-3-carboxaldehyde (400 mg, 1.91 mmol) and (1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (1.55 g, 2.87 mmol) (source HW082029) in 1,4-dioxane (10 mL), and the reaction solution was stirred at 100 ° C for 12 hours. After the reaction is completed, the mixed solution is concentrated to obtain a crude product, which is separated and purified by column chromatography to obtain (1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-23B) (297.8 mg, yield 41.2%).

[0774] Step 3: Synthesis of (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-23C)

[0775] methyl(1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)c yclohexane-1-carboxylate(I-23C)

[0776]

[0777] Sodium borohydride (59.1 mg, 1.57 mmol) was added to a solution of (1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (297.8 mg, 788.94 umol) in methanol (5 mL) at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, dilute hydrochloric acid was added dropwise to quench the reaction, and the crude product was concentrated to obtain a crude product, which was purified by chromatography on silica gel plates to obtain a yellow oil (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-23C) (200 mg, yield 66%).

[0778] Step 4: Synthesis of methyl (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-23D)

[0779] methyl(1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-23D)

[0780]

[0781] At 0 °C, phenyl 4-nitrochloroformate (849.93 mg, 4.22 mmol) was added to a solution of methyl (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (800 mg, 2.11 mmol) and pyridine (500.31 mg, 6.33 mmol, 510.52 μL) in dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was washed three times with saturated aqueous sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil of methyl (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-23D) (1.4 g, crude), which was used directly in the next step.

[0782] Step 5: Synthesis of methyl (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-23E)

[0783] methyl(1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-23E)

[0784]

[0785] At room temperature, methyl (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (350 mg, 642.74 μmol) and N-methylpropan-1-amine hydrochloride (176.11 mg, 1.61 mmol) were added to tetrahydrofuran (3.5 mL), and then N,N-diisopropylethylamine (290.74 mg, 2.25 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h, and the reaction mixture was prepared into a yellow oily compound, methyl (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-23E) (164 mg, yield 53.3%).

[0786] Step 6: Synthesis of (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-23)

[0787] (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-23)

[0788]

[0789] At room temperature, methyl (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (164 mg, 342.68 μmol) was dissolved in tetrahydrofuran (1.6 mL), then water (0.3 mL) and lithium hydroxide monohydrate (143.80 mg, 3.43 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 4 - 5 with 1N aqueous hydrochloric acid, and then extracted with ethyl acetate (5 mL x 2), and the organic phase was concentrated to obtain the crude product. Then the crude product was separated by preparative (column: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: A = water + 0.225 vol% formic acid (99%), B = acetonitrile; gradient elution: 52% - 85% B, 11 minutes) to obtain the compound (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-23) (55.36 mg, yield 40.3%).

[0790] 1 H NMR(400MHz,CDCl3)δ7.29(s,1H),7.12(d,1H),6.52(d,1H),5.22(s,2H),4.67(s,1H), 3.24(td,2H),2.94-2.83(m,4H),2.50(s,3H),2.25-2.10(m,1H),2.06-1.99(m,1H),1.97-1.87(m,2H),1.74-1.47(m,6H),0.92-0.83(m,3H).

[0791] LC-MS,M / Z(ESI):465.2[M+H] +

[0792] Example 24: Preparation of target compound I-24

[0793] (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24)

[0794] (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-24)

[0795]

[0796] The synthetic route of Target Compound I-24 is as follows:

[0797]

[0798] The first step: Synthesis of methyl (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-24A)

[0799] methyl(1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-24A)

[0800]

[0801] At room temperature, to a solution of methyl (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (350 mg, 642 μmol) (I-3E) and N,N-diisopropylethylamine (332 mg, 2.57 mmol) in tetrahydrofuran (3.5 mL) was added N-methylbutanamine (112 mg, 1.29 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was prepared by chromatography silica gel plate to obtain the yellow oily compound methyl (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-24A) (120 mg, yield 37.9%).

[0802] Step 2: Synthesis of (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-24)

[0803] (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-24)

[0804]

[0805] At room temperature, lithium hydroxide monohydrate (51.1 mg, 1.22 mmol) was added to a mixed solution of methyl (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (120 mg, 243 μmol) in methanol (2.5 mL) and water (0.5 mL). The mixture was stirred at 25 °C for 12 hours. The reaction solution was acidified to pH 4 with dilute hydrochloric acid, extracted with ethyl acetate (5 mL x 2), and concentrated. The residue was obtained as a white solid (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-24) (64.3 mg, yield 54.6%) by preparative (Column: Phenomenex Synergi C18 150*25mm*10μm; Mobile phase: A = water + 0.225 vol% formic acid (99%), B = acetonitrile; Gradient elution: 56% - 89% B, 11 minutes).

[0806] 11H NMR (400 MHz, CDCl3) δ 7.29 (d, 1H), 7.13 (d, 1H), 6.52 (d, 1H), 5.21 (s, 2H), 4.68 (s, 1H), 3.35 - 3.20 (m, 2H), 3.00 - 2.81 (m, 4H), 2.50 (s, 3H), 2.16 (d, 1H), 2.15 - 2.00 (m, 1H), 1.97 - 1.87 (m, 2H), 1.82 - 1.71 (m, 1H), 1.70 - 1.60 (m, 3H), 1.57–1.40 (m, 2H), 1.36–1.25 (m, 2H), 0.96 - 0.84 (m, 3H).

[0807] LC - MS, M / Z (ESI): 479.2 [M + H] +

[0808] Example 25: Preparation of the target compound I - 25

[0809] (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I - 25)

[0810] (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I - 25)

[0811]

[0812] The synthetic route of the target compound I - 25 is as follows:

[0813]

[0814] The first step: Synthesis of methyl (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I - 25A)

[0815] methyl(1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothio phen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-25A)

[0816]

[0817] At room temperature, methyl (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (350 mg, 642.74 μmol) and 1-cyclobutyl-N-methylmethanamine (synthesized according to Compound I-7D in Example 7) (174 mg, 1.29 mmol) were added to tetrahydrofuran (3.5 mL), and then N,N-diisopropylethylamine (290.74 mg, 2.25 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h, and the reaction mixture was purified by preparative TLC silica gel plate to obtain the yellow oily compound methyl (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-25A) (120 mg, yield 33.0%).

[0818] Step 2: Synthesis of (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-25)

[0819] (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid(TargetCompoundI-25)

[0820]

[0821] At room temperature, methyl (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (120 mg, 237 μmol) was dissolved in methanol (2.5 mL), then water (0.5 mL) and lithium hydroxide monohydrate (50.0 mg, 1.20 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 4-5 with 1N aqueous hydrochloric acid, and then extracted with ethyl acetate (5 mL x 2), and the organic phase was concentrated to obtain a crude product. The residue was purified by preparative purification (column: Phenomenex Synergi C18 150*25mm*10um; solvent: A = water + 0.225 vol% formic acid (99%), B = acetonitrile; gradient: 58%-91% B, 11 minutes) to obtain a gray solid (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-25) (62.7 mg, yield 51.5%).

[0822] 1 H NMR(400MHz,CDCl3)δ7.29(s,1H),7.12(d,1H),6.53(s,1H),5.20(s,2H),4.68(s, 1H),3.31(dd,2H),2.94-2.84(m,4H),2.52-2.62(m,1H),2.50(s,3H),2.21-1.98(m,5H),1.96-1.82(m,5H),1.81-1.70(m,4H).

[0823] LC-MS,M / Z(ESI):491.2[M+H] +

[0824] Example 26: Preparation of target compound I-26

[0825] (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26)

[0826] (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2 -yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (the target compound I-26)

[0827]

[0828] The synthetic route of the target compound I-26 is as follows:

[0829]

[0830] The first step: Synthesis of methyl (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-26A)

[0831] methyl(1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothio phen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-26A)

[0832]

[0833] At room temperature, methyl (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (350 mg, 642.74 μmol) (I-3E) and 2-cyclopropyl-N-methylethylamine hydrochloride (217.94 mg, 1.61 mmol) were added to tetrahydrofuran (3.5 mL), and then N,N-diisopropylethylamine (290.74 mg, 2.25 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h, and the reaction mixture was prepared into a yellow oily compound, methyl (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-26A) (260 mg, yield 80.1%) by preparative chromatography silica gel plate.

[0834] Step 2: Synthesis of (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-26)

[0835] (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-26)

[0836]

[0837] At room temperature, dissolve methyl (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (260 mg, 515.25 μmol) in tetrahydrofuran (2.6 mL), then add water (0.5 mL) and lithium hydroxide monohydrate (216.22 mg, 5.15 mmol) thereto, and then stir the mixture at room temperature for 12 hours. After the reaction is completed, adjust the pH of the reaction solution to 4 - 5 with 1N aqueous hydrochloric acid, then extract with ethyl acetate (5 mL x 2), and concentrate the organic phase to obtain the crude product. Then, the crude product is prepared (chromatographic column: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: A = water + 0.225 vol% formic acid (99%), B = acetonitrile; gradient: 56% - 89% B, 11 minutes) to obtain the target compound (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-26) (43.49 mg, yield 17.2%).

[0838] 1HNMR(400MHz,CDCl3)δ7.30(s,1H),7.12(d,1H),6.52(s,1H),5.22(s,2H),4.67(br s,1H),3.35(td,2H),2.93(br d,3H),2.50(s,3H),2.20 - 2.18(m,1H),1.96 - 1.92(m,4H),1.69 - 1.65(m,3H),1.44 - 1.41(m,3H),0.65 - 0.59(m,1H),0.43(br dd,2H),0.07 - 0.01(m,2H).

[0839] LC - MS,M / Z(ESI):491.2[M + H] +

[0840] Example 27: Preparation of Target Compound I - 27

[0841] (1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I - 27)

[0842] (1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid( Target Compound I - 27)

[0843]

[0844] The synthetic route of the target compound I - 27 is as follows:

[0845]

[0846] The first step: Synthesis of methyl ((1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I - 27A)

[0847] methyl(1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

[0848]

[0849] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (250 mg, 0.446 mmol) and N-methyl-1-(oxetan-3-yl)methanamine (135 mg, 1.337 mmol) were added to 5 ml of tetrahydrofuran, and N,N-diisopropylethylamine (0.39 mL, 3.23 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)aminocarbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-27A) (100 mg, yield 12.9%).

[0850] LC-MS, M / Z (ESI): 523.2 [M+H]+

[0851] Step 2: (1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)aminocarbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-27)

[0852] (1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-27)

[0853]

[0854] (1S,3S)-Methyl 3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)ethoxy)cyclohexane-1-carboxylate (100 mg, 0.191 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water, and lithium hydroxide (22.9 mg, 0.956 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in water (10 mL), and the pH was adjusted to 2 with 2 M hydrochloric acid. The solution was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V:V) = 1:1) to give the title compound as a white solid, (1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-27) (30.9 mg, yield 31.8%).

[0855] LC-MS, M / Z (ESI): 509.1 [M+H] +

[0856] 1 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.13 (d, 1H), 6.92 (s, 1H), 5.24 (s, 2H), 4.77 - 4.79 (m, 2H), 4.64 (s, 1H), 4.51 (s, 1H), 4.40 (s, 1H), 3.59 - 3.60 (m, 2H), 3.21 - 3.30 (m, 1H), 2.85 - 2.90 (m, 4H), 2.49 (s, 3H), 2.10 - 2.13 (m, 1H), 1.90 - 1.99 (m, 3H), 1.63 - 1.76 (m, 4H).

[0857] Example 28: Preparation of Target Compound I-28

[0858] (1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-28)

[0859] (1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-28)

[0860]

[0861] The synthetic route of Target Compound I-28 is as follows:

[0862]

[0863] The first step: Methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-28A)

[0864] methyl(1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-28A)

[0865]

[0866] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (250 mg, 0.446 mmol) and 2,2,2-trifluoro-N-methylethylamine (151 mg, 1.337 mmol) were added to 5 mL of tetrahydrofuran, and N,N-diisopropylethylamine (0.39 mL, 2.23 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-28A) (160 mg, yield 67.1%).

[0867] LC-MS, M / Z(ESI): 535.1 [M+H]+

[0868] Step 2: (1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-28)

[0869] (1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-28)

[0870]

[0871] Methyl (1S,3S)-3-((6-(5-chloro-3-((((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-28A) (160 mg, 0.299 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water, and lithium hydroxide (21.49 mg, 0.897 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated, water (10 mL) was added to dissolve, the pH was adjusted to 2 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by a preparative plate (petroleum ether:ethyl acetate (V:V) = 1:1) to obtain a white solid (1S,3S)-3-((6-(5-chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-28) (26.9 mg, yield 17.27%).

[0872] LC-MS, M / Z(ESI): 521.1 [M+H]+

[0873] 11H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.11 (d, 1H), 6.92 (d, 1H), 5.30 (d, 2H), 4.67 (s, 1H), 3.81 - 3.96 (m, 2H), 3.03 - 3.06 (d, 3H), 2.84 - 2.89 (m, 1H), 2.49 (s, 3H), 2.13 - 2.17 (m, 1H), 1.76 - 2.00 (m, 3H), 1.63 - 1.75 (m, 4H).

[0874] Example 29: Synthesis of Target Compound I-29

[0875] (1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-29)

[0876] (1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-29)

[0877]

[0878] The synthetic route of Target Compound I-29 is as follows:

[0879]

[0880] First step: Methyl (1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-29A)

[0881] methyl(1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-29A)

[0882]

[0883] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (250 mg, 0.446 mmol) and N-methylethylamine (79 mg, 1.337 mmol) were added to 5 mL of tetrahydrofuran. N,N-Diisopropylethylamine (0.39 mL, 2.23 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-29A) (160 mg, yield 74.6%).

[0884] LC-MS, M / Z (ESI): 481.1 [M+H] +

[0885] Step 2: (1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)hexane-1-carboxylic acid (Target Compound I-29)

[0886] (1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-29)

[0887]

[0888] (1S,3S)-Methyl 3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (160 mg, 0.333 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water, and lithium hydroxide (23.9 mg, 0.998 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Water (10 mL) was added to dissolve the residue, and the pH was adjusted to 2 with 2 M hydrochloric acid. The solution was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative TLC (petroleum ether:ethyl acetate (V:V) = 1:1) to give the white solid (1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)hexane-1-carboxylic acid (Target Compound I-29) (50.4 mg, yield 32.4%).

[0889] LC-MS, M / Z (ESI): 467.1 [M+H] +

[0890] 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 1H), 7.11 (d, 1H), 6.94 (s, 1H), 5.23 (s, 2H), 4.67 (s, 1H), 3.30 - 3.34 (m, 2H), 2.86 - 2.90 (m, 4H), 2.49 (s, 3H), 2.11 - 2.13 (m, 1H), 1.91 - 1.95 (m, 3H), 1.63 - 1.67 (m, 4H), 1.11 (t, 3H).

[0891] Example 30: Synthesis of Target Compound I-30

[0892] (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-30)

[0893] (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-30)

[0894]

[0895] The synthetic route of the target compound I-30 is as follows:

[0896]

[0897] Step 1: Methyl (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-30A)

[0898] methyl(1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpy ridin-3-yl)oxy)cyclohexane-1-carboxylate(I-30A)

[0899]

[0900] Methyl (1S,3S)-3-((6-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (250 mg, 0.446 mmol) and n-propylamine (79 mg, 1.337 mmol) were added to 5 mL of tetrahydrofuran, and N,N-diisopropylethylamine (0.39 mL, 2.23 mmol) was added. The mixture was stirred at room temperature for 12 hours. After evaporation to dryness, the residue was purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1) to obtain methyl (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-30A) (160 mg, yield 74.63%).

[0901] LC-MS, M / Z (ESI): 481.1 [M+H] +

[0902] Step 2: (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-30)

[0903] (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-30)

[0904]

[0905] Methyl (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (160 mg, 0.333 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water, and lithium hydroxide (23.9 mg, 0.998 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in water (10 mL). The pH was adjusted to 2 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V:V) = 1:1) to obtain the white solid (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-30) (34.7 mg, yield 22.34%).

[0906] LC-MS, M / Z (ESI): 467.1 [M+H] +

[0907] 1 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 1H), 7.12 (d, 1H), 6.95 (s, 1H), 5.21 (s, 2H), 4.78 (s, 1H), 4.66 (s, 1H), 3.14 - 3.19 (m, 2H), 2.84 - 2.87 (m, 1H), 2.49 (s, 3H), 1.95 - 2.13 (m, 1H), 1.66 - 1.931 (m, 3H), 1.54 - 1.63 (m, 4H), 1.50 - 1.52 (m, 2H), 0.92 (t, 3H).

[0908] Example 31: Synthesis of Target Compound I-31

[0909] (1S,3S)-3-((2-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (Target Compound I-31)

[0910] (1S,3S)-3-((2-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4 -methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylicacid

[0911]

[0912] Target Compound I-31 was synthesized with reference to I-9, except that 2-cyclopropylethyl-1-amine hydrochloride was replaced by 4-fluorobutyl-1-amine hydrochloride.

[0913] LC-MS, M / Z(ESI): 514.2 [M+H]+

[0914] Test Examples of Biological Activity and Related Properties

[0915] Test Example 1: In Vitro Calcium Flux Assay for LPAR1

[0916] The determination of the antagonistic effect of the compound on LPAR1 was carried out in a CHO stable transfection cell line highly expressing human LPAR1. 18 hours before the experiment, the cells were seeded at a density of 15,000 cells / well in a 384-well black-wall transparent bottom plate containing 20 μL of DMEM / F12 (1:1) medium and incubated at 37°C / 5% CO2 for 18 hours. Then, 20 μL / well of the dye solution was added to each well of the cells, and the cells were returned to the 37°C incubator and incubated in the dark for another 30 min. Then, the cells were incubated in the dark at room temperature for 10 min. Different final concentrations of the compound were added to the cells at 10 μL / well, and after equilibration for 20 min, finally, 12.5 μL / well of the LPA solution (final concentration 5 nM) was added to the cells, and the fluorescence signal value was detected by FLIPR. With the compound concentration as the X-axis and the fluorescence signal value as the Y-axis, the antagonistic effect (IC 50 value) of the compound was calculated using the software GraphPad Prism 8.0.

[0917] Table 1 Antagonistic Effect of Test Compounds on LPAR1

[0918]

[0919]

[0920] The results of the calcium flux assay of LPAR1 indicate that the compounds of the present invention have good antagonistic effects on LPAR1. Compared with the control compounds, most of the compounds of the present invention show more excellent LPAR1 antagonistic effects.

[0921] Test Example 2: In vitro calcium flux assay of LPAR3

[0922] The determination of the antagonistic effect of the compound on LPAR3 was carried out in a CHO stable cell line highly expressing human LPAR3. 18 hours before the test, the cells were seeded at a density of 15,000 cells / well in a 384-well black-wall clear bottom plate containing 20 μL of DMEM / F12 (1:1) medium and incubated at 37 °C / 5% CO2 for 18 hours. Then, 20 μL / well of the dye solution was added to each well of the cells, and the cells were returned to the 37 °C incubator and incubated in the dark for another 30 min. Then, the cells were incubated in the dark at room temperature for 10 min. Different final concentrations of the compound were added to the cells at 10 μL / well, and the cells were equilibrated for 20 min. Finally, 12.5 μL / well of the LPA solution (final concentration 5 nM) was added to the cells, and the fluorescence signal value was detected by FLIPR. With the compound concentration as the X-axis and the fluorescence signal value as the Y-axis, the antagonistic effect (IC 50 value) of the compound was calculated by the software Prism.

[0923] Table 2 Antagonistic effects of the test compounds on LPAR3

[0924]

[0925]

[0926] The results of the calcium flux assay of LPAR3 indicate that the compounds of the present invention have weak antagonistic effects on LPAR3. Compared with the control compounds, the compounds of the present invention show more excellent LPAR1 selective inhibitory activities.

[0927] Test Example 3: Test for hepatotoxicity of the compound

[0928] The cytotoxicity test of the compound on hepatocytes was carried out on HepG2 (ATCC, HB - 8065) cells. The cell viability was measured using the CellTiter - Glo Luminescent Cell Viability Assay kit (Promega, G7573), and the toxicity of the compound was characterized by the inhibition of the viability of HepG2 cells. Logarithmic - phase HepG2 cells were collected, the concentration of the cell suspension was adjusted, and plated at 5000 cells / well in a 96 - well cell culture plate. The cells were incubated overnight in a cell culture incubator with 5% CO2 at 37°C. The next day, the medium was changed and the compound with a final concentration of 30 μM was added. At the same time, a negative control group (cells + DMSO) and a blank control group (medium + DMSO) were set up, and incubated in a cell culture incubator with 5% CO2 at 37°C for 72 hours. After the treatment, the operation was carried out according to the kit instructions, and the luminescence signal values in different wells were detected on an EnVision plate reader (2104). The inhibition of the viability of HepG2 cells by different compounds at 30 μM was calculated according to the following formula.

[0929]

[0930] Table 3 Inhibition of the viability of HepG2 cells by the tested compounds

[0931] Test compound Inhibition rate (%) at 30 μM Control compound 1 30.19 I-3 0 I-19 0 I-20 0

[0932] The results of the hepatocyte cytotoxicity test showed that the compounds of the present invention exhibited good safety, had no inhibitory effect on HepG2 cells at 30 μM, and the safety was significantly better than that of the control compound.

[0933] Test Example 4: Pharmacokinetic experiment

[0934] For the pharmacokinetic experiment of mice, male ICR mice, 20 - 25 g, were fasted overnight. Three mice were taken and administered orally by gavage at a dose of 10 mg / kg. Blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after administration. The blood samples were centrifuged at 6800 g at 2 - 8°C for 6 minutes, the plasma was collected and stored at - 80°C. Plasma samples at each time point were taken, added with 3 - 5 times the volume of acetonitrile solution containing internal standard and mixed, vortex - mixed for 1 minute, centrifuged at 13000 rpm at 4°C for 10 minutes, the supernatant was taken and added with 3 times the volume of water and mixed, and an appropriate amount of the mixed solution was subjected to LC - MS / MS analysis. The main pharmacokinetic parameters were analyzed by the non - compartmental model using WinNonlin 7.0 software.

[0935] Table 4 Results of the pharmacokinetic experiment of oral gavage administration in mice

[0936]

[0937] The results of the mouse pharmacokinetic experiments showed that, compared with the control compound, the compounds of the present invention exhibited more excellent pharmacokinetic properties and good drug-likeness.

[0938] Test Example 6: Pharmacodynamic experiment of bleomycin-induced pulmonary fibrosis

[0939] After male mice were adaptively fed for 1 week and their body weights reached the standard, they were randomly divided into a normal control group, a model group, and a dosing group according to their body weights. After anesthesia with isoflurane: 50 μL of bleomycin was evenly administered into the lungs of the model group and the dosing group to establish a mouse pulmonary fibrosis model, while 50 μL of normal saline was evenly administered into the lungs of the control group; after 7 days, the drug was administered continuously for 15 days, twice a day. After the drug administration was completed, the animals were euthanized, and the left lungs of the animals were fixed in 10% neutral formalin buffer for the preparation of pathological tissue sections, and the left lung tissues were scored for pulmonary fibrosis. One-way ANOVA or Two-way ANOVA was used for analysis; when comparing between two groups, a two-tailed test between the two groups was performed using the T-test. When p < 0.05, there was a significant difference between the two groups. The results are as Figure 1 shown, where, T-test: ****p < 0.0001 vs. normal control group; #p < 0.05 vs. model group; &p < 0.05 vs. control compound 330 mg / kg.

[0940] The results showed that the compounds of the present invention could significantly reduce the bleomycin-induced pulmonary fibrosis score in mice by antagonizing LPAR1, and the effect was significantly better than that of the control compound.

Claims

1. A compound which is a compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt of the compound represented by formula (I): Wherein: R 1 selected from C 1-6 alkyl; R 2 selected from Cl; X 1 、X 2 selected from C, X 3 selected from N; R 3 selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl; R 4 selected from -H, halogen, unsubstituted or substituted by R g substituted with the following groups: C 1-6 alkyl, C 3-4 cycloalkyl, 5-8 membered aryl; R g selected from halogens; L 1 selected from unsubstituted C 1-3 alkylene group.

2. The compound according to claim 1, characterized in that, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.

3. The compound according to claim 1, characterized in that, When R 3 is C 1-3 alkyl, the C 1-3 alkyl is methyl, ethyl, n-propyl, or isopropyl.

4. The compound according to claim 1, wherein When R 3 is a C 1-3 alkyl group substituted by halogen, the C 1-3 alkyl group is methyl, ethyl, n-propyl or isopropyl.

5. The compound according to claim 1, characterized in that, When R 3 is a C 1-3 alkyl substituted by halogen, the number of said halogen is one or more, and when there are multiple halogens, the halogens are the same or different.

6. The compound according to claim 1, characterized in that, When R 3 is a C 1-3 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine.

7. The compound according to claim 1, wherein R 3 Selected from methyl, ethyl.

8. The compound according to claim 1, wherein When R 4 is a halogen, the halogen is fluorine, chlorine, bromine or iodine.

9. The compound according to claim 1, wherein When R 4 is an unsubstituted or R g substituted group selected from the following: C 1-6 alkyl, C 3-4 cycloalkyl, 5- to 8-membered aryl, the number of R g is one or more. When there are multiple R g groups, the R g groups may be the same or different.

10. The compound according to claim 1, wherein When R 4 is an unsubstituted or R g -substituted following group: C 1-6 alkyl, C 3-4 cycloalkyl, 5- to 8-membered aryl, the number of said R g is one or more, and said R g is selected from fluorine, chlorine, bromine, and iodine.

11. The compound according to claim 1, wherein When R 4 is unsubstituted or substituted by R g to form C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.

12. The compound according to claim 1, wherein When R 4 is unsubstituted or substituted by R g and is a C 3-4 cycloalkyl, the C 3-4 cycloalkyl is cyclopropyl or cyclobutyl.

13. The compound according to claim 1, wherein, When R 4 is an unsubstituted or R g -substituted 5- to 8-membered aryl group, the 5- to 8-membered aryl group is selected from phenyl groups.

14. The compound according to claim 1, wherein When R 4 is an unsubstituted C 1-6 alkyl, R 4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and n-pentyl.

15. The compound according to claim 1, characterized in that, When R 4 is an unsubstituted C 3-4 cycloalkyl, R 4 is selected from cyclopropyl and cyclobutyl.

16. The compound according to claim 1, wherein When R 4 is an unsubstituted 5- to 8-membered aryl group, R 4 is selected from phenyl.

17. The compound according to claim 1, wherein When R 4 is a C g alkyl group substituted by R 1-6 , R 4 is selected from -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CF3, -CH2CH2F, -(CH2)2CH2F, -CH(CH3)(CH2F), -CH2CH2Cl, -(CH2)2CH2Cl, -CH(CH3)(CH2Cl).

18. The compound according to claim 1, characterized in that, R 4 selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, phenyl, -CF3.

19. The compound according to claim 1, wherein L 1 selected from 20. The compound according to claim 1, wherein Selected from 21. The compound according to claim 1, wherein selected from wherein R 1 is selected from C 1-3 alkyl; R 2 selected from Cl; R 3 Selected from C 1-3 alkyl; R 4 selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, phenyl, -CF3; L 1 selected from 22. The compound according to claim 1, wherein The group of the compound represented by formula I is defined as described in the following scheme: For R 1 is methyl; R 2 selected from -Cl; R 3 selected from methyl; R 4 selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, phenyl, -CF3; L 1 selected from 23. The compound according to claim 1, wherein The compound represented by formula (I) is a compound represented by formula (I-0): Wherein: R 1 selected from -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2; R 2 Selected from -Cl; X 1 、X 2 is selected from C, X 3 is selected from N; R 3 selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl; R 4 selected from -H, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, phenyl, -CF3; L 1 selected from unsubstituted C 1-3 alkylene group.

24. The compound according to claim 1, characterized in that, The compound represented by formula (I) is a compound represented by formula (I-0): Wherein: R 1 selected from -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2; R 2 selected from -Cl; X 1 、X 2 selected from C, X 3 selected from N; Selected from 25. The compound according to claim 1, characterized in that, The compound represented by formula (I) is a compound represented by formula (I-1’): Among them, R 4 is selected from C 1-6 alkyl, C alkyl substituted by halogen 1-6 alkyl; X 1 、X 2 selected from C, X 3 selected from N.

26. The compound according to claim 25, wherein, R 1 is methyl, R 2 is -Cl, R 3 is methyl, selected from 27. A compound represented by the following formula, or a stereoisomer or a pharmaceutically acceptable salt thereof:

28. A pharmaceutical composition, characterized in that, Comprising an effective dose of the compound according to any one of claims 1 to 27.

29. Use of the compound according to any one of claims 1 to 27, or the pharmaceutical composition according to claim 28, in the preparation of a medicament for treating an LPAR-related disease.

30. The use according to claim 29, wherein the LPAR-related disease is selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus.

31. The use according to claim 29, wherein the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumors, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus.

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