WO2022100624A1 - Composé à base de thiophène aminocarbonate oxy-substitué et son utilisation - Google Patents

Composé à base de thiophène aminocarbonate oxy-substitué et son utilisation Download PDF

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WO2022100624A1
WO2022100624A1 PCT/CN2021/129864 CN2021129864W WO2022100624A1 WO 2022100624 A1 WO2022100624 A1 WO 2022100624A1 CN 2021129864 W CN2021129864 W CN 2021129864W WO 2022100624 A1 WO2022100624 A1 WO 2022100624A1
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methyl
och
oxy
alkyl
substituted
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张学军
常少华
臧杨
李学强
王洪强
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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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry, specifically, the invention relates to oxygen-substituted aminocarbonate thiophenes, more specifically, the invention relates to oxygen-substituted aminocarbonate thiophenes and their use in preparing medicines.
  • 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 alveolar tissue, which triggers a series of physiopathological events, including (I) disruption of homeostasis; (II) inflammatory response; (III) cell proliferation, migration, and differentiation; (IV) Matrix and tissue remodeling; and (V) wound contracture and scarring, many of these events are controlled by the coordinated release of biochemical factors in and around the injury site, in which LPA plays an important role.
  • LPA is one of the main mediators of fibroblast migration in the BALF of injured lung tissue (Tager AM et al., Proceedings of the American Thoracic Society, 2008.), and BALF (alveolar lavage fluid) LPA levels in IPF patients are higher than In the normal control group, inhibition of LPA signaling significantly reduced the chemotactic response of fibroblasts to IPF BALF.
  • 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 vascular permeability promotes fibrosis develop.
  • 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 can inhibit the expression of fibroblast-promoting cytokines transforming growth factor ⁇ 1 and connective tissue growth factor in vivo, resulting in decreased fibroblast proliferation in mice. Slows the progression of radiation pulmonary fibrosis, suggesting that LPAR1 antagonists also have the potential to treat radiation pulmonary fibrosis (Xiang H et al, J Cancer. 2020;11(12):3519-3535.).
  • LPAR1 is closely related to the occurrence of liver fibrosis. Studies have shown that the ATX-LPA signaling axis activates PI3K and stabilizes the mRNA of hypoxia-inducible factor HIF-1, thereby promoting the replication of hepatitis C virus, and inhibiting ATX-LPA signaling reduces the replication of hepatitis C virus. This process may be related to LPAR1 and LPAR3 are related, and hepatitis is a key factor in the development of liver fibrosis, suggesting that antagonism of LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol.
  • 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.
  • 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, reduced inflammation and bone erosion. (Kaffe E et al. Cancers (Basel). 2019; 11(11):1626. Published 2019 Oct 23. doi:10.3390/cancers11111626).
  • Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and sensitizes them to tumor necrosis factor (TNF)-mediated apoptosis, and LPA is also involved in interleukin (IL)- 6. Production of IL-8 and cyclooxygenase-2 (COX-2). These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals of the Rheumatic Diseases, 2014, 73(1):298-305.).
  • 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 ⁇ described "C 1-6 alkyl "such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R b is one or more (the number of which is subject to the substituted group conforming to the valence bond theory and stable existence.
  • halogen such as fluorine, chlorine, bromine or iodine
  • -ZR a C 1-6 alkyl unsubstituted or substituted by R b ⁇ described "C 1-6 alkyl "such as methyl, ethyl, n-propyl, isopropyl, n-buty
  • R b when there are multiple R b , the R b is the same or different ⁇ , Unsubstituted or R b substituted C 3-6 cycloalkyl (the "C 3-6 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or R b substituted C 1-6 alkylamino (the "C 1-6 alkylamino” such as wherein m1 and m2 are each independently selected from integers from 0 to 6, the sum of m1 and m2 does not exceed 6, and/or m1 and m2 are not both 0), unsubstituted or substituted by R b C 1-6 alkoxy group (the "C 1-6 alkoxy group” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy base, hexyloxy);
  • Z is selected from single bond or -O-, -S-;
  • R a is selected from C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1 substituted by halogen -6 alkyl
  • 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
  • the 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, the sum of n1 and n2 does not exceed 6, and/or n1 and n2 are not both 0), unsubstituted or substituted C 1-6 alkoxy with Re group (the "C 1-6 alkoxy group” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy base, hexyloxy);
  • Y is selected from a single bond, -O- or -S-;
  • R d is selected from C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1 substituted by halogen -6 alkyl
  • halogen is such as fluorine, chlorine, bromine or iodine
  • the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different ⁇ ;
  • R e is selected from -CN, halogen (eg fluorine, chlorine, bromine or iodine), C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) butyl, pentyl, hexyl), C 1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy, hexyloxy);
  • X 1 , X 2 and X 3 are each independently selected from C or N, and X 1 , X 2 and X 3 are not N at the same time;
  • 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 single bond, unsubstituted C 1-3 alkylene (for example ) or C 1-3 alkylene substituted with C 1-3 alkyl (eg ).
  • 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, n-propyl , isopropyl, n-butyl, n-pentyl.
  • 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 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 4 is selected from -H, -F, methyl, Ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, -CH 2 F, -CH 2 CH 2 F, -CF 3 , -CH 2 CF 3 .
  • R 1 is selected from -CN, halogen (eg fluorine), C 1-3 alkyl (eg methyl, ethyl, n-propyl, isopropyl);
  • R 2 is selected from -H, -CN, halogen (eg Fluorine, chlorine), C 1-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl);
  • R 3 is selected from -H, C 1-3 alkyl (such as methyl, ethyl, n-propyl) propyl, isopropyl);
  • R 4 is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclo
  • R 1 is selected from -F, methyl
  • R 2 is selected from -F, -Cl
  • R 3 is selected from methyl
  • R 4 is selected from C 3-8 cycloalkyl
  • L 1 is selected from single bond.
  • R 1 is methyl
  • R 2 is selected from -F, -Cl
  • R 3 is selected from -H, methyl
  • R 4 is selected from -H, -F, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, -CH 2 F, -CH 2 CH 2 F, -CF 3 , -CH 2 CF 3
  • L 1 is selected from single bond
  • R 1 is selected from methyl
  • R 2 is selected from -F, -Cl
  • R 3 is selected from methyl
  • R 4 is selected from -H, -F, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl base, cyclopentyl, phenyl, -CH 2 F, -CH 2 CH 2 F
  • L 1 is selected from single bond
  • R 1 is selected from methyl
  • R 2 is selected from -F, -Cl
  • R 3 is selected from -H, methyl
  • R 4 is selected from methyl, ethyl, cyclobutyl, cyclopentyl
  • L 1 is selected from mono key
  • the compound represented by the formula (I) is further 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 ) 3 F, -OCH(CH 3 )(CH 2 F),
  • R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 3 F, -OCH(CH 3 )(CH 2 F),
  • R 3 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • R 4 is selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopropyl amyl, Phenyl , pyridyl, naphthalene ring, -CH2F , -CHF2 , -CF3 , -CF2CH3 , -CH2CF3 , -CH2CH2F , - ( CH2 ) 2CH2F , -CH( CH3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
  • L 1 is selected from single bond, unsubstituted or C 1-6 alkylene substituted by C 1-3 alkyl.
  • the compound represented by the formula (I) is further 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),
  • R 3 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • R 4 is selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopropyl amyl, Phenyl , pyridyl, naphthalene ring, -CH2F , -CHF2 , -CF3 , -CF2CH3 , -CH2CF3 , -CH2CH2F , - ( CH2 ) 2CH2F , -CH( CH3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
  • the compound represented by the formula (I) is further the compound represented by the formula (I-1'):
  • R 4 is selected from C 1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl), C 1-6 alkyl substituted by halogen ⁇ described
  • halogen is such as fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number is subject to the substituted group conforming to the valence bond theory and stable existence.
  • halogens when there are multiple halogens, the halogens are the same or different ⁇ ; X 1 , X 2 , X 3 are independently selected from C or N, and X 1 , X 2 and X 3 are different when is N.
  • R 1 is methyl
  • R 2 is halogen
  • R 3 is methyl selected from
  • 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 provides a pharmaceutical composition comprising an effective amount of a compound as previously described.
  • FIG. 1 is the experimental result of reducing bleomycin-induced pulmonary fibrosis in mice by antagonizing LPAR1 by compounds according to the embodiments of the present invention.
  • 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).
  • 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 straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2 , 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbuty
  • 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, no hepatotoxicity; the compound of the present invention has excellent pharmacokinetic properties and good druggability; the compound of the present invention can significantly inhibit LPA-induced histamine release by antagonizing LPAR1, and at the same time significantly improve bleomycin-induced mouse pulmonary fibrosis Symptoms.
  • 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 equivalent to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • 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
  • DIBAL-H Diisobutylaluminum hydride
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • NMM N-Methylmorpholine, aka N-Methylmorpholine
  • T 3 P propylphosphoric acid tricyclic anhydride, that is, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide or 1-propyl phosphoric anhydride
  • 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:
  • N-Bromosuccinimide (15.59 g, 88 mmol) was slowly added to a solution of thiophen-3-ylmethanol (10 g, 88 mmol) in tetrahydrofuran (70 mL) and water (5 mL) at 0 °C. Stir at room temperature for 1 h.
  • the second step the synthesis of (2-bromothiophen-3-yl) methyl (4-nitrophenyl) carbonate (I-1C)
  • the third step the synthesis of (2-bromothiophen-3-yl) methylcyclopentyl (methyl) carbamate (I-1D)
  • the fourth step the synthesis of (2-bromo-5-chlorothiophen-3-yl) methylcyclopentyl (methyl) carbamate (I-1E)
  • N-chlorosuccinimide (0.766 g, 5.74 mmol) was slowly added to the mixture containing (2-bromothiophen-3-yl)methylcyclopentyl(methyl)carbamate (1.66 g) , 5.22 mmol) in DMF (15 mL). Stir overnight at 70°C. After the reaction of the raw materials, distilled water (50 mL) was added to dilute, extracted with ethyl acetate (60 mL ⁇ 3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL), and the layers were separated.
  • Tri-tert-butylphosphine (0.645 g, 2.460 mmol), diisopropyl azodicarboxylate (0.478 mL, 2.460 mmol), (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester ( 0.259 g, 1.640 mmol) was added with (5-chloro-2-(4-hydroxyphenyl)thiophen-3-yl)methylcyclopentyl(methyl)carbamate (0.3 g, 0.820 mmol) in THF (10 mL), stirred at 60°C overnight under nitrogen protection.
  • Lithium hydroxide monohydrate (32.3 mg, 0.771 mmol) was added to the compound containing (1S,3S)-3-(4-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy) )methyl)thiophen-2-yl)phenoxy)cyclohexane-1-carboxylic acid methyl ester (130 mg, 0.257 mmol) in a mixed solution of THF (2 mL) and MeOH (2 mL) was stirred at room temperature overnight.
  • distilled water (5 mL) was added to dilute, and the pH was adjusted to 3-4 with dilute hydrochloric acid (1N), then extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, and the organic phase was washed with saturated brine (10 mL).
  • the 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 (5.5 g, 29.3 mmol) was added to 20 mL of anhydrous DCM at room temperature, and pyridine hydrochloride (0.735 g, 2.93 mmol), 3,4-dihydrochloride was added.
  • Hydropyran (3.69 g, 43.9 mmol) was stirred at room temperature for 16 h.
  • the second step Synthesis of 2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophene-3-carbaldehyde (I-2C)
  • the fifth step (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl) ) synthesis of carbamate (I-2G)
  • the sixth step (2-(6-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-2-yl)thiophen-3-yl)methyl(cyclobutylmethyl) ) (methyl) carbamate (I-2H) synthesis
  • Step 8 (1S,3S)-3-((6-(5-chloro-3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-2J) synthesis
  • the synthetic route of the target compound I-3 is as follows:
  • Step 7 (1S,3S)-3-((6-(5-chloro-3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)thiophene -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
  • the synthetic route of the target compound I-4 is as follows:
  • the synthetic route of the target compound I-5 is as follows:
  • the first step the synthesis of isoamyl carbamate tert-butyl ester (I-5B)
  • the second step the synthesis of isoamyl (methyl) tert-butyl carbamate (I-5C)
  • the third step the synthesis of N,3-dimethylbutane-1-amine hydrochloride (I-5D)
  • Step 5 (1S,3S)-3-((6-(5-Chloro-3-(((isoamyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5F)
  • Step 6 (1S,3S)-3-((6-(5-Chloro-3-(((isoamyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
  • 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)
  • Step 6 (1S,3S)-3-((2-(5-Chloro-3-((((4-nitrophenoxy)carbonyl)oxy)methyl)thiophen-2-yl)- Synthesis of methyl 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6H)
  • Step 7 (1S,3S)-3-((2-(5-Chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of methyl 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-6I)
  • Step 8 (1S,3S)-3-((2-(5-Chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6)
  • the synthetic route of the target compound I-7 is as follows:
  • the first step Synthesis of (cyclobutylmethyl)aminocarboxylate tert-butyl ester (I-7B)
  • the second step the synthesis of (cyclobutylmethyl) (methyl) aminocarboxylate tert-butyl ester (I-7C)
  • the third step the synthesis of 1-cyclobutyl-N-methyl methylamine hydrochloride (I-7D)
  • the synthetic route of the target compound I-8 is as follows:
  • the synthetic method refers to the synthesis of compound I-7 in Example 7, and the starting material cyclobutylmethylamine hydrochloride is replaced with 2-cyclopropylethyl-1-amine hydrochloride.
  • the synthetic route of the target compound I-10 is as follows:
  • the synthetic route of the target compound I-11 is as follows:
  • the second step the synthesis of (1S,3S)-3-(4-bromo-2-fluorophenoxy) cyclohexane-1-carboxylate methyl ester (I-11C)
  • the synthetic route of the target compound I-12 is as follows:
  • Step 6 (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of methyl 3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-12G)
  • Step 7 (1S,3S)-3-((5-(5-chloro-3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)thiophen-2-yl)- Synthesis of 3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-12)
  • the synthetic route of the target compound I-13 is as follows:
  • the first step synthesis of tert-butyldimethyl(thiophen-3-ylmethoxy)silane (I-13A)
  • 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 reaction was quenched with water (100 mL), extracted twice with ethyl acetate (100 mL), and the organic phases were combined and concentrated to give the crude product.
  • the crude product was dissolved in tetrahydrofuran (200 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (70 mL) was added, and the mixture was stirred at room temperature overnight.
  • the third step the synthesis of (2-bromo-5-fluorothiophen-3-yl) methanol (I-13C)
  • the fourth step the synthesis of (2-bromo-5-fluorothiophen-3-yl) methylcyclopentyl (methyl) carbamate (I-13D)
  • Step 5 (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)- Synthesis of methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-13E)
  • Step 6 (1S,3S)-3-((6-(3-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-5-fluorothiophen-2-yl)- Synthesis of 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-13)
  • the synthetic route of the target compound I-14 is as follows:
  • the first step the synthesis of (R)-(1-cyclopropylethyl) tert-butyl carbamate (I-14B)
  • the second step the synthesis of (R)-(1-cyclopropylethyl) (methyl) tert-butyl carbamate (I-14C)
  • the third step the synthesis of (R)-1-cyclopropyl-N-methylethylamine hydrochloride (I-14D)
  • the synthetic method of the target compound I-15 is referred to compound I-14, and (R)-1-cyclopropylethylamine hydrochloride is replaced by (S)-1-cyclopropylethylamine hydrochloride.
  • the synthetic route of the target compound I-16 is as follows:
  • the synthetic route of the target compound I-17 is as follows:
  • the synthetic route of the target compound I-18 is as follows:
  • the synthetic route of the target compound I-19 is as follows:
  • the synthetic route of the target compound I-20 is as follows:
  • the synthetic route of the target compound I-21 is as follows:
  • the synthetic route of the target compound I-23 is as follows:
  • the first step the synthesis of 2-bromo-5-fluorothiophene-3-carbaldehyde (I-23A)
  • the synthetic route of the target compound I-24 is as follows:
  • reaction mixture was prepared by chromatography on silica gel plate to give yellow oily compound (1S,3S)-3-((6-(3-(((butyl(methyl)carbamoyl)oxy)methyl)-5- Fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-24A) (120 mg, 37.9% yield).
  • the synthetic route of the target compound I-25 is as follows:
  • Example 7 Compound I-7D synthesis) (174 mg, 1.29 mmol) was added to tetrahydrofuran (3.5 mL), then N,N-diisopropylethylamine (290.74 mg, 2.25 mmol) was added dropwise, and stirred at room temperature for 0.5 hour, the reaction mixture was prepared by chromatography on silica gel plate to give the compound (1S,3S)-3-((6-(3-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methan as a yellow oil (1-25A) (120 mg, 33.0% yield).
  • Step 2 (1S,3S)-3-((6-(3-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-5-fluorothiophene Synthesis of -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26)
  • the first step ((1S,3S)-3-((6-(5-chloro-3-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl )
  • the synthetic route of the target compound I-28 is as follows:
  • the synthetic route of the target compound I-29 is as follows:
  • the synthetic route of the target compound I-30 is as follows:

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Abstract

L'invention concerne un nouveau composé capable d'antagoniser efficacement LPAR. Le nouveau composé est un composé représenté par la formule suivante, ou est un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable, ou un promédicament du composé représenté par la formule suivante.
PCT/CN2021/129864 2020-11-10 2021-11-10 Composé à base de thiophène aminocarbonate oxy-substitué et son utilisation WO2022100624A1 (fr)

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Publication number Priority date Publication date Assignee Title
US11548871B2 (en) 2019-11-15 2023-01-10 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11584738B2 (en) 2020-06-03 2023-02-21 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
WO2023109878A1 (fr) * 2021-12-15 2023-06-22 武汉人福创新药物研发中心有限公司 Antagoniste de lpar1 triazaspiro et son utilisation
US11702407B2 (en) 2020-06-03 2023-07-18 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11939318B2 (en) 2021-12-08 2024-03-26 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11980609B2 (en) 2021-05-11 2024-05-14 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof

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WO2017223016A1 (fr) * 2016-06-21 2017-12-28 Bristol-Myers Squibb Company Acides carbamoyloxyméthyl triazole cyclohexyliques en tant qu'antagonistes de lpa
WO2019126098A1 (fr) * 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Acides carbamoyle cyclohexyliques à liaison o pyrazole utilisés en tant qu'antagonistes de lpa
WO2019126084A1 (fr) * 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Acides carbamoyle cyclohexyliques à liaison o isoxazole utilisés en tant qu'antagonistes de lpa
CN111434655A (zh) * 2019-01-15 2020-07-21 武汉朗来科技发展有限公司 溶血磷脂酸受体拮抗剂及其制备方法

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Publication number Priority date Publication date Assignee Title
WO2017223016A1 (fr) * 2016-06-21 2017-12-28 Bristol-Myers Squibb Company Acides carbamoyloxyméthyl triazole cyclohexyliques en tant qu'antagonistes de lpa
WO2019126098A1 (fr) * 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Acides carbamoyle cyclohexyliques à liaison o pyrazole utilisés en tant qu'antagonistes de lpa
WO2019126084A1 (fr) * 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Acides carbamoyle cyclohexyliques à liaison o isoxazole utilisés en tant qu'antagonistes de lpa
CN111434655A (zh) * 2019-01-15 2020-07-21 武汉朗来科技发展有限公司 溶血磷脂酸受体拮抗剂及其制备方法

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11548871B2 (en) 2019-11-15 2023-01-10 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11584738B2 (en) 2020-06-03 2023-02-21 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11702407B2 (en) 2020-06-03 2023-07-18 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11912686B2 (en) 2020-06-03 2024-02-27 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11980609B2 (en) 2021-05-11 2024-05-14 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11939318B2 (en) 2021-12-08 2024-03-26 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
WO2023109878A1 (fr) * 2021-12-15 2023-06-22 武汉人福创新药物研发中心有限公司 Antagoniste de lpar1 triazaspiro et son utilisation

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