WO2022100625A1 - 氮取代氨基碳酸酯噻吩类化合物及其用途 - Google Patents

氮取代氨基碳酸酯噻吩类化合物及其用途 Download PDF

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WO2022100625A1
WO2022100625A1 PCT/CN2021/129865 CN2021129865W WO2022100625A1 WO 2022100625 A1 WO2022100625 A1 WO 2022100625A1 CN 2021129865 W CN2021129865 W CN 2021129865W WO 2022100625 A1 WO2022100625 A1 WO 2022100625A1
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och
alkyl
methyl
substituted
halogen
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张学军
常少华
叶大炳
王永刚
李群
刘勇
孙红娜
刘哲
杨俊�
李莉娥
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武汉人福创新药物研发中心有限公司
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Definitions

  • the present invention belongs to the field of medicinal chemistry, in particular, the present invention relates to nitrogen-substituted aminocarbonate thiophenes, more particularly, the present invention relates to nitrogen-substituted aminocarbonate thiophenes and their use in preparing medicines.
  • Lysophosphatidic acid 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 G ⁇ I/o, G ⁇ Q/11, and G ⁇ 12/13, 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 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 the tissue of alveolar tissue, and this damage 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 at and around the injury site, in which LPA plays an important role.
  • LPA extracellular matrix
  • LPA induces endothelial cell barrier dysfunction and vascular leakage.
  • increased vascular permeability can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated increased vascular permeability promotes fibrosis development.
  • 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.
  • LPAR1 is a promising target for the treatment of IPF
  • 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 inhibited the expression of the pro-fibrocytokines transforming growth factor ⁇ 1 and connective tissue growth factor in vivo, resulting in decreased fibroblast proliferation in mice and slowing the progression of radiation-induced pulmonary fibrosis, suggesting that LPAR1 antagonists are also therapeutic Potential for radiation pulmonary fibrosis (Xiang H et al., JCancer. 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.
  • LPA promotes the progression of renal fibrosis through LPAR1.
  • UUO unilateral ureteral obstruction
  • TNF renal interstitial fibrosis
  • 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 was also significantly down-regulated upon interruption. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.
  • Fetal hydrocephalus is a common neurological disease in neonates, and its occurrence is closely related to LPAR1 signaling.
  • LPAR1 expressed by neural precursor cells NPCs
  • NPCs neural precursor cells
  • Ki16425 an LPAR1/3 antagonist
  • PHL hemorrhagic 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.
  • neuropathic pain a painful state
  • symptoms including persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia
  • 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.
  • LPA-LPAR1 signaling plays a critical role in the initiation of neuropathic pain and that 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 is a chronic autoimmune disease
  • LPAR1 signaling is related to the occurrence of RA.
  • 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, inflammation and bone erosion were reduced (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.).
  • 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):
  • 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 ⁇ the "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 is subject to the substituted group conforming to the valence bond theory and stable existence.
  • halogen such as fluorine, chlorine, bromine or iodine
  • R b when there are multiple R b , the R b is the same or different ⁇ , unsubstituted or C 3-6 cycloalkyl substituted by R b (the "C 3-6 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or C 1 substituted by R b -6 alkylamino (the "C 1-6 alkylamino" such as wherein m1 and m2 are each independently selected from integers from 0 to 6, and the sum of m1 and m2 does not exceed 6, and/or m1 and m2 are not both 0), unsubstituted or substituted C 1-6 alkanes by R b Oxy group (the "C 1-6 alkoxy group” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy
  • 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
  • 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);
  • halogen eg fluorine, chlorine, bromine or iodine
  • C 1-6 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyloxy
  • C 1-6 alkyl eg
  • 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.
  • 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, isobuty
  • Re 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, and the sum of n1 and n2 does not exceed 6, and/or n1 and n2 are not both 0, ), unsubstituted or substituted by Re 1-6 Alkoxy (the "C 1-6 alkoxy” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 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
  • 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 independently C or N, respectively, and X 1 , X 2 , and X 3 are not N at the same time;
  • 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.
  • R g 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 benzen
  • 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);
  • halogen eg fluorine, chlorine, bromine, iodine
  • C 1-6 alkyl eg
  • L 1 is selected from -CO-O- or -SO 2 -;
  • L 2 is selected from single bond, unsubstituted or C 1-3 alkyl substituted C 1-3 alkylene, unsubstituted or C 1-3 alkyl substituted cyclopropyl, for example
  • R 1 is selected from fluorine, chlorine or bromine.
  • 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 ).
  • 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 ).
  • 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 .
  • 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,
  • R 2 is selected from fluorine, chlorine or bromine.
  • 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 ).
  • 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 ).
  • 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 .
  • 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), -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,
  • R 3 is selected from -H, methyl, ethyl, -CF3 , -CH2CH2F .
  • R 4 is selected from methyl, ethyl, isopropyl .
  • R 4 is selected from cyclopropyl, cyclobutyl, cyclopropyl amyl.
  • R 4 is selected from phenyl and naphthalene ring.
  • R 4 is selected from pyridyl.
  • 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 ).
  • R 4 is selected from
  • 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(
  • 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(
  • R 1 is selected from -H, -F, methyl, Cyclopropyl.
  • R 2 is selected from -H, -F, -Cl, -CH3 .
  • R 3 is selected from methyl, ethyl, n-propyl ,Isopropyl.
  • R 4 is selected from methyl, ethyl, isopropyl , cyclopropyl, cyclobutyl , phenyl, -CH2F , -CH2CH2F .
  • L 1 is selected from -CO-O- or -SO 2 -.
  • R 1 is selected from -F, 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 Selected from C 1-3 alkyl, C 3-6 cycloalkyl, phenyl, -CH 2 F, -CH 2 CH 2 F
  • L 1 is selected from -CO-O- or -SO 2 -
  • L 2 is selected since
  • R 1 is selected from -F, C 1-3 alkyl
  • R 2 is selected from -H, halogen, C 1-3 alkyl
  • R 3 is selected from -H, C 1-3 alkyl
  • R 4 is selected from methyl , ethyl, cyclobutyl, phenyl, -CH 2 F, -CH 2 CH 2 F
  • L 1 is selected from -CO-O-
  • L 2 is selected from
  • R 1 is selected from -F, C 1-3 alkyl
  • R 2 is selected from -H, halogen, C 1-3 alkyl
  • R 3 is selected from -H, C 1-3 alkyl
  • R 4 is selected from methyl , ethyl, cyclobutyl, phenyl, -CH 2 F, -CH 2 CH 2 F
  • L 1 is selected from -CO-O- or -SO 2 -
  • L 2 is selected from
  • R 1 is selected from -F, C 1-3 alkyl
  • R 2 is selected from -H, halogen, C 1-3 alkyl
  • R 3 is selected from -H, C 1-3 alkyl
  • R 4 is selected from methyl , ethyl, cyclobutyl, phenyl, -CH 2 F, -CH 2 CH 2 F
  • L 1 is selected from -CO-O- or -SO 2 -
  • L 2 is selected from
  • R 1 is selected from -F, C 1-3 alkyl
  • R 2 is selected from -H, halogen, C 1-3 alkyl
  • R 3 is selected from -H, C 1-3 alkyl
  • R 4 is selected from methyl , ethyl, cyclobutyl, phenyl, -CH 2 F, -CH 2 CH 2 F
  • L 1 is selected from -CO-O- or -SO 2 -
  • L 2 is selected from
  • R 1 is selected from -F, C 1-3 alkyl
  • R 2 is selected from -H, halogen, C 1-3 alkyl
  • R 3 is selected from -H
  • R 4 is selected from the following unsubstituted or substituted by R g Group: C 3-8 cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl
  • L 1 is selected from -CO-O-
  • L 2 is selected from
  • the compound represented by the formula (I) is further represented by the compound represented by the formula (I-0):
  • 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 independently C or N, respectively, 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, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 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 -CO-O- or -SO 2 -;
  • L 2 is selected from single bond, unsubstituted C 1-3 alkylene (for example ), C 1-3 alkylene substituted by C 1-3 alkyl (such as ), unsubstituted or C 1-3 alkyl substituted cyclopropyl (such as ).
  • the compound represented by the formula (I) is further represented by the compound represented by the formula (I-0):
  • 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 independently C or N, respectively, 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, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Phenyl , pyridyl, naphthalene ring, -CH2F , -CHF2 , -CF3 , -CF2CH3 , -CH2CF3 , -CH2CH2F , - ( CH2 ) 2CH2F , -CH( CH3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
  • the compound represented by the formula (I) is further represented by the compound represented by the formula (I-1'):
  • R 1 is selected from -H, C 1-3 alkyl
  • R 2 is selected from -H, halogen
  • R 3 is selected from -H, C 1-3 alkyl
  • R 4 is selected from -H, C 1-6 Alkyl, C 3-8 cycloalkyl, phenyl
  • L 2 is selected from single bond
  • the compound represented by the formula (I) is further represented by the compound represented by the formula (I-2'):
  • 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 alkane Amino or 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 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy ;
  • R 3 is -H
  • Ring A is the following groups unsubstituted or substituted by R g : C 3-8 cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; L 2 is selected from Single bond, unsubstituted C 1-3 alkylene, unsubstituted cyclopropyl.
  • the compound represented by the formula (I) is further represented by the compound represented by the formula (I-2'):
  • 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 alkane Amino or 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 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy ;
  • R 3 is -H
  • Ring A is the following groups unsubstituted or substituted by R g : C 3-8 cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;
  • L 2 is selected from C 1-3 alkylene substituted with C 1-3 alkyl or cyclopropyl substituted with C 1-3 alkyl.
  • the compound represented by the formula (I) may be any of the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.
  • 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) 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.
  • the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  • 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.
  • the present invention also provides a method of treating or preventing LPAR-related diseases.
  • the method comprises administering to the patient a pharmaceutically acceptable dose of the aforementioned compound, or the aforementioned pharmaceutical composition.
  • the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  • the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus .
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ - D and L forms of camphorsulfonic acid.
  • 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 ⁇ - D and L forms of camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include ⁇ -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).
  • 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.
  • 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.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • 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.
  • an "effective dose” 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.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
  • 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.
  • 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.
  • 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.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
  • C 1-6 alkyl is understood to mean a linear 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,
  • 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.
  • 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.
  • C 1-6 alkylamino refers to “alkylamino” or “alkylamino” having 1 to 6 carbon atoms.
  • C 1-6 alkoxy is to be understood as -O-(C 1-6 alkyl), wherein “C 1-6 alkyl” has the above definition.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • halo or halogen is fluorine, chlorine, bromine and iodine.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • 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.
  • 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; 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 the symptoms of bleomycin-induced pulmonary fibrosis in mice.
  • 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.
  • 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.
  • equivalent replacements, or equivalents 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).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • 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 was determined by a Waters Acquity H-class Uplc-QDA mass spectrometer, monitored using an ACQUITY UPLC BEH C18, 2.1*50mm, 1.7 ⁇ m 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.
  • IC 50 half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
  • M mol/L
  • N equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • PE petroleum ether
  • 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.
  • the synthetic route of the target compound I-1 is as follows:
  • the first step Synthesis of (2,5-dioxopyrrolidin-1-yl) cyclobutyl methyl ester of carboxylate (I-1C)
  • the starting material 6-(3-(aminomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-ol (I-1D) (2.15 g, 8.44 mmol) was added to 60 mL of THF at room temperature , potassium carbonate (4.66 g, 33.76 mmol), cyclobutylmethyl (2,5-dioxopyrrolidin-1-yl)carboxylate (4.22 g, 18.57 mmol) were added. Stir at room temperature for 16h.
  • the third step Synthesis of ((5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)yl)carboxylate cyclobutyl methyl ester (I-1F)
  • the starting material ((5-chloro-2-(5-(((cyclobutylmethoxy)carbonyl)oxy)-6-methylpyridin-2-yl)thiophen-3-yl)methyl)carboxylate cyclobutylmethyl) was prepared at room temperature Ester (I-1E) (2.5 g, 5.22 mmol) was added to 21 mL of methanol and 21 mL of THF, 1 mol/L lithium hydroxide solution (21 mL, 21 mmol) was added, and the mixture was stirred for 3 h.
  • the starting material ((5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)yl)carboxylate cyclobutylmethyl ester (I-1F) (780 mg, 1.62 mmol) at room temperature It was added to 10 mL of THF, and (1S,3R)-methyl 3-cyclohexane-1-carboxylate (606 mg, 3.26 mmol), triphenylphosphine (1.28 g, 4.88 mmol) and azodicarboxylate were added under nitrogen protection tert-Butyl ester (1.12 g, 4.88 mmol) was microwaved to 65°C and stirred for 4 h.
  • the starting material (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methyl was prepared at room temperature Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1G) (1.7 g, 3.18 mmol) was added to 20 mL of methanol and 10 mL of THF, followed by 1 M lithium hydroxide solution (16 mL, 16 mmol) , stirred for 16h.
  • 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)
  • the starting material 6-bromo-2-methylpyridin-3-ol (I-2A) (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) was added, 3,4-Dihydropyran (3.69 g, 43.9 mmol) was added, and the mixture was stirred at room temperature for 16 h.
  • the second step Synthesis of 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C)
  • the starting material 5-chloro-2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2D) was prepared at room temperature (110 mg, 0.33 mmol) was added to 8 mL of ethanol, hydroxylamine hydrochloride (67 mg, 0.98 mmol) and sodium acetate (107 mg, 1.30 mmol) were added, and the mixture was stirred at room temperature for 16 h.
  • the fifth step the synthesis of 6-(3-(aminomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-ol (I-1D)
  • the sixth step benzyl ((2-(5-(((benzyloxy)carbonyl)oxy)-6-methylpyridin-2-yl)-5-chlorothiophen-3-yl)methyl)formate ( 1-2F) synthesis
  • the starting material 6-(3-(aminomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-ol (I-1D) (1.0 g, 3.93 mmol) was added to 30 mL of THF at room temperature , potassium carbonate (2.17 g, 11.78 mmol), benzyl chloroformate (2.0 g, 11.78 mmol) were added. Stir at room temperature for 16h.
  • Step 7 Synthesis of ((5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)yl)formic acid benzyl ester (I-2G)
  • the starting material ((2-(5-(((benzyloxy)carbonyl)oxy)-6-methylpyridin-2-yl)-5-chlorothiophen-3-yl)methyl)carboxylate (benzyl)carboxylate ( 1-2F) (1.8 g, 3.44 mmol) was added to 20 mL of methanol and 20 mL of THF, 1 M lithium hydroxide solution (17 mL, 17 mmol) was added, and the mixture was stirred for 3 h.
  • Step 9 (1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridine Synthesis of -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)
  • the synthetic route of the target compound I-3 is as follows:
  • the synthetic route of the target compound I-5 is as follows:
  • the first step the synthesis of benzyl (4-nitrophenyl) carbonate (I-5B)
  • 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)
  • N-chlorosuccinimide (1.12 g, 8.42 mmol) was added to a solution of methyl acid methyl ester (I-6D) (2.76 g, 7.66 mmol) in N,N-dimethylformamide (20 mL), followed by the reaction The solution was stirred at 40° C. for 1 hour. The reaction solution was extracted with ethyl acetate (25 mL ⁇ 3), and the organic layers were combined to obtain a crude product.
  • Step 7 (1S,3S)-3-((2-(5-chloro-3-(((R)-1-phenethoxy)carbonyl)amino)methyl)thiophen-2-yl)- Synthesis of methyl 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6H)
  • the synthetic route of the target compound I-7 is as follows:
  • the synthetic route of the target compound I-8 is as follows:
  • the synthetic route of the target compound I-9 is as follows:
  • the synthetic route of the target compound I-10 is as follows:
  • the first step Synthesis of tert-butyldimethyl(thiophen-3-ylmethoxy)silane (I-10B)
  • 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 second step the synthesis of (5-fluorothiophen-3-yl) methanol (I-10C)
  • tert-butyldimethyl(thiophen-3-ylmethoxy)silane (I-10B) (16 g, 70.04 mmol) in tetrahydrofuran (200 mL), cool it to -78 °C, and under nitrogen protection, slowly Sec-butyllithium (1.3 M, 70.72 mL) was added dropwise, and after the addition was complete, 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 solution in tetrahydrofuran (70 mL) was added, and the mixture was stirred at room temperature overnight.
  • the third step synthesis of (2-bromo-5-fluorothiophen-3-yl) methanol (I-10D)
  • the fourth step the synthesis of 2-bromo-3-(chloromethyl)-5-fluorothiophene (I-10E)
  • the fifth step the synthesis of (2-bromo-5-fluorothiophen-3-yl) methylamine (I-10F)
  • Step 7 (1S,3S)-3-((6-(5-Fluoro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophene-2- Synthesis of methyl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-10H)
  • the reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane to give a residue.
  • reaction mixture was diluted with water (3 mL) and acidified to pH 2 with 1 M hydrochloric acid (2 mL), followed by ethyl acetate. Ester (2 mL x 2) was extracted and the combined organic phases were concentrated under reduced pressure to give a residue.
  • the synthetic route of the target compound I-11 is as follows:
  • the synthetic route of the target compound I-12 is as follows:
  • the first step the synthesis of 4-nitrophenyl butyl carbonate (I-12B)
  • the synthetic route of the target compound I-13 is as follows:
  • the first step the synthesis of 4-nitrophenyl propyl carbonate (I-13B)
  • the target compound I-14 was synthesized with reference to compound I-12, except that (1S,3S)-3-((6-(5-chloro-3-((methylamino)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-5C) was replaced by (1S,3S)-3-((6-(5-fluoro-3 -((methylamino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester.
  • the target compound I-15 was synthesized with reference to compound I-13, except that (4-nitrophenyl) propyl carbonate (I-13B) was replaced by 4-fluorobutyl (4--nitrophenyl) carbonic acid ester.
  • 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 ⁇ L of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours 20 ⁇ L/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 ⁇ L/well of compounds of different final concentrations into the cells, and equilibrate.
  • test compound IC50(nM) Control compound 1 117.9 Control compound 2 243.8 Control compound 3 251.6 Control compound 4 243.3 Control compound 5 109.5 I-1 8.05 I-2 6.37 I-3 16.97 I-4 193.0 I-5 12.71 I-6 40.4 I-7 66.67 I-8 87.15 I-9 18.36 I-10 16.52 I-11 50.53 I-13 56.12
  • 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. Eighteen 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 ⁇ L of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours. 20 ⁇ L/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 ⁇ L/well of compounds of different final concentrations into the cells, and equilibrate.
  • the results of the LPAR3 calcium flux assay showed that the compounds of the present invention had a weak antagonistic effect on LPAR3, and compared with the control compounds, the compounds of the present invention showed more excellent LPAR1 selective antagonistic activity.
  • Test Example 3 Test test for the inhibitory effect of compounds on bile efflux transporters
  • NC negative control
  • PC positive control
  • the assay was terminated with pre-chilled Buffer B1 (10 ⁇ Buffer B1 (Stopping and Washing Buffer): 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose). Transfer the test sample to a 96-well filter plate, filter it with a vacuum pump, and then repeatedly wash it with 0.2 mL of pre-cooled Buffer B1 for 5 times, dissolve the vesicles on the filter plate with 50 ⁇ L of 80% methanol, and centrifuge at 2000 rpm for 2 minutes after collection. The filtrate was collected and repeated once. The two filtrates were combined and mixed to obtain about 100 ⁇ L of the filtrate.
  • Buffer B1 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose.
  • mice pharmacokinetic test show that, compared with the control compound, the compound of the present invention exhibits better pharmacokinetic properties and good druggability.
  • LPA-induced mouse histamine release assays were performed with 20-25 g female Balb/c mice. Compounds and positive control groups were set up in three administration groups, each group of 6 mice, orally administered 1, 3, 10mpk, respectively, blank group and negative control group were given the same volume of vehicle (5% DMSO + 5% Solutol+90%Saline). After 2 hours of administration, mice in each administration group were injected with 300 ⁇ g/mouse LPA in the tail vein, while the blank group and the negative control group were injected with an equal volume of vehicle (4 mg/ml BSA/PBS) in the tail vein, and the blood was collected after 2 minutes of stimulation, and the mice were collected on wet ice.
  • vehicle 5% DMSO + 5% Solutol+90%Saline
  • the samples were stored at 2-8 degrees, centrifuged at 5000 rpm for 5 min within 20 min, and the plasma was collected, and the histamine concentration in the plasma was detected using the HTRF kit (Cisbio, 62HTMDPEG).
  • the inhibition rates of different concentrations of compounds on LPA-induced histamine release were calculated using the histamine concentration data in plasma.
  • the results of the histamine release test showed that, compared with the control compound, the compounds of the present invention were significantly higher than the control compound in inhibiting the LPA-induced histamine release efficiency at three concentrations.
  • Test Example 6 Efficacy test of bleomycin-induced pulmonary fibrosis
  • mice were reared adaptively for 1 week, and after reaching the target body weight, they were randomly divided into the control group, the model group and the administration group according to the body weight of the animals.
  • the model group and the administration group were evenly given 50 ⁇ L of bleomycin in the lungs to establish a mouse pulmonary fibrosis model, while the control group was evenly given 50 ⁇ L of normal saline in the lungs;
  • the animals were deeply anesthetized with sodium pentobarbital, and the bronchoalveolar lavage fluid (BALF) was collected and temporarily stored in a wet ice box for subsequent index detection; some animal lungs were placed in 10% neutral fortification.
  • BALF bronchoalveolar lavage fluid

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Abstract

涉及一类有效拮抗LPAR的新化合物，其为下式（I）所示化合物，或者下式示化合物的立体异构体、水合物、溶剂化物、药学可接受的盐或前药：

Description

氮取代氨基碳酸酯噻吩类化合物及其用途
优先权信息
本申请请求2020年11月10日向中国国家知识产权局提交的、专利申请号为202011249976.4的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明属于药物化学领域，具体地，本发明涉及氮取代氨基碳酸酯噻吩类化合物，更具体地，本发明涉及氮取代氨基碳酸酯噻吩类化合物及其在制备药物中的用途。
背景技术
溶血磷脂酸(LPA)是一类分子量为430-480Da的关键内源性脂质信号分子，其广泛存在于人体各组织中的胞内和胞外，如各种体液，唾液、尿液、脑脊液、血液、支气管肺泡灌洗液(BALF)等(Kaffe E等人，Cancers(Basel).2019；11(11):1626.)。LPA主要是以膜磷脂为原料通过以下两条途径产生的：(1)磷脂酶D(PLD)-磷脂酶A2(PLA2)途径；(2)PLA2-溶血磷脂酶D(LysoPLD)途径。Enpp2基因编码的自体趋化蛋白(ATX)是一种焦磷酸酶/磷酸二酯酶，其具有溶血磷脂酶D(LysoPLD)活性，能将胞外溶血磷脂酰胆碱(LPC)水解成相应的LPA和游离胆碱(Choi JW等人，AnnuRevPharmacolToxicol.2010；50:157186.)，这一反应是LPA的主要来源，抑制ATX活性能抑制全身80％以上LPA的产生(Kaffe E等人，Cancers(Basel).2019；11(11):1626.)。
LPA通过与G蛋白偶联受体作用介导多种功能，包括细胞存活、细胞增殖、细胞粘附、细胞迁移、细胞骨架改变、钙动员、增加血管通透性和血管形成、免疫功能和髓鞘形成等。LPA可与六种溶血磷脂酸受体(LPAR)结合并发挥功能，分别为：LPAR1-LPAR6。LPA通过与6种LPAR结合调节多种生理/病理过程，包括血管和神经发育、毛囊发育、淋巴细胞转运、骨发育、纤维化、脂肪量调节、胆汁淤积性瘙痒、神经性疼痛、胚胎植入、肥胖和葡萄糖稳态、精子产生、慢性炎症、细胞增殖、细胞趋化、伤口愈合、肿瘤进展、胎儿脑积水等(Fang Yang等人，World journal of gastroenterology,2018,24(36):4132.)。
LPAR1是最早被鉴定和分布最广的LPA受体，其是一个41kDa的膜蛋白，由364个氨基酸组成，在人体各组织器官中广泛表达，其中脑、心、结肠、小肠和胎盘的mRNA水平较高，而在其他器官和组织中的mRNA水平相对较低。LPAR1通过与GαI/o、GαQ/11 和Gα12/13偶联，激活Akt、Rho、丝裂原活化蛋白激酶和磷脂酶C等下游通路，虽然已证明LPA-LPAR1信号在神经系统的发育阶段有重要作用，但成年个体的全身抑制未发现明显毒性。但LPAR3信号被抑制会产生显著的生殖毒性，因此化合物需避免对LPAR3信号的抑制。
与LPAR1具有显著相关性的疾病主要是纤维化疾病、肿瘤、神经性疼痛、RA(类风湿性关节炎)、某些中枢性疾病等。
特发性肺纤维化(idiopathic pulmonary fibrosis，IPF)是一种病因不明，以弥漫性肺泡炎和肺泡结构紊乱为特征的慢性、进行性、纤维化性间质性肺炎，在影像学和病理组织学中主要表现为普通型间质性肺炎。IPF起源于肺泡组织的组织的反复损伤，而这种损伤会引发一系列生理病理事件，包括(I)破坏内稳态；(II)引起炎症反应；(III)细胞增殖、迁移和分化；(IV)基质和组织重建；以及(V)伤口挛缩和瘢痕形成，这些事件中的许多是由损伤部位及其周围的生化因子的协调释放控制的，而LPA在其中起重要作用。病理升高的LPA浓度可能会继续激活肺细胞上的LPAR1受体，从而增强组织炎症并刺激过度的细胞外基质(ECM)产生。LPA是受损肺组织BALF中的成纤维细胞迁移的主要介质之一(Tager A M等人，Proceedings of the American Thoracic Society,2008.)，IPF患者的BALF(肺泡灌洗液)LPA水平高于正常对照组，抑制LPA信号显著降低成纤维细胞对IPF BALF的趋化反应。
在临床前研究中，用博莱霉素处理LPAR1基因缺陷小鼠，结果发现LPAR1基因敲除对小鼠具有明显的保护作用，而且在LPAR1缺陷的小鼠中，博莱霉素处理后的成纤维细胞聚集明显减少。LPA诱导内皮细胞屏障功能障碍和血管渗漏，在组织损伤修复的早期阶段，血管通透性增加，能加快组织修复，但在IPF进程中，LPA-LPAR1介导的血管通透性增加促进纤维化发展。在另一项博来霉素诱导的IPF临床前模型中，博来霉素处理导致肺损伤后支气管肺泡灌洗液中LPA水平显著升高，并引起肺纤维化、血管渗漏和死亡，这些病理改变在LPAR1 -/-小鼠中明显减轻；LPAR1拮抗剂AM966降低了博来霉素模型中肺泡灌洗液中总蛋白质含量和LDH活性，表明AM966减少了LPA介导的IPF和其他间质性肺疾病中血管渗漏和上皮细胞死亡。这些内容表明LPAR1是治疗IPF有前途的靶点，在一项随机、双盲、安慰剂对照的临床试验中，LPAR1拮抗剂BMS-986020的使用显著减缓了特发性肺纤维化患者肺活量的下降，并减轻了临床症状，其二代化合物BMS-986278正在开展治疗IPF的II期临床试验(Swaney JS等人，Br J Pharmacol.2010；160(7):1699-1713.)。
放射性肺纤维化是肺癌放射治疗常见而严重的并发症。LPAR1/LPAR3拮抗剂VPC12249可在体内抑制促成纤维细胞因子转化生长因子β1和结缔组织生长因子的表达， 导致小鼠成纤维细胞增殖减少，减慢放射性肺纤维化进展，这说明LPAR1拮抗剂也有治疗放射性肺纤维化的潜力(Xiang H等人，JCancer.2020；11(12):3519-3535.)。
LPAR1与肝纤维化的发生有密切关联。研究证明ATX-LPA信号轴激活PI3K并稳定缺氧诱导因子HIF-1的mRNA，从而促进丙型肝炎病毒的复制，抑制ATX-LPA信号则减少了丙型肝炎病毒的复制，这一过程可能与LPAR1和LPAR3有关，而肝炎是肝纤维化发生的关键因素，这表明拮抗LPAR1可能具有治疗肝纤维化的潜力(Farquhar MJ等人，J Hepatol.2017；66(5):919-929.)；在另一项研究中，下调LPAR1信号，降低了α-SMA、CTGF和TGF-β1表达，从而显著改善硫代乙酰胺诱导的肝纤维化，这更证明了LPAR1拮抗剂可以用于治疗肝纤维化。
LPA通过LPAR1促进肾纤维化的进展。在单侧输尿管梗阻(UUO)诱导的肾间质纤维化(TIF)小鼠中，ATX和LPA浓度升高，LPAR1显著上调，而LPAR3显著下调(Sakai N等人，FASEB J.2013；27(5):1830-1846.)。ATX-LPA-LPAR1信号可刺激成纤维细胞迁移和增殖，在LPAR1 -/-小鼠上或使用LPAR1/3拮抗剂Ki16425预处理后，UUO诱导的肾脏纤维化显著减轻，且当LPAR1信号被阻断时，促纤维化细胞因子的表达(结缔组织生长因子和转化生长因子-β)也显著下调。这表明LPAR1拮抗剂可能可以用于肾纤维化的治疗。
胎儿脑积水(FH)是新生儿常见的神经系统疾病，其发生与LPAR1信号密切相关。在临床前的小鼠颅内出血模型中，通过将小鼠胚胎脑暴露在血液或LPA中，神经前体细胞(NPC)表达的LPAR1被过度激活，导致皮层破坏和变薄，最终导致FH。(Yung YC等人，Sci Transl Med.2011；3(99):99ra87.)。在小鼠相关模型使用Ki16425(LPAR1/3拮抗剂)预处理，可降低出血性脑积水(PHH)产生的概率和严重程度，提示LPAR1拮抗剂可能用于治疗胎儿脑积水。
LPA-LPAR1信号具有显著的促肿瘤作用。LPA在体外促进肿瘤细胞存活、增殖、增加迁移和组织侵袭、激活血管内皮生长因子和激活金属基质蛋白酶，促进肿瘤细胞对顺铂耐药。LPAR1信号下调肝癌细胞中肿瘤抑制因子p53的表达；LPA通过LPAR1激活PI3K和P38MPAK信号通路，促进MMP-9的表达和HCC的侵袭；LPA-LPAR1也能通过GTPase RhoA和Rho相关蛋白激酶(ROCK)促进侵袭性；它还诱导蛋白激酶C(PKC)和核因子κB(NF-kB)促进上皮向间充质转化(EMT)；另外，LPA-LPAR1对血管生成的积极作用也能促进癌症的发展，因为新生血管对于实体肿瘤的发展是必不可少的。这些研究结果表明LPAR1拮抗剂在相关肿瘤的治疗方面具有巨大潜力(Xiang H等人，J Cancer.2020；11(12):3519-3535.)。
人类周围神经损伤可导致一种称为神经病理性疼痛的疼痛状态，症状包括持续的烧灼 性疼痛和异常感觉，如超敏和痛觉过敏，LPAR1信号与神经性疼痛的发生有关。神经系统受损导致损伤部位血清渗漏，使神经细胞大量暴露在LPA中可能是神经病理性疼痛的病因之一。Makoto Inoue等的研究表明神经损伤引起的行为异常和痛敏动物模型可通过LPAR1的拮抗剂预处理或靶向删除LPAR1来消除痛敏症状，并可通过鞘内注射LPA来模拟。另一项研究表明LPA可通过激活LPAR1，释放伤害性因子P物质而引起神经病理性疼痛，且LPAR1 -/-小鼠对部分坐骨神经结扎引起的神经病理性疼痛具有抵抗力。这些结果表明，LPA-LPAR1信号在神经病理性疼痛的启动中起关键作用，LPAR1拮抗剂可能有希望作为止痛剂用于神经病理性疼痛的治疗(Inoue M等人，ERRATUM:Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling[J].2004,10(7):755-755.)。
类风湿性关节炎(RA)是一种慢性自身免疫性的疾病，LPAR1信号与RA的发生有关。与骨关节炎患者相比，类风湿性关节炎患者滑膜中LPAR1和/或LPAR2表达水平升高，临床前研究表明LPAR1的基因敲除完全消除了RA症状，LPAR1的药理拮抗降低了疾病的严重程度，减轻了炎症和骨质侵蚀(Kaffe E等人，Cancers(Basel).2019；11(11):1626.Published 2019 Oct 23.doi:10.3390/cancers11111626)。拮抗LPAR1信号还减少RA患者FLS(滑膜成纤维细胞)的增殖，并使其对肿瘤坏死因子(TNF)介导的凋亡敏感，另外LPA还参与了RA FLS中白细胞介素(IL)-6、IL-8和环氧合酶-2(COX-2)的产生。这些结果显示LPAR1是治疗类风湿性关节炎的一个很有前途的靶点(Orosa B等人，Annals of the Rheumatic Diseases,2014,73(1):298-305.)。
发明内容
本发明旨在至少在一定程度上解决上述技术问题之一或至少提供一种有用的商业选择。
本发明提供了一种如式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2021129865-appb-000001
其中，R 1选自-H，-CN，卤素(例如氟、氯、溴或碘)，-Z-R a，无取代或被R b取代的C 1-6烷基{所述的“C 1-6烷基”例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；所述的R b的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个R b时，所述的R b相同或不同}，无取代或被R b取代的C 3-6环烷基(所述的“C 3-6环烷基”例如环丙基、环丁基、环戊基)、无取代或被R b取代的C 1-6烷氨基(所述的“C 1-6烷氨基”例如
Figure PCTCN2021129865-appb-000002
其中m1和m2各自独立地选自0-6的整数，且m1和m2的和不超过6，和/或m1和m2不同时为0)，无取代或被R b取代的C 1-6烷氧基(所述的“C 1-6烷氧基”例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)；
Z选自单键或-O-、-S-；
R a选自C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，被卤素取代的C 1-6烷基{所述的“卤素”例如氟、氯、溴或碘；所述的卤素的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个卤素时，所述的卤素相同或不同}；
R b选自-CN，卤素(例如氟、氯、溴或碘)，C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，C 1-6烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)；
R 2选自-H，-CN，卤素(例如氟、氯、溴或碘)，-Y-R d，无取代或被R e取代的C 1-6烷基{所述的“C 1-6烷基”例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；所述的R e的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个R e时，所述的R e相同或不同}、无取代或被R e取代的C 3-6环烷基(所述的“C 3-6环烷基”例如环丙基、环丁基、环戊基)、无取代或被R e取代的C 1-6烷氨基(所述的“C 1-6烷氨基”例如
Figure PCTCN2021129865-appb-000003
其中n1和n2各自独立地选自0-6的整数，且n1和n2的和不超过6，和/或n1和n2不同时为0，)、无取代或被R e取代的C 1-6烷氧基(所述的“C 1-6烷氧基”例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)；
Y选自单键、-O-或-S-；
R d选自C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，被卤素取代的C 1-6烷基{所述的“卤素”例如氟、氯、溴或碘；所述的卤素的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个卤素时，所述的卤素相同或不同}；
R e选自-CN，卤素(例如氟、氯、溴或碘)，C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，C 1-6烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)；
X 1、X 2、X 3分别独立地为C或N，且X 1、X 2、X 3不同时为N；
Figure PCTCN2021129865-appb-000004
选自被R 1取代的苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，例如
Figure PCTCN2021129865-appb-000005
Figure PCTCN2021129865-appb-000006
R 3选自-H、C 1-3烷基(例如甲基、乙基、正丙基、异丙基)、被卤素取代的C 1-3烷基{所述的“卤素”例如氟、氯、溴或碘；所述的卤素的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个卤素时，所述的卤素相同或不同}；
R 4选自-H、-CN、卤素(例如氟、氯、溴或碘)、无取代或被R g取代的C 1-6烷基{所述的“C 1-6烷基”例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；所述的R g的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个R g时，所述的R g相同或不同}、无取代或被R g取代的C 3-8环烷基(所述的“C 3-6环烷基”例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基)、无取代或被R g取代的4-8元杂环基{所述的“4-8元杂环基”中杂原子选自N、O和S；所述杂原子数为1-2个(其个数以取代后的基团符合价键理论、稳定存在为准)，当存在多个杂原子时，所述的杂原子相同或不同}、无取代或被R g取代的5-8元芳基(例如苯基、萘环)、无取代或被R g取代的5-8元杂芳基(例如噻吩、呋喃、噁唑、噻唑、三氮唑、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、吡唑基、咪唑基)；
R g选自-H、卤素(例如氟、氯、溴、碘)、C 1-6烷基(例如)、C 1-6环烷基(例如甲基、乙基、正丙基、异丙基、正丁基、正戊基)、卤素取代的C 1-6烷基(例如氟代烷基，又例如三氟甲基)、C 1-6烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)、卤素取代的C 1-6烷氧基(例如二氟甲氧基)；
L 1选自-CO-O-或-SO 2-；
L 2选自单键、无取代或被C 1-3烷基取代的C 1-3亚烷基、无取代或被C 1-3烷基取代的环丙基，例如
Figure PCTCN2021129865-appb-000007
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129865-appb-000008
选自
Figure PCTCN2021129865-appb-000009
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自氟、氯或溴。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000010
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
Figure PCTCN2021129865-appb-000011
-NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、-NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、-OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000012
-NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
Figure PCTCN2021129865-appb-000013
-NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
Figure PCTCN2021129865-appb-000014
Figure PCTCN2021129865-appb-000015
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自氟、氯或溴。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000016
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、 -O(CH 2) 2CH 3、-OCH(CH 3) 2。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
Figure PCTCN2021129865-appb-000017
-NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、-NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、-OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000018
-NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
Figure PCTCN2021129865-appb-000019
-NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
Figure PCTCN2021129865-appb-000020
Figure PCTCN2021129865-appb-000021
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 3选自-H、甲基、乙基、-CF 3、-CH 2CH 2F。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自甲基、乙基、异丙基。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自环丙基、环丁基、环戊基。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自
Figure PCTCN2021129865-appb-000022
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自苯基、萘环。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自吡啶基。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自
Figure PCTCN2021129865-appb-000023
Figure PCTCN2021129865-appb-000024
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自
Figure PCTCN2021129865-appb-000025
Figure PCTCN2021129865-appb-000026
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自
Figure PCTCN2021129865-appb-000027
Figure PCTCN2021129865-appb-000028
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
R 4选自
Figure PCTCN2021129865-appb-000029
Figure PCTCN2021129865-appb-000030
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000031
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000032
Figure PCTCN2021129865-appb-000033
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000034
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000035
Figure PCTCN2021129865-appb-000036
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前 任一方案所述：
Figure PCTCN2021129865-appb-000037
选自
Figure PCTCN2021129865-appb-000038
Figure PCTCN2021129865-appb-000039
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-H、-F、甲基、环丙基。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-H、-F、-Cl、-CH 3。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 3选自甲基、乙基、正丙基、异丙基。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自甲基、乙基、异丙基、环丙基、环丁基、苯基、-CH 2F、-CH 2CH 2F。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：L 1选自-CO-O-或-SO 2-。
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：L 2选自
Figure PCTCN2021129865-appb-000040
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129865-appb-000041
选自
Figure PCTCN2021129865-appb-000042
其中R 1选自-F、C 1-3烷基；R 2选自-H、-CN、卤素、C 1-3烷基；R 3选自-H、C 1-3烷基；R 4选自C 1-3烷基、 C 3-6环烷基、苯基、-CH 2F、-CH 2CH 2F；L 1选自-CO-O-或-SO 2-；L 2选自
Figure PCTCN2021129865-appb-000043
Figure PCTCN2021129865-appb-000044
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129865-appb-000045
为
Figure PCTCN2021129865-appb-000046
R 1选自-F、C 1-3烷基；R 2选自-H、卤素、C 1-3烷基；R 3选自-H、C 1-3烷基；R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；L 1选自-CO-O-；L 2选自
Figure PCTCN2021129865-appb-000047
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129865-appb-000048
为
Figure PCTCN2021129865-appb-000049
R 1选自-F、C 1-3烷基；R 2选自-H、卤素、C 1-3烷基；R 3选自-H、C 1-3烷基；R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；L 1选自-CO-O-或-SO 2-；L 2选自
Figure PCTCN2021129865-appb-000050
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129865-appb-000051
为
Figure PCTCN2021129865-appb-000052
R 1选自-F、C 1-3烷基；R 2选自-H、卤素、C 1-3烷基；R 3选自-H、C 1-3烷基；R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；L 1选自-CO-O-或-SO 2-；L 2选自
Figure PCTCN2021129865-appb-000053
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前 任一方案所述：
Figure PCTCN2021129865-appb-000054
为
Figure PCTCN2021129865-appb-000055
R 1选自-F、C 1-3烷基；R 2选自-H、卤素、C 1-3烷基；R 3选自-H、C 1-3烷基；R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；L 1选自-CO-O-或-SO 2-；L 2选自
Figure PCTCN2021129865-appb-000056
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129865-appb-000057
为
Figure PCTCN2021129865-appb-000058
R 1选自-F、C 1-3烷基；R 2选自-H、卤素、C 1-3烷基；R 3选自-H；R 4选自无取代或被R g取代的以下基团：C 3-8环烷基、4-8元杂环基、5-8元芳基、5-8元杂芳基；L 1选自-CO-O-；L 2选自
Figure PCTCN2021129865-appb-000059
在某一方案中，所述的式(I)所示化合物的进一步为式(I-0)所示化合物：
Figure PCTCN2021129865-appb-000060
其中，R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000061
Figure PCTCN2021129865-appb-000062
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000063
Figure PCTCN2021129865-appb-000064
R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000065
Figure PCTCN2021129865-appb-000066
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000067
Figure PCTCN2021129865-appb-000068
X 1、X 2、X 3分别独立地为C或N，且X 1、X 2、X 3不同时为N；
R 3选自-H、C 1-3烷基、被卤素取代的C 1-3烷基；
R 4选自-H、-CN、-F、-Cl、-Br、甲基、乙基、异丙基、环丙基、环丁基、环戊基、
Figure PCTCN2021129865-appb-000069
Figure PCTCN2021129865-appb-000070
苯基、吡啶基、萘环、-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
Figure PCTCN2021129865-appb-000071
Figure PCTCN2021129865-appb-000072
Figure PCTCN2021129865-appb-000073
L 1选自-CO-O-或-SO 2-；
L 2选自单键、无取代的C 1-3亚烷基(例如
Figure PCTCN2021129865-appb-000074
)、被C 1-3烷基取代的C 1-3亚烷基(例如
Figure PCTCN2021129865-appb-000075
)、无取代或被C 1-3烷基取代的环丙基(例如
Figure PCTCN2021129865-appb-000076
)。
在某一方案中，所述的式(I)所示化合物的进一步为式(I-0)所示化合物：
Figure PCTCN2021129865-appb-000077
其中，R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000078
Figure PCTCN2021129865-appb-000079
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000080
Figure PCTCN2021129865-appb-000081
R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129865-appb-000082
Figure PCTCN2021129865-appb-000083
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129865-appb-000084
Figure PCTCN2021129865-appb-000085
X 1、X 2、X 3分别独立地为C或N，且X 1、X 2、X 3不同时为N；
R 3选自-H、C 1-3烷基、被卤素取代的C 1-3烷基；
R 4选自-H、-CN、-F、-Cl、-Br、甲基、乙基、异丙基、环丙基、环丁基、环戊基、
Figure PCTCN2021129865-appb-000086
Figure PCTCN2021129865-appb-000087
苯基、吡啶基、萘环、-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
Figure PCTCN2021129865-appb-000088
Figure PCTCN2021129865-appb-000089
Figure PCTCN2021129865-appb-000090
Figure PCTCN2021129865-appb-000091
选自
Figure PCTCN2021129865-appb-000092
Figure PCTCN2021129865-appb-000093
在某一方案中，所述的式(I)所示化合物的进一步为式(I-1’)所示化合物：
Figure PCTCN2021129865-appb-000094
其中，R 1选自-H、C 1-3烷基；R 2选自-H、卤素；R 3选自-H、C 1-3烷基；R 4选自-H、C 1-6烷基、C 3-8环烷基、苯基；L 2选自单键、
Figure PCTCN2021129865-appb-000095
在某一方案中，所述的式(I)所示化合物的进一步为式(I-2’)所示化合物：
Figure PCTCN2021129865-appb-000096
其中，R 1选自-H，-CN，卤素，-Z-R a，无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基或C 1-6烷氧基；Z选自单键或-O-、-S-；
R a选自C 1-6烷基，被卤素取代的C 1-6烷基；
R b选自-CN，卤素，C 1-6烷基，C 1-6烷氧基；
R 2选自-H，-CN，卤素，-Y-R d，无取代或被R e取代的以下基团：C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基；
R 3为-H；
环A为无取代或被R g取代的以下基团：C 3-8环烷基、4-8元杂环基、5-8元芳基、5-8元杂芳基；L 2选自单键、无取代的C 1-3亚烷基、无取代的环丙基。
在某一方案中，所述的式(I)所示化合物的进一步为式(I-2’)所示化合物：
Figure PCTCN2021129865-appb-000097
其中，R 1选自-H，-CN，卤素，-Z-R a，无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基或C 1-6烷氧基；Z选自单键或-O-、-S-；
R a选自C 1-6烷基，被卤素取代的C 1-6烷基；
R b选自-CN，卤素，C 1-6烷基，C 1-6烷氧基；
R 2选自-H，-CN，卤素，-Y-R d，无取代或被R e取代的以下基团：C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基；
R 3为-H；
环A为无取代或被R g取代的以下基团：C 3-8环烷基、4-8元杂环基、5-8元芳基、5-8 元杂芳基；
L 2选自被C 1-3烷基取代的C 1-3亚烷基或被C 1-3烷基取代的环丙基。
在某一方案中，所述的式(I)所示化合物可为如下任一化合物：
Figure PCTCN2021129865-appb-000098
Figure PCTCN2021129865-appb-000099
本发明还提供了一种药物组合物，其包含上述的式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。
在所述的药物组合物中，所述的式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的药物组合物可为治疗有效剂量。
本发明还提供了一种上述的式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与LPAR相关疾病的药物中的用途。
在所述的用途中，所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
在所述的用途中，所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
本发明还提供了一种治疗或预防LPAR相关疾病的方法。根据本发明的实施例，所述方法包括给与患者药学上可接受剂量的前面所述化合物，或前面所述的药物组合物。
在所述方法中，所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
在所述方法中，所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。
除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。本发明使用的立体化学定义和惯例大体上按照S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill  Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994来定义。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的化合物中，且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。
旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的柱子上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以 由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本发明所描述化合物的任何对映体或非对映体。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
针对药物或药理学活性剂而言，术语“有效剂量”、“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。
术语“C 1-6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。
术语“C 3-6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。如环丙基、环丁基、环戊基、环己基。
术语“烷氨基”或“烷基氨基”是指氨基中的一个或两个氢原子被烷基取代，包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基(甲氨基)，N-乙氨基(乙氨基)，N,N-二甲氨基(二甲氨基)，N,N-二乙氨基(二乙氨基)等等。所述烷氨基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“C 1-6烷氨基”是指具有1至6个碳原子的“烷氨基”或“烷基氨基”。
术语“C 1-6烷氧基”应理解为-O-(C 1-6烷基)，其中“C 1-6烷基”具有上述定义。
术语“4-8元杂环基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的单环、二环或三环，其中1、2、3、4或5个环原子选自N、O和S，除非另有说明，其可通过碳或氮连接，其中-CH 2-基团任选被-C(O)-代替；及其中除非另有相反说明，环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化；其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代；及环任选被一个或多个卤素取代。应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为二环或三环，则至少一个环可任选为杂芳族环或芳族环，条件是至少一个环是非杂芳族的。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢 噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。
术语“5-8元芳基”应理解为具有5-8个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；当所述5-8元芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
术语“5-8元杂芳基”应理解为具有5-8个环原子——特别是5或6个碳原子——且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“卤代基”或“卤素”为氟、氯、溴和碘。
“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
有益效果
根据本发明的具体示例，本发明所述式(I)所示化合物，其立体异构体、水合物、溶剂化物、药学上可接受的盐或前药对LPAR1具有良好的拮抗作用。
根据本发明的具体示例，本发明化合物对LPAR1具有良好的拮抗作用，对LPAR3的拮抗作用很弱，亦即本发明化合物显示出优异的选择性；本发明化合物安全性更优，无胆汁淤积毒性风险；本发明化合物药代动力学性质优良，成药性好；本发明化合物能通过拮抗LPAR1显著抑制LPA诱导的组胺释，同时显著改善博来霉素诱导的小鼠肺纤维化症状。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
具体实施方式
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注 明生产厂商者，均为可以通过市购获得的常规产品。
本发明的实施例提供了式(I)所示化合物，其药学上可接受的盐、互变异构体、立体异构体、水合物、溶剂化物、共晶或前药，制备式(I)所示化合物或其药学上可接受的盐、互变异构体、立体异构体、水合物、溶剂化物、共晶或前药的方法和中间体、药物组合物、以及本发明的化合物和药物组合物在制备药物中的用途。
本发明所述的各反应步骤所使用的反应溶剂没有特别限制，任何在一定程度上能溶解起始原料并且不抑制反应的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。
液质联用(LC-MS)由Waters Acquity H-class Uplc-QDA质谱仪测定，使用ACQUITY UPLC BEH C18，2.1*50mm，1.7μm色谱柱监测。梯度洗脱条件：以1.0mL/min流速，95—5％溶剂A1和5-95％溶剂B1，然后95％B1和5％A1保持0.5min，百分数为某一溶剂占总溶剂体积的体积百分数。其中溶剂A1：0.1％甲酸的水溶液；溶剂B1：0.1％甲酸的乙腈溶液。百分数为溶质占溶液的体积百分数。
本发明的缩写定义如下：
符号或单位：
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度
M：mol/L，例如正丁基锂(14.56mL，29.1mmol，2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液
RT：保留时间
试剂：
DCM：二氯甲烷
DIPEA：也可写为DIEA，二异丙基乙胺，亦即N,N-二异丙基乙胺
DMF：N,N-二甲基甲酰胺
DMSO：二甲基亚砜
EA：乙酸乙酯
Et 3N：三乙胺
MeOH：甲醇
PE：石油醚
THF：四氢呋喃
试验或检测方法：
HPLC：高效液相色谱
SFC：超临界流体色谱
除非作出相反的指示，本文例举的化合物使用ChemBioDraw Ultra 13.0命名和编号。
对照例1：对照化合物1及其制备
Figure PCTCN2021129865-appb-000100
对照化合物1参考专利申请WO2010141768A2合成。
对照例2：对照化合物2及其制备
Figure PCTCN2021129865-appb-000101
对照化合物2参考专利申请WO2017223016A1合成。
对照例3：对照化合物3及其制备
Figure PCTCN2021129865-appb-000102
对照化合物3参考专利申请WO2017223016A1合成。
对照例4：对照化合物4及其制备
Figure PCTCN2021129865-appb-000103
对照化合物4参考专利申请WO2019126098A1合成。
对照例5：对照化合物5及其制备
Figure PCTCN2021129865-appb-000104
对照化合物5参考专利申请WO2019126084A1合成。
制备例1：中间体A的制备
(1S,3R)-3-羟基环己烷-1-甲酸甲酯(中间体A)
methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate(中间体A)
Figure PCTCN2021129865-appb-000105
中间体A的合成路线如下所示：
Figure PCTCN2021129865-appb-000106
第一步：(1S,5S)-4-碘-6-氧杂环[3.2.1]辛烷-7-酮(A-2)的合成
(1S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one(A-2)
Figure PCTCN2021129865-appb-000107
将(S)-环己-3-烯-1-羧酸(8.1g)溶于DCM(135mL)和水(270mL)中，碳酸氢钠(10.79g，128.3mmol)，碘化钾(64.0g，385.5mmol)和碘(48.9g，192.6mmol)加入反应液。避光室温搅拌过夜。TLC监控反应完全，分液，水相用甲基叔丁基醚萃取(100mL×3)，合并有机相，无水硫酸钠干燥，浓缩得到产品(1S,5S)-4-碘-6-氧杂环[3.2.1]辛烷-7-酮(A-2)(13.6g，产率84％)，直接用于下一步反应。
第二步：(1S,5R)-6-氧杂环[3.2.1]辛烷-7-酮(A-3)的合成
(1S,5R)-6-oxabicyclo[3.2.1]octan-7-one(A-3)
Figure PCTCN2021129865-appb-000108
将(1S,5S)-4-碘-6-氧杂环[3.2.1]辛烷-7-酮(A-2)(13.2g，52.4mmol)溶于MeOH(150mL)中，加入乙酸钠(4.30g，52.4mmol)，氯化锂(2.22g，52.4mmol)和含量10％的干钯碳(1.115g)。氢气置换三次，氢气球室温搅拌反应过夜。反应液硅藻土过滤，浓缩，残余物加入甲基叔丁基醚(100mL)溶解，饱和碳酸氢钠洗涤一次，饱和亚硫酸钠洗涤一次，无水硫酸钠干燥，浓缩，柱层析分离(石油醚：乙酸乙酯(V/V)＝100:1～20:1)得到白色固体(1S,5R)-6-氧杂环[3.2.1]辛烷-7-酮(A-3)(3.88g，产率58.7％)。
第三步：(1S,3R)-3-羟基环己烷-1-羧酸甲酯(中间体A)的合成
methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate(中间体A)
Figure PCTCN2021129865-appb-000109
将(1S,5R)-6-氧杂环[3.2.1]辛烷-7-酮(A-3)(4.2g，33.3mmol)溶于MeOH(150mL)， 反应液冷却至0-5℃，乙酰氯(7.5mL)滴加入反应液中，滴加完毕，升温至室温反应3h。TLC监测反应完毕，加入水(150mL)，二氯甲烷萃取(100mL×3)。有机相用无水硫酸钠干燥，浓缩至干，得到浅黄色油状物(1S,3R)-3-羟基环己烷-1-羧酸甲酯(中间体A)(4.63g，收率88％)。
1H NMR(400MHz,CDCl 3)δ3.66(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).
制备例2：中间体B的制备
(1S,3S)-3-((6-溴-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体B)
methyl(1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(中间体B)
Figure PCTCN2021129865-appb-000110
中间体B的合成路线如下所示：
Figure PCTCN2021129865-appb-000111
在0℃下，向(1S,3R)-3-羟基环己烷-1-甲酸甲酯(中间体A)(1.10g，6.95mmol)，6-溴-2-甲基-吡啶-3-醇(1.19g，6.31mmol)和三丁基膦(2.55g，12.6mmol)的甲苯(20.0mL)溶液中滴加偶氮二甲酰二哌啶(3.19g，10.7mmol)，然后将混合物在氮气下80℃搅拌反应10小时。反应完成后，将反应液浓缩得到粗品，用硅胶柱分离纯化(石油醚：乙酸乙酯(V/V)＝1:0-20:1)得到(1S,3S)-3-((6-溴-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体B)(0.580g，产率30.3％)。
实施例1：目标化合物I-1的制备
(1S,3S)-3-((6-(5-氯-3-((((环叔丁基甲氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基) 氧)环己烷-1-羧酸(目标化合物I-1)
(1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-1)
Figure PCTCN2021129865-appb-000112
目标化合物I-1的合成路线如下所示：
Figure PCTCN2021129865-appb-000113
第一步：(2,5-二氧吡咯烷-1-基)甲酸环丁基甲酯(I-1C)的合成
cyclobutylmethyl(2,5-dioxopyrrolidin-1-yl)carbonate(I-1C)
Figure PCTCN2021129865-appb-000114
室温下将原料环丁基甲醇(I-1A)(500mg，5.80mmol)加入到20mL乙腈中，加入双(2,5-二氧吡咯烷-1-基)碳酸酯(I-1B)(2.98g，11.61mmol)，三乙胺(1.17g，11.61mmol)，搅拌16h。加入水(400mL)，用乙酸乙酯(80mL×3)萃取，合并有机相，用无水硫酸钠干燥，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝8:1)得白色固体(2,5-二氧吡咯烷-1-基)甲酸环丁基甲酯(I-1C)(800mg，收率60.6％)。
第二步：((5-氯-2-(5-(((环丁基甲氧基)羰基)氧)-6-甲基吡啶-2-基)噻吩-3-基)甲基)甲酸环丁基甲酯(I-1E)的合成
cyclobutylmethyl((5-chloro-2-(5-(((cyclobutylmethoxy)carbonyl)oxy)-6-methylpyridin-2-yl)thiophen-3-yl)methyl)carbamate(I-1E)
Figure PCTCN2021129865-appb-000115
室温下将原料6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-醇(I-1D)(2.15g，8.44mmol)加入到60mLTHF中，加入碳酸钾(4.66g，33.76mmol)，(2,5-二氧吡咯烷-1-基)甲酸环丁基甲酯(4.22g，18.57mmol)。室温搅拌16h。加入水(500mL)，用乙酸乙酯(80mL×3)萃取，合并有机相，用无水硫酸钠干燥，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得无色液体((5-氯-2-(5-(((环丁基甲氧基)羰基)氧)-6-甲基吡啶-2-基)噻吩-3-基)甲基)甲酸环丁基甲酯(I-1E)(2.5g，收率61.8％)。
LC-MS,M/Z(ESI):479.4[M+H] +
第三步：((5-氯-2-(5-羟基-6-甲基吡啶-2-基)噻吩-3-基)基)甲酸环丁基甲酯(I-1F)的合成
cyclobutylmethyl((5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl)carbamate(I-1F)
Figure PCTCN2021129865-appb-000116
室温下将原料((5-氯-2-(5-(((环丁基甲氧基)羰基)氧)-6-甲基吡啶-2-基)噻吩-3-基)甲基) 甲酸环丁基甲酯(I-1E)(2.5g，5.22mmol)加入到21mL甲醇和21mL THF中，加入1mol/L的氢氧化锂溶液(21mL，21mmol)，搅拌3h。加入水(25mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)得白色固体((5-氯-2-(5-羟基-6-甲基吡啶-2-基)噻吩-3-基)基)甲酸环丁基甲酯(I-1F)(880mg，产率45.9％)。
第四步：(1S,3S)-3-((6-(5-氯-3-((((环丁基甲氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-1G)的合成
methyl(1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1G)
Figure PCTCN2021129865-appb-000117
室温下将原料((5-氯-2-(5-羟基-6-甲基吡啶-2-基)噻吩-3-基)基)甲酸环丁基甲酯(I-1F)(780mg，1.62mmol)加入到10mLTHF中，氮气保护下加入(1S,3R)-3-环己烷-1-甲酸甲酯(606mg，3.26mmol)、三苯基膦(1.28g，4.88mmol)和偶氮二甲酸二叔丁酯(1.12g，4.88mmol)，微波加热至65℃，搅拌4h。将反应液浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)得粗品白色固体(1S,3S)-3-((6-(5-氯-3-((((环丁基甲氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-1G)(1.7g)。
第五步：(1S,3S)-3-((6-(5-氯-3-((((环叔丁基甲氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸(目标化合物I-1)的合成
(1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-1)
Figure PCTCN2021129865-appb-000118
室温下将原料(1S,3S)-3-((6-(5-氯-3-((((环丁基甲氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-甲酸甲酯(I-1G)(1.7g，3.18mmol)加入到20mL甲醇和10mL THF中，加入1M的氢氧化锂溶液(16mL，16mmol)，搅拌16h。将反应液浓缩，残留物用硅胶板纯化得标题化合物白色固体(1S,3S)-3-((6-(5-氯-3-((((环叔丁基甲氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸(目标化合物I-1)(200mg，产率12.7％)。
LC-MS,M/Z(ESI):493.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),7.72(t,1H),7.46-7.40(m,2H),6.96(s,1H),4.78(s,1H),4.33(d,2H),3.96(d,2H),2.53-2.49(m,2H),2.39(s,3H),2.0-1.94(m,3H),1.86-1.69(m,7H),1.63-1.51(m,4H).
实施例2：目标化合物I-2的制备
(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸(目标化合物I-2)
(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-2)
Figure PCTCN2021129865-appb-000119
目标化合物I-2的合成路线如下所示：
Figure PCTCN2021129865-appb-000120
第一步：6-溴-2-甲基-3-((四氢-2H-吡喃-2-基)氧)吡啶(I-2B)的合成
6-bromo-2-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pyridine(I-2B)
Figure PCTCN2021129865-appb-000121
室温下将原料6-溴-2-甲基吡啶-3-醇(I-2A)(5.5g，29.3mmol)加入到20mL无水DCM中，加入吡啶盐酸盐(0.735g，2.93mmol)，加入3,4-二氢吡喃(3.69g，43.9mmol)，室温下搅拌16h。加入水(400mL)，用DCM(100mL×3)萃取，分液，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)得无色液体6-溴-2-甲基-3-((四氢-2H-吡喃-2-基)氧)吡啶(I-2B)(6.2g，收率77.9％)
第二步：2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛(I-2C)的合成
2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde(I-2C)
Figure PCTCN2021129865-appb-000122
室温下将原料6-溴-2-甲基-3-((四氢-2H-吡喃-2-基)氧)吡啶(I-2B)(200mg，0.74mmol)加入到15mLDMF中，氮气保护下加入3-甲酰基-2-噻吩硼酸(149mg，0.96mmol)，二(三叔丁基膦)钯(38mg，0.074mmol)，无水碳酸钾(304mg，2.20mmol)，加热至90℃，搅拌16h。加入水(200mL)稀释，用乙酸乙酯(80mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝4:1)得无色液体2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛(I-2C)(200mg，产率89.7％)。
第三步：5-氯-2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛(I-2D)的合成
5-chloro-2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde(I-2D)
Figure PCTCN2021129865-appb-000123
室温下将原料2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛(I-2C)(635mg，2.09mmol)加入到12mL无水DMF中，加入N-氯代丁二酰亚胺(419mg，3.14mmol)，搅拌16h。加入水(200mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝4:1)得无色液体5-氯-2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛(I-2D)(330mg，产率46.6％)。
第四步：5-氯-2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛肟(I-2E)的合成
5-chloro-2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde oxime(I-2E)
Figure PCTCN2021129865-appb-000124
室温下将原料5-氯-2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛(I-2D)(110mg，0.33mmol)加入到8mL乙醇中，加入盐酸羟胺(67mg，0.98mmol)，醋酸钠(107mg，1.30mmol)，室温搅拌16h。加入水(200mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，浓缩，得粗品无色固体5-氯-2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛肟(I-2E)(130mg，粗品)，直接用于下一步反应。
第五步：6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-醇(I-1D)的合成
6-(3-(aminomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-ol(I-1D)
Figure PCTCN2021129865-appb-000125
室温下将原料5-氯-2-(6-甲基-5-((四氢-2H-吡喃-2-基)氧)吡啶-2-基)噻吩-3-甲醛肟(I-2E)(1.8g，5.31mmol)加入到30mL乙酸中，然后加入锌粉(10.4g，159.36mmol)，加热至35℃，搅拌16h。冷却至室温，过滤，滤饼用THF(30mL×3)淋洗，合并有机相，浓缩得粗品无色液体6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-醇(I-1D)(2.3g，粗品)，直接用于下一步反应。
第六步：((2-(5-(((苄氧基)羰基)氧)-6-甲基吡啶-2-基)-5-氯噻吩-3-基)甲基)甲酸苄酯(I-2F)的合成
benzyl((2-(5-(((benzyloxy)carbonyl)oxy)-6-methylpyridin-2-yl)-5-chlorothiophen-3-yl)methyl)carbamate(I-2F)
Figure PCTCN2021129865-appb-000126
室温下将原料6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-醇(I-1D)(1.0g，3.93mmol)加入到30mLTHF中，加入碳酸钾(2.17g，11.78mmol)，氯甲酸苄酯(2.0g，11.78mmol)。室温搅拌16h。加入水(300mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得白色固体((2-(5-(((苄氧基)羰基)氧)-6-甲基吡啶-2-基)-5-氯噻吩-3-基)甲基)甲酸苄酯(I-2F)(1.8g，产率87.6％)。
第七步：((5-氯-2-(5-羟基-6-甲基吡啶-2-基)噻吩-3-基)基)甲酸苄酯(I-2G)的合成
benzyl((5-chloro-2-(5-hydroxy-6-methylpyridin-2-yl)thiophen-3-yl)methyl)carbamate(I-2G)
Figure PCTCN2021129865-appb-000127
室温下将原料((2-(5-(((苄氧基)羰基)氧)-6-甲基吡啶-2-基)-5-氯噻吩-3-基)甲基)甲酸苄酯(I-2F)(1.8g，3.44mmol)加入到20mL甲醇和20mLTHF中，加入1M的氢氧化锂溶液(17mL，17mmol)，搅拌3h。加入水(300mL)，用乙酸乙酯(80mL×3)萃取，合并有机相，用无水硫酸钠干燥，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:1)得无色固体((5-氯-2-(5-羟基-6-甲基吡啶-2-基)噻吩-3-基)基)甲酸苄酯(I-2G)(500mg，产率37.4％)。
第八步：(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-2H)
methyl(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2H)
Figure PCTCN2021129865-appb-000128
室温下将原料((5-氯-2-(5-羟基-6-甲基吡啶-2-基)噻吩-3-基)基)甲酸苄酯(I-2G)(400mg，1.03mmol)加入到12mLTHF中，氮气保护下加入(1S,3R)-3-羟基环己烷-1-甲酸甲酯(中间体A)(421mg，2.26mmol)、三苯基膦(808mg，3.08mmol)和偶氮二甲酸二叔丁酯(730mg，3.17mmol)，微波加热至65℃，搅拌3h。将反应液浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)得粗品无色液体(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-2H)(1.5g)。
第九步：(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸(目标化合物I-2)的合成
(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-2)
Figure PCTCN2021129865-appb-000129
室温下将原料(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-2H)(1.5g，2.69mmol)加入到11mL甲醇和11mL THF中，加入1M的氢氧化锂溶液(11mL，11mmol)，搅拌16h。将反应液浓缩，残留物用硅胶板分离得白色固体(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸(目标化合物I-2)(110mg，产率7.94％)。
LC-MS,M/Z(ESI):515.6[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),7.87(t,1H),7.45-7.30(m,7H),6.97(s,1H),5.05(s,2H),4.77(s,1H),4.36(d,2H),2.65-2.62(m,1H),2.39(s,3H),2.01(d,1H),1.86-1.74(m,3H),1.64-1.50(m,4H).
实施例3：目标化合物I-3的制备
(1S,3S)-3-((6-(5-氯-3-((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-乙氧基)环己烷-1-羧酸(目标化合物I-3)
(1S,3S)-3-((6-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-3)
Figure PCTCN2021129865-appb-000130
目标化合物I-3的合成路线如下所示：
Figure PCTCN2021129865-appb-000131
第一步：(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-3B)的合成
(R)-4-nitrophenyl(1-phenylethyl)carbonate(I-3B)
Figure PCTCN2021129865-appb-000132
室温下，往(R)-1-苯基乙-1-醇(I-3A)(0.5g，4.09mmol)的二氯甲烷(10mL)溶液中，缓慢加入4-硝基苯基碳酰氯(0.99g，8.03mmol)和吡啶(0.647g，8.19mmol)，室温3h，浓缩，残留物用硅胶柱分离纯化得黄色固体(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-3B)(0.7g， 产率59.5％)。
第二步：(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3D)的合成
methyl(1S,3S)-3-((6-(5-chloro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3D)
Figure PCTCN2021129865-appb-000133
室温下，向(1S,3S)-3-(((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3C)((9g，25.04mmol)的DMF(100mL)溶液中加入N-氯代丁二酰亚胺(6.69g，50.08mmol)，70℃下反应过夜，体系冷却至室温后，旋干溶剂后，加水(300mL)并用乙酸乙酯萃取(100mL×3)，合并有机相，浓缩得到产物(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3D)(3.8g，产率38.5％)。
第三步：(1S,3S)-3-((6-(5-氯-3-((E)-(羟基亚氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3E)的合成
methyl(1S,3S)-3-((6-(5-chloro-3-((E)-(hydroxyimino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3E)
Figure PCTCN2021129865-appb-000134
室温下，向(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3D)(1g，2.54mmol)的乙醇(20mL)溶液中加入盐酸羟胺(0.529g，7.62mmol)和乙酸钠(0.833g，10.16mmol)，40℃下反应过夜，体系冷却至室温后，旋干溶剂后，加水(60mL)并用乙酸乙酯萃取(30mL×3)，合并有机相，浓缩得到产物(1S,3S)-3-((6-(5-氯-3-((E)-(羟基亚氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3E)(1 g，产率96％)。
第四步：(1S,3S)-3-((6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3F)的合成
methyl(1S,3S)-3-((6-(3-(aminomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3F)
Figure PCTCN2021129865-appb-000135
室温下，将(1S,3S)-3-((6-(5-氯-3-((E)-(羟基亚氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲(I-3E)(1g，2.446mmol)的醋酸(20mL)溶液中加入锌粉(3.2g，48.9mmol)，随后室温下反应过夜。过滤，浓缩滤液得到黄色固体(1S,3S)-3-((6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3F)(0.7g，产率72.5％)。
第五步：(1S,3S)-3-((6-(5-氯-3-((((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3G)的合成
methyl(1S,3S)-3-((6-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3G)
Figure PCTCN2021129865-appb-000136
将(1S,3S)-3-((6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3F)(110mg，0.279mmol)、(R)-4-硝基苯基(1-苯基乙基)碳酸酯(96mg，0.334mmol)溶于四氢呋喃(6mL)中，再加入吡啶(33mg，0.418mmol)，室温搅拌过夜。将反应体系浓缩，残留物用硅胶板分离纯化黄色固体化合物(1S,3S)-3-((6-(5-氯-3-((((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3G)(70mg，产率 46.3％)。
第六步：(1S,3S)-3-((6-(5-氯-3-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-乙氧基)环己烷-1-羧酸(目标化合物I-3)的合成
(1S,3S)-3-((6-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-3)
Figure PCTCN2021129865-appb-000137
室温下，将(1S,3S)-3-((6-(5-氯-3-((((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3G)(70mg，0.129mmol)的四氢呋喃(3mL)、甲醇(1mL)和水(1mL)的混合溶液中，加入一水和氢氧化锂(10.8mg，0.258mmol)，室温反应过夜，后用1N盐酸溶液调节pH到3，浓缩，残留物用硅胶板分离纯化得白色固体化合物(1S,3S)-3-((6-(5-氯-3-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-乙氧基)环己烷-1-羧酸(目标化合物I-3)(27.8mg，产率40.8％)。
LC-MS,M/Z(ESI):529.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.77(t,1H),7.38–7.26(m,6H),7.25–7.18(m,1H),6.85(s,1H),5.63(q,1H),4.70(s,1H),4.25(d,2H),2.60–2.50(m,1H),2.33(s,3H),1.93(d,1H),1.83–1.66(dt,H),1.60–1.43(m,4H),1.39(d,3H).
实施例4：目标化合物I-4的制备
(1S,3S)-3-((6-(5-氯-3-(((((S)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-乙氧基)环己烷-1-羧酸(目标化合物I-4)
(1S,3S)-3-((6-(5-chloro-3-(((((S)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-4)
Figure PCTCN2021129865-appb-000138
其合成方法参照实施例3目标化合物I-3的合成，将原料(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-3B)换成(S)-4-硝基苯基(1-苯基乙基)碳酸酯，其他步骤同实施例3。
LC-MS,M/Z(ESI):529.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),7.77(t,1H),7.39–7.13(m,7H),6.85(s,1H),5.62(q,1H),4.70(s,1H),4.25(d,2H),2.60–2.50(m,1H),2.32(s,3H),1.92(d,,1H),1.82–1.66(m,3H),1.61–1.42(m,4H),1.39(d,3H).
实施例5：目标化合物I-5的制备
(1S,3S)-3-((6-(3-((((苄氧基)羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-5)
(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)(methyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-5)
Figure PCTCN2021129865-appb-000139
目标化合物I-5的合成路线如下所示：
Figure PCTCN2021129865-appb-000140
第一步：苄基(4-硝基苯基)碳酸酯(I-5B)的合成
benzyl(4-nitrophenyl)carbonate(I-5B)
Figure PCTCN2021129865-appb-000141
室温下，往苄醇(I-5A)(0.3g，2.77mmol)的二氯甲烷(10mL)溶液中，缓慢加入4-硝基苯基碳酰氯(0.671g，3.33mmol)和吡啶(0.329g，4.16mmol)，室温3h，浓缩，残留物用硅胶柱分离纯化得黄色固体苄基(4-硝基苯基)碳酸酯(I-5B)(0.4g，产率52.8％)。
第二步：(1S,3S)-3-((6-(5-氯-3-((甲基氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸甲酯的(I-5C)合成
methyl(1S,3S)-3-((6-(5-chloro-3-((methylamino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5C)
Figure PCTCN2021129865-appb-000142
0℃下，向(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(0.3g，0.762mmol)(I-3D)的甲醇(6mL)溶液中加入30％的甲胺的甲醇溶液(0.158g，1.523mmol)，0℃下反应20min，随后加入硼氢化钠(14.41mg，0.381mmol)，0℃下反应30min，减压旋蒸出去有机溶剂，残留物用硅胶板分离纯化黄色固体化合物(1S,3S)-3-((6-(5-氯-3-((甲基氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-5C)(0.3g，产率96％)。
第三步：(1S,3S)-3-((6-(3-((((苄氧基)羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)-环己烷-1-羧酸甲酯(I-5D)的合成
methyl(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)(methyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5D)
Figure PCTCN2021129865-appb-000143
将(1S,3S)-3-((6-(5-氯-3-((甲基氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(120mg，0.293mmol)、苄基(4-硝基苯基)碳酸酯(96mg，0.352mmol)溶于四氢呋喃(6mL)中，再加入N,N-二异丙基乙基胺(76mg，0.587mmol)，室温搅拌过夜。将反应体系浓缩，残留物用硅胶板分离纯化黄色固体化合物(1S,3S)-3-((6-(3-((((苄氧基)羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)-环己烷-1-羧酸甲酯(100mg，产率62.8％)。
第四步：(1S,3S)-3-((6-(3-((((苄氧基)羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-5)的合成
(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)(methyl)amino)methyl)-5-chlorothiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-5)
Figure PCTCN2021129865-appb-000144
室温下，将(1S,3S)-3-((6-(3-((((苄氧基)羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)-环己烷-1-羧酸甲酯(I-5D)(100mg，0.184mmol)的四氢呋喃(3mL)、甲醇(1mL)和水(1mL)的混合溶液中，加入一水和氢氧化锂(23.18mg，0.552mmol)，室温反应过夜，后用1N盐酸溶液调节pH到3，浓缩，残留物用硅胶板分离纯化得白色固体化合物(1S,3S)-3-((6-(3-((((苄氧基)羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-5)(25.8mg，产率26.5％)。
LC-MS,M/Z(ESI):529.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.41–7.12(m,7H),6.77(s,1H),5.04(d,2H),4.69(s,1H),4.61(s,2H),2.79(s,3H),2.58–2.50(m,1H),2.33(s,3H),1.97–1.87(m,1H),1.83–1.67(m,3H),1.60–1.40(m,4H).
实施例6：目标化合物I-6的制备
(1S,3S)-3-((2-(5-氯-3-(((((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-6)
(1S,3S)-3-((2-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-6)
Figure PCTCN2021129865-appb-000145
目标化合物I-6的合成路线如下所示：
Figure PCTCN2021129865-appb-000146
第一步：2-溴-4-甲基嘧啶-5-酚(I-6B)的合成
2-bromo-4-methylpyrimidin-5-ol(I-6B)
Figure PCTCN2021129865-appb-000147
在室温下，将2-氯-4-甲基嘧啶-5-酚(I-6A)(7g，48.42mmol)加入到溴化氢(104.30g，386.72mmol，70.00mL)中，然后在100℃下搅拌1小时。待反应液冷却到室温后，将反应液倒入冰水(100mL)中，然后用乙酸乙酯(100mL×3)萃取，合并有机层，旋干得到2-溴-4-甲基嘧啶-5-酚(I-6B)(8.5g，产率92.87％)。直接用于下一步。
第二步：(1S,3S)-3-((2-溴-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6C)的合成
methyl(1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6C)
Figure PCTCN2021129865-appb-000148
在0℃氮气保护下，向2-溴-4-甲基嘧啶-5-酚(I-6B)(5g，26.45mmol)，(1S,3R)-甲基3-羟基环己羧酸基酯(8.37g，52.91mmol)和三苯基膦(13.88g，52.91mmol)的四氢呋喃(50mL)溶液中加入偶氮二羧酸二异丙酯(10.70g，52.91mmol)，然后反应液在室温下搅拌12小时。将反应液减压浓缩得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝5:1-1:1)得(1S,3S)-3-((2-溴-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6C)(6g，产率68.90％)。
第三步：(1S,3S)-3-(((2-(3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6D)的合成
methyl(1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6D)
Figure PCTCN2021129865-appb-000149
在室温下，将(3-甲酰基噻吩-2-基)硼酸(2.13g,13.67mmol)，(1S,3S)-3-((2-溴-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6C)(3g，9.11mmol)，三叔丁基磷烷钯(400mg,782.70umol)和氟化钾(3.18g,54.68mmol)加入到四氢呋喃(50mL)溶液中，置换氮气，然后在室温下搅拌10小时。将反应液减压浓缩得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝10:1-5:1)得(1S,3S)-3-(((2-(3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6D)(2.5g，产率76.11％)。
第四步：(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6E)的合成
methyl(1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohe xane-1-carboxylate(I-6E)
Figure PCTCN2021129865-appb-000150
在室温下，向(1S,3S)-3-(((2-(3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6D)(2.76g，7.66mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入N-氯代丁二酰亚胺(1.12g，8.42mmol)，然后反应液在40℃下搅拌1小时。反应液用乙酸乙酯(25mL×3)萃取，合并有机层，得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝15:1-1:1)得(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6E)(2.3g，产率76.06％)。
第五步：(1S,3S)-3-((2-(5-氯-3-((E)-(羟亚胺)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6F)的合成
methyl(1S,3S)-3-((2-(5-chloro-3-((E)-(hydroxyimino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6F)
Figure PCTCN2021129865-appb-000151
将(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6E)(150mg，0.380mmol)，醋酸钠(79mg，1.519mmol)，盐酸羟胺(79mg，1.140mmol)加入到4mL乙醇中，40℃搅拌12小时。旋干，加入水(30mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得黄色固体(1S,3S)-3-((2-(5-氯-3-((E)-(羟亚胺)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6F)(150mg，产率96％)。
第六步：(1S,3S)-3-((2-(3-(氨基甲基)-5-氯噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6G)的合成
methyl(1S,3S)-3-((2-(3-(aminomethyl)-5-chlorothiophen-2-yl)-4-methylpyrimidin-5-yl)oxy) cyclohexane-1-carboxylate(I-6G)
Figure PCTCN2021129865-appb-000152
将(1S,3S)-3-((2-(5-氯-3-((E)-(羟亚胺)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6F)(150mg，0.366mmol)，加入到2mL醋酸中，35℃搅拌12小时。缓慢加入到饱和碳酸氢钠水溶液(30mL)中，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液浓缩得粗品棕色油状物(1S,3S)-3-((2-(3-(氨基甲基)-5-氯噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6G)(207mg)。
第七步：(1S,3S)-3-((2-(5-氯-3-(((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6H)的合成
methyl(1S,3S)-3-((2-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-6H)
Figure PCTCN2021129865-appb-000153
将(1S,3S)-3-((2-(3-(氨基甲基)-5-氯噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6G)(207mg，0.522mmol)和(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-3B)(100mg，0.348mmol)加入到2mL二氯甲烷中，加入三乙胺(106mg，1.044mmol)，室温搅拌过夜，旋干，柱层析(石油醚：乙酸乙酯(V:V)＝3:1)分离得(1S,3S)-3-((2-(5-氯-3-(((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6H)(50mg，产率26.4％)。
第八步：(1S,3S)-3-((2-(5-氯-3-(((((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-6)
(1S,3S)-3-((2-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-4- methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-6)
Figure PCTCN2021129865-appb-000154
将(1S,3S)-3-((2-(5-氯-3-(((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-6H)(40mg，0.074mmol)加入到2mL四氢呋喃，2mL甲醇和0.5mL水的混合溶剂中，加入氢氧化锂(8.80mg，0.368mmol)，室温搅拌过夜。旋干，加入水(10mL)，用2M盐酸调pH至2，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩。浓缩物经硅胶板(石油醚：乙酸乙酯(V:V)＝1:1)纯化得(1S,3S)-3-((2-(5-氯-3-(((((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-6)(22.2mg，产率57％)。
LC-MS,M/Z(ESI):530.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.20(s,1H),7.34-7.36(m,4H),6.92(s,1H),6.10-6.13(m,1H),5.80-5.82(m,1H),4.75(s,1H),4.53(dd,2H),2.86-2.88(m,1H),2.49(s,3H),2.11-2.14(m,1H),1.97-2.01(m,3H),1.70-1.74(m,4H),1.52(dd,3H).
实施例7：目标化合物I-7的制备
(1S,3S)-3-((5-(5-氯-3-(((((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸(目标化合物I-7)
(1S,3S)-3-((5-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-7)
Figure PCTCN2021129865-appb-000155
目标化合物I-7的合成路线如下所示：
Figure PCTCN2021129865-appb-000156
第一步：(1S,3S)-3-((5-溴-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7B)的合成
methyl(1S,3S)-3-((5-bromo-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7B)
Figure PCTCN2021129865-appb-000157
在氮气保护下，将5-溴-3-甲基吡嗪-2-醇(I-7A)(1.5g，7.94mmol)，(1S,3R)-3-羟基环己烷-1-羧酸甲酯(中间体A)(2.51g，15.87mmol)和三苯基磷(4.16g，15.87mmol)的四氢呋喃(30mL)的混合物降温到0℃，缓慢加入偶氮二甲酸二异丙酯(3.21g，15.87 mmol)，然后缓慢升到室温，在室温搅拌10小时，将反应混合物减压浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝100:1-10:1)得无色油状(1S,3S)-3-((5-溴-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7B)(2.5g，产率95.69％)。
第二步：(1S,3S)-3-((5-(3-甲酰基噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7C)的合成
methyl(1S,3S)-3-((5-(3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7C)
Figure PCTCN2021129865-appb-000158
在氮气保护下，将(1S,3S)-3-((5-溴-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7B)(2.2g，6.68mmol)，(3-甲酰基噻吩-2-基)硼酸(1.56g，10.02mmol)，氟化钾(2.33g,40.10mmol)，双(三叔丁基膦)钯(273.23mg，534.65umol)和四氢呋喃(50mL)的混合溶液，在室温搅拌10小时。冷却至室温，将反应混合物浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝100:0-50:1)得(1S,3S)-3-((5-(3-甲酰基噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7C)(2g，收率83.03％)。
第三步：(1S,3S)-3-((5-(3-(羟甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7D)的合成
methyl(1S,3S)-3-((5-(3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7D)
Figure PCTCN2021129865-appb-000159
在0℃下，向(1S,3S)-3-((5-(3-甲酰基噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7C)(2g，5.55mmol)的甲醇(10mL)溶液中分批加入硼氢化钠(209.93mg，5.55 mmol)，在0℃下搅拌0.5小时。反应完全后，将反应液用水(50mL)淬灭，用乙酸乙酯(50mL×2)萃取，合并有机相，浓缩得化合物(1S,3S)-3-((5-(3-(羟甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7D)(2.5g，粗品)。
第四步：(1S,3S)-3-((5-(5-氯-3-(羟甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7E)的合成
methyl(1S,3S)-3-((5-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7E)
Figure PCTCN2021129865-appb-000160
室温下，向(1S,3S)-3-((5-(3-(羟甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7D)(2g，5.52mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入N-氯代丁二酰亚胺(1.11g，8.28mmol)，在45℃搅拌10小时。反应完全后，将反应液用水(30mL)淬灭，用乙酸乙酯(30mL×2)萃取，合并有机相用饱和食盐水(30mL×2)洗，减压蒸馏得到粗品，粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:0-1:1)得白色固体(1S,3S)-3-((5-(5-氯-3-(羟甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-7E)(1.8g，产率82.19％)。
第五步：(1S,3S)-3-((5-(5-氯-3-甲酰基噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7F)的合成
methyl(1S,3S)-3-((5-(5-chloro-3-formylthiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7F)
Figure PCTCN2021129865-appb-000161
将(1S,3S)-3-((5-(5-氯-3-(羟甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-甲酸甲酯 (I-7E)(0.3g，0.756mmol)溶于15mL二氯甲烷中，冷却至0℃，再加入戴斯-马丁氧化剂(0.374g，0.907mmol)，反应2h，TLC(PE:EA＝3:1)显示原料反应完，加入饱和碳酸氢钠调节pH至碱性，分液，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)得油状物(1S,3S)-3-((5-(5-氯-3-甲酰基噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7F)(0.25g，产率84％)。
第六步：(1S,3S)-3-((5-(5-氯-3-((E)-(羟基亚胺基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7G)的合成
methyl(1S,3S)-3-((5-(5-chloro-3-((E)-(hydroxyimino)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7G)
Figure PCTCN2021129865-appb-000162
将(1S,3S)-3-((5-(5-氯-3-甲酰基噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7F)(0.25g，0.633mmol)溶于5mL乙醇中，加入羟胺盐酸盐(0.132g，1.899mmol)、乙酸钠(0.208g，2.53mmol)，40℃搅拌反应过夜，TLC(PE:EA＝3:1)显示原料反应完，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)得浅黄色油状化合物(1S,3S)-3-((5-(5-氯-3-((E)-(羟基亚胺基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7G)(0.25g，产率96％)。
第七步：(1S,3S)-3-((5-(3-(氨基甲基)-5-氯噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7H)的合成
methyl(1S,3S)-3-((5-(3-(aminomethyl)-5-chlorothiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7H)
Figure PCTCN2021129865-appb-000163
将(1S,3S)-3-((5-(5-氯-3-((E)-(羟基亚胺基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7G)(0.25g，0.610mmol)、溶于1mL冰醋酸中，再加入锌粉(0.798g，12.20mmol)，40℃反应1h，TLC(PE:EA＝1:1)显示原料反应完，加入饱和碳酸氢钠调节pH至碱性，二氯甲烷(20mL×3)萃取，无水硫酸钠干燥，浓缩干，得红色固体粗品(1S,3S)-3-((5-(3-(氨基甲基)-5-氯噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7H)(200mg，产率83％)。
第八步：(1S,3S)-3-((5-(5-氯-3-((((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7I)的合成
methyl(1S,3S)-3-((5-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-7I)
Figure PCTCN2021129865-appb-000164
将(1S,3S)-3-((5-(3-(氨基甲基)-5-氯噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7H)(0.2g，0.505mmol)溶于4mL四氢呋喃中，再加入二异丙基乙胺(0.261g，2.021mmol)，(R)-4-硝基苯基(1-苯基乙基)碳酸酯(0.290g，1.010mmol)(I-3B)，30℃反应4h，TLC(PE:EA＝3:1)显示原料反应完，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝4:1)得无色油状物(1S,3S)-3-((5-(5-氯-3-((((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7I)(40mg，产率14.6％)。
第九步：(1S,3S)-3-((5-(5-氯-3-(((((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸(I-7)的合成
(1S,3S)-3-((5-(5-chloro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid(I-7)
Figure PCTCN2021129865-appb-000165
将(1S,3S)-3-((5-(5-氯-3-((((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸甲酯(I-7I)(0.04g，0.074mmol)加至2mL的四氢呋喃溶液中，再加入0.2mL水，氢氧化锂(0.053g，2.22mmol)，室温反应4h，用4M氯化氢的1,4-二氧六环溶液调节pH到酸性，浓缩干，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:2)得白色固体(1S,3S)-3-((5-(5-氯-3-(((((R)-1-苯乙氧基)羰基)氨基)甲基)噻吩-2-基)-3-甲基吡嗪-2-基)氧基)环己烷-1-羧酸(I-7)(10mg，产率25.6％)。
LC-MS,M/Z(ESI):530.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.27(s,1H),7.86(s,1H),7.42-7.23(m,5H),6.97(s,1H),5.68(q,1H),5.36(s,1H),4.29(d,2H),2.43(s,3H),2.09(d,1H),1.92-1.72(m,3H),1.68-1.55(m,3H),1.54-1.38(m,4H),1.23(s,1H)。
实施例8：目标化合物I-8的制备
(1S,3S)-3-((6-(5-氯-3-(((2-苯乙基)磺酰胺基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-8)
(1S,3S)-3-((6-(5-chloro-3-(((2-phenylethyl)sulfonamido)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-8)
Figure PCTCN2021129865-appb-000166
目标化合物I-8的合成路线如下所示：
Figure PCTCN2021129865-appb-000167
第一步：(1S,3S)-3-((6-(5-氯-3-(((2-苯乙基)磺酰胺基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-8A)的合成
methyl(1S,3S)-3-((6-(5-chloro-3-(((2-phenylethyl)sulfonamido)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-8A)
Figure PCTCN2021129865-appb-000168
将(1S,3S)-3-((6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3F)(120mg，0.304mmol)、2-苯基乙烷-1-磺酰氯(68.4mg，0.344mmol)溶于二氯甲烷(6mL)中，再加入N,N-二异丙基乙基胺(46.1mg，0.456mmol)，室温搅拌过夜。将反应体系浓缩，残留物用硅胶板分离纯化黄色固体化合物(1S,3S)-3-((6-(5-氯-3-(((2-苯乙基)磺酰胺基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-8A)(10mg，产率58.4％)。
第二步：(1S,3S)-3-((6-(5-氯-3-(((2-苯乙基)磺酰胺基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-8)的合成
(1S,3S)-3-((6-(5-chloro-3-(((2-phenylethyl)sulfonamido)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-8)
Figure PCTCN2021129865-appb-000169
室温下，将(1S,3S)-3-((6-(5-氯-3-(((2-苯乙基)磺酰胺基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-8A)(100mg，0.178mmol)的四氢呋喃(3mL)、甲醇(1mL)和水(1mL)的混合溶液中，加入一水和氢氧化锂(22.36mg，0.533mmol)，室温反应过夜，后用1N HCl溶液调节pH到3，浓缩，残留物用硅胶板分离纯化得白色固体化合物(1S,3S)-3-((6-(5-氯-3-(((2-苯乙基)磺酰胺基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-8)(59.8mg，产率61.3％)。
LC-MS,M/Z(ESI):549.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.75(t,1H),7.42(q,2H),7.27(t,2H),7.21–7.13(m,4H),4.76(s,1H),4.34(d,2H),3.26–3.21(m,2H),2.94–2.84(m,2H),2.64–2.54(m,1H),2.37(s,3H),2.25–1.91(m,1H),1.87–1.7(m,3H),1.64–1.42(m,4H).
实施例9：目标化合物I-9的制备
(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-9)
(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)amino)methyl)-5-methylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-9)
Figure PCTCN2021129865-appb-000170
目标化合物I-9的合成路线如下所示：
Figure PCTCN2021129865-appb-000171
第一步：(1S,3S)-3-(((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3C)的合成
methyl(1S,3S)-3-((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3C)
Figure PCTCN2021129865-appb-000172
在室温下，将(1S,3S)-3-((6-溴-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体B)(2.2g，6.70mmol)，(3-甲酰基-2-噻嗯基)硼酸(2.09g,13.41mmol)和氟化钾(2.34g，40.22mmol)加入到四氢呋喃(30mL)中，然后在氮气保护下加入双(三特丁基膦)钯(274.06mg，536.26μmol)，在室温搅拌4小时，将反应液用水(30mL)稀释，然后用乙酸乙酯(30mL×2) 萃取，合并有机层，得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝15:1-1:1)得黄色油状化合物(1S,3S)-3-(((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3C)(2.25g，产率93.38％)。
第二步：(1S,3S)-3-((6-(5-溴-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9B)的合成
methyl(1S,3S)-3-((6-(5-bromo-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-9B)
Figure PCTCN2021129865-appb-000173
在0℃下，向(1S,3S)-3-((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3C)(1g，2.78mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入N-溴代丁二酰亚胺(544.69mg，3.06mmol)，在30℃下搅拌2小时。反应完全后，将反应混合物加入水(15mL)，用乙酸乙酯(10mL×2)萃取，减压浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1-1:1)得(1S,3S)-3-((6-(5-溴-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9B)(1.2g，产率98.40％)。
第三步：(1S,3S)-3-((6-(3-甲酰基-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9C)的合成
methyl(1S,3S)-3-((6-(3-formyl-5-methylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-9C)
Figure PCTCN2021129865-appb-000174
将(1S,3S)-3-((6-(5-溴-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9B)(1g，2.28mmol)，三甲基环三硼氧烷(1.72g，6.84mmol)，1,1-双(二苯基磷)二 茂铁氯化钯(166.93mg,228.14μmol)和碳酸铯1.49g，4.56mmol)的二氧六环(10mL)和水(2mL)溶液在氮气保护下，在100℃搅拌2小时。反应完全后，减压浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝25:1-1:1)得(1S,3S)-3-((6-(3-甲酰基-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9C)(0.78g，产率91.55％)。
第四步：(1S,3S)-3-((6-(3-(氨基甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9D)的合成
methyl(1S,3S)-3-((6-(3-(aminomethyl)-5-methylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-9D)
Figure PCTCN2021129865-appb-000175
在室温下，向(1S,3S)-3-((6-(3-甲酰基-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9C)(0.73g，1.95mmol)的甲醇(5mL)溶液中，加入醋酸铵(1.51g，19.55mmol)和氰基硼氢化钠(85.98mg，1.37mmol)，用氮气置换3次，在室温下搅拌12小时。反应完全后，减压浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-0:1)得(1S,3S)-3-((6-(3-(氨基甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-9D)(0.73g,1.95mmol，产率99.72％)。
第五步：(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)-1-羧酸甲酯(I-9E)的合成
methyl(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)amino)methyl)-5-methylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-9E)
Figure PCTCN2021129865-appb-000176
在0℃下，向(1S,3S)-3-((6-(3-(氨基甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己 烷-1-羧酸甲酯(I-9D)(0.35g，934.59umol)和氯甲酸苄酯(191.32mg，1.12mmol)的二氯甲烷(2mL)溶液中，加入三乙胺(113.49mg，1.12mmol)和氰基硼氢化钠(85.98mg，1.37mmol)，用氮气置换3次，在室温下搅拌2小时。反应完全后，向反应液中加入水(10mL)，用二氯甲烷(5mL×3)萃取，减压浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝15:1-1:1)得标题化合物(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)-1-羧酸甲酯(I-9E)(0.4g，产率84.15％)。
第六步：(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-9)
(1S,3S)-3-((6-(3-((((benzyloxy)carbonyl)amino)methyl)-5-methylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-9)
Figure PCTCN2021129865-appb-000177
室温下，向(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)-1-羧酸甲酯(I-9E)(0.4g，786.43μmol)的四氢呋喃(2mL)中，再加入1M氢氧化锂溶液(3.93mL，3.93mmol)，在室温搅拌2小时。将反应液用饱和柠檬酸水溶液调至pH＝7，加入水(10mL)，用乙酸乙酯(10mL×3)萃取减压浓缩得粗品，粗品经过制备分离(分离方法：柱子:Phenomenex Luna C18 150*25mm*10μm；溶剂:A＝水+0.225体积％甲酸(99％)，B＝乙腈；梯度：34％-78％B，11分钟)得灰白色固体状化合物(1S,3S)-3-((6-(3-((((苄氧基)羰基)氨基)甲基)-5-甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-9)(0.028g，产率6.81％)。
LC-MS,M/Z(ESI):495.4[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.29-7.44(m,6H),6.82(s,1H),6.56(s,1H),5.14(s,2H),4.73(s,1H),4.37(s,2H),2.89(s,1H),2.42-2.67(d,6H),1.85-2.26(m,4H),1.59-1.81(m,4H).
实施例10：目标化合物I-10的制备
(1S,3S)-3-((6-(5-氟-3-((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-乙氧基)环己烷-1-羧酸(目标化合物I-10)
(1S,3S)-3-((6-(5-fluoro-3-((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-10)
Figure PCTCN2021129865-appb-000178
目标化合物I-10的合成路线如下所示：
Figure PCTCN2021129865-appb-000179
第一步：叔丁基二甲基(噻吩-3-基甲氧基)硅烷(I-10B)的合成
tert-butyldimethyl(thiophen-3-ylmethoxy)silane(I-10B)
Figure PCTCN2021129865-appb-000180
在室温下，将噻吩-3-基甲醇(I-10A)(10g，87.59mmol)和叔丁基二甲基氯硅烷(15.84g，105.11mmol，12.88mL)溶解在N,N-二甲基甲酰胺(200mL)中，然后加入三乙胺(17.73 g，175.18mmol，24.38mL)，然后在60℃下搅拌3小时。待反应液冷却到室温后，将反应液倒入冰水(400mL)中，然后用乙酸乙酯(200mL×2)萃取，合并有机层，用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝10:1-5:1)得到叔丁基二甲基(噻吩-3-基甲氧基)硅烷(I-10B)(16g，收率79.97％)。
第二步：(5-氟噻吩-3-基)甲醇(I-10C)的合成
(5-fluorothiophen-3-yl)methanol(I-10C)
Figure PCTCN2021129865-appb-000181
将叔丁基二甲基(噻吩-3-基甲氧基)硅烷(I-10B)(16g，70.04mmol)溶解在四氢呋喃(200mL)中，冷却到-78℃，在氮气保护下，慢慢地滴加仲丁基锂(1.3M，70.72mL)，滴加完后，继续搅拌30分钟。然后加入N-氟代双苯磺酰胺(21.26g，67.42mmol)，在-78℃继续搅拌1小时，然后升到室温，搅拌1小时。反应用水(100mL)淬灭，乙酸乙酯(100mL)萃取两次，合并有机相，浓缩得到粗品。粗品溶解在四氢呋喃(200mL)中，添加1M四丁基氟化铵四氢呋喃溶液(70mL)，室温搅拌过夜。反应液浓缩得到粗品，用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝10:1-2:1)得(5-氟噻吩-3-基)甲醇(I-10C)(3.5g，收率43.21％)。
第三步：(2-溴-5-氟噻吩-3-基)甲醇(I-10D)的合成
(2-bromo-5-fluorothiophen-3-yl)methanol(I-10D)
Figure PCTCN2021129865-appb-000182
将(5-氟噻吩-3-基)甲醇(I-10C)(3g，22.70mmol)溶解在N,N-二甲基甲酰胺(30mL)中，冷却到0℃，加入N-溴代丁二酰亚胺(4.04g，22.70mmol)，在室温下搅拌10小时。将反应液倒入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机层，用无水硫酸钠干燥，过滤，浓缩得到粗品。减压浓缩得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝20:1-1:1)得(2-溴-5-氟噻吩-3-基)甲醇(I-10D)(4g，产率83.49％)。
第四步：2-溴-3-(氯甲基)-5-氟噻吩(I-10E)的合成
2-bromo-3-(chloromethyl)-5-fluorothiophene(I-10E)
Figure PCTCN2021129865-appb-000183
在0℃下，向(2-溴-5-氟噻吩-3-基)甲醇(I-10D)(150mg，710μmol)的二氯甲烷(2.0mL)溶液中滴加二氯亚砜(169mg，1.42mmol)，溶液在25℃下搅拌两个小时。反应完成后将溶液浓缩到粗品2-溴-3-(氯甲基)-5-氟噻吩(I-10E)(150mg)。粗品直接用于下一步。
第五步：(2-溴-5-氟噻吩-3-基)甲胺(I-10F)的合成
(2-bromo-5-fluorothiophen-3-yl)methanamine(I-10F)
Figure PCTCN2021129865-appb-000184
将2-溴-3-(氯甲基)-5-氟噻吩(I-10E)(150mg，653μmol)，氨水(14M，466μL)在乙醇(2mL)中的混合物在氮气保护下50℃下搅拌12小时。将反应混合物减压浓缩除去乙醇得到粗产物(2-溴-5-氟-3-噻吩基)甲胺(I-10F)(120mg)。
第六步：(R)-1-苯基乙基((2-溴-5-氟噻吩-3-基)甲基)氨基甲酸酯(I-10G)的合成
(R)-1-phenylethyl((2-bromo-5-fluorothiophen-3-yl)methyl)carbamate(I-10G)
Figure PCTCN2021129865-appb-000185
向(2-溴-5-氟-3-噻吩基)甲胺(I-10F)(120mg，571μmol)和三乙胺(173mg，1.71mmol)的二氯甲烷(2mL)中加入(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-3B)(213mg，742μmol)，并将反应液在25℃下搅拌12小时。将反应混合物用水(5mL)稀释，用二氯甲烷(1mL×3)萃取，将合并的有机相减压浓缩，得到残余物。将残余物通过制备TLC纯化(石油醚：乙酸乙酯＝3∶1)得到化合物(R)-1-苯基乙基((2-溴-5-氟噻吩-3-基)甲基)氨基甲酸酯(I-10G)(80mg，产率39.1％)。
1H NMR(400MHz,CDCl 3)δ7.39-7.28(m,6H),6.40-6.30(m,1H),5.02(br s,1H),4.27-4.12(m,2H),1.60-1.51(m,3H).
第七步：(1S,3S)-3-((6-(5-氟-3-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲基(I-10H)的合成
methyl(1S,3S)-3-((6-(5-fluoro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-10H)
Figure PCTCN2021129865-appb-000186
将(R)-1-苯基乙基((2-溴-5-氟噻吩-3-基)甲基)氨基甲酸酯(I-10G)(80mg，223μmol)，(1S,3S)-3-((2-甲基-6-(三丁基锡烷基)吡啶-3-基)氧基)环己烷-1-S羧酸甲酯(180mg，335μmol)，四三苯基磷钯(25.8mg，22.3μmol)溶解在1,4-二氧六环(3mL)中，然后将混合物在氮气保护下在100℃下搅拌12小时。减压浓缩反应混合物以除去1,4-二氧六环，得到残余物。残余物通过硅胶板纯化(SiO 2，石油醚：乙酸乙酯＝2∶1)得到(1S,3S)-3-((6-(5-氟-3-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲基(I-10H)(30mg，产率22.9％)。
第八步：(1S,3S)-3-((6-(5-氟-3-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-乙氧基)环己烷-1-羧酸(I-10)的合成
(1S,3S)-3-((6-(5-fluoro-3-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(I-10)
Figure PCTCN2021129865-appb-000187
向((1S,3S)-3-((6-(5-氟-3-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲基(I-10H)(30mg，56.9μmol)的四氢呋喃(0.6mL)和水(0.3mL)的混合液中加入一水氢氧化锂(11.9mg，284.84μmol)，将反应液在25℃下搅拌12小时。将反应混合物用水(3mL)稀释，并用1M盐酸(2mL)酸化至pH为2，用乙酸乙酯(2mL×2)萃取，将合并的有机相减压浓缩，得到残余物。残余物通过制备色谱法纯化(柱子:Phenomenex luna C 18 150*25mm*10um；溶剂：A＝水+0.225体积％甲酸(99％)，B＝ 乙腈；梯度：56％-86％B，11分钟)得化合物(1S,3S)-3-((6-(5-氟-3-((((R)-1-苯基乙氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-乙氧基)环己烷-1-羧酸(目标化合物I-10)(5.52mg，收率16.9％)。
LC-MS,M/Z(ESI):513.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.36-7.29(m,5H),7.19-7.12(m,2H),6.48(s,1H),6.25-6.23(m,1H),5.84-5.79(m,1H),4.67(s,1H),4.41-4.31(m,2H),2.90-2.85(m,1H),2.52(s,3H),2.18-2.13(m,1H),2.02-1.93(m,5H),1.83-1.79(m,2H),1.54-1.53(m,3H).
实施例11：目标化合物I-11的制备
(1S,3S)-3-((6-(5-氯-3-((((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-11)
(1S,3S)-3-((6-(5-chloro-3-((((((R)-pentan-2-yl)oxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-11)
Figure PCTCN2021129865-appb-000188
目标化合物I-11的合成路线如下所示：
Figure PCTCN2021129865-appb-000189
第一步：(R)-4-硝基苯基戊烷-2-基碳酸酯(I-11B)的合成
(R)-4-nitrophenyl pentan-2-yl carbonate(I-11B)
Figure PCTCN2021129865-appb-000190
将(R)-戊烷-2-醇(I-11A)(0.1g，1.13mmol)溶于10mL二氯甲烷，加入吡啶(0.18g，2.27mmol)、4-硝基氯甲酸苯酯(0.27g，1.36mmol)，室温搅拌过夜，浓缩，残留物用硅胶柱分离纯化得浅黄色油状化合物(R)-4-硝基苯基戊烷-2-基碳酸酯(I-11B)(0.16g，产率55.7％)。
第二步：(1S,3S)-3-((6-(5-氯-3-((((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-11C)的合成
methyl(1S,3S)-3-((6-(5-chloro-3-((((((R)-pentan-2-yl)oxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-11C)
Figure PCTCN2021129865-appb-000191
将(1S,3S)-3-((6-(3-(氨基甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3F)(0.1g，0.253mmol)、(R)-4-硝基苯基戊烷-2-基碳酸酯(I-11B)(0.121g，0.506mmol)溶于10mL四氢呋喃中，再加入N,N-二异丙基乙胺(0.98g，0.76mmol)，室温搅拌0.5h，浓缩，残留物用硅胶柱分离纯化得无色油状化合物(1S,3S)-3-((6-(5-氯-3-((((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-11C)(100mg，产率80％)。
第三步：(1S,3S)-3-((6-(5-氯-3-((((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-11)的合成
(1S,3S)-3-((6-(5-chloro-3-((((((R)-pentan-2-yl)oxy)carbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-11)
Figure PCTCN2021129865-appb-000192
室温下，将(1S,3S)-3-((6-(5-氯-3-((((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-11C)(100mg，0.202mmol)溶解在四氢呋喃(5mL)，甲醇(1mL)和水(1mL)的混合溶液中，再加入一水合氢氧化锂(33.9mg，0.808mmol)，室温反应过夜，用1M盐酸调节pH到3，浓缩干，残留物用硅胶板分离纯化得白色固体化合物(1S,3S)-3-((6-(5-氯-3-((((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-11)(30.9mg，产率31.8％)。
LC-MS,M/Z(ESI):495.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.21(d,1H),7.12(d,1H),6.92(s,1H),6.07(s,1H),4.86–4.76(m,1H),4.70–4.60(s,1H),4.37(s,2H),2.93–2.81(m,1H),2.51(s,3H),2.18–2.09(m,1H),2.03–1.88(m,3H),1.84–1.62(m,6H),1.40–1.30(m,2H),1.20(d,3H),0.90(t,3H).
实施例12：目标化合物I-12的制备
(1S,3S)-3-((6-(3-(((丁氧基羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-12)
(1S,3S)-3-((6-(3-(((butoxycarbonyl)(methyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-12)
Figure PCTCN2021129865-appb-000193
目标化合物I-12的合成路线如下所示：
Figure PCTCN2021129865-appb-000194
第一步：4-硝基苯基碳酸丁酯(I-12B)的合成
butyl(4-nitrophenyl)carbonate(I-12B)
Figure PCTCN2021129865-appb-000195
将正丁醇(I-12A)(0.2g，2.7mmol)溶于15mL二氯甲烷，加入吡啶(0.427g，5.4mmol)、4-硝基氯甲酸苯酯(0.653g，3.24mmol)，室温搅拌过夜，浓缩，残留物用硅胶柱分离纯化得浅黄色油状化合物4-硝基苯基碳酸丁酯(I-12B)(0.54g，产率84％)。
第二步：(1S,3S)-3-((6-(3-(((丁氧基羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-12C)的合成
methyl(1S,3S)-3-((6-(3-(((butoxycarbonyl)(methyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-12C)
Figure PCTCN2021129865-appb-000196
将(1S,3S)-3-((6-(5-氯-3-((甲基氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸甲酯的(I-5C)(90mg，0.22mmol)、4-硝基苯基碳酸丁酯(I-12B)(105mg，0.44mmol)溶于5mL四氢呋喃中，再加入N,N-二异丙基乙胺(85mg，0.66mmol)，室温搅拌0.5h，浓缩，残留物用硅胶板分离纯化得无色油状化合物(1S,3S)-3-((6-(3-(((丁氧基羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-12C)(60mg，产率53.6％)。
第三步：(1S,3S)-3-((6-(3-(((丁氧基羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3- 基)氧基)环己烷-1-羧酸(I-12)的合成
(1S,3S)-3-((6-(3-(((butoxycarbonyl)(methyl)amino)methyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(I-12)
Figure PCTCN2021129865-appb-000197
室温下，将(1S,3S)-3-((6-(3-(((丁氧基羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-12C)(60mg，0.118mmol)溶解在四氢呋喃(5mL)、甲醇(1mL)和水(1mL)的混合溶液中，再加入一水合氢氧化锂(24.7mg，0.589mmol)，室温反应过夜，用1M盐酸调节pH到3，浓缩干，残留物用硅胶板分离纯化得白色固体化合物(1S,3S)-3-((6-(3-(((丁氧基羰基)(甲基)氨基)甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(I-12)(16.7mg，产率28.6％)。
LC-MS,M/Z(ESI):495.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.17(s,1H),7.11(d,1H),6.78(d,1H),4.69(d,3H),4.12(t,2H),2.92-2.76(s,4H),2.49(s,3H),2.19-2.09(m,1H),2.08-1.86(m,3H),1.82-1.72(m,1H),1.71-1.57(m,5H),1.46-1.31(m,2H),1.00-0.88(m,3H).
实施例13：目标化合物I-13的制备
(1S,3S)-3-((6-(5-氯-3-((甲基(丙氧羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-13)
(1S,3S)-3-((6-(5-chloro-3-((methyl(propoxycarbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-13)
Figure PCTCN2021129865-appb-000198
目标化合物I-13的合成路线如下所示：
Figure PCTCN2021129865-appb-000199
第一步：4-硝基苯基碳酸丙酯(I-13B)的合成
4-nitrophenyl propyl carbonate(I-13B)
Figure PCTCN2021129865-appb-000200
将正丙醇(I-13A)(0.2g，3.33mmol)溶于15mL二氯甲烷，加入吡啶(0.526g，6.66mmol)、4-硝基氯甲酸苯酯(0.805g，3.99mmol)，室温搅拌过夜，浓缩，残留物用硅胶柱分离纯化得浅黄色油状化合物4-硝基苯基碳酸丙酯(I-13B)(0.57g，产率76％)。
第二步：(1S,3S)-3-((6-(5-氯-3-((甲基(丙氧羰基)氨基)甲基)噻吩-2-基))-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-13C)合成
methyl(1S,3S)-3-((6-(5-chloro-3-((methyl(propoxycarbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-13C)
Figure PCTCN2021129865-appb-000201
将(1S,3S)-3-((6-(5-氯-3-((甲基氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸甲酯的(I-5C)(90mg，0.22mmol)、(4-硝基苯基)碳酸丙酯(I-13B)(99mg，0.44mmol)溶于5mL四氢呋喃中，再加入N,N-二异丙基乙胺(85mg，0.66mmol)，室温搅拌0.5h，浓缩，残留物用硅胶板分离纯化得无色油状化合物(1S,3S)-3-((6-(5-氯-3-((甲基(丙氧羰基)氨基)甲基)噻吩-2-基))-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-13C)(60mg，产率55.1％)。
第三步：(1S,3S)-3-((6-(5-氯-3-((甲基(丙氧羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基) 氧基)环己烷-1-羧酸(I-13)的合成
(1S,3S)-3-((6-(5-chloro-3-((methyl(propoxycarbonyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(I-13)
Figure PCTCN2021129865-appb-000202
室温下，将(1S,3S)-3-((6-(5-氯-3-((甲基(丙氧羰基)氨基)甲基)噻吩-2-基))-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-13C)(60mg，0.121mmol)溶解在四氢呋喃(5mL)、甲醇(1mL)和水(1mL)的混合溶液中，再加入一水合氢氧化锂(25.4mg，0.606mmol)，室温反应过夜，用1M盐酸调节pH到3，浓缩干，残留物用硅胶板分离纯化得白色固体化合物(1S,3S)-3-((6-(5-氯-3-((甲基(丙氧羰基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(I-13)(30.9mg，产率53％)。
LC-MS,M/Z(ESI):481.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.16(s,1H),7.11(d,1H),6.78(d,1H),4.69(d,3H),4.08(t,2H),2.90–2.75(m,4H),2.49(s,3H),2.18–2.09(d,1H),2.05–1.88(m,3H),1.79–1.60(m,6H),0.94(s,3H).
实施例14：目标化合物I-14的制备
(1S,3S)-3-((6-(3-(((丁氧基羰基)(甲基)氨基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-14)
(1S,3S)-3-((6-(3-(((butoxycarbonyl)(methyl)amino)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
Figure PCTCN2021129865-appb-000203
目标化合物I-14参考化合物I-12合成，不同之处在于将(1S,3S)-3-((6-(5-氯-3-((甲基氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸甲酯的(I-5C)替换为(1S,3S)-3-((6-(5-氟-3-((甲基氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸甲酯。
LC-MS,M/Z(ESI):479.2[M+H] +
实施例15：目标化合物I-15的制备
(1S,3S)-3-((6-(5-氯-3-)((((4-氟丁氧基)羰基)(甲基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-15)
(1S,3S)-3-((6-(5-chloro-3-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
Figure PCTCN2021129865-appb-000204
目标化合物I-15参考化合物I-13合成，不同之处在于将(4-硝基苯基)碳酸丙酯(I-13B)替换为4-氟丁基(4--硝基苯基)碳酸酯。
LC-MS,M/Z(ESI):513.2[M+H] +
生物学活性及相关性质测试例
测试例1：LPAR1体外钙流测定试验
化合物对LPAR1拮抗作用的测定在高表达人LPAR1的CHO稳转细胞株中进行。试验前18小时，将细胞以15,000细胞/孔的密度接种在含20μL DMEM/F12(1：1)培养基的384孔黑壁透明底板中，并保持在37℃/5％CO 2中孵育18小时，然后每孔细胞内加入20μL/孔染料溶液，放回37℃培养箱中继续避光孵育30min，再在室温避光条件下孵育10min，细胞内加入10μL/孔不同终浓度的化合物，平衡20min，最后向细胞中加入12.5μL/孔的LPA溶液(终浓度5nM)，用FLIPR检测荧光信号值。以化合物浓度为X轴，荧光信号值为Y轴，通过软件Prism计算化合物的拮抗作用(IC 50值)。
表1测试化合物对LPAR1的拮抗作用
测试化合物 IC50(nM)
对照化合物1 117.9
对照化合物2 243.8
对照化合物3 251.6
对照化合物4 243.3
对照化合物5 109.5
I-1 8.05
I-2 6.37
I-3 16.97
I-4 193.0
I-5 12.71
I-6 40.4
I-7 66.67
I-8 87.15
I-9 18.36
I-10 16.52
I-11 50.53
I-13 56.12
LPAR1实验钙流试验结果表明，本发明化合物对LPAR1具有良好的拮抗作用，与对照化合物相比，大多数发明化合物显示出更优异的LPAR1拮抗作用。
测试例2：LPAR3体外钙流测定试验
化合物对LPAR3拮抗作用的测定在高表达人LPAR3的CHO稳转细胞株中进行。实验前18小时，将细胞以15,000细胞/孔的密度接种在含20μL DMEM/F12(1：1)培养基的384孔黑壁透明底板中，并保持在37℃/5％CO 2中孵育18小时，然后每孔细胞内加入20μL/孔染料溶液，放回37℃培养箱中继续避光孵育30min，再在室温避光条件下孵育10min，细胞内加入10μL/孔不同终浓度的化合物，平衡20min，最后向细胞中加入12.5μL/孔的LPA溶液(终浓度5nM)，用FLIPR检测荧光信号值。以化合物浓度为X轴，荧光信号值为Y轴，通过软件Prism计算化合物的拮抗作用(IC 50值)。
表2测试化合物对LPAR3的拮抗作用
Figure PCTCN2021129865-appb-000205
LPAR3钙流试实验结果表明，本发明化合物对LPAR3的拮抗作用很较弱，与对照化合物相比，本发明化合物显示出更优异的LPAR1选择拮抗活性。
测试例3：化合物物对胆汁外排转运体的抑制作用测试试验
化合物物对胆汁外排转运体的抑制作用测试试验使用表达人源性胆汁外排转运体的囊泡(GenoMembrane)来进行。不同浓度的化合物与囊泡预孵育5分钟，同时设置阴性对照(NC)组和阳性对照(PC)组：NC组为囊泡与空白缓冲液37℃预孵育5分钟，PC组为阳性抑制剂与囊泡37℃预孵育5分钟。随后在分别加入ATP或AMP的条件下，与探针底物在37℃孵育5分钟。用预冷的Buffer B1(10×Buffer B1(Stopping and Washing Buffer):100mM Hepes-Tris,1000mM KNO3,500mM Sucrose)终止试验。将试验样本转移到96孔滤板上，用真空泵抽滤，随后用0.2mL预冷的Buffer B1反复洗5次，用50μL 80％甲醇溶解滤板上的囊泡，收集后2000转离心2分钟收集滤液，重复一次，将两次的滤液合并在一起，混匀，得到大约100μL的滤液，加入含内标的预冷甲醇，于12,000转离心5min。取上清液用于LC-MS/MS定量检测被转运的底物的含量。以化合物浓度为X轴，相对活性(％ofNC)为Y轴，通过软件Prism计算化合物抑制胆汁外排转运体活性的IC 50值以及抑制率。
按以下公式计算不同条件下的转运速率(活性)和相对活性：
Figure PCTCN2021129865-appb-000206
Figure PCTCN2021129865-appb-000207
胆汁外排转运体的抑制试验结果表明，本发明化合物对胆汁外排转运体无明显抑制作 用，无胆汁淤积毒性风险。
测试例4：药代动力学试验
小鼠药代动力学试验，使用雄性ICR小鼠，20-25g，禁食过夜。取3只小鼠，口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
表4小鼠口服灌胃给药药代动力学试验结果
Figure PCTCN2021129865-appb-000208
小鼠药代动力学试验实验结果表明，与对照化合物相比，本发明化合物表现出更优良的药代动力学性质，成药性好。
测试例5：LPA诱导的小鼠组胺释放试验
LPA诱导的小鼠组胺释放试验用20-25g的雌性Balb/c小鼠开展。化合物与阳性对照分别设置三个给药组，每组6只小鼠，分别口服灌胃给药1，3，10mpk，空白组和阴性对照组则灌胃相同体积溶媒(5％DMSO+5％Solutol+90％Saline)。给药2h后，各给药组小鼠尾静脉注射300μg/mouse LPA，而空白组和阴性对照组则尾静脉注射等体积溶媒(4mg/ml BSA/PBS)，刺激2min后取血，湿冰上或2-8度保存，20min内5000rpm低温离心5min，取血浆，使用HTRF试剂盒(Cisbio，62HTMDPEG)检测血浆中histamine浓度。利用血浆中histamine浓度数据计算不同浓度化合物对LPA诱导的组胺释放的抑制率。
表5 LPA诱导的小鼠组胺释放试验
Figure PCTCN2021129865-appb-000209
Figure PCTCN2021129865-appb-000210
组胺释放试验结果表明，与对照化合物相比，本发明化合物在3个浓度下都有显著高于对照化合物的抑制LPA诱导的组胺释放的效率。
测试例6：博来霉素诱导的肺纤维化药效试验
雄性小鼠适应性饲养1周，并体重达标后，根据动物体重随机分为对照组组，模型组和给药组。异氟烷麻醉后：模型组和给药组肺内均匀给予50μL的博来霉素以建立小鼠肺纤维化模型，而对照组肺内均匀给予50μL生理盐水；7天后连续给药15天，给药完成后，动物经戊巴比妥钠深度麻醉，收集肺泡灌洗液(BALF)，并立即放到湿冰盒暂存，用于后续指标检测；部分动物肺放入10％中性福尔马林缓冲液固定，用于制备病理组织切片；另一部分动物肺准确称取重量并记录后，置于冻存管，立即放入液氮，和收集的BALF上清一并转移至超低温-80℃冰箱保存，用于后续检测肺泡灌洗液和肺组织羟脯氨酸水平、Collagen I表达情况等指标。
博来霉素诱导的肺纤维化药效试验结果表明，本发明化合物能通过拮抗LPAR1显著改善博来霉素诱导的小鼠肺纤维化症状。

Claims (22)

  1. 一种化合物，所述化合物为式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2021129865-appb-100001
    其中：
    R 1选自-H，-CN，卤素，-Z-R a，无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基或C 1-6烷氧基；
    Z选自单键或-O-、-S-；
    R a选自C 1-6烷基，被卤素取代的C 1-6烷基；
    R b选自-CN，卤素，C 1-6烷基，C 1-6烷氧基；
    R 2选自-H，-CN，卤素，-Y-R d，无取代或被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基；
    Y选自单键或-O-、-S-；
    R d选自C 1-6烷基，被卤素取代的C 1-6烷基；
    R e选自-CN，卤素，C 1-6烷基，C 1-6烷氧基；
    X 1、X 2、X 3分别独立地为C或N，且X 1、X 2、X 3不同时为N；
    R 3选自-H、C 1-3烷基、被卤素取代的C 1-3烷基；
    R 4选自-H、-CN、卤素、无取代或被R g取代的以下基团：C 1-6烷基、C 3-8环烷基、4-8元杂环基、5-8元芳基、5-8元杂芳基；
    R g选自-H、卤素、C 1-6烷基、C 1-6环烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、卤素取代的C 1-6烷氧基；
    L 1选自-CO-O-或-SO 2-；
    L 2选自单键、无取代或被C 1-3烷基取代的C 1-3亚烷基、无取代或被C 1-3烷基取代的环 丙基。
  2. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129865-appb-100002
    选自被R 1取代的苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基。
  3. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129865-appb-100003
    选自
    Figure PCTCN2021129865-appb-100004
    Figure PCTCN2021129865-appb-100005
    和/或，当R 1为卤素时，所述卤素为氟、氯、溴或碘；
    和/或，当R 1为-Z-R a、R a为C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；
    和/或，当R 1为-Z-R a、R a为被卤素取代的C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；
    和/或，当R 1为-Z-R a、R a为被卤素取代的C 1-6烷基时，所述的卤素的个数为一个或多个，当存在多个卤素时，所述的卤素相同或不同；
    和/或，当R 1为-Z-R a、R a为被卤素取代的C 1-6烷基时，所述的卤素为氟、氯、溴或碘；
    和/或，当R 1为无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R b的个数为一个或多个，当存在多个R b时，所述R b相同或不同；
    和/或，当R 1为无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R b的个数为一个或多个，所述R b选自-CN，氟、氯、溴、碘，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基；
    和/或，当R 1为无取代或被R b取代的C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；
    和/或，当R 1为无取代或被R b取代的C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基；
    和/或，当R 1为无取代或被R b取代的C 1-6烷氨基时，所述的C 1-6烷氨基为
    Figure PCTCN2021129865-appb-100006
    其中m1和m2各自独立地选自0-6的整数，且m1和m2不同时为0且m1和m2的和不超过6；
    和/或，当R 1为无取代或被R b取代的C 1-6烷氧基时，所述的C 1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基；
    和/或，当R 2为卤素时，所述卤素为氟、氯、溴或碘；
    和/或，当R 2为-Y-R d、R d为C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；
    和/或，当R 2为-Y-R d、R d为被卤素取代的C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；
    和/或，当R 2为-Y-R d、R d为被卤素取代的C 1-6烷基时，所述的卤素的个数为一个或多个，当存在多个卤素时，所述的卤素相同或不同；
    和/或，当R 2为-Y-R d、R d为被卤素取代的C 1-6烷基时，所述的卤素为氟、氯、溴或碘；
    和/或，当R 2为无取代或被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R e的个数为一个或多个，当存在多个R e时，所述R e相同或不同；
    和/或，当R 2为无取代或被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R e的个数为一个或多个，所述R e选自-CN，氟、氯、溴、碘，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基；
    和/或，当R 2为无取代或被R e取代的C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；
    和/或，当R 2为无取代或被R e取代的C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基；
    和/或，当R 2为无取代或被R e取代的C 1-6烷氨基时，所述的C 1-6烷氨基为
    Figure PCTCN2021129865-appb-100007
    其中n1和n2各自独立地选自0-6的整数，且n1和n2不同时为零且n1和n2的和不超过6；
    和/或，当R 2为无取代或被R e取代的C 1-6烷氧基时，所述的C 1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基；
    和/或，当R 3为C 1-3烷基时，所述C 1-3烷基为甲基、乙基、正丙基、异丙基；
    和/或，当R 3为被卤素取代的C 1-3烷基时，所述的C 1-3烷基为甲基、乙基、正丙基、异丙基；
    和/或，当R 3为被卤素取代的C 1-3烷基时，所述的卤素的个数为一个或多个，当存在多个卤素时，所述的卤素相同或不同；
    和/或，当R 3为被卤素取代的C 1-3烷基时，所述的卤素为氟、氯、溴或碘；
    和/或，当R 4为卤素时，所述卤素为氟、氯、溴或碘；
    和/或，当R 4为无取代或被R g取代的以下基团：C 1-6烷基、C 3-8环烷基、4～8元杂环基、5～8元芳基、5～8元杂芳基时，所述R g的个数为一个或多个，当存在多个R g时，所述R g相同或不同；
    和/或，当R 4为无取代或被R g取代的以下基团：C 1-6烷基、C 3-8环烷基、4～8元杂环基、5～8元芳基、5～8元杂芳基时，所述R g的个数为一个或多个，所述R g选自-H，氟、氯、溴、碘，甲基、乙基、正丙基、异丙基、正丁基、正戊基、三氟甲基、二氟甲氧基；
    和/或，当R 4为无取代或被R g取代的C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；
    和/或，当R 4为无取代或被R g取代的C 3-8环烷基时，所述的C 3-8环烷基为环丙基、环丁基、环戊基、环己基、环庚基、环辛基；
    和/或，当R 4为无取代或被R g取代的4-8元杂环基时，所述杂原子选自N、O和S；
    和/或，当R 4为无取代或被R g取代的4～8元杂环基时，所述杂原子数为1-2个；
    和/或，当R 4为无取代或被R g取代的5-8元芳基时，所述5～8元芳基选自苯基、萘环；
    和/或，当R 4为无取代或被R g取代的5-8元杂芳基时，所述5～8元杂芳基选自噻吩、呋喃、噁唑、噻唑、三氮唑、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、吡唑基、咪唑基；
    和/或，L 1选自-CO-O-或-SO 2-；
    和/或，L 2选自
    Figure PCTCN2021129865-appb-100008
  4. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129865-appb-100009
    选自
    Figure PCTCN2021129865-appb-100010
    Figure PCTCN2021129865-appb-100011
    和/或，当R 1为卤素时，所述卤素为氟、氯或溴；
    和/或，当R 1为-Z-R a，Z为-O-时，R 1选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)；
    和/或，当R 1为-Z-R a，Z为-S-时，R 1选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)；
    和/或，当R 1为无取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基、C 1-6烷氧基，R 1选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100012
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2；
    和/或，当R 1为被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，R 1选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
    Figure PCTCN2021129865-appb-100013
    Figure PCTCN2021129865-appb-100014
    -NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、-NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、-OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100015
    -NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、 -(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129865-appb-100016
    -NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129865-appb-100017
    Figure PCTCN2021129865-appb-100018
    和/或，当R 2为卤素时，所述卤素为氟、氯或溴；
    和/或，当R 2为-Y-R d，Y为-O-时，R 2选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)；
    和/或，当R 2为Y-R d，Y为-S-时，R 2选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)；
    和/或，当R 2为无取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基、C 1-6烷氧基，R 2选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100019
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2；
    和/或，当R 2为被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，R 2选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
    Figure PCTCN2021129865-appb-100020
    Figure PCTCN2021129865-appb-100021
    -NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、-NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、-OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100022
    -NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、 -OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129865-appb-100023
    -NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129865-appb-100024
    Figure PCTCN2021129865-appb-100025
    和/或，R 3选自-H、甲基、乙基、-CF 3、-CH 2CH 2F；
    和/或，当R 4为无取代的C 1-6烷基时，R 4选自甲基、乙基、异丙基；
    和/或，当R 4为无取代的C 3-8环烷基时，R 4选自环丙基、环丁基、环戊基；
    和/或，当R 4为无取代的4-8元杂环基时，R 4选自
    Figure PCTCN2021129865-appb-100026
    和/或，当R 4为无取代的5-8元芳基时，R 4选自苯基、萘环；
    和/或，当R 4为无取代的5-8元杂芳基时，R 4选自吡啶基；
    和/或，当R 4为被R g取代的C 1-6烷基时，R 4选自-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)；
    和/或，当R 4为被R g取代的C 3-8环烷基时，R 4选自
    Figure PCTCN2021129865-appb-100027
    Figure PCTCN2021129865-appb-100028
    和/或，当R 4为被R g取代的4-8元杂环基时，R 4选自
    Figure PCTCN2021129865-appb-100029
    Figure PCTCN2021129865-appb-100030
    和/或，当R 4为被R g取代的5-8元芳基时，R 4选自
    Figure PCTCN2021129865-appb-100031
    Figure PCTCN2021129865-appb-100032
    和/或，当R 4为被R g取代的5-8元杂芳基时，R 4选自
    Figure PCTCN2021129865-appb-100033
    Figure PCTCN2021129865-appb-100034
  5. 根据权利要求1所述的化合物，其特征在于，R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100035
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100036
    Figure PCTCN2021129865-appb-100037
    和/或，R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100038
    Figure PCTCN2021129865-appb-100039
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100040
    Figure PCTCN2021129865-appb-100041
    和/或，
    Figure PCTCN2021129865-appb-100042
    选自
    Figure PCTCN2021129865-appb-100043
    Figure PCTCN2021129865-appb-100044
  6. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129865-appb-100045
    选自
    Figure PCTCN2021129865-appb-100046
    Figure PCTCN2021129865-appb-100047
    和/或，R 1选自-H、-F、甲基、环丙基；
    和/或，R 2选自-H、-F、-Cl、-CH 3；
    和/或，当R 3为C 1-3烷基时，所述C 1-3烷基为甲基、乙基、正丙基、异丙基；
    和/或，当R 3为被卤素取代的C 1-3烷基时，所述的C 1-3烷基为甲基、乙基、正丙基、异丙基；
    和/或，当R 3为被卤素取代的C 1-3烷基时，所述的卤素的个数为一个或多个，当存在多 个卤素时，所述的卤素相同或不同；
    和/或，当R 3为被卤素取代的C 1-3烷基时，所述的卤素为氟、氯、溴或碘；
    和/或，R 4选自甲基、乙基、异丙基、环丙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；
    和/或，L 1选自-CO-O-或-SO 2-；
    和/或，L 2选自
    Figure PCTCN2021129865-appb-100048
  7. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129865-appb-100049
    选自
    Figure PCTCN2021129865-appb-100050
    Figure PCTCN2021129865-appb-100051
    其中R 1选自-F、C 1-3烷基；
    R 2选自-H、-CN、卤素、C 1-3烷基；
    R 3选自-H、C 1-3烷基；
    R 4选自C 1-3烷基、C 3-6环烷基、苯基、-CH 2F、-CH 2CH 2F；
    L 1选自-CO-O-或-SO 2-；
    L 2选自
    Figure PCTCN2021129865-appb-100052
  8. 根据权利要求1所述的化合物，其特征在于，所述的式I所示化合物的基团定义如下任一方案所述：
    方案一：
    Figure PCTCN2021129865-appb-100053
    为
    Figure PCTCN2021129865-appb-100054
    R 1选自-F、C 1-3烷基；
    R 2选自-H、卤素、C 1-3烷基；
    R 3选自-H、C 1-3烷基；
    R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；
    L 1选自-CO-O-；
    L 2选自
    Figure PCTCN2021129865-appb-100055
    方案二：
    Figure PCTCN2021129865-appb-100056
    为
    Figure PCTCN2021129865-appb-100057
    R 1选自-F、C 1-3烷基；
    R 2选自-H、卤素、C 1-3烷基；
    R 3选自-H、C 1-3烷基；
    R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；
    L 1选自-CO-O-或-SO 2-；
    L 2选自
    Figure PCTCN2021129865-appb-100058
    方案三：
    Figure PCTCN2021129865-appb-100059
    为
    Figure PCTCN2021129865-appb-100060
    R 1选自-F、C 1-3烷基；
    R 2选自-H、卤素、C 1-3烷基；
    R 3选自-H、C 1-3烷基；
    R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；
    L 1选自-CO-O-或-SO 2-；
    L 2选自
    Figure PCTCN2021129865-appb-100061
    方案四：
    Figure PCTCN2021129865-appb-100062
    为
    Figure PCTCN2021129865-appb-100063
    R 1选自-F、C 1-3烷基；
    R 2选自-H、卤素、C 1-3烷基；
    R 3选自-H、C 1-3烷基；
    R 4选自甲基、乙基、环丁基、苯基、-CH 2F、-CH 2CH 2F；
    L 1选自-CO-O-或-SO 2-；
    L 2选自
    Figure PCTCN2021129865-appb-100064
    方案五：
    Figure PCTCN2021129865-appb-100065
    为
    Figure PCTCN2021129865-appb-100066
    R 1选自-F、C 1-3烷基；
    R 2选自-H、卤素；
    R 3选自-H；
    R 4选自无取代或被R g取代的以下基团：C 3-8环烷基、4-8元杂环基、5-8元芳基、5-8元杂芳基；
    L 1选自-CO-O-；
    L 2选自
    Figure PCTCN2021129865-appb-100067
  9. 根据权利要求1所述的化合物，其特征在于，所述的式(I)所示化合物为式(I-0)所示化合物：
    Figure PCTCN2021129865-appb-100068
    其中：
    R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100069
    Figure PCTCN2021129865-appb-100070
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100071
    Figure PCTCN2021129865-appb-100072
    R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100073
    Figure PCTCN2021129865-appb-100074
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100075
    Figure PCTCN2021129865-appb-100076
    X 1、X 2、X 3分别独立地为C或N，且X 1、X 2、X 3不同时为N；
    R 3选自-H、C 1-3烷基、被卤素取代的C 1-3烷基；
    R 4选自-H、-CN、-F、-Cl、-Br、甲基、乙基、异丙基、环丙基、环丁基、环戊基、
    Figure PCTCN2021129865-appb-100077
    Figure PCTCN2021129865-appb-100078
    苯基、吡啶基、萘环、-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、 -CH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129865-appb-100079
    Figure PCTCN2021129865-appb-100080
    L 1选自-CO-O-或-SO 2-；
    L 2选自单键、无取代或被C 1-3烷基取代的C 1-3亚烷基、无取代或被C 1-3烷基取代的环丙基。
  10. 根据权利要求1所述的化合物，其特征在于，所述的式(I)所示化合物为式(I-0)所示化合物：
    Figure PCTCN2021129865-appb-100081
    其中：
    R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100082
    Figure PCTCN2021129865-appb-100083
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、 -OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100084
    Figure PCTCN2021129865-appb-100085
    R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129865-appb-100086
    Figure PCTCN2021129865-appb-100087
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129865-appb-100088
    Figure PCTCN2021129865-appb-100089
    X 1、X 2、X 3分别独立地为C或N，且X 1、X 2、X 3不同时为N；
    R 3选自-H、C 1-3烷基、被卤素取代的C 1-3烷基；
    R 4选自-H、-CN、-F、-Cl、-Br、甲基、乙基、异丙基、环丙基、环丁基、环戊基、
    Figure PCTCN2021129865-appb-100090
    Figure PCTCN2021129865-appb-100091
    苯基、吡啶基、萘环、-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、 -CH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129865-appb-100092
    Figure PCTCN2021129865-appb-100093
    Figure PCTCN2021129865-appb-100094
    选自
    Figure PCTCN2021129865-appb-100095
    Figure PCTCN2021129865-appb-100096
  11. 根据权利要求1所述的化合物，其特征在于，所述的式(I)所示化合物为式(I-1’)所示化合物：
    Figure PCTCN2021129865-appb-100097
    其中：
    R 1选自-H、C 1-3烷基；
    R 2选自-H、卤素；
    R 3选自-H、C 1-3烷基；
    R 4选自-H、C 1-6烷基、C 3-8环烷基、苯基；
    L 2选自单键、
    Figure PCTCN2021129865-appb-100098
  12. 根据权利要求1所述的化合物，其特征在于，所述的式(I)所示化合物为式(I-2’)所示化合物：
    Figure PCTCN2021129865-appb-100099
    其中，R 1选自-H，-CN，卤素，-Z-R a，无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基或C 1-6烷氧基；Z选自单键或-O-、-S-；
    R a选自C 1-6烷基，被卤素取代的C 1-6烷基；
    R b选自-CN，卤素，C 1-6烷基，C 1-6烷氧基；
    R 2选自-H，-CN，卤素，-Y-R d，无取代或被R e取代的以下基团：C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基；
    R 3为-H；
    环A为无取代或被R g取代的以下基团：C 3-8环烷基、4-8元杂环基、5-8元芳基、5-8元杂芳基；
    L 2选自单键、无取代或被C 1-3烷基取代的C 1-3亚烷基、无取代或被C 1-3烷基取代的环丙基。
  13. 根据权利要求12所述的化合物，其特征在于，R 2选自-H，-CN，卤素；L 2选自被C 1-3烷基取代的C 1-3亚烷基或被C 1-3烷基取代的环丙基。
  14. 根据权利要求12所述的化合物，其特征在于，R 2选自-H，-CN，卤素；L 2选自单键、无取代的C 1-3亚烷基、无取代的环丙基。
  15. 下式所示化合物，或其立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2021129865-appb-100100
    Figure PCTCN2021129865-appb-100101
  16. 一种药物组合物，其特征在于，包含有效剂量的权利要求1～15中任一项所述的化合物。
  17. 权利要求1～15中任一项所述化合物，或权利要求16所述的药物组合物在制备治疗与LPAR相关疾病的药物中的用途。
  18. 根据权利要求17所述的用途，其中所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
  19. 根据权利要求17所述的用途，其中所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
  20. 一种治疗或预防LPAR相关疾病的方法，其特征在于，给与患者药学上可接受剂量的权利要求1～15中任一项所述化合物，或权利要求16所述的药物组合物。
  21. 根据权利要求20所述的方法，其特征在于，所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
  22. 根据权利要求20所述的方法，其特征在于，所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。
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