WO2022100624A1

WO2022100624A1 - Oxy-substituted aminocarbonate thiophene-based compound and use thereof

Info

Publication number: WO2022100624A1
Application number: PCT/CN2021/129864
Authority: WO
Inventors: 张学军; 常少华; 臧杨; 李学强; 王洪强; 杨俊�; 李莉娥
Original assignee: 武汉人福创新药物研发中心有限公司
Priority date: 2020-11-10
Filing date: 2021-11-10
Publication date: 2022-05-19
Also published as: CN114456147A

Abstract

A new compound effectively antagonizing LPAR. The new compound is a compound represented by the following formula, or is a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug of the compound represented by the following formula.

Description

Oxy-substituted aminocarbonate thiophene compounds and their uses

priority information

This application claims the priority and rights of patent application No. 202011249593.7 filed with the State Intellectual Property Office of China on November 10, 2020, and is hereby incorporated by reference in its entirety.

technical field

The invention belongs to the field of medicinal chemistry, specifically, the invention relates to oxygen-substituted aminocarbonate thiophenes, more specifically, the invention relates to oxygen-substituted aminocarbonate thiophenes and their use in preparing medicines.

Background technique

Lysophosphatidic acid (LPA) is a key endogenous lipid signaling molecule with a molecular weight of 430-480Da, which is widely present in various tissues of the human body intracellular and extracellular, 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) phospholipase D (PLD)-phospholipase A2 (PLA2) pathway; (2) PLA2-lysophospholipase D (LysoPLD) pathway. Autochemotactic protein (ATX) encoded by 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., AnnuRev Pharmacol Toxicol. 2010;50:157186.), this response is the main source of LPA, and inhibition of ATX activity can inhibit LPA production in the body by more than 80% (Kaffe E et al. Cancers ( Basel). 2019;11(11):1626.).

LPA mediates a variety of functions by interacting with 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 myeloid Sheath formation, etc. LPA can bind and function with six lysophosphatidic acid receptors (LPARs), namely: LPAR1-LPAR6. LPA regulates a variety of physiological/pathological processes by binding to 6 LPARs, including vascular and neural development, hair follicle development, lymphocyte transport, bone development, fibrosis, fat mass regulation, 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 .).)

LPAR1 is the earliest identified and most widely distributed LPA receptor. It is a 41kDa membrane protein composed of 364 amino acids. It is widely expressed in various tissues and organs of the human body, among which the mRNA levels of brain, heart, colon, small intestine and placenta are high, while mRNA levels in other organs and tissues were relatively low. LPAR1 activates downstream pathways such as Akt, Rho, mitogen-activated protein kinase, and phospholipase C by coupling to GαI/o, GαQ/11, and Gα12/13, although LPA-LPAR1 signaling has been shown to play a role in the developmental stages of the nervous system. important effects, but no apparent toxicity was found for systemic inhibition in adults. However, inhibition of LPAR3 signaling can produce significant reproductive toxicity, so compounds need to avoid inhibition of LPAR3 signaling.

The diseases that are significantly related to LPAR1 are mainly fibrotic diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), some central diseases and so on.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology characterized by diffuse alveolitis and alveolar structural disorders. The main manifestation is common interstitial pneumonia. IPF originates from repeated damage to alveolar tissue, which triggers a series of physiopathological events, including (I) disruption of homeostasis; (II) inflammatory response; (III) cell proliferation, migration, and differentiation; (IV) Matrix and tissue remodeling; and (V) wound contracture and scarring, many of these events are controlled by the coordinated release of biochemical factors in and around the injury site, in which LPA plays an important role. Pathologically elevated LPA concentrations may persistently activate LPAR1 receptors 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 BALF of injured lung tissue (Tager AM et al., Proceedings of the American Thoracic Society, 2008.), and BALF (alveolar lavage fluid) LPA levels in IPF patients are higher than In the normal control group, inhibition of LPA signaling significantly reduced the chemotactic response of fibroblasts to IPF BALF.

In preclinical studies, LPAR1 gene-deficient mice were treated with bleomycin, and it was found that LPAR1 gene knockout had a significant protective effect in mice, and in LPAR1-deficient mice, the effect of bleomycin treatment Fibrocyte aggregation was significantly reduced. LPA induces endothelial cell barrier dysfunction and vascular leakage. In the early stages of tissue damage repair, increased vascular permeability can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated vascular permeability promotes fibrosis develop. In another preclinical model of bleomycin-induced IPF, bleomycin treatment resulted in a marked increase in LPA levels in bronchoalveolar lavage fluid following lung injury and caused pulmonary fibrosis, vascular leakage, and death, which Pathological changes were significantly attenuated in LPAR1 ^-/- mice; LPAR1 antagonist AM966 reduced total protein content and LDH activity in bronchoalveolar lavage fluid in a bleomycin model, indicating that AM966 reduces LPA-mediated IPF and other interstitial Vascular leakage and epithelial cell death in sexual lung disease. These findings suggest that LPAR1 is a promising target for the treatment of IPF, and the use of the LPAR1 antagonist BMS-986020 significantly slowed the decline in lung capacity in patients with idiopathic pulmonary fibrosis in a randomized, double-blind, placebo-controlled clinical trial , and alleviated clinical symptoms, and its second-generation compound BMS-986278 is undergoing Phase II clinical trials for the treatment of IPF (Swaney JS et al., Br J Pharmacol. 2010; 160(7): 1699-1713.).

Radiation pulmonary fibrosis is a common and serious complication of radiation therapy for lung cancer. The LPAR1/LPAR3 antagonist VPC12249 can inhibit the expression of fibroblast-promoting cytokines transforming growth factor β1 and connective tissue growth factor in vivo, resulting in decreased fibroblast proliferation in mice. Slows the progression of radiation pulmonary fibrosis, suggesting that LPAR1 antagonists also have the potential to treat radiation pulmonary fibrosis (Xiang H et al, J Cancer. 2020;11(12):3519-3535.).

LPAR1 is closely related to the occurrence 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, and inhibiting ATX-LPA signaling reduces the replication of hepatitis C virus. This process may be related to LPAR1 and LPAR3 are related, and hepatitis is a key factor in the development of liver fibrosis, suggesting that antagonism of LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol. 2017;66(5):919-929.); In another study, down-regulation of LPAR1 signaling reduced α-SMA, CTGF, and TGF-β1 expression, thereby significantly improving thioacetamide-induced liver fibrosis, further demonstrating that LPAR1 antagonists can be used to treat liver fibrosis change.

LPA promotes the progression of renal fibrosis through LPAR1. In mice with unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis (TIF), ATX and LPA concentrations were elevated, LPAR1 was significantly up-regulated, and LPAR3 was significantly down-regulated (Sakai N et al., FASEB J. 2013; 27( 5): 1830-1846.). ATX-LPA-LPAR1 signaling stimulates fibroblast migration and proliferation, and UUO-induced renal fibrosis is significantly attenuated on LPAR1 ^-/- mice or after pretreatment with the LPAR1/3 antagonist Ki16425, and when LPAR1 signaling is blocked The expression of pro-fibrotic cytokines (connective tissue growth factor and transforming growth factor-beta) was also significantly down-regulated upon interruption. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.

Fetal hydrocephalus (FH) is a common neurological disease in neonates, and its occurrence is closely related to LPAR1 signaling. In a preclinical mouse model of intracranial hemorrhage, by exposing mouse embryonic brains to blood or LPA, LPAR1 expressed by neural precursor cells (NPCs) was hyperactivated, leading to cortical disruption and thinning, ultimately leading to FH. (Yung YC et al. Sci Transl Med. 2011;3(99):99ra87.). Pretreatment with Ki16425 (an LPAR1/3 antagonist) in a mouse-related model can reduce the probability and severity of hemorrhagic hydrocephalus (PHH), suggesting that LPAR1 antagonists may be useful in the treatment of fetal hydrocephalus.

LPA-LPAR1 signaling has a significant tumor-promoting effect. LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion, activates vascular endothelial growth factor and activates metalloproteinases, and promotes tumor cell resistance to cisplatin in vitro. LPAR1 signaling downregulates the expression of tumor suppressor p53 in hepatoma cells; LPA activates PI3K and P38MPAK signaling pathways through LPAR1 to promote MMP-9 expression and HCC invasion; LPA-LPAR1 can also activate GTPase RhoA and Rho-related protein kinase (ROCK) Promotes invasiveness; it also induces protein kinase C (PKC) and nuclear factor kappa B (NF-kB) to promote epithelial-to-mesenchymal transition (EMT); in addition, the positive effect of LPA-LPAR1 on angiogenesis also promotes cancer development , because neovascularization is essential for the development of solid tumors. These findings suggest that LPAR1 antagonists have great potential in the treatment of related tumors (Xiang H et al, J Cancer. 2020;11(12):3519-3535.).

Peripheral nerve injury in humans can lead to a painful state called neuropathic pain, with symptoms including persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia, and LPAR1 signaling has been implicated in the development of neuropathic pain. Injury to the nervous system leads to serum leakage from the injury site, which exposes nerve cells to LPA and may be one of the causes of neuropathic pain. The study by Makoto Inoue et al. showed that the behavioral abnormalities and hyperalgesia induced by nerve injury in animal models can be eliminated by pretreatment with LPAR1 antagonists or targeted deletion of LPAR1, and can be simulated by intrathecal injection of LPA. Another study showed that LPA could induce neuropathic pain by activating LPAR1 to release the nociceptive factor substance P, and that LPAR1 ^-/- mice were resistant to neuropathic pain induced by partial sciatic nerve ligation. These results suggest that LPA-LPAR1 signaling plays a critical 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 of neuropathic pain requires lysophosphatidic acid receptor signaling [J]. 2004, 10(7):755-755.).

Rheumatoid arthritis (RA) is a chronic autoimmune disease, and LPAR1 signaling is related to the occurrence of RA. Compared with patients with osteoarthritis, LPAR1 and/or LPAR2 expression levels are increased in the synovium of patients with rheumatoid arthritis, preclinical studies have shown that gene knockout of LPAR1 completely abolished RA symptoms, and pharmacological antagonism of LPAR1 reduced the severity of the disease. Severity, reduced inflammation and bone erosion. (Kaffe E et al. Cancers (Basel). 2019; 11(11):1626. Published 2019 Oct 23. doi:10.3390/cancers11111626). Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and sensitizes them to tumor necrosis factor (TNF)-mediated apoptosis, and LPA is also involved in interleukin (IL)- 6. Production of IL-8 and cyclooxygenase-2 (COX-2). These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals of the Rheumatic Diseases, 2014, 73(1):298-305.).

SUMMARY OF THE INVENTION

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

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):

wherein, R ¹ is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), -ZR ^a , C _1-6 alkyl unsubstituted or substituted by R ^b {described "C _1-6 alkyl "such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R ^b is one or more (the number of which is subject to the substituted group conforming to the valence bond theory and stable existence. For example, 1, 2 or 3), when there are multiple R ^b , the R ^b is the same or different}, Unsubstituted or R ^b substituted C _3-6 cycloalkyl (the "C _3-6 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or 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 C _1-6 alkoxy group (the "C _1-6 alkoxy group" such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy base, hexyloxy);

Z is selected from single bond or -O-, -S-;

R ^a is selected from C _1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C ₁ substituted by halogen _-6 alkyl {The "halogen" is such as fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different};

R ^b is selected from -CN, halogen (eg fluorine, chlorine, bromine or iodine), C _1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, pentyl, hexyl), C _1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy, hexyloxy);

R ² is selected from -H, -CN, halogen (eg fluorine, chlorine, bromine or iodine), ^-YR ^d , unsubstituted or substituted C _1-6 alkyl {the "C _1-6 alkane""base" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the ^Re is one or more (the The number is subject to the substituted group conforming to the valence bond theory and stable existence. For example, 1, 2 or 3), when there are multiple ^Re , the ^Re is the same or different}, unsubstituted or by ^Re -substituted C _3-6 cycloalkyl (the "C _3-6 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or R ^substituted C _1-6 Alkylamino (the "C _1-6 alkylamino" such as

wherein n1 and n2 are each independently selected from integers from 0 to 6, the sum of n1 and n2 does not exceed 6, and/or n1 and n2 are not both 0), unsubstituted or substituted C _1-6 alkoxy with ^Re group (the "C _1-6 alkoxy group" such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy base, hexyloxy);

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

R ^d is selected from C _1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C ₁ substituted by halogen _-6 alkyl {The "halogen" is such as fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different};

R ^e is selected from -CN, halogen (eg fluorine, chlorine, bromine or iodine), C _1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) butyl, pentyl, hexyl), C _1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy, hexyloxy);

X ¹ , X ² and X ³ are each independently selected from C or N, and X ¹ , X ² and X ³ are not N at the same time;

^Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R, such as

^R is selected from -H, C _1-3 alkyl (eg methyl, ethyl, n-propyl, isopropyl), C _1-3 alkyl substituted by halogen { said "halogen" such as fluorine, Chlorine, bromine or iodine; the number of the halogen is one or more (the number is subject to the substituted group conforming to the valence bond theory and stable existence. For example, 1, 2 or 3), when When there are multiple halogens, the halogens are the same or different};

R ⁴ is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), C _1-6 alkyl unsubstituted or substituted by R ^g { said "C _1-6 alkyl" such as methyl base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R ^g is one or more (the number is after the substitution The group conforms to the valence bond theory and is subject to stable existence. For example, 1, 2 or 3), when there are multiple R ^g , the R ^g is the same or different}, unsubstituted or substituted by R ^g C _3-8 cycloalkyl (the "C _3-6 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), unsubstituted or by R ^g -substituted 4-8-membered heterocyclic group {heteroatoms in said "4-8-membered heterocyclic group" are selected from N, O and S; the number of said heteroatoms is 1-2 (the number of which is substituted by The latter group conforms to the valence bond theory and is subject to stable existence), when there are multiple heteroatoms, the heteroatoms are the same or different}, unsubstituted or substituted by R ^g 5-8-membered aryl group (such as benzene (such as thiophene, furan, oxazole, thiazole, triazole, pyridyl, ^pyrazinyl , pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl);

R ^g is selected from -H, halogen (eg fluorine, chlorine, bromine, iodine), C _1-6 alkyl (eg ), C _1-6 cycloalkyl (eg methyl, ethyl, n-propyl, isopropyl) base, n-butyl, n-pentyl), halogen-substituted C _1-6 alkyl (such as fluoroalkyl, also such as trifluoromethyl), C _1-6 alkoxy (such as methoxy, ethoxy group, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy), halogen-substituted C _1-6 alkoxy (e.g. difluoro methoxy);

L ¹ is selected from single bond, unsubstituted C _1-3 alkylene (for example

) or C _1-3 alkylene substituted with C _1-3 alkyl (eg

).

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ¹ is selected from fluorine, chlorine or bromine.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ¹ is selected from -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ OCH ₃ , -OCH ₂ F, -OCH ₂ CH ₂ F, -O(CH ₂ ) ₂ CH ₂ F. -OCH( _CH3 )( _CH2F ).

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ¹ is selected from -SCH ₃ , -SCH ₂ CH ₃ , -S(CH ₂ ) ₂ CH ₃ , -SCH(CH ₃ ) ₂ , -SCH ₂ F, -SCH ₂ CH ₂ F, -S(CH ₂ ) ₂ CH ₂ F, -SCH(CH ₃ )(CH _2F ).

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ¹ is selected from -CH ₃ , -CH ₂ CH ₃ , -(CH ₂ ) ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

-NH ₂ , -NH-CH ₃ , -N(CH ₃ ) ₂ , -NH-CH ₂ CH ₃ , -NH-(CH ₂ ) ₂ CH ₃ , -NH-CH(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCH(CH ₃ ) ₂ ;

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ¹ is selected from -CH ₂ CN, -CH ₂ CH ₂ CN, -(CH ₂ ) ₂ CH ₂ CN, -CH(CH ₃ )(CH ₂ CN),

-NH _- CH2CN, -N( _CH3 )( _CH2CN ), -NH- _CH2CH2CH2CN , -NH-( _CH2 ₎ _2CH2CN , -NH- _CH ( _CH3 ₎ (CH ₂ CN), -OCH ₂ CN, -OCH ₂ CH ₂ CN, -O(CH ₂ ) ₂ CH ₂ CN, -OCH(CH ₃ )(CH ₂ CN), -CH ₂ F, -CHF ₂ , CF ₃ , -CF ₂ CH ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ F, -(CH ₂ ) ₂ CH ₂ F, -CH(CH ₃ )(CH ₂ F),

-NH- _CH2F , -N( _CH3 )( _CH2F ), -NH- _CH2CH2CH2F , -NH-( _CH2 ₎ _2CH2F , -NH- _CH ( _CH3 ₎ (CH ₂ F), -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CF ₃ , -O(CH ₂ ) ₂ CH ₂ F, -OCH(CH ₃ )( _CH2F ), _-CH2CH2Cl , -( _CH2 ₎ 2CH2Cl, -CH( _CH3 ₎ ₍ _CH2Cl ),

-NH- _CH2Cl , -N( _CH3 )( _CH2Cl ), -NH- _CH2CH2CH2Cl , -NH-( _CH2 ₎ _2CH2Cl , -NH- _CH ( _CH3 ₎ (CH ₂ Cl), -OCH ₂ Cl, -OCH ₂ CH ₂ Cl, -O(CH ₂ ) ₂ CH ₂ Cl, -OCH(CH ₃ )(CH ₂ Cl),

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ² is selected from fluorine, chlorine or bromine.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ² is selected from -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ OCH ₃ , -OCH ₂ F, -OCH ₂ CH ₂ F, -O(CH ₂ ) ₂ CH ₂ F. -OCH( _CH3 )( _CH2F ).

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ² is selected from -SCH ₃ , -SCH ₂ CH ₃ , -S(CH ₂ ) ₂ CH ₃ , -SCH(CH ₃ ) ₂ , -SCH ₂ F, -SCH ₂ CH ₂ F, -S(CH ₂ ) ₂ CH ₂ F, -SCH(CH ₃ )(CH _2F ).

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ² is selected from -CH ₃ , -CH ₂ CH ₃ , -(CH ₂ ) ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

-NH ₂ , -NH-CH ₃ , -N(CH ₃ ) ₂ , -NH-CH ₂ CH ₃ , -NH-(CH ₂ ) ₂ CH ₃ , -NH-CH(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCH(CH ₃ ) ₂ .

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ² is selected from -CH ₂ CN, -CH ₂ CH ₂ CN, -(CH ₂ ) ₂ CH ₂ CN, -CH(CH ₃ )(CH ₂ CN),

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ³ is selected from -H, methyl, ethyl, _-CF3 , _-CH2CH2F _.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ⁴ is selected from methyl, ethyl, n-propyl , isopropyl, n-butyl, n-pentyl.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ⁴ is selected from cyclopropyl, cyclobutyl, cyclopropyl amyl.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ⁴ is selected from

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ⁴ is selected from phenyl and naphthalene ring.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ⁴ is selected from pyridyl.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ⁴ is selected from -CH ₂ F, -CHF ₂ , _-CF3 , _-CF2CH3 , _-CH2CF3 , _-CH2CH2F , _- ( _CH2 ₎ _2CH2F , -CH( _CH3 ₎ ₍ _CH2F ₎ , _-CH2CH2 Cl, -( _CH2 )2CH2Cl, -CH( _CH3 ₎ ₍ _CH2Cl ).

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ¹ is selected from -H, -CN, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -(CH ₂ ) ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

-NH ₂ , -NH-CH ₃ , -N(CH ₃ ) ₂ , -NH-CH ₂ CH ₃ -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CH ₂ CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CF ₃ , -O(CH ₂ ) ₂ CH ₂ F, -OCH(CH ₃ )(CH ₂ F),

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ² is selected from -H, -CN, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -(CH ₂ ) ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

In a certain scheme, the definitions of some groups of the compound represented by the formula (I) are as follows, and the undefined groups are as described in any of the previous schemes:

selected from

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ¹ is selected from -H, -F, methyl, Cyclopropyl.

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ² is selected from -H, -F, -Cl, _-CH3 .

In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R ⁴ is selected from -H, -F, methyl, Ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl,

-CH ₂ F, -CH ₂ CH ₂ F, -CF ₃ , -CH ₂ CF ₃ .

selected from

wherein R ¹ is selected from -CN, halogen (eg fluorine), C _1-3 alkyl (eg methyl, ethyl, n-propyl, isopropyl); R ² is selected from -H, -CN, halogen (eg 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) propyl, isopropyl); R ⁴ is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl base, phenyl,

-CH ₂ F, -CH ₂ CH ₂ F, -CF ₃ , -CH ₂ CF ₃ ; L ¹ is selected from single bond,

for

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 single bond.

for

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,

for

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 base, cyclopentyl, phenyl, -CH ₂ F, -CH ₂ CH ₂ F; L ¹ is selected from single bond,

for

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 mono key,

In a certain scheme, the compound represented by the formula (I) is further the compound represented by the formula (I-0):

Wherein, R ¹ is selected from -H, -CN, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -(CH ₂ ) ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

-NH ₂ , -NH-CH ₃ , -N(CH ₃ ) ₂ , -NH-CH ₂ CH ₃ -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -CH ₂ CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CF ₃ , -O(CH ₂ ) ₃ F, -OCH(CH ₃ )(CH ₂ F),

R ² is selected from -H, -CN, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -(CH ₂ ) ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R ¹ ;

R ³ is selected from -H, C _1-3 alkyl, C _1-3 alkyl substituted by halogen;

R ⁴ is selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopropyl amyl,

_Phenyl , pyridyl, naphthalene ring, _-CH2F , _-CHF2 , _-CF3 , _-CF2CH3 , _-CH2CF3 , _-CH2CH2F , _- ₍ _CH2 ₎ _2CH2F , -CH( _CH3 )( _CH2F ), _-CH2CH2Cl , -( _CH2 ₎ 2CH2Cl, -CH( _CH3 ₎ ₍ _CH2Cl ),

L ¹ is selected from single bond, unsubstituted or C _1-6 alkylene substituted by C _1-3 alkyl.

R ³ is selected from -H, C _1-3 alkyl, C _1-3 alkyl substituted by halogen;

selected from

In a certain scheme, the compound represented by the formula (I) is further the compound represented by the formula (I-1'):

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 {described The "halogen" is such as fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number is subject to the substituted group conforming to the valence bond theory and stable existence. 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 independently selected from C or N, and X ¹ , X ² and X ³ are different when is N.

In one scheme, R ¹ is methyl, R ² is halogen, and R ³ is methyl

selected from

In a certain scheme, the compound represented by the formula (I) may be any of the following compounds:

The present invention also provides a pharmaceutical composition comprising the above-mentioned compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

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

The present invention also provides a compound represented by the above formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) in the preparation of therapeutic and Use in medicine for LPAR-related diseases.

In the use, the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.

In said use, said LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal brain volume water.

In some embodiments, the present invention provides a pharmaceutical composition comprising an effective amount of a compound as previously described.

Description of drawings

FIG. 1 is the experimental result of reducing bleomycin-induced pulmonary fibrosis in mice by antagonizing LPAR1 by compounds according to the embodiments of the present invention.

Definition and Explanation of Terms

Unless otherwise stated, definitions of groups and terms set forth in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations, group definitions and compound structures after the combination should fall within the scope described in the specification of the present application.

Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms in this document, the definitions in this chapter shall prevail.

Unless otherwise stated, conventional methods within the skill in the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in this application. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds. When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _CH2O is equivalent to _OCH2 .

The numerical range described in the specification and claims of the present application, when the numerical range is understood as an "integer", should be understood as describing the two endpoints of the range and each integer in the range. For example, "an integer of 1 to 6" should be understood as reciting each integer of 0, 1, 2, 3, 4, 5, and 6. When such a numerical range is read as a "number," it should be understood as reciting both endpoints of the range and each integer within the range and every decimal point within the range. For example, "a number from 1 to 10" should be understood as not only reciting each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also reciting at least that each integer is respectively associated with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

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 human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

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

In addition to the pharmaceutically acceptable salts, other salts are also contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.

The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers. Stereochemical definitions and conventions used herein are generally in accordance with 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”, defined by John Wiley & Sons, Inc., New York, 1994.

Depending on the choice of starting materials and methods, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers. A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing an optically active compound, 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 (or centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane polarized light 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. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl group may be in the cis- or trans- (cis- or trans-) configuration.

When the bond to the chiral carbon in the formula of the present invention is depicted in line, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of this formula. A schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge and dashed bonds are used to indicate the absolute configuration of a stereocenter.

Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for the fractional recrystallization process 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 β- D and L forms of camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Selection of specific methods, elution conditions, and selection of chromatographic columns can be selected by those skilled in the art according to the structures of compounds and test results. Further, any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

The terms "effective dose", "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refer to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of one active substance in a 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, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

The term "solvate" means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.

The term "prodrug" refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound. The prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds. Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.

The term "C _1-6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, ₂ , 3, 4, 5 or 6 carbon atoms. The alkyl group is, 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, etc. or their isomers. In particular, the groups have 1, 2 or ₃ carbon atoms (" _C1 -C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

The term "C3-6cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having ₃ to ₆ carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "alkylamino" or "alkylamino" refers to an amino group substituted with one or two hydrogen atoms by an alkyl group, including "N-alkylamino" and "N,N-dialkylamino", wherein the amino group The groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meanings as defined herein. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "C _1-6 alkylamino" refers to "alkylamino" or "alkylamino" having 1 to 6 carbon atoms.

The term "C _1-6 alkoxy" is to be understood as _{-O-(C 1-6} _alkyl ₎ , wherein "C _1-6 _alkyl " has the above definition.

The term "4-8 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, of which 1, 2, 3, 4 or 5 rings Atoms are selected from N, O, and S, which, unless otherwise specified, may be attached through carbon or nitrogen, wherein the _-CH2- group is optionally replaced by -C(O)-; and wherein, unless otherwise specified, the ring nitrogen Atoms or ring sulfur atoms are optionally oxidized to form N-oxides or S-oxides or ring nitrogen atoms are optionally quaternized; wherein -NH in the ring is optionally acetyl, formyl, methyl or methyl sulfonyl substitution; and the ring is optionally substituted with 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 heterocyclyl 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 heterocyclyl group is monocyclic, it must not be aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indoline, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 -Dioximidazolidinyl.

The term "5-8 membered aryl" is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 5-8 carbon atoms, especially a ring having 6 carbon atoms (" C ₆ aryl"), such as phenyl; when the 5-8 membered aryl is substituted, it may be mono- or poly-substituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.

The term "5-8 membered heteroaryl" is to be understood as having 5-8 ring atoms - in particular 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S A monovalent monocyclic, bicyclic or tricyclic aromatic ring group. 1-3 monovalent monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and, in addition, in each case may be benzo-fused . In particular, heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; group, carbazolyl group, acridine group, phenazinyl group, phenothiazinyl group, phenoxazinyl group and the like.

The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.

"Haloalkyl" is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (eg -CvFw, where v=1 to 3, w=1 to (2v+ 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

beneficial effect

According to a specific example of the present invention, the compound represented by formula (I), its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the present invention has a good antagonistic effect on LPAR1.

According to the specific example of the present invention, the compound of the present invention has a good antagonistic effect on LPAR1, but a 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 and no cholestatic toxicity. Risk, no hepatotoxicity; the compound of the present invention has excellent pharmacokinetic properties and good druggability; the compound of the present invention can significantly inhibit LPA-induced histamine release by antagonizing LPAR1, and at the same time significantly improve bleomycin-induced mouse pulmonary fibrosis Symptoms.

Additional aspects and advantages of the present invention will be set forth, in part, from the following description, and in part will be apparent from the following description, or may be learned by practice of the invention.

Detailed ways

The solution of the present invention will be explained below in conjunction with the embodiments. Those skilled in the art will understand that the following examples are only used to illustrate the present invention, and should not be construed as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used. The reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.

The embodiments of the present invention provide compounds represented by formula (I), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs thereof, to prepare formula (I) ) of the compound or its pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs, methods and intermediates, pharmaceutical compositions, and compounds of the present invention and the use of the pharmaceutical composition in the preparation of medicine.

The reaction solvent used in each reaction step of the present invention is not particularly limited, and 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 in the art, equivalent replacements, or equivalent to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are ^10-6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

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

Abbreviations of the present invention are defined as follows:

Symbol or unit:

IC ₅₀ : half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved

M: mol/L, for example n-butyllithium (14.56mL, 29.1mmol, 2.5M n-hexane solution) represents a n-butyl lithium solution with a molar concentration of 2.5mol/L in n-hexane

N: equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution

RT: retention time

Reagents:

CuI: cuprous iodide

DCM: dichloromethane

DIBAL-H: Diisobutylaluminum hydride

DIPEA: can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine

DMF: N,N-Dimethylformamide

DMSO: Dimethyl Sulfoxide

Et ₃ N: triethylamine

HATU: 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

MeOH: methanol

NADPH: reduced coenzyme II

NaH: sodium hydrogen, sodium hydride

NMM: N-Methylmorpholine, aka N-Methylmorpholine

NMP: N-Methylpyrrolidone

T ₃ P: propylphosphoric acid tricyclic anhydride, that is, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide or 1-propyl phosphoric anhydride

THF: Tetrahydrofuran

TMSN ₃ : azidotrimethylsilane

TsCl: p-toluenesulfonyl chloride

Test or detection method:

HPLC: High Performance Liquid Chromatography

SFC: Supercritical Fluid Chromatography

Unless indicated to the contrary, compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.

Comparative Example 1: Comparative Compound 1 and its preparation

Reference compound 1 was synthesized with reference to patent application WO2010141768A2.

Comparative Example 2: Comparative Compound 2 and its preparation

Reference compound 2 was synthesized with reference to patent application WO2017223016A1.

Comparative Example 3: Comparative Compound 3 and its preparation

Reference compound 3 was synthesized with reference to patent application WO2017223016A1.

Comparative Example 4: Comparative Compound 4 and its preparation

Control compound 4 was synthesized with reference to patent application WO2019126098A1.

Comparative Example 5: Comparative Compound 5 and its preparation

Control compound 5 was synthesized with reference to patent application WO2019126084A1.

Preparation Example 1: Preparation of Intermediate A

(1S,3R)-Methyl 3-hydroxycyclohexane-1-carboxylate (Intermediate A)

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

The synthetic route of intermediate A is as follows:

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

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

(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. Stir overnight at room temperature in the dark. TLC monitored the completion of the reaction, the liquid was separated, 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-oxygen Heterocyclo[3.2.1]octan-7-one (A-2) (13.6 g, 84% yield) was used directly in the next reaction.

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

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

(1S,5S)-4-iodo-6-oxacyclo[3.2.1]octan-7-one (A-2) (13.2 g, 52.4 mmol) was dissolved in MeOH (150 mL) and sodium acetate was added (4.30 g, 52.4 mmol), lithium chloride (2.22 g, 52.4 mmol) and 10% dry palladium on carbon (1.115 g). The hydrogen was replaced three times, and the reaction was stirred overnight with a hydrogen balloon at room temperature. The reaction solution was filtered through celite, concentrated, and 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 a white solid (1S,5R)-6-oxacyclo[3.2.1]octan-7-one (A-3) (3.88 g, 58.7% yield).

The third step: Synthesis of (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (intermediate A)

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

(1S,5R)-6-oxacyclo[3.2.1]octan-7-one (A-3) (4.2 g, 33.3 mmol) was dissolved in MeOH (150 mL), and the reaction solution was cooled to 0-5 °C , acetyl chloride (7.5 mL) was added dropwise to the reaction solution, the dropwise addition was completed, and the temperature was raised to room temperature for 3 h. The completion of the reaction was monitored by TLC, 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 give (1S,3R)-methyl 3-hydroxycyclohexane-1-carboxylate (Intermediate A) (4.63 g, 88% yield) as a pale yellow oil. ).

¹ H NMR (400MHz, CDCl ₃ ) 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).

Preparation Example 2: Preparation of Intermediate B

Methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate B)

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

The synthetic route of intermediate B is shown below:

To (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (Intermediate A) (1.10 g, 6.95 mmol), 6-bromo-2-methyl-pyridine-3- at 0 °C To a solution of alcohol (1.19 g, 6.31 mmol) and tributylphosphine (2.55 g, 12.6 mmol) in toluene (20.0 mL) was added azodicarbonyldipiperidine (3.19 g, 10.7 mmol) dropwise, then the mixture was added to The reaction was stirred at 80°C for 10 hours under nitrogen. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain (1S,3S)-3-((6- Bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (Intermediate B) (0.580 g, 30.3% yield).

Preparation Example 3: Synthesis of Intermediate C

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

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

The synthetic route of intermediate C is as follows:

To (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (Intermediate B) (0.5 g, 1.52 mmol) Add tetrakistriphenylphosphonium palladium (88.02 mg, 76.17 μmol), hexa-n-butylditin (5.30 g, 9.14 mmol, 4.57 mL) to the xylene (10 mL) solution, under nitrogen atmosphere, heat to 135 ° C and stir 2h. Cool to room temperature, then add saturated potassium fluoride solution (10 mL) to quench, then extract with ethyl acetate (10 mL×2), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate to obtain compound (1S,3S)-3- Methyl ((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate C) (0.82 g, crude).

Example 1: Preparation of target compound I-1

(1S,3S)-3-(4-(5-Chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexyl Alkane-1-carboxylic acid (target compound I-1)

(1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid (target compound I -1)

The synthetic route of the target compound I-1 is as follows:

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

(2-bromothiophen-3-yl)methanol(I-1B)

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) at 0 °C. Stir at room temperature for 1 h. After the raw materials were reacted, distilled water (30 mL) was added to dilute, extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phase was washed with saturated brine (30 mL), the layers were separated, and the organic phase was dried over anhydrous sodium sulfate, Filtration, concentration, and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1) to give (2-bromothiophen-3-yl)methanol (I-1B) (12.3 g) as a yellow oil , yield 72.7%).

¹ H NMR (400MHz, DMSO-d6)δ7.54(d,1H), 7.05(d,1H), 4.38(s,2H).

The second step: the synthesis of (2-bromothiophen-3-yl) methyl (4-nitrophenyl) carbonate (I-1C)

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

Pyridine (10.89 mL, 135 mmol), phenyl 4-nitrochloroformate (16.29 g, 81 mmol) were added sequentially to dichloromethane (50 mL) containing (2-bromothiophen-3-yl)methanol (5.2 g, 26.9 mmol) ) solution and stirred at room temperature overnight. After the raw materials were reacted, the reaction solution was directly concentrated, and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1) to obtain (2-bromothiophen-3-yl)methyl (4 -Nitrophenyl)carbonate (I-1C) (5.4 g, 56.0% yield).

¹ H NMR (400MHz, DMSO-d6)δ8.34-8.30(m,1H), 7.67(d,1H), 7.58(d,2H), 7.15(d,1H), 5.24(s,2H).

The third step: the synthesis of (2-bromothiophen-3-yl) methylcyclopentyl (methyl) carbamate (I-1D)

(2-bromothiophen-3-yl)methylcyclopentyl(methyl)carbamate(I-1D)

DIEA (4.75 mL, 27.2 mmol) was added dropwise to the mixture containing (2-bromothiophen-3-yl)methyl(4-nitrophenyl)carbonate (3.9 g, 10.89 mmol), N-methylcyclopentylamine The hydrochloride (1.625 g, 11.98 mmol) in THF (30 mL) was reacted overnight at room temperature. After the raw materials were reacted, distilled water (10 mL) was added to dilute, extracted with ethyl acetate (30 mL×3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, Filtration, concentration, and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1) to give (2-bromothiophen-3-yl)methylcyclopentyl(methyl)amino as yellow oil Formate (I-1D) (3.04 g, 88% yield).

¹ H NMR (400MHz, DMSO-d6)δ7.60(d,1H), 7.05(d,1H), 4.96(s,2H), 2.71(s,3H), 1.73-1.44(m,9H).

The fourth step: the synthesis of (2-bromo-5-chlorothiophen-3-yl) methylcyclopentyl (methyl) carbamate (I-1E)

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

At 0 °C, N-chlorosuccinimide (0.766 g, 5.74 mmol) was slowly added to the mixture containing (2-bromothiophen-3-yl)methylcyclopentyl(methyl)carbamate (1.66 g) , 5.22 mmol) in DMF (15 mL). Stir overnight at 70°C. After the reaction of the raw materials, distilled water (50 mL) was added to dilute, extracted with ethyl acetate (60 mL×3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, Filtration, concentration, and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1) to give (2-bromo-5-chlorothiophen-3-yl)methylcyclopentyl as a yellow oil (Methyl)carbamate (I-1E) (1.55 g, 84% yield).

¹ H NMR (400MHz, DMSO-d6)δ7.12(s,1H),4.86(s,2H),2.71(s,3H),1.49-1.70(m,9H).

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

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

[1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.322 g, 0.439 mmol) was added to a compound containing (2-bromo-5-chlorothiophen-3-yl)methylcyclopentane yl(methyl)carbamate (1.55 g, 4.39 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) In a reaction solution of phenol (0.967 g, 4.39 mmol), 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 completion of the reaction, filter and concentrate the filtrate directly. The residue was purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:1) to obtain (5-chloro-2-(4-hydroxyphenyl)thiophen-3-yl)methylcyclopentane as a yellow solid (Methyl)carbamate (I-1F) (910 mg, 56.6% yield).

¹ H NMR(400MHz, DMSO-d6)δ9.81(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).

The sixth step: (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy Synthesis of methyl) cyclohexane-1-carboxylate (I-1G)

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

Tri-tert-butylphosphine (0.645 g, 2.460 mmol), diisopropyl azodicarboxylate (0.478 mL, 2.460 mmol), (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester ( 0.259 g, 1.640 mmol) was added with (5-chloro-2-(4-hydroxyphenyl)thiophen-3-yl)methylcyclopentyl(methyl)carbamate (0.3 g, 0.820 mmol) in THF (10 mL), stirred at 60°C overnight under nitrogen protection. After the reaction, add distilled water (20 mL) to dilute, extract with ethyl acetate (30 mL×3), combine the organic phases, wash the organic phase with saturated brine (10 mL), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter , concentrated, and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:1) to give (1S,3S)-3-(4-(5-chloro-3-(() as a yellow oil. (Cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (I-1G) (110 mg, 26.5% yield) ).

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).

The seventh step: (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy Synthesis of cyclohexane-1-carboxylic acid (target compound I-1)

(1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid (target compound I- 1)

Lithium hydroxide monohydrate (32.3 mg, 0.771 mmol) was added to the compound containing (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy) )methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester (130 mg, 0.257 mmol) in a mixed solution of THF (2 mL) and MeOH (2 mL) was stirred at room temperature overnight. After the reaction, distilled water (5 mL) was added to dilute, and the pH was adjusted to 3-4 with dilute hydrochloric acid (1N), then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phase was washed with saturated brine (10 mL). , the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified with a preparative plate (ethyl acetate) to give a 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%).

¹ H NMR (400MHz, DMSO-d6)δ7.37(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).

LC-MS, M/Z (ESI): 492.1 [M+H] ⁺ .

Example 2: Preparation of target compound I-2

(1S,3S)-3-((6-(5-Chloro-3-(((((cyclobutylmethyl)(methyl)aminocarbonyl)oxo)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxo)cyclohexane-1-carboxylic acid (target compound I-2)

(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)

The synthetic route of the target compound I-2 is as follows:

The first step: the synthesis of 6-bromo-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pyridine (I-2B)

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

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

LC-MS, M/Z(ESI): 272.3[M+H] ⁺

The second step: Synthesis of 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C)

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

The raw material 6-bromo-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pyridine (200mg, 0.74mmol) was added to 15mL DMF at room temperature, and 3- Formyl-2-thiopheneboronic acid (149 mg, 0.96 mmol), bis(tri-tert-butylphosphine)palladium (38 mg, 0.074 mmol), anhydrous potassium carbonate (304 mg, 2.20 mmol), heated to 90° C. and stirred for 16 h. Water (200 mL) was added to dilute, 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 (petroleum ether: ethyl acetate (V/ V)=4:1) to give the title compound as a colorless liquid 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C) (200 mg, 89.7% yield).

LC-MS, M/Z(ESI): 304.4[M+H] ⁺

The third step: (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methanol (I-2D) Synthesis

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

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 methanol (30 mL) solution, sodium borohydride (709.3 mg, 18.75 mmol) was added at 0°C, and the reaction was stirred at 0°C for 2 hours. The reaction solution was quenched with water (20 mL), then extracted with ethyl acetate (30 mL×2), and the organic layers were combined to obtain a crude product. Separation and purification by silica gel column gave (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methanol (I- 2D) (3.1 g, 81.2% yield).

The fourth step: (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(4-nitro Synthesis of phenyl)carbonate (I-2F)

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

To (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methanol (I-2D) at room temperature (1 g, 3.27 mmol) and phenyl 4-nitrochloroformate (0.99 g, 4.91 mmol) in dichloromethane (20 mL) were added pyridine (0.78 g, 9.82 mmol) and stirred at room temperature overnight. After the reaction was completed, the crude product was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by a silica gel column to obtain a brown liquid compound (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridine- 2-yl)thiophen-3-yl)methyl(4-nitrophenyl)carbonate (I-2F) (1.1 g, 71.4% yield).

The fifth step: (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl) ) synthesis of carbamate (I-2G)

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

to (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 stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether:ethyl acetate (V/V)=20:1) to obtain 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%).

The sixth step: (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl) ) (methyl) carbamate (I-2H) synthesis

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

Under ice bath, (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl) yl)carbamate (I-2G) (1.9 g, 6.25 mmol) in DMF (20 mL) was added sodium hydride (0.500 g, 12.49 mmol, 60% purity) followed by iodomethane (0.778 mL, 12.49 mmol) ), removed the ice bath, and reacted at room temperature overnight. Water (20 mL) was added to quench, extracted with ethyl acetate (30 mL×2), the organic phase was concentrated, and the residue was purified by silica gel column to obtain 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, 75% yield).

The seventh step: (5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl)(methyl)carbamate (I- 2I) Synthesis

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

To (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl) at room temperature To a solution of N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (0.34 mg). , 2.51 mmol), then stirred at 80 °C overnight. After the reaction was completed, the reaction mixture was diluted with water (30 mL), and then extracted with ethyl acetate (20 mL×2). The organic phase was washed with an aqueous solution of sodium chloride (30 mL×2), the organic layers were combined, and the concentrated residue was used Silica gel column purification gave yellow solid compound (5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl)(methyl)carbamate (I-2I) (0.22 g, 46.1% yield).

Step 8: (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-2J) synthesis

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)

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), (1S,3R)-methyl 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 with nitrogen gas, diisopropyl azodicarboxylate (143.34 mg, 708.87 μmol) was slowly added, 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)=20:1-2:1) to get (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) (0.3g) ,Crude).

The ninth step: (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)aminocarbonyl)oxo)methyl)thiophen-2-yl) Synthesis of -2-methylpyridin-3-yl)oxo)cyclohexane-1-carboxylic acid (target compound I-2)

(1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) at room temperature Methyl 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) followed by Aqueous 1M lithium hydroxide solution (1.02 mL, 1.02 mmol) was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH=5 with 1M hydrochloric acid, and concentrated under reduced pressure to obtain a crude product, which was separated by preparation (separation method: chromatographic column: Phenomenex Luna C18 150*25mm*10 μm; mobile phase: A=water+0.05% by volume hydrochloric acid ( 36.5%), B=acetonitrile; gradient elution: 59%-89% B, 10 minutes)) to give 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 1 -2) (0.024 g, 22.63% yield).

¹ H NMR (400MHz, CDCl ₃ )δ7.30(br s,1H),7.14(br s,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).

LC-MS, M/Z (ESI): 507.2 [M+H] ⁺ .

Example 3: Preparation of target compound I-3

(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)

(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)

The synthetic route of the target compound I-3 is as follows:

The first step: (1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid Synthesis of methyl ester (I-3B)

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

At room temperature, methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (3 g, 9.14 mmol) (middle Compound 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) followed by bis(tri-tert-butylphosphine) ) palladium (373.71 mg, 731.26 μmol), the reaction solution was protected with nitrogen, stirred at 25° C. for 4 hours, the reaction mixture was diluted with ethyl acetate (30 mL), and then extracted with saturated aqueous sodium chloride solution (30 mL), and the organic layer and concentrated to give the title compound (1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- Methyl carboxylate (I-3B) (3.12 g, 94.96% yield).

The second step: (1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- Synthesis of Methyl Carboxylate (I-3C)

methyl(1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3C)

To (1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- To a methanol solution (10 mL) of methyl carboxylate (1.5 g, 4.17 mmol), sodium borohydride (236.82 mg, 6.26 mmol) was added in portions, and the mixture was stirred at 0 °C for 0.5 h. After the reaction was completed, the reaction mixture was washed with water (10 mL). ) was quenched, 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-carboxylate (I-3C) (1.4 g, 92.81% yield).

The third step: (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Synthesis of methyl alkane-1-carboxylate (I-3D)

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

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

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

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)

To (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl at room temperature Methyl alkane-1-carboxylate (1.05 g, 2.65 mmol) and phenyl 4-nitrochloroformate (1.60 g, 7.96 mmol) in dichloromethane (10 mL) was added pyridine (1.05 g, 13.26 mmol), in Stir at room temperature for 2 hours. After the reaction was completed, the crude product was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-1:1) to obtain (1S,3S)-3-((6- (5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane -Methyl 1-carboxylate (I-3E) (0.96 g, 64.52% yield).

The fifth step: (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-3F) synthesis

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)

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

The sixth step: (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophene Synthesis of -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-3G)

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)

To (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 iodomethane (524.88 mg, 3.70 mmol) in N,N-dimethylformamide ( Sodium hydrogen (142 mg, 3.55 mmol, 60% content) was added to 5 mL), and the mixture was stirred at 25° C. for 1 hour. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL×2), the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL×2), and the organic phase was spin-dried under reduced pressure to obtain The crude product, the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=15:1-1:1) to obtain the title compound (1S,3S)-3-((6-(5-chloro- 3-((((2-Cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Methyl alkane-1-carboxylate (I-3G) (0.55 g, 71.36% yield).

Step 7: (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophene -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)

To (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl) at room temperature Thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (0.2g, 383.83umol) in tetrahydrofuran (5mL) was added lithium hydroxide aqueous solution (1M , 1.92 mL), stirred at 20 °C for 5 hours. After the completion of the reaction, the reaction solution was adjusted to pH=6 with saturated aqueous citric acid solution, concentrated under reduced pressure to obtain the 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%).

LC-MS, M/Z (ESI): 507.2 [M+H] ⁺ .

¹ H NMR(400MHz, CDCl ₃ )δ7.53(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).

Example 4: Preparation of target compound I-4

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

(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)

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

The first step: (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-4A)

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)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl Methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (180 mg, 0.321 mmol), N-methylbenzylamine (46.7 mg, 0.385 mmol) in dichloromethane (6 mL), N,N-diisopropylethylamine (83 mg, 0.642 mmol) was added, and the mixture was 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 yellow solid compound (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl) Methyl 5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-4A) (110 mg, 63.1% yield).

The second step: (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)

(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)

At room temperature, (1S,3S)-3-((6-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2 -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (100mg, 0.184mmol) in tetrahydrofuran (3mL), methanol (1mL) and water (1mL) mixed solution, added a Water and lithium hydroxide (23.18 mg, 0.552 mmol) were reacted at room temperature overnight, then adjusted to pH 3 with 1N HCl solution, concentrated, and 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-chlorothien-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Alkane-1-carboxylic acid (62 mg, 63.6% yield).

LC-MS, M/Z(ESI): 529.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d6) δ7.50-6.80(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).

Example 5: Preparation of target compound I-5

(1S,3S)-3-((6-(5-Chloro-3-(((isoamyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)

(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)

The synthetic route of the target compound I-5 is as follows:

The first step: the synthesis of isoamyl carbamate tert-butyl ester (I-5B)

tert-butyl isopentylcarbamate(I-5B)

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), reacted at room temperature overnight after the addition, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1) to obtain tert-butyl isoamylcarbamate as a colorless oily compound (I-5B) (1.4 g, 65.2% yield).

The second step: the synthesis of isoamyl (methyl) tert-butyl carbamate (I-5C)

tert-butyl isopentyl(methyl)carbamate(I-5C)

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

The third step: the synthesis of N,3-dimethylbutane-1-amine hydrochloride (I-5D)

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

Tert-butyl isoamyl(methyl)carbamate (I-5C) (1.3 g, 6.46 mmol) was added to 4 mL of a 4M solution of hydrogen chloride in 1,4-dioxane, stirred at room temperature for 3 h, and concentrated to obtain White solid compound N,3-dimethylbutan-1-amine hydrochloride (I-5D) (0.89 g, 100% yield).

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

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)

(1S,3S)-3-((6-(5-Chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1 -Methyl 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-nitrochloroformic acid (0.15 g, 0.758 mmol) were added, and the mixture was stirred at room temperature 3h, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1) to obtain light yellow oily compound (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-5E) (0.2 g, 70.6% yield).

Step 5: (1S,3S)-3-((6-(5-Chloro-3-(((isoamyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5F)

methyl(1S,3S)-3-((6-(5-chloro-3-(((isopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) cyclohexane-1-carboxylate

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5E) (0.14 g, 0.250 mmol), N,3-dimethylbutan-1-amine hydrochloride ( 026D) (0.103 g, 0.749 mmol) was dissolved in 4 mL of tetrahydrofuran, then diisopropylethylamine (0.194 g, 1.50 mmol) was added, stirred at room temperature for 24 h, concentrated, and the residue was separated and purified by silica gel column (petroleum ether: ethyl acetate) Ester (V/V)=3:1) to give colorless oily compound (1S,3S)-3-((6-(5-chloro-3-(((isoamyl(methyl)carbamoyl)oxy) (1-5F) (80 mg, 60.3% yield).

Step 6: (1S,3S)-3-((6-(5-Chloro-3-(((isoamyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)

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

LC-MS, M/Z(ESI): 509.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d6)δ12.18(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).

Example 6: Preparation of target compound I-6

(1S,3S)-3-((2-(5-Chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methyl Pyrimidine-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6)

(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)

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

The first step: the synthesis of 2-bromo-4-methylpyrimidin-5-ol (I-6B)

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

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) at room temperature, followed by stirring at 100° C. for 1 hour. After the reaction solution was cooled to room temperature, the reaction solution was poured into ice water (100 mL), then extracted with ethyl acetate (100 mL×3), the organic layers were combined, and spin-dried to obtain the title compound 2-bromo-4-methylpyrimidine -5-phenol (I-6B) (8.5 g, 92.87% yield). used directly in the next step.

The second step: Synthesis of (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-6C)

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

To 2-bromo-4-methylpyrimidin-5-ol (5 g, 26.45 mmol), (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (8.37 g, To a solution of 52.91 mmol) and triphenylphosphine (13.88 g, 52.91 mmol) in tetrahydrofuran (50 mL) was added diisopropyl azodicarboxylate (10.70 g, 52.91 mmol), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The title compound (1S,3S)-3-((2-bromo-4-methylpyrimidine-5) was obtained by separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) -yl)oxy)cyclohexane-1-carboxylate (I-6C) (6 g, 18.23 mmol, 68.90% yield).

The third step: (1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl Synthesis of Ester (I-6E)

methyl(1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6E)

At room temperature, (3-formylthiophen-2-yl)boronic acid (2.13 g, 13.67 mmol), (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy yl)cyclohexane-1-carboxylate (3 g, 9.11 mmol), palladium ditri-tert-butylphosphine (400 mg, 782.70 umol) and potassium fluoride (3.18 g, 54.68 mmol) were added to a solution of tetrahydrofuran (50 mL) was replaced with nitrogen three times, followed by stirring at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The title compound (1S,3S)-3-((2-(3-formylthiophene-2-) was obtained by separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-5:1) (1-6E) (2.5 g, 76.11% yield).

The fourth step: (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1 -Synthesis of methyl carboxylate (I-6F)

methyl(1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6F)

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

LC-MS, M/Z (ESI): 395.0 [M+H] ⁺ .

The fifth step: (1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexyl Synthesis of Methyl Alkane-1-carboxylate (I-6G)

methyl(1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6G)

To (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane at 0 °C To a solution of methyl-1-carboxylate (I-6F) (1 g, 2.53 mmol) in methanol (2 mL) was added sodium borohydride (95.81 mg, 2.53 mmol) in portions, and the mixture was stirred at 0°C for 0.5 h. The reaction was quenched with 1M 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 (petroleum ether:ethyl acetate (V/V)=15:1-1 : 1) to obtain compound (1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy) ring Methyl hexane-1-carboxylate (I-6G) (0.5 g crude).

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

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)

To the (1S,3S)-3-((2-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy) ring at room temperature To a solution of methyl hexane-1-carboxylate (0.4 g, 1.01 mmol) and phenyl 4-nitrochloroformate (43 mg, 3.02 mmol) in dichloromethane (5 mL) was added pyridine (398.60 mg, 5.04 mmol) 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 obtain compound (1S,3S)-3-((2-(5- Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1- Methyl carboxylate (I-6H) (0.45 g, 44.8% yield).

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

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)

To (1S,3S)-3-((2-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl) at room temperature -4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (0.4 g, 711.76 μmol) and N-methylcyclopentylamine hydrochloride (96.54 mg, 711.76 μmol) To a solution of tetrahydrofuran (5 mL), N,N-diisopropylethylamine (275.97 mg, 2.14 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL), and then added with ethyl acetate (10 mL). ×2) extraction and concentration under reduced pressure to obtain the title compound (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, 80.7% yield).

Step 8: (1S,3S)-3-((2-(5-Chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6)

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

LC-MS, M/Z (ESI): 508.3 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.20(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).

Example 7: Preparation of target compound I-7

(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)

(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)

The synthetic route of the target compound I-7 is as follows:

The first step: Synthesis of (cyclobutylmethyl)aminocarboxylate tert-butyl ester (I-7B)

tert-butyl(cyclobutylmethyl)carbamate(I-7B)

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 ( 1.795g, 8.22mmol), reacted at room temperature overnight after the addition, concentrated, and the residue was separated and purified by silica gel column to obtain a colorless oily compound (cyclobutylmethyl)aminocarboxylate tert-butyl ester (I-7B) (1.27g, yield 83%).

The second step: the synthesis of (cyclobutylmethyl) (methyl) aminocarboxylate tert-butyl ester (I-7C)

tert-butyl(cyclobutylmethyl)(methyl)carbamate(I-7C)

(Cyclobutylmethyl)aminocarboxylate tert-butyl ester (I-7B) (1.27g, 6.86mmol) was added to 20mL of tetrahydrofuran, cooled to 0°C, added with 60% sodium hydride (0.329g, 8.23mmol), After stirring 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 for quenching and concentration, and the residue was separated and purified by silica gel column to obtain a colorless oily compound (cyclobutylmethyl)(methyl)aminocarboxylate tert-butyl ester (I-7C) (0.33 g, yield 24.16%).

The third step: the synthesis of 1-cyclobutyl-N-methyl methylamine hydrochloride (I-7D)

1-cyclobutyl-N-methylmethanamine hydrochloride(I-7D)

(Cyclobutylmethyl)(methyl)aminocarboxylate tert-butyl ester (0.33 g, 1.656 mmol) was added to 4 mL of 4 mol/L hydrogen chloride solution in 1,4-dioxane, stirred at room temperature for 3 h, and concentrated to obtain The white solid compound 1-cyclobutyl-N-methylmethanamine hydrochloride (I-7D) (0.2 g, 89.5% yield).

The fourth step: (1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl )-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-7E)

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)

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

The fifth step: (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) synthesis

(1S,3S)-3-((2-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) at room temperature -4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (100 mg, 0.192 mmol) was added to 3 mL of tetrahydrofuran solution, then 1 mL of water and 1 mL of methanol, followed by a Water and lithium hydroxide (16.08 mg, 0.383 mmol) were reacted at room temperature overnight, adjusted to pH 3 with 1 M hydrogen chloride solution in 1,4-dioxane, concentrated to dryness, and the residue was separated and purified by silica gel plate to obtain a white solid compound ( 1S,3S)-3-((2-(5-Chloro-3-(((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-7) (10.2 mg, 10.48% yield).

LC-MS, M/Z(ESI): 508.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 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).

Example 8: Preparation of target compound I-8

(1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidine -5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8)

(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)

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

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

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)

(1S,3S)-3-((2-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methyl pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6H) (0.2 g, 0.356 mmol), N-methyl-1-phenylmethanamine (0.108 g, 0.890 mmol) ) was dissolved in 4 mL of tetrahydrofuran, then N,N-diisopropylethylamine (0.184 g, 1.424 mmol) was added, stirred at room temperature for 24 h, TLC (PE:EA=5:1) showed that the raw materials were reacted, concentrated, and the residue Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=3:1) gave colorless oily compound (1S,3S)-3-((2-(3-(((benzyl(methyl) )carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-8A) (100 mg, 51.6% yield).

The second step: (1S,3S)-3-((2-(3-(((benzyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4 Synthesis of -methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8)

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

LC-MS, M/Z(ESI): 530.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)δ12.20(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).

Example 9: Preparation of target compound I-9

(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)

(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)

The synthetic method refers to the synthesis of compound I-7 in Example 7, and the starting material cyclobutylmethylamine hydrochloride is replaced with 2-cyclopropylethyl-1-amine hydrochloride.

LC-MS, M/Z(ESI): 508.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 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).

Example 10: Preparation of target compound I-10

(1S,3S)-3-((6-(5-Chloro-3-((((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)

(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)

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

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

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)

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

The third step: (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)

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

To (1S,3S)-3-((6-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) at room temperature To a solution of methyl-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.26 g, 498.98 μmol) in tetrahydrofuran (5 mL) was added an aqueous solution of lithium hydroxide (1 M, 2.49 mL) , and then stirred at room temperature for 2 hours. The reaction solution was adjusted to neutral pH with citric acid, extracted with ethyl acetate (10 mL×2), and the organic layers were combined to obtain a crude product. Purified by silica gel plate to give (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%).

LC-MS, M/Z (ESI): 507.2 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ7.49-7.45(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).

Example 11: Preparation of target compound I-11

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

(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)

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

The first step: Synthesis of 4-nitrophenylcyclopentyl(methyl)carbamate (I-11A)

4-nitrophenyl cyclopentyl(methyl)carbamate(I-11A)

DIEA (4.75 mL, 27.2 mmol) was added dropwise to THF (30 mL) containing phenyl 4-nitrochloroformate (3.9 g, 19.4 mmol), N-methylcyclopentylamine hydrochloride (3.95 g, 29.1 mmol) ) solution at room temperature overnight. After the reaction of the raw materials, distilled water (10 mL) was added to dilute, extracted with ethyl acetate (30 mL×3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. Filtration, concentration, and purification of the residue by silica gel column gave 4-nitrophenylcyclopentyl(methyl)carbamate (I-11A) (3.0 g, 58.7% yield) as a yellow oil.

The second step: the synthesis of (1S,3S)-3-(4-bromo-2-fluorophenoxy) cyclohexane-1-carboxylate methyl ester (I-11C)

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

4-Bromo-2-fluoro-phenol (5 g, 26.18 mmol) and (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (8.28 g, 52.36 mmol) were added to tetrahydrofuran ( 50 mL), then diisopropyl azodicarboxylate (10.59 g, 52.36 mmol) and triphenylphosphine (13.73 g, 52.36 mmol) were added in sequence, then stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue The compound was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=40:1-5:1) to obtain yellow oily compound (1S,3S)-3-(4-bromo-2-fluorophenoxy) ) methyl cyclohexane-1-carboxylate (I-11C) (4.5 g, 51.9% yield).

The third step: methyl ester of (1S,3S)-3-(2-fluoro-4-(3-formylthiophen-2-yl)phenoxy)cyclohexane-1-carboxylate (I-11D) synthesis

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

Under nitrogen protection, methyl (1S,3S)-3-(4-bromo-2-fluorophenoxy)cyclohexane-1-carboxylate (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), followed by bis(tri-tert-butylphosphine)palladium(0) (60 mg, 117.40 umol), and the mixture Stir 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 with a 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-carboxylate methyl ester (I -11D) (420 mg, 76.7% yield).

The fourth step: (1S,3S)-3-(2-fluoro-4-(3-(hydroxymethyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylate methyl ester (I- 11E) Synthesis

methyl(1S,3S)-3-(2-fluoro-4-(3-(hydroxymethyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylate(I-11E)

To (1S,3S)-3-(2-fluoro-4-(3-formylthiophen-2-yl)phenoxy)cyclohexane-1-carboxylate methyl ester (420 mg, 1.16 mmol) in methanol (5 mL) was added sodium borohydride (65.77 mg, 1.74 mmol), followed by stirring at 0°C for half an hour. The reaction mixture was quenched with water (10 mL), then extracted with ethyl acetate (15 mL×2), and the organic layers were combined to give crude (1S,3S)-3-(2-fluoro-4-(3-(hydroxymethyl)) )thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester (I-11E) (420 mg, 99.5% yield). used directly in the next reaction.

The fifth step: (1S,3S)-3-(4-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic acid methyl Synthesis of Esters (I-11F)

methyl(1S,3S)-3-(4-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1-carboxylate(I-11F)

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, followed by stirring at 45°C 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 with a silica gel column (petroleum ether:ethyl acetate (V/V)=1:0- 20:1) yellow oily compound (1S,3S)-3-(4-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-fluorophenoxy)cyclohexane-1 was obtained - Methyl carboxylate (I-11F) (350 mg, 76.1% yield).

The sixth step: (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 - Synthesis of methyl fluorophenoxy)cyclohexane-1-carboxylate (I-11G)

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

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

The seventh step: (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 Synthesis of -Fluorophenoxy)cyclohexane-1-carboxylic acid (target compound I-11)

At room temperature, (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 Methyl fluorophenoxy)cyclohexane-1-carboxylate (197 mg, 375.92 μmol) and lithium hydroxide monohydrate (200 mg, 4.77 mmol) were added to tetrahydrofuran (2 mL), followed by stirring 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 solution, and then extracted with ethyl acetate (15 mL×3). The organic layers were combined to obtain a crude product, which was separated and purified on a silica gel plate to obtain an off-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, 35.7% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.20 (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).

LC-MS, M/Z (ESI): 532.1 [M+Na] ⁺ .

Example 12: Preparation of target compound I-12

(1S,3S)-3-((5-(5-Chloro-3-((((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-3-methyl Pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-12)

(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)

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

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

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

Under nitrogen protection, 5-bromo-3-methylpyrazin-2-ol (1.5 g, 7.94 mmol), (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (2.51 g, A mixture of 15.87 mmol) and triphenylphosphorus (4.16 g, 15.87 mmol) in tetrahydrofuran (30 mL) was cooled to 0 °C, diisopropyl azodicarboxylate (3.21 g, 15.87 mmol) was slowly added, and then slowly warmed to room temperature 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 (petroleum ether:ethyl acetate (V/V)=100:1-10:1) to obtain the title compound (1S, 3S) -Methyl 3-((5-bromo-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12B) (2.5 g, 95.7% yield).

The second step: (1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid Synthesis of methyl ester (I-12C)

methyl(1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-12C)

Under nitrogen protection, methyl (1S,3S)-3-((5-bromo-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (2.2 g, 6.68 mmol ), (3-formylthiophen-2-yl)boronic 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 The mixed solution of tetrahydrofuran (50 mL) was stirred at room temperature for 10 hours. After cooling to room temperature, the reaction mixture was concentrated to obtain crude product, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=100:1-50:1) to obtain the title compound (1S,3S)-3- ((5-(3-Formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12C) (2 g, yield 83.0%).

The third step: (1S,3S)-3-((5-(3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1 -Synthesis of methyl carboxylate (I-12D)

methyl(1S,3S)-3-((5-(3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-12D)

To (1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1- To a methanol (10 mL) solution of methyl carboxylate (2 g, 5.55 mmol) was added sodium borohydride (209.93 mg, 5.55 mmol) in portions, and the mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, and the concentrated title compound (1S,3S)-3-((5-(3-(hydroxyl) Methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12D) (2.5 g, crude).

The fourth step: (1S,3S)-3-((5-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy) ring Synthesis of hexane-1-carboxylate methyl ester (I-12E)

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

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

The fifth step: (1S,3S)-3-((5-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)- Synthesis of methyl 3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12F)

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)

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

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

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)

To (1S,3S)-3-((5-(5-chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl) at room temperature To a solution of methyl 3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (0.2 g, 355.88 μmol) in tetrahydrofuran (10 mL) was added N,N-diisopropylethylamine (137.98 mg, 1.07 mmol) and cyclopentylmethylamine hydrochloride (48.27 mg, 358.6 umol), and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was spin-dried under reduced pressure to obtain (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).

Step 7: (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of 3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-12)

To (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) at room temperature -3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate methyl ester (0.2g, 383.10umol) in tetrahydrofuran (5mL) was added 1M lithium hydroxide solution (536.34μL), Stir at room temperature for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 6 with 1M hydrochloric acid, and the organic phases were combined with ethyl acetate (30 mL×2) and concentrated under reduced pressure to obtain the crude product. The crude product was separated on a silica gel plate to obtain (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, 29.6% yield).

LC-MS, M/Z(ESI): 508.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)δ8.24(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).

Example 13: Preparation of target compound I-13

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

(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)

The synthetic route of the target compound I-13 is as follows:

The first step: synthesis of tert-butyldimethyl(thiophen-3-ylmethoxy)silane (I-13A)

tert-butyldimethyl(thiophen-3-ylmethoxy)silane(I-13A)

Thiophen-3-ylmethanol (10 g, 87.59 mmol) and tert-butyldimethylsilyl chloride (15.84 g, 105.11 mmol, 12.88 mL) were dissolved in N,N-dimethylformamide (200 mL) at room temperature Then, triethylamine (17.73 g, 175.18 mmol, 24.38 mL) was added, followed by stirring at 60°C for 3 hours. After the reaction solution was cooled to room temperature, the reaction solution 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 (petroleum ether:ethyl acetate (V/V)=10:1-5:1) to obtain the title compound tert-butyldimethyl(thiophen-3-ylmethoxy)silane (I- 13A) (16 g, 79.9% yield).

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

(5-fluorothiophen-3-yl)methanol(I-13B)

Dissolve tert-butyldimethyl(thiophen-3-ylmethoxy)silane (16 g, 70.04 mmol) in tetrahydrofuran (200 mL), cool to -78°C, and slowly add sec-butyl dropwise under nitrogen protection Lithium (1.3M, 70.72 mL) was added dropwise and stirring was continued for 30 minutes. Then N-fluorobisbenzenesulfonamide (21.26 g, 67.42 mmol) was added and stirring was continued at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was quenched with water (100 mL), extracted twice with ethyl acetate (100 mL), and the organic phases were combined and concentrated to give the crude product. The crude product was dissolved in tetrahydrofuran (200 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (70 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated to obtain crude product, which was separated and purified by silica gel column (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, 37.8% yield).

The third step: the synthesis of (2-bromo-5-fluorothiophen-3-yl) methanol (I-13C)

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

(5-Fluorothiophen-3-yl)methanol (3 g, 22.70 mmol) was dissolved in N,N-dimethylformamide (30 mL), cooled to 0 °C, and N-bromosuccinimide ( 4.04 g, 22.70 mmol), stirred at room temperature for 10 hours. The reaction solution was poured into water (50 mL), then extracted with ethyl acetate (50 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Concentration under reduced pressure gave crude product. The title compound (2-bromo-5-fluorothiophen-3-yl)methanol (I-13C)( 4 g, 83.5% yield).

The fourth step: the synthesis of (2-bromo-5-fluorothiophen-3-yl) methylcyclopentyl (methyl) carbamate (I-13D)

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

Combine (2-bromo-5-fluorothiophen-3-yl)methanol (0.5 g, 2.37 mmol) and 4-nitrophenylcyclopentyl(methyl)carbamate (I-11A) (626.09 mg, 2.37mmol) was dissolved in N,N-dimethylformamide (10mL), at 15°C, bis(trimethylsilyl)potassium amide (1M, 2.40mL) was added dropwise, and then the reaction solution was heated at 15°C Stir 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. Separation and purification with 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, 62.8% yield).

Step 5: (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)- Synthesis of methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-13E)

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)

Under nitrogen atmosphere, (2-bromo-5-fluorothiophen-3-yl)methylcyclopentyl(methyl)carbamate (320 mg, 951.76 μmol), (1S,3S)-3- Methyl ((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (768.57 mg, 1.43 mmol) and tetrakistriphenylphosphonium palladium (109.98 mg, 95.18 μmol), was added 1,4-dioxane (10 mL), heated to 100° C., stirred for 4 hours, then cooled and concentrated to a crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V))=10:1-5:1) to obtain (1S,3S)-3-((6-(3-(((cyclopentyl( Methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I- 13E) (200 mg, 41.6% yield).

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

To (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl) at room temperature Methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (6) (200 mg, 396.34 umol) in methanol (5 mL) and water (1 mL) was added with lithium hydroxide monohydrate ( 83.16 mg, 1.98 mmol), the mixture was stirred at room temperature for 10 hours, the reaction solution was concentrated, adjusted to pH=3～4 with 1M hydrochloric acid solution, extracted with ethyl acetate (10 mL×2), and the organic layers were combined to obtain the 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 min) to give (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, 18.4% yield).

LC-MS, M/Z (ESI): 491.2 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.24-7.52 (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).

Example 14: Preparation of target compound I-14

(1S,3S)-3-((6-(5-Chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophene -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-14)

(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)

The synthetic route of the target compound I-14 is as follows:

The first step: the synthesis of (R)-(1-cyclopropylethyl) tert-butyl carbamate (I-14B)

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

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

The second step: the synthesis of (R)-(1-cyclopropylethyl) (methyl) tert-butyl carbamate (I-14C)

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

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

The third step: the synthesis of (R)-1-cyclopropyl-N-methylethylamine hydrochloride (I-14D)

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

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

The fourth step: (1S,3S)-3-((6-(5-chloro-3-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy) Synthesis of methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-14E)

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)

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

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

(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)

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

LC-MS, M/Z(ESI): 507.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ12.22(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).

Example 15: Preparation of target compound I-15

(1S,3S)-3-((6-(5-Chloro-3-(((((S)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophene -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-15)

(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)

The synthetic method of the target compound I-15 is referred to compound I-14, and (R)-1-cyclopropylethylamine hydrochloride is replaced by (S)-1-cyclopropylethylamine hydrochloride.

LC-MS, M/Z(ESI): 507.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 16: Preparation of target compound I-16

(1S,3S)-3-((6-(5-Chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine-3- yl)oxy)cyclohexane-1-carboxylic acid (target compound I-16)

(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)

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

The first step: (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl Synthesis of Methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-16A)

methyl(1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- carboxylate(I-16A)

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

The second step: (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl Synthesis of Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-16)

To (1S,3S)-3-((6-(5-chloro-3-(((cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl at room temperature Pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (3) (0.26g, 512.78umol, crude product) in a mixed solution of water (5mL) and tetrahydrofuran (5mL), was added hydrogen hydroxide monohydrate Lithium (107.59 mg, 2.56 mmol), stirred at room temperature for 8 hours. The reaction solution was adjusted to pH=3～4 with 1M hydrochloric acid solution, then concentrated under reduced pressure to obtain the crude product, which was separated by preparation (separation method: chromatographic column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.225 % formic acid (99%) by volume, B=acetonitrile; gradient: 55%-85% B, 10 min) to give compound (1S,3S)-3-((6-(5-chloro-3-(() as a white solid (Cyclopentylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-16) ( 88.41 mg, 34.97% yield).

LC-MS, M/Z (ESI): 493.3 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) 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).

Example 17: Preparation of target compound I-17

(1S,3S)-3-((2-(5-Chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methylpyrimidine -5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)

(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)

The synthetic route of the target compound I-17 is as follows:

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

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)

(1S,3S)-3-((2-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methyl 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. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the title compound (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, 73.9% yield).

LC-MS, M/Z(ESI): 496.2[M+H] ⁺

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

(1S,3S)-3-((2-(5-Chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-4-methyl Pyrimidine-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (150mg, 0.302mmol) was added to a mixed solvent of 2mL tetrahydrofuran, 2mL methanol and 1mL water, and lithium hydroxide (72.4mg, 3.02mmol) was added ) and stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL×3), combine organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (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, 27.4% yield).

LC-MS, M/Z(ESI): 482.1[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 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).

Example: Preparation of target compound I-18

(1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidine -5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-18)

(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)

The synthetic route of the target compound I-18 is as follows:

The first step: (1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4 Synthesis of -methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-18A)

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)

(1S,3S)-3-((2-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-4-methyl (1-6H) and N-methyl-n-butylamine (194 mg, 2.224 mmol) were added to 5 mL of tetrahydrofuran , N,N-diisopropylethylamine (0.23 mL, 1.335 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the compound (1S,3S)-3-((2-(3-(((butyl(methyl) )carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-18A) (150 mg, 66.1% yield).

LC-MS, M/Z(ESI): 510.2[M+H] ⁺

The second step: (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)

(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)

(1S,3S)-3-((2-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-4-methyl Pyrimidine-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (150mg, 0.294mmol) was added to a mixed solvent of 2mL tetrahydrofuran, 2mL methanol and 1mL water, and lithium hydroxide (35.2mg, 1.47mmol) was added ) and stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (petroleum ether:ethyl acetate (V:V)=1:1) to give (1S,3S)-3-((2-(3-(((butyl(methyl)) carbamoyl)oxy)methyl)-5-chlorothien-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-18)( 60 mg, 41.1% yield).

LC-MS, M/Z(ESI): 4962.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 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).

Example 19: Preparation of target compound I-19

(1S,3S)-3-((6-(5-Chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-19)

(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)

The synthetic route of the target compound I-19 is as follows:

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

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)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (381 mg, 0.679 mmol) (081010 product of the fourth step) and N-methyl-n-propylamine (149 mg, 2.037 mmol) were added to 5 mL of tetrahydrofuran To the solution, N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the title compound (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, 76% yield).

LC-MS, M/Z(ESI): 495.2[M+H] ⁺

The second step: (1S,3S)-3-((6-(5-chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-19)

(1S,3S)-3-((6-(5-Chloro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (056B) (255mg, 0.516mmol) was added to a mixed solvent of 2mL tetrahydrofuran, 2mL methanol and 1mL water, and lithium hydroxide (61.8mg) was added. , 2.58 mmol), stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (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, 24.2% yield).

LC-MS, M/Z(ESI): 481.1[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.28(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)

Example 20: Preparation of target compound I-20

(1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)

(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)

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

The first step: (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-20A)

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)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (286 mg, 0.509 mmol) (081010 4th step product) and N-methyl-n-butylamine (133 mg, 1.528 mmol) were added to 5 mL To tetrahydrofuran, N,N-diisopropylethylamine (0.45 mL, 2.55 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Spin dry, column chromatography (petroleum ether: ethyl acetate (V:V)=3:1) to separate and purify the compound (1S,3S)-3-((6-(3-(((butyl(methyl) )carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-20A) (217 mg, 84% yield).

LC-MS, M/Z(ESI): 509.2[M+H] ⁺

The second step: (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)

(1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-chlorothiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (217mg, 0.428mmol) was added to a mixed solvent of 2mL tetrahydrofuran, 2mL methanol and 1mL water, lithium hydroxide (51.3mg, 2.14mmol) was added ) and stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (petroleum ether:ethyl acetate (V:V)=1:1) to give (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, 37.7% yield).

LC-MS, M/Z(ESI): 495.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.28(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)

Example 21: Preparation of target compound I-21

(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)

(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)

The synthetic route of the target compound I-21 is as follows:

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

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)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl (1-3E) and 4-(methylamino)butanol (263 mg, 2.55 mmol) were added to 5 mL To tetrahydrofuran, N,N-diisopropylethylamine (0.74 mL, 4.24 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to separate and purify the title compound (1S, 3S)-3-((6-(5-chloro-3-(((( (4-Hydroxybutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl Ester (I-21A) (409 mg, 92% yield).

LC-MS, M/Z(ESI): 525.2[M+H] ⁺

The second step: (1S,3S)-3-((6-(5-chloro-3-(((methyl(4-(toluenesulfonyloxy)butyl)carbamoyl)oxy)methyl ) The synthesis of thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-21B)

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)

(1S,3S)-3-((6-(5-chloro-3-((((4-hydroxybutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) Methyl-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, 0 4-Dimethylaminopyridine (9.5 mg, 0.078 mmol) and triethylamine (0.22 mL, 1.55 mmol) were added at °C, and the mixture was stirred at room temperature for 12 hours. Spin to dry, column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to separate and purify the compound (1S,3S)-3-(((6-(5-chloro-3-(((methyl) (4-(toluenesulfonyloxy)butyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- Methyl carboxylate (I-21B) (307 mg, 58.2% yield).

LC-MS, M/Z(ESI): 679.2[M+H] ⁺

The third step: (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophene-2 - Synthesis of methyl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21C)

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)

(1S,3S)-3-((6-(5-chloro-3-(((methyl(4-(toluenesulfonyloxy)butyl)carbamoyl)oxy)methyl)thiophene- Methyl 2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (307 mg, 0.452 mmol) was added to a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to separate and purify 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-carboxylate methyl Ester (I-21C) (219 mg, 92% yield).

LC-MS, M/Z(ESI): 527.2[M+H] ⁺

The fourth step: (1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophene-2 Synthesis of -yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-21)

(1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl) -2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (219mg, 0.414mmol) was added to a mixed solvent of 2mL of tetrahydrofuran, 2mL of methanol and 1mL of water, and lithium hydroxide ( 99 mg, 4.14 mmol), stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (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 ( The target compound I-21) (80 mg, yield 37.7%).

LC-MS, M/Z(ESI): 513.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.27(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)

Example 22: Preparation of target compound I-22

(1S,3S)-3-((6-(5-Chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-22)

(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)

The synthetic route of the target compound target compound I-22 is shown below:

The first step: (1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-22A)

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)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (371 mg, 0.662 mmol) (081010 4th step product) and N-methyl-n-pentylamine (201 mg, 1.986 mmol) were added to 5 mL To tetrahydrofuran, N,N-diisopropylethylamine (0.58 mL, 3.31 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the compound (1S,3S)-3-(((6-(5-chloro-3-(((methyl) Methyl (pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-22A) (218 mg, 63% yield).

LC-MS, M/Z(ESI): 523.2[M+H] ⁺

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

(1S,3S)-3-((6-(5-chloro-3-(((methyl(pentyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (218mg, 0.417mmol) was added to a mixed solvent of 2mL tetrahydrofuran, 2mL methanol and 1mL water, and lithium hydroxide (100mg, 4.17mmol) was added , and stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (petroleum ether:ethyl acetate (V:V)=1:1) to give (1S,3S)-3-(((6-(5-chloro-3-(((methyl) (Amyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-22) ( 60 mg, 28.2% yield).

LC-MS, M/Z(ESI): 509.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.28(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).

Example 23: Preparation of target compound I-23

(1S,3S)-3-((6-(5-Fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-23)

(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)

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

The first step: the synthesis of 2-bromo-5-fluorothiophene-3-carbaldehyde (I-23A)

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

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

The second step: (1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1 -Synthesis of methyl carboxylate (I-23B)

methyl(1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-23B)

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

The third step: (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Synthesis of Alkane-1-Carboxylic Acid Methyl (I-23C)

methyl(1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-23C)

To (1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane at 0 °C To a solution of methyl-1-carboxylate (297.8 mg, 788.94 umol) in methanol (5 mL) was added sodium borohydride (59.1 mg, 1.57 mmol), and the reaction solution was stirred at 0° C. for 0.5 hour. After the completion of the reaction, dilute hydrochloric acid was added dropwise to quench the reaction, and the crude product was obtained by concentration. The crude product was purified by silica gel plate chromatography to obtain (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl) as a yellow oil. )thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-23C) (200 mg, 66% yield).

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

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)

To (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) at 0 °C To a solution of methyl cyclohexane-1-carboxylate (800 mg, 2.11 mmol) and pyridine (500.31 mg, 6.33 mmol, 510.52 uL) in dichloromethane (8 mL) was added phenyl 4-nitrochloroformate (849.93 mg, 4.22 mmol), the reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was washed three times with saturated aqueous sodium carbonate solution, and the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oil (1S,3S)-3-((6-(5-fluoro-3-(( Methyl ((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 reaction.

The fifth step: (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-23E)

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)

At room temperature, (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl) Methyl 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) was added to tetrahydrofuran (3.5 mL), then N,N-diisopropylethylamine (290.74 mg, 2.25 mmol) was added dropwise, stirred at room temperature for 0.5 h, the reaction mixture was chromatographed on silica gel plate to prepare a yellow oily compound (1S,3S)-3-((6-(5-Fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine Methyl-3-yl)oxy)cyclohexane-1-carboxylate (I-23E) (164 mg, 53.3% yield).

The sixth step: (1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-23)

(1S,3S)-3-((6-(5-fluoro-3-(((methyl(propyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2 at room temperature -Methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (164mg, 342.68umol) was dissolved in tetrahydrofuran (1.6mL), then water (0.3ml) and hydrogen monohydrate were added thereto Lithium oxide (143.80 mg, 3.43 mmol) and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 1N aqueous hydrochloric acid solution, then extracted with ethyl acetate (5 mL×2), and the organic phase was concentrated to obtain a crude product. The crude product was then prepared (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 ) was isolated to obtain 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%).

¹ H NMR (400MHz, CDCl ₃ )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).

LC-MS, M/Z(ESI): 465.2[M+H] ⁺

Example 24: Preparation of target compound I-24

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

(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)

The synthetic route of the target compound I-24 is as follows:

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

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)

To (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl) at room temperature Methyl 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-methyl-n-butylamine (112 mg, 1.29 mmol, ), and the mixture was stirred at 25° C. for 0.5 hr. The reaction mixture was prepared by chromatography on silica gel plate to give yellow oily compound (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, 37.9% yield).

The second step: (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24)

To (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2 at room temperature -Methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (120mg, 243umol) in methanol (2.5mL) and water (0.5mL) was added lithium hydroxide monohydrate (51.1mL) mg, 1.22 mmol) and 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×2) and concentrated. The residue was prepared 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 min ) to give (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)-2 as a white solid -Methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24) (64.3 mg, yield 54.6%).

¹ H NMR (400MHz, CDCl ₃ )δ7.29(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).

LC-MS, M/Z(ESI): 479.2[M+H] ⁺

Example 25: Preparation of target compound I-25

(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)

(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)

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

The first step: (1S,3S)-3-((6-(3-(((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-25A) synthesis

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)

At room temperature, (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl) Methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (350 mg, 642.74 μmol) and 1-cyclobutyl-N-methylmethylamine (ref. Example 7 Compound I-7D synthesis) (174 mg, 1.29 mmol) was added to tetrahydrofuran (3.5 mL), then N,N-diisopropylethylamine (290.74 mg, 2.25 mmol) was added dropwise, and stirred at room temperature for 0.5 hour, the reaction mixture was prepared by chromatography on silica gel plate to give the compound (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methan as a yellow oil (1-25A) (120 mg, 33.0% yield).

The second step: (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) synthesis

At room temperature, (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophene-2- methyl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (120 mg, 237 μmol) was dissolved in methanol (2.5 mL), to which was added water (0.5 mL) and Lithium hydroxide monohydrate (50.0 mg, 1.20 mmol) was then stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 1N aqueous hydrochloric acid solution, then extracted with ethyl acetate (5 mL×2), and the organic phase was concentrated to obtain a crude product. The residue was preparatively purified (column: Phenomenex Synergi C18 150*25mm*10um; solvent: A=water+0.225 vol% formic acid (99%), B=acetonitrile; gradient: 58%-91%B, 11 min) to give grey 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%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.29(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).

LC-MS, M/Z(ESI): 491.2[M+H] ⁺

Example 26: Preparation of target compound I-26

(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)

(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)

The synthetic route of the target compound I-26 is shown below:

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

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)

At room temperature, (1S,3S)-3-((6-(5-fluoro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl) Methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (350 mg, 642.74 μmol) (I-3E) and 2-cyclopropyl-N-methylethylamine hydrochloride The salt (217.94 mg, 1.61 mmol) was added to tetrahydrofuran (3.5 mL), then N,N-diisopropylethylamine (290.74 mg, 2.25 mmol) was added dropwise, stirred at room temperature for 0.5 h, and the reaction mixture was passed through the layers The compound (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)- Methyl 5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-26A) (260 mg, 80.1% yield).

Step 2: (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophene Synthesis of -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26)

(1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluoro Thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (260 mg, 515.25 μmol) was dissolved in tetrahydrofuran (2.6 mL), to which was added water (0.5 ml) and lithium hydroxide monohydrate (216.22 mg, 5.15 mmol), then the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 1N aqueous hydrochloric acid solution, then extracted with ethyl acetate (5 mL×2), and the organic phase was concentrated to obtain a crude product. The crude product was then prepared (column: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: A=water+0.225 vol% formic acid (99%), B=acetonitrile; gradient: 56%-89%B, 11 min) The target compound (1S,3S)-3-((6-(3-(((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophene-2 -yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26) (43.49 mg, 17.2% yield).

¹ H NMR (400MHz, CDCl ₃ )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).

LC-MS, M/Z(ESI): 491.2[M+H] ⁺

Example 27: Preparation of target compound I-27

(1S,3S)-3-((6-(5-Chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophene-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-27)

(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)

The synthetic route of the target compound I-27 is shown below:

The first step: ((1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl ) The synthesis of thiophen-2-yl)-2-methylpyridine-3-ethoxy) cyclohexane-1-carboxylic acid methyl ester (I-27A)

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

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (250 mg, 0.446 mmol) and N-methyl-1-(oxetan-3-yl)methyl The amine (135 mg, 1.337 mmol) was added to 5 ml of tetrahydrofuran, N,N-diisopropylethylamine (0.39 mL, 3.23 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the compound (1S,3S)-3-(((6-(5-chloro-3-(((methyl) (oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine-3-ethoxy)cyclohexane-1-carboxylic acid methyl Ester (I-27A) (100 mg, 12.9% yield).

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

The second step: (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)

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

(1S,3S)-3-((6-(5-Chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)thiophene-2 -yl)-2-methylpyridine-3-ethoxy)cyclohexane-1-carboxylic acid methyl ester (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 was added (22.9 mg, 0.956 mmol), stirred at room temperature overnight. Swirl to dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL×3), combine the organic phases, and dry over anhydrous sodium sulfate , filtered and concentrated. The concentrate was purified by preparative plate (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) ring Hexane-1-carboxylic acid (target compound I-27) (30.9 mg, 31.8% yield).

LC-MS, M/Z(ESI): 509.1[M+H] ⁺

¹ H NMR(400MHz, CDCl3)δ7.26(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).

Example 28: Preparation of target compound I-28

(1S,3S)-3-((6-(5-Chloro-3-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophene-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-28)

(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)

The synthetic route of the target compound I-28 is as follows:

The first step: (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 methyl ester (I-28A)

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)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-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) was 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. Spin to dry, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the compound (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- Methyl formate (I-28A) (160 mg, 67.1% yield).

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

The second step: (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)

(1S,3S)-3-((6-(5-Chloro-3-(((((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)thiophene- 2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-28A) (160 mg, 0.299 mmol) was added to a mixture of 2 mL of tetrahydrofuran, 2 mL of methanol and 1 mL of water Lithium hydroxide (21.49 mg, 0.897 mmol) was added to the solvent, stirred overnight at room temperature, spin-dried, dissolved in water (10 mL), adjusted to pH 2 with 2M hydrochloric acid, extracted with ethyl acetate (10 mL×3), combined with organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by 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, 17.27% yield).

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

¹ H NMR (400MHz, CDCl ₃ )δ7.24(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).

Example 29: Synthesis of target compound I-29

(1S,3S)-3-((6-(5-Chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)hexane-1-carboxylic acid (target compound I-29)

(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)

The synthetic route of the target compound I-29 is as follows:

The first step: (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)

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)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-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. Spin to dry, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the compound (1S,3S)-3-((6-(5-chloro-3-((((ethyl) Methyl (methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-29A) (160 mg, 74.6% yield).

LC-MS, M/Z(ESI): 481.1[M+H] ⁺

The second step: (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)

(1S,3S)-3-((6-(5-chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylp yridin-3-yl)oxy) cyclohexane-1-carboxylic acid (target compound I-29)

(1S,3S)-3-((6-(5-Chloro-3-(((ethyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (160mg, 0.333mmol) was added to a mixed solvent of 2mL tetrahydrofuran, 2mL methanol and 1mL water, and lithium hydroxide (23.9mg, 0.998mmol) was added ) and stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL×3), combine organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (petroleum ether:ethyl acetate (V:V)=1:1) to give (1S,3S)-3-(((6-(5-chloro-3-(((ethyl) as a white solid) (Methyl)carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)hexane-1-carboxylic acid (target compound I-29) (50.4 mg, 32.4% yield).

LC-MS, M/Z(ESI): 467.1[M+H] ⁺

1H NMR(400MHz, CDCl3)δ7.28(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).

Example 30: Synthesis of target compound I-30

(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)

(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)

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

The first step: (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-30A)

methyl(1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- carboxylate(I-30A)

(1S,3S)-3-((6-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-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 stirred at room temperature for 12 hours. Spin to dryness, column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to separate and purify the compound (1S,3S)-3-((6-(5-chloro-3-((((propyl) carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-30A) (160 mg, yielded rate 74.63%).

LC-MS, M/Z(ESI): 481.1[M+H] ⁺

The second step: (1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-30)

(1S,3S)-3-((6-(5-chloro-3-(((propylcarbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridine-3- (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, lithium hydroxide (23.9 mg, 0.998 mmol) was added, and the mixture was stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (10 mL×3), combine organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (petroleum ether:ethyl acetate (V:V)=1:1) to give (1S,3S)-3-((6-(5-chloro-3-(((propyl propyl) Carbamoyl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-30) (34.7 mg, yielded rate 22.34%).

LC-MS, M/Z(ESI): 467.1[M+H] ⁺

¹ H NMR(400MHz, CDCl3)δ7.28(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).

Example 31: Synthesis of target compound I-31

(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)

(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

The target compound I-31 was synthesized with reference to I-9, except that 2-cyclopropylethan-1-amine hydrochloride was replaced by 4-fluorobutan-1-amine hydrochloride.

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

Biological Activity and Related Properties Test Examples

Test Example 1: LPAR1 In Vitro Calcium Flux Assay

The antagonism of compounds on LPAR1 was determined in a CHO cell line stably expressing human LPAR1. 18 hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 μL of DMEM/F12 (1:1) medium and kept at 37°C/5% _CO for incubation for 18 hrs. 20 μL/well of dye solution was added to each well of cells, placed back in a 37°C incubator for 30 min in the dark, and then incubated at room temperature for 10 min in the dark. Add 10 μL/well of compounds of different final concentrations into the cells, and equilibrate. After 20 min, 12.5 μL/well of LPA solution (final concentration 5 nM) was finally added to the cells, and the fluorescence signal value was detected by FLIPR. Taking the compound concentration as the X-axis and the fluorescence signal value as the Y-axis, the antagonism (IC ₅₀ value) of the compound was calculated by the software GraphPad Prism 8.0.

Table 1 Antagonism of test compounds on LPAR1

测试化合物test compound	IC ₅₀nM) IC ₅₀ nM)
对照化合物1Control compound 1	117.9117.9
对照化合物2Control compound 2	243.8243.8
对照化合物3Control compound 3	251.6251.6
对照化合物4Control compound 4	243.3243.3
对照化合物5 Control compound 5	109.5109.5
I-1I-1	43.8243.82
I-2I-2	10.2810.28
I-3I-3	16.2316.23
I-4I-4	8.9878.987
I-5I-5	3.6693.669
I-6I-6	56.956.9
I-7I-7	61.3161.31
I-8I-8	42.6342.63
I-9I-9	43.4443.44
I-10I-10	25.1325.13
I-11I-11	25.5625.56
I-12I-12	30.6230.62
I-13I-13	30.3630.36
I-14I-14	16.9916.99
I-15I-15	95.9595.95
I-16I-16	35.2135.21
I-17I-17	47.1447.14
I-19I-19	8.928.92
I-20I-20	7.637.63
I-21I-21	14.2414.24
I-22I-22	17.0917.09
I-25I-25	64.164.1
I-26I-26	5.6295.629
I-27I-27	76.5676.56

The results of the LPAR1 calcium flux test showed that the compounds of the present invention had a good antagonistic effect on LPAR1. Compared with the control compounds, most of the inventive compounds showed more excellent antagonistic effects on LPAR1.

Test Example 2: LPAR3 In Vitro Calcium Flux Assay

The antagonism of compounds on LPAR3 was determined in a CHO cell line stably expressing human LPAR3. 18 hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 μL DMEM/F12 (1:1) medium and kept at 37°C/5% _CO for 18 hours , and then add 20 μL/well of dye solution into each well of cells, put it back in a 37°C incubator and continue to incubate in the dark for 30 min, then incubate for 10 min at room temperature in the dark, add 10 μL/well of compounds of different final concentrations into cells, and equilibrate for 20 min , and finally 12.5 μL/well of LPA solution (final concentration 5nM) was added to the cells, and the fluorescence signal value was detected by FLIPR. Taking the compound concentration as the X-axis and the fluorescence signal value as the Y-axis, the antagonism (IC ₅₀ value) of the compound was calculated by the software Prism.

Table 2 Antagonism of test compounds on LPAR3

The results of the LPAR3 calcium flux test showed that the compounds of the present invention had weak antagonistic effect on LPAR3, and compared with the control compounds, the compounds of the present invention showed more excellent selective inhibitory activity against LPAR1.

Test Example 3: Test Test for Compound Toxicity to Hepatocytes

Compounds were tested for hepatotoxicity on HepG2 (ATCC, HB-8065) cells, and cell viability was determined using the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7573) to characterize the toxicity of compounds by viability inhibition on HepG2 cells . Collect log-phase HepG2 cells, adjust the concentration of cell suspension, plate them in a 96-well cell culture plate at 5000 cells/well, place the cells in a cell culture incubator at 5% CO ₂ and incubate overnight at 37°C, and change the medium the next day. Compounds with a final concentration of 30 □M were added, and a negative control group (cells + DMSO) and a blank control group (medium + DMSO) were set at the same time, and incubated in a 5%, 37°C cell incubator for 72 hours. After the treatment, operate according to the kit instructions, and detect the luminescence signal values in different wells on the EnVision plate reader (2104), and calculate the viability inhibition of HepG2 cells by different compounds at 30 □M according to the following formula.

Table 4 Viability inhibition of HepG2 cells by test compounds

测试化合物test compound	30M的抑制率(％)30M inhibition rate (%)
对照化合物1Control compound 1	30.1930.19
I-3I-3	00
I-19I-19	00
I-20I-20	00

The results of the liver cytotoxicity test showed that the compounds of the present invention showed good safety, 30□M had no inhibitory effect on HepG2 cells, and the safety was significantly better than that of the control compounds.

Test Example 4: Pharmacokinetic Test

Pharmacokinetic test in mice, using male ICR mice, 20-25 g, fasted overnight. Three mice were taken and administered orally orally at 10 mg/kg. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the volume of acetonitrile solution containing the internal standard to mix, vortex for 1 minute, centrifuge at 13,000 rpm for 10 minutes at 4°C, take the supernatant and add 3 times the volume of water to mix, take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

Table 5 Pharmacokinetic test results of oral gavage in mice

The results of the mouse pharmacokinetic test show that, compared with the control compound, the compound of the present invention exhibits better pharmacokinetic properties and better drug-forming properties.

Test Example 6: Efficacy test of bleomycin-induced pulmonary fibrosis

After the male mice were adaptively reared for 1 week and reached the body weight, they were randomly divided into the normal control group, the model group and the administration group according to the body weight of the animals. After isoflurane anesthesia: the model group and the administration group were evenly given 50 μL of bleomycin in the lungs to establish a mouse pulmonary fibrosis model, while the control group was evenly given 50 μL of normal saline in the lungs; The animals were euthanized after the administration was completed, and the left lungs of the animals were fixed in 10% neutral buffered formalin for preparing pathological tissue sections and scoring the left lung tissue for pulmonary fibrosis. One-way ANOVA or Two-way ANOVA was used for analysis; when comparing between two groups, T-test was used for two-tailed test between two groups. When p<0.05, there was a significant difference between the two groups. The results are shown in Figure 1. shown, wherein, T-test: ****p<0.0001vs. normal control group; #p<0.05vs. model group; &p<0.05vs. control compound 330 mg/kg.

The results show that the compound of the present invention can significantly reduce the bleomycin-induced pulmonary fibrosis score in mice by antagonizing LPAR1, and the effect is significantly better than that of the control compound.

Claims

A compound, which is a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

in:

R 1 is selected from -H, -CN, halogen, -ZR a , the following groups unsubstituted or substituted by R b : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy;

Z is selected from single bond or -O-, -S-;

R a is selected from C 1-6 alkyl, C 1-6 alkyl substituted by halogen;

R b is selected from -CN, halogen, C 1-6 alkyl, C 1-6 alkoxy;

R 2 is selected from -H, -CN, halogen, -YR d , the following groups unsubstituted or substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy;

Y is selected from single bond or -O-, -S-;

R d is selected from C 1-6 alkyl, C 1-6 alkyl substituted by halogen;

R e is selected from -CN, halogen, C 1-6 alkyl, C 1-6 alkoxy;

X 1 , X 2 and X 3 are each independently selected from C or N, and X 1 , X 2 and X 3 are not N at the same time;

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

R 4 is selected from -H, -CN, halogen, unsubstituted or substituted by R g of the following groups: C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, 5-8 aryl, 5-8-membered heteroaryl;

R g is selected from halogen, C 1-6 alkyl, C 1-6 cycloalkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy;

L 1 is selected from single bond, unsubstituted or C 1-3 alkylene substituted by C 1-3 alkyl.
The compound of claim 1, wherein
Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R1.
The compound of claim 1, wherein
selected from

and/or, when R 1 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 1 is -ZR a and R a is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, pentyl, hexyl;

And/or, when R 1 is -ZR a and R a is C 1-6 alkyl substituted by halogen, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, pentyl, hexyl;

And/or, when R 1 is -ZR a and R a is a C 1-6 alkyl group substituted by halogen, the number of the halogen is one or more, and when there are multiple halogens, the halogen The halogens are the same or different;

And/or, when R 1 is -ZR a and R a is C 1-6 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 1 is unsubstituted or substituted by R b the following groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the R b is one or more, and when there are multiple R b , the R b is the same or different;

And/or, when R 1 is unsubstituted or substituted by R b the following groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the R b is one or more, the R b is selected from -CN, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyl Oxygen;

And/or, when R 1 is an unsubstituted or R b substituted C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, pentyl, hexyl;

And/or, when R 1 is an unsubstituted or R b substituted C 3-6 cycloalkyl group, the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, and cyclopentyl;

And/or, when R 1 is C 1-6 alkylamino unsubstituted or substituted by R b , the C 1-6 alkylamino group is
wherein m1 and m2 are each independently selected from an integer from 0 to 6, and m1 and m2 are not simultaneously 0 and the sum of m1 and m2 does not exceed 6;

And/or, when R 1 is unsubstituted or C 1-6 alkoxy substituted by R b , the C 1-6 alkoxy is methoxy, ethoxy, n-propoxy, iso- Propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy;

and/or, when R 2 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 2 is -YR d and R d is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, pentyl, hexyl;

And/or, when R 2 is -YR d and R d is C 1-6 alkyl substituted by halogen, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, pentyl, hexyl;

And/or, when R 2 is -YR d and R d is C 1-6 alkyl substituted by halogen, the number of the halogen is one or more, and when there are multiple halogens, the halogen The halogens are the same or different;

And/or, when R 2 is -YR d and R d is C 1-6 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 2 is the following groups unsubstituted or substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the Re is one or more, and when there are multiple Re , the Re is the same or different;

And/or, when R 2 is the following groups unsubstituted or substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the Re is one or more, and the Re is selected from -CN, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyl Oxygen;

And/or, when R 2 is unsubstituted or C 1-6 alkyl substituted by Re , the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, pentyl, hexyl;

And/or, when R 2 is unsubstituted or C 3-6 cycloalkyl substituted by R e , the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, and cyclopentyl;

And/or, when R 2 is unsubstituted or substituted C 1-6 alkylamino group by Re , the C 1-6 alkylamino group is
wherein n1 and n2 are each independently selected from an integer from 0 to 6, and n1 and n2 are not 0 at the same time, and the sum of n1 and n2 does not exceed 6;

And/or, when R 2 is unsubstituted or C 1-6 alkoxy substituted by Re , the C 1-6 alkoxy is methoxy, ethoxy, n-propoxy, isopropyl Propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy;

And/or, when R 3 is C 1-3 alkyl, the C 1-3 alkyl is methyl, ethyl, n-propyl, isopropyl;

And/or, when R 3 is a C 1-3 alkyl group substituted by halogen, the C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl;

And/or, when R 3 is a C 1-3 alkyl substituted by halogen, the number of the halogen is one or more, and when there are multiple halogens, the halogens are the same or different;

And/or, when R 3 is C 1-3 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine;

and/or, when R4 is halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, when R 4 is unsubstituted or substituted by R g the following groups: C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclic group, 5-8 membered aryl, In the case of a 5- to 8-membered heteroaryl group, the number of the R g is one or more, and when there are multiple R g , the R g is the same or different;

And/or, when R 4 is unsubstituted or substituted by R g the following groups: C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclic group, 5-8 membered aryl, In the case of a 5- to 8-membered heteroaryl group, the number of the R g is one or more, and the R g is selected from -H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl Propyl, n-butyl, n-pentyl, fluoroalkane, trifluoromethyl, difluoromethoxy;

And/or, when R 4 is unsubstituted or C 1-6 alkyl substituted by R g , the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, pentyl, hexyl;

And/or, when R 4 is unsubstituted or C 3-8 cycloalkyl substituted by R g , said C 3-8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl;

And/or, when R 4 is a 4-8-membered heterocyclic group unsubstituted or substituted by R g , the heteroatom is selected from N, O and S; when R 4 is an unsubstituted or substituted 4 by R g When ~8-membered heterocyclic group, the number of said heteroatoms is 1-2;

And/or, when R 4 is an unsubstituted or 5-8-membered aryl group substituted by R g , the 5-8-membered aryl group is selected from phenyl and naphthalene ring;

And/or, when R 4 is an unsubstituted or substituted 5-8-membered heteroaryl group, the 5-8-membered heteroaryl group is selected from thiophene, furan, oxazole, thiazole, triazole, pyridine base, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl;

And/or, L 1 is selected from single bond,
The compound of claim 1, wherein
selected from

and/or, when R 1 is halogen, the halogen is fluorine, chlorine or bromine;

And/or, when R 1 is -ZR a and Z is -O-, R 1 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -O(CH 2 ) 2 F, -O(CH 2 ) 3 F, -OCH(CH 3 )(CH 2 F);

And/or, when R 1 is -ZR a and Z is -S-, R 1 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH 2 F, -S(CH 2 ) 2 F, -S(CH 2 ) 3 F, -SCH(CH 3 )(CH 2 F);

And/or, when R 1 is the following unsubstituted groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R b is -CN , halogen, C 1-6 alkyl or C 1-6 alkoxy, R 1 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -NH-(CH 2 ) 2 CH 3 , -NH-CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 ;

And/or, when R 1 is the following group substituted by R b : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R 1 Selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN),

-NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F, -CH(CH 3 )(CH 2 F),
-NH- CH2F , -N( CH3 )( CH2F ), -NH- CH2CH2CH2F , -NH-( CH2 ) 2CH2F , -NH- CH ( CH3 ) (CH 2 F), -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
-NH- CH2Cl , -N( CH3 )( CH2Cl ), -NH- CH2CH2CH2Cl , -NH-( CH2 ) 2CH2Cl , -NH- CH ( CH3 ) (CH 2 Cl), -OCH 2 Cl, -OCH 2 CH 2 Cl, -O(CH 2 ) 2 CH 2 Cl, -OCH(CH 3 )(CH 2 Cl),

and/or, when R 2 is halogen, the halogen is fluorine, chlorine or bromine;

And/or, when R 2 is -YR d and Y is -O-, R 2 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -OCH 2 CH 2 F, -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F);

And/or, when R 2 is YR d and Y is -O-, R 2 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH2F, -SCH2CH2F, -S( CH2 ) 2CH2F , -SCH ( CH3 ) ( CH2F ) ;

And/or, when R 2 is the following unsubstituted groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R b is -CN , halogen, C 1-6 alkyl or C 1-6 alkoxy, R 2 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -NH-(CH 2 ) 2 CH 3 , -NH-CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 ;

And/or, when R 2 is the following groups substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R 2 Selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN),

-NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F, -CH(CH 3 )(CH 2 F),
-NH- CH2F , -N( CH3 )( CH2F ), -NH- CH2CH2CH2F , -NH-( CH2 ) 2CH2F , -NH- CH ( CH3 ) (CH 2 F), -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
-NH- CH2Cl , -N( CH3 )( CH2Cl ), -NH- CH2CH2CH2Cl , -NH-( CH2 ) 2CH2Cl , -NH- CH ( CH3 ) (CH 2 Cl), -OCH 2 Cl, -OCH 2 CH 2 Cl, -O(CH 2 ) 2 CH 2 Cl, -OCH(CH 3 )(CH 2 Cl),

and/or, R 3 is selected from -H, methyl, ethyl, -CF 3 , -CH 2 CH 2 F;

And/or, when R 4 is unsubstituted C 1-6 alkyl, R 4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl;

And/or, when R 4 is unsubstituted C 3-8 cycloalkyl, R 4 is selected from cyclopropyl, cyclobutyl, and cyclopentyl;

And/or, when R 4 is an unsubstituted 4-8 membered heterocyclic group, R 4 is selected from

And/or, when R 4 is an unsubstituted 5-8-membered aryl group, R 4 is selected from phenyl, naphthalene ring;

And/or, when R 4 is unsubstituted 5-8 membered heteroaryl, R 4 is selected from pyridyl;

And/or, when R 4 is C 1-6 alkyl substituted by R g , R 4 is selected from -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH2CH2F, -( CH2 ) 2CH2F , -CH( CH3 ) ( CH2F ) , -CH2CH2Cl , - ( CH2 ) 2CH2Cl , -CH( CH 3 ) ( CH2Cl );

And/or, when R 4 is C 3-8 cycloalkyl substituted by R g , R 4 is selected from

And/or, when R 4 is a 4-8 membered heterocyclyl substituted by R g , R 4 is selected from

And/or, when R 4 is 5-8 membered aryl substituted by R g , R 4 is selected from

And/or, when R 4 is a 5-8 membered heteroaryl substituted by R g , R 4 is selected from
The compound of claim 1, wherein R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F),

And/or, R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,

-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F),

and / or,
selected from
The compound of claim 1, wherein
selected from

And/or, R 1 is selected from -H, -F, methyl, cyclopropyl;

And/or, R 2 is selected from -H, -F, -Cl, -CH 3 ;

And/or, when R 3 is C 1-3 alkyl, the C 1-3 alkyl is methyl, ethyl, n-propyl, isopropyl;

And/or, when R 3 is a C 1-3 alkyl group substituted by halogen, the C 1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl;

And/or, when R 3 is a C 1-3 alkyl substituted by halogen, the number of the halogen is one or more, and when there are multiple halogens, the halogens are the same or different;

And/or, when R 3 is C 1-3 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine;

And/or, R 4 is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl ,
-CH 2 F, -CH 2 CH 2 F, -CF 3 , -CH 2 CF 3 ;

And/or, L 1 is selected from single bond,
The compound of claim 1, wherein
selected from

wherein R 1 is selected from -CN, halogen, C 1-3 alkyl;

R 2 is selected from -H, -CN, halogen, C 1-3 alkyl;

R 3 is selected from -H, C 1-3 alkyl;

R 4 is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl,
-CH 2 F, -CH 2 CH 2 F, -CF 3 , -CH 2 CF 3 ;

L 1 is selected from single bond,
The compound according to claim 1, wherein the group definition of the compound shown in the formula I is as described in any of the following schemes:

Option One:
for

R 1 is selected from -F, methyl;

R 2 is selected from -F, -Cl;

R is selected from methyl;

R 4 is selected from C 3-8 cycloalkyl;

L 1 is selected from a single bond;

Option II:
for

R 1 is methyl;

R 2 is selected from -F, -Cl;

R 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,
-CH 2 F, -CH 2 CH 2 F, -CF 3 , -CH 2 CF 3 ;

L 1 is selected from single bond,

third solution:
for

R 1 is selected from methyl;

R 2 is selected from -F, -Cl;

R is selected from methyl;

R4 is selected from -H, -F, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl , cyclopentyl, phenyl, -CH2F , -CH2CH2F ;

L 1 is selected from single bond,

Option four:
for

R 1 is selected from methyl;

R 2 is selected from -F, -Cl;

R is selected from -H, methyl;

R 4 is selected from methyl, ethyl, cyclobutyl, cyclopentyl;

L 1 is selected from single bond,
The compound according to claim 1, wherein the compound represented by the formula (I) is the compound represented by the formula (I-0):

in:

R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,

-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 3 F, -OCH(CH 3 )(CH 2 F),

R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,

-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 3 F, -OCH(CH 3 )(CH 2 F),

X 1 , X 2 and X 3 are each independently selected from C or N, and X 1 , X 2 and X 3 are not N at the same time;

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

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

L 1 is selected from single bond, unsubstituted or C 1-6 alkylene substituted by C 1-3 alkyl.
The compound according to claim 1, wherein the compound represented by the formula (I) is the compound represented by the formula (I-0):

in:

R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,

-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F),

R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,

-NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F),

X 1 , X 2 and X 3 are each independently selected from C or N, and X 1 , X 2 and X 3 are not N at the same time;

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

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

selected from
The compound according to claim 1, wherein the compound represented by the formula (I) is a compound represented by the formula (I-1'):

Wherein, R 4 is selected from C 1-6 alkyl, C 1-6 alkyl substituted by halogen;

X 1 , X 2 and X 3 are each independently selected from C or N, and X 1 , X 2 and X 3 are not N at the same time.
The compound according to claim 11, wherein R 1 is methyl, R 2 is halogen, R 3 is methyl,
selected from
A compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
A pharmaceutical composition, characterized by comprising an effective dose of the compound according to any one of claims 1 to 13.
Use of the compound according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating LPAR-related diseases.
The use according to claim 15, wherein the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
The use according to claim 15, wherein the LPAR-related disease is selected from the group consisting of idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, Fetal hydrocephalus.
A method for treating or preventing LPAR-related diseases, characterized by administering to a patient a pharmaceutically acceptable dose of the compound of any one of claims 1 to 13, or the pharmaceutical composition of claim 14.
The method of claim 18, wherein the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
The method according to claim 18, wherein the LPAR-related disease is selected from the group consisting of idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid Arthritis, fetal hydrocephalus.