WO2023109878A1 - Antagoniste de lpar1 triazaspiro et son utilisation - Google Patents

Antagoniste de lpar1 triazaspiro et son utilisation Download PDF

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WO2023109878A1
WO2023109878A1 PCT/CN2022/139166 CN2022139166W WO2023109878A1 WO 2023109878 A1 WO2023109878 A1 WO 2023109878A1 CN 2022139166 W CN2022139166 W CN 2022139166W WO 2023109878 A1 WO2023109878 A1 WO 2023109878A1
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methyl
oxy
triazol
cyclopropyl
cyclohexane
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Chinese (zh)
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张学军
臧杨
杨辉
雷四军
王洪强
杨俊�
李莉娥
常少华
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武汉人福创新药物研发中心有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to triazole LPAR1 antagonists. More specifically, the present invention relates to triazole LPR1 antagonists and their use in the preparation of medicines.
  • Lysophosphatidic acid is a key endogenous lipid signaling molecule with a molecular weight of 430-480Da, which widely exists in the intracellular and extracellular tissues of the human body, such as various body fluids, saliva, urine, and 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.
  • the autologous chemoattractant protein (ATX) encoded by the Enpp2 gene is a pyrophosphatase/phosphodiesterase with lysophospholipase D (LysoPLD) activity, which can hydrolyze extracellular lysophosphatidylcholine (LPC) into the corresponding LPA and free choline (Choi JW et al., AnnuRevPharmacolToxicol.2010; 50:157186.), this reaction is the main source of LPA, inhibiting ATX activity can inhibit the production of more than 80% of LPA in the whole body (Kaffe E et al., Cancers ( Basel). 2019;11(11):1626.).
  • LPA mediates multiple 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 to and function with six lysophosphatidic acid receptors (LPAR), namely: LPAR1-LPAR6.
  • LPA regulates various physiological/pathological processes including vascular and neural development, hair follicle development, lymphocyte trafficking, bone development, fibrosis, fat mass regulation, cholestatic pruritus, neuropathic pain, embryo implantation by binding to 6 LPARs , obesity and glucose homeostasis, sperm production, chronic inflammation, cell proliferation, cell chemotaxis, wound healing, tumor progression, fetal hydrocephalus, etc.
  • LPAR1 is the earliest identified and most widely distributed LPA receptor. It is a 41kDa membrane protein consisting of 364 amino acids and widely expressed in various tissues and organs of the human body. The mRNA levels of the brain, heart, colon, small intestine and placenta Higher, 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 with G ⁇ I/o, G ⁇ Q/11, and G ⁇ 12/13, although it has been demonstrated that LPA-LPAR1 signaling has a role in the developmental stages of the nervous system. important role, but no significant toxicity was found in adult individuals with systemic inhibition. However, inhibition of LPAR3 signaling can produce significant reproductive toxicity, so compounds need to avoid inhibition of LPAR3 signaling.
  • the diseases that have a significant correlation with LPAR1 are mainly fibrotic diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), certain central nervous system diseases and the like.
  • Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology characterized by diffuse alveolitis and alveolar structural disorder. The clinical manifestation is common interstitial pneumonia. IPF originates from the repeated injury of alveolar tissue, and this injury will trigger a series of physiological and pathological events, including (I) disrupting homeostasis; (II) causing 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 extracellular matrix
  • LPA induces endothelial cell barrier dysfunction and vascular leakage, and increases vascular permeability in the early stages of tissue injury repair, which can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated increased vascular permeability promotes fibroblasts development.
  • bleomycin treatment resulted in a significant increase in LPA levels in bronchoalveolar lavage fluid after lung injury and caused pulmonary fibrosis, vascular leakage, and death, which Pathological changes were significantly attenuated in LPAR1 -/- mice; the LPAR1 antagonist AM966 reduced total protein content and LDH activity in alveolar lavage fluid in the bleomycin model, suggesting that AM966 reduces LPA-mediated IPF and other interstitial Vascular leakage and epithelial cell death in acute lung disease.
  • LPAR1 is a promising target for the treatment of IPF, and in a randomized, double-blind, placebo-controlled clinical trial, administration of the LPAR1 antagonist BMS-986020 significantly slowed the decline in lung capacity in patients with idiopathic pulmonary fibrosis , and relieved clinical symptoms, and its second-generation compound BMS-986278 is conducting phase II clinical trials for the treatment of IPF (Swaney JS et al., Br J Pharmacol.2010; 160(7):1699-1713.).
  • LPAR1/LPAR3 antagonist VPC12249 inhibited the expression of the pro-fibroblast cytokines transforming growth factor ⁇ 1 and connective tissue growth factor in vivo, resulting in decreased proliferation of fibroblasts in mice and slower progression of radiation-induced lung fibrosis, suggesting that LPAR1 antagonists are also therapeutically Potential for radiation-induced 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 occurrence of liver fibrosis, which suggests that antagonizing LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol.2017; 66(5):919-929.);
  • down-regulation of LPAR1 signaling decreased the expression of ⁇ -SMA, CTGF and TGF- ⁇ 1, thereby significantly improving thioacetamide-induced liver fibrosis, which further proves that LPAR1 antagonists can be used to treat liver fibrosis change.
  • LPA promotes the progression of renal fibrosis through LPAR1.
  • UUO unilateral ureteral obstruction
  • TIF renal interstitial fibrosis mice
  • ATX and LPA concentrations were elevated, LPAR1 was significantly upregulated, and LPAR3 was significantly downregulated (Sakai N et al., FASEB J. 2013; 27( 5): 1830-1846.).
  • ATX-LPA-LPAR1 signaling can stimulate fibroblast migration and proliferation
  • UUO-induced renal fibrosis was significantly attenuated in LPAR1 -/- mice or after pretreatment with the LPAR1/3 antagonist Ki16425, and when LPAR1 signaling was blocked
  • the expression of pro-fibrotic cytokines was also significantly downregulated when it was disconnected. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.
  • Fetal hydrocephalus is a common neurological disease in newborns, and its occurrence is closely related to LPAR1 signaling.
  • NPC neural progenitor cell
  • LPAR1 neural progenitor cell
  • LPA-LPAR1 signaling has a prominent tumor-promoting effect.
  • LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion, activates vascular endothelial growth factor and metal matrix protease in vitro, and promotes tumor cell resistance to cisplatin.
  • LPA-LPAR1 signaling down-regulates the expression of tumor suppressor p53 in liver cancer cells; LPA activates PI3K and P38MPAK signaling pathways through LPAR1, and promotes the expression of MMP-9 and the invasion of HCC; LPA-LPAR1 can also pass 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 can also promote cancer development , because neovascularization is essential for the development of solid tumors.
  • neuropathic pain a pain state
  • Symptoms include persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia.
  • LPAR1 signaling has been implicated in the development of neuropathic pain. Damage to the nervous system leads to serum leakage at the injury site, exposing a large number of nerve cells to LPA, which may be one of the etiologies of neuropathic pain.
  • LPA Low-power neuropeptidetyline
  • Makoto Inoue et al. have shown that animal models of behavioral abnormalities and pain sensitivity caused by nerve injury can be eliminated by pretreatment of LPAR1 antagonists or targeted deletion of LPAR1, and can be simulated by intrathecal injection of LPA.
  • LPA can induce neuropathic pain by activating LPAR1 and releasing nociceptive factor P, and LPAR1 -/- mice are resistant to neuropathic pain caused by partial sciatic nerve ligation.
  • LPA-LPAR1 signaling plays a key 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 in the synovium of patients with rheumatoid arthritis are increased.
  • Preclinical studies have shown that gene knockout of LPAR1 completely eliminates RA symptoms, and pharmacological antagonism of LPAR1 reduces 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 at solving one of the above technical problems at least to a certain extent or at least providing a useful commercial choice.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs:
  • R 1 is selected from unsubstituted or substituted by R 1a C 3-6 cycloalkyl, unsubstituted or substituted by R 1a 3-6 membered heterocyclic group;
  • the R 1a is selected from -CN, halogen
  • X 1 and X 2 are each independently selected from C(R 1b ) and N, and X 1 and X 2 are not N at the same time, said R 1b is selected from -H, -CN, halogen, -OH, optionally substituted C 1-6 alkyl;
  • R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
  • L 1 is absent, or selected from -N(R 4 )-, -O-, -N(R 4 )-CO-O- and -O-CO-N(R 4 )-;
  • R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
  • R 5 is selected from -H, -F, methyl.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs:
  • R 1 is selected from -H, unsubstituted or substituted by R 1a C 3-6 cycloalkyl, unsubstituted or substituted by R 1a C 3-6 heterocycloalkyl; said R 1a is selected from -CN, halogen ;
  • X 1 and X 2 are each independently selected from C(R 1 ) and N, and X 1 and X 2 are not N at the same time;
  • R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 yuan heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen substituted
  • L 1 is absent, or selected from -N(R 4 )- and -N(R 4 )-CO-O-;
  • R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
  • R is selected from -F, methyl
  • the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine, chlorine, and bromine;
  • the alkyl group includes linear alkyl group and branched chain alkyl group.
  • R 1 when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the number of R 1a is one or more When there are multiple R 1a , the R 1a is the same or different.
  • R 1 when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the R 1a is selected from -CN, fluorine, Chlorine, Bromine, Iodine.
  • the C 3-6 cycloalkyl group is selected from Cyclopropyl, cyclobutyl, cyclopentyl.
  • R 1 is C 3-6 heterocycloalkyl unsubstituted or substituted by R c
  • the C 3-6 heterocycloalkyl The heteroatoms in are selected from O, N, S.
  • R 1 is cyclopropyl unsubstituted or substituted by R 1a , and R 1a is selected from -CN, fluorine, chlorine.
  • R 1 is cyclopropyl
  • R 2 when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more , when there are multiple R 2a , the R 2a are the same or different.
  • R 2 when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more , when there are multiple R 2a , said R 2a is selected from -CN, fluorine, chlorine.
  • the C 1-6 alkyl group is selected from methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
  • R 2 is methyl that is unsubstituted or substituted by R 2a , and the R 2a is selected from -CN, fluorine, and chlorine.
  • R 2 is methyl
  • R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4
  • R 3a When ⁇ 8-membered heterocyclic group, phenyl, C 3-8 bridged cycloalkyl, 5-8-membered heteroaryl group, the number of R 3a is one or more, when there are multiple R 3a , all The above R 3a are the same or different.
  • R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4 ⁇ 8-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group, the number of R 3a is one or more, when there are multiple R 3a , the R 3a is the same or different.
  • R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4
  • R 3a is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, Isopropyl, n-butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.
  • R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4
  • R 3a is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n- Butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.
  • the C 1-6 alkyl is methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
  • the C 3-8 cycloalkyl group is Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • R 3 is a 4-8 membered heterocyclic group unsubstituted or substituted by R 3a
  • the heteroatom is selected from N, O and S
  • the number of heteroatoms is 1-2.
  • the 5-8 membered heteroaryl group is selected from Thiophene, furan, oxazole, thiazole, triazole, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl.
  • R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Phenyl, -CH 2 F, -CHF 2 , -CF 3 , -CHF-CH 3 , -CF 2 -CH 3 .
  • R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Phenyl, -CH 2 F, -CHF 2 , -CF 3 , -CHF-CH 3 , -CF 2 -CH 3 .
  • R 4 when R 4 is a C 1-3 alkyl group or a C 1-3 alkyl group substituted by halogen, the C 1-3 alkyl group is Methyl, ethyl, n-propyl, isopropyl.
  • L 2 does not exist, or is selected from
  • the compound represented by the formula (I) is a compound represented by the formula (I-A):
  • R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
  • L 1 is absent, or selected from -N(R 4 )-, -O-, -N(R 4 )-CO-O- and -O-CO-N(R 4 )-;
  • R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
  • R 5 is selected from -H, -F, methyl.
  • the compound represented by the formula (I) is a compound represented by the formula (I-A):
  • R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl;
  • the R 3a is selected from halogen, C 3-6 cycloalkyl;
  • L 1 is absent, or selected from -N(R 4 )- or -N(R 4 )-CO-O-;
  • R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, preferably, R 2 is selected from methyl;
  • R is selected from -F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, phenyl, pyridyl, cyclopropyl, cyclo butyl,
  • L 1 is absent, or selected from -NH-, -N(CH 3 )-, -O-, -NH-CO-O-, -N(CH 3 )-CO-O-, -O-CO-N (CH 3 )-, -O-CO-NH-;
  • L2 is absent, or selected from
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl, preferably, R 2 is selected from methyl;
  • R is selected from -F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, phenyl, pyridyl, cyclopropyl, cyclobutyl,
  • L 1 does not exist, or is selected from -NH-, -N(CH 3 )-, -NH-CO-O-, -N(CH 3 )-CO-O-;
  • L2 is absent, or selected from
  • -L 1 -L 2 -R 3 is selected from Undefined groups are as described in any previous scheme.
  • -L 1 -L 2 -R 3 is selected from Undefined groups are as described in any previous scheme.
  • the compound represented by the formula (I) is a compound represented by the formula (I-B):
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
  • the compound represented by the formula (I) is a compound represented by the formula (I-B):
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl;
  • the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen substituted C 1-6 alkyl;
  • L 2 is absent, or selected from C 1-3 alkylene unsubstituted or substituted by C 1-3 alkyl.
  • R 3 is selected from -H, -CN, -F, -Cl, the following groups that are unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, phenyl, pyridyl, undefined groups are as described in any previous scheme.
  • R 3 is selected from -H, -CN, -F, -Cl, the following groups that are unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, pyridyl, undefined groups are as described in any previous scheme.
  • -L 2 -R 3 is selected from n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl , fluoro-n-butyl, Undefined groups are as described in any previous scheme.
  • -L 2 -R 3 is selected from n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl , fluoro-n-butyl, Undefined groups are as described in any previous scheme.
  • the compound represented by the formula (I) is a compound represented by the formula (I-C):
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
  • R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
  • the compound represented by the formula (I) is a compound represented by the formula (I-D):
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
  • R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
  • the compound represented by the formula (I) is a compound represented by the formula (I-E):
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
  • the compound represented by the formula (I) is a compound represented by the formula (I-F):
  • R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
  • L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
  • the compound represented by the formula (I) can 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, or solvate of the compound represented by formula (I) , a 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 compound of the compound represented by formula (I) Use of salt or prodrug in preparation of medicine for treating diseases related to LPAR.
  • a method for treating LPAR-related diseases comprising the step of: administering an effective amount of the compound represented by the formula (I) described in the first aspect of the present invention, or the compound represented by the formula (I) to the subject in need Stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compounds shown, or pharmaceutical compositions as described in the second aspect.
  • the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  • the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  • the compound represented by formula (I) described in the first aspect of the present invention or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt of the compound represented by formula (I) Or a prodrug, or a pharmaceutical composition as described in the second aspect, for treating diseases related to LPAR.
  • the pharmaceutical composition is used for treating LPAR-related diseases, and the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  • the pharmaceutical composition is used for treating LPAR-related diseases, and the LPAR-related diseases are selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid Arthritis, fetal hydrocephalus.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes 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 recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers 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 which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • salts are 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 useful in the identification, characterization or purification of compounds of the invention.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • Stereochemical definitions and conventions used in the present invention 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”, John Wiley & Sons, Inc., New York, 1994 to define.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • 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 a compound, where (-) or L indicates that the compound is levorotatory.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
  • Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid.
  • 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 stereomerically pure form (e.g., S and R forms or in diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
  • Resolution of racemic mixtures 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 isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • 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 with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • the term "effective dose”, “effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, 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 Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-d
  • C 3-8 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • 3-6 membered heterocyclyl is understood to mean a saturated, unsaturated or partially saturated monocyclic or bicyclic ring having 3 to 6 atoms, wherein 1, 2, or 3 ring atoms are selected from N, O and S.
  • 4-8 membered heterocyclyl is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 rings The atoms are selected from N, O and S.
  • the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form N-oxide or S-oxide or ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted by acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted by One or more halogen substitutions. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other.
  • heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is monocyclic, it must not be aromatic.
  • heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuryl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 - dioxoimidazolidinyl.
  • 5-8 membered heteroaryl is understood as having 5-8 ring atoms - especially 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 Preferably 1 to 3 - monovalent monocyclic, bicyclic or tricyclic aromatic ring radicals of heteroatoms independently selected from N, O and S, and, additionally, in each case may be benzofused .
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridyl, pteridine carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
  • bridged ring refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly connected, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc.
  • Non-limiting examples include:
  • C 4-8 bridged cycloalkyl refers to a bridged ring with 4-8 carbon atoms, and the definition of the bridged ring is as described above.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • the compound represented by formula (I) of the present invention has a good antagonistic effect on LPAR1.
  • the compound of the present invention has a good antagonistic effect on LPAR1 and 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 the release of histamine induced by LPA by antagonizing LPAR1, and at the same time significantly improve the symptoms of pulmonary fibrosis induced by bleomycin in mice and rats .
  • the embodiment of the present invention provides the compound shown in formula (I), its pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, co-crystal or prodrug, preparation formula (I) ) or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs and intermediates, pharmaceutical compositions, and compounds of the present invention and the use of the pharmaceutical composition in the preparation of medicaments.
  • 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.
  • many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are considered to be within the scope of the present invention.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • Liquid-mass spectrometry was determined by Waters Acquity H-class Uplc-QDA mass spectrometer and monitored by ACQUITY UPLC BEH C18, 2.1*50mm, 1.7 ⁇ m chromatographic column. Gradient elution conditions: at a 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 percentage of the solute in the solution.
  • IC 50 half inhibitory concentration, which 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
  • DIPEA It 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 WO2017223016A1.
  • Comparative Example 2 Comparative Compound 2 and its preparation
  • Reference compound 2 was synthesized with reference to patent application WO2017223016A1.
  • Embodiment 1 the preparation of target compound I-1
  • the synthetic route of target compound 1-1 is as follows:
  • the first step the synthesis of (R)-4-nitrophenyl (1-phenylethyl) carbonate (I-1B)
  • 2-bromo-6-iodopyridin-3-ol (5g, 16.67mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (2.34g, 16.67mmol), cuprous iodide (317.53mg, 1.67mmol), triethylamine (5.06g, 50.02mmol) and bis(triphenylphosphine)palladium dichloride (1.17g, 1.67mmol) were added to tetrahydrofuran (50mL ), react at room temperature for 1 hour under the protection of nitrogen.
  • the seventh step (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-methyl carboxylate (I-1I) synthesis
  • Step 10 (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino) Synthesis of methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1L)
  • Embodiment 2 the preparation of target compound 1-2
  • the pH of the reaction solution was adjusted to 3-4 with 1M hydrochloric acid at 0-10°C, extracted with dichloromethane (15 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
  • Embodiment 3 the preparation of target compound 1-3
  • the first step the synthesis of (cyclobutylmethyl) tert-butyl carbamate (I-3B)
  • the second step the synthesis of (cyclobutylmethyl) (methyl) tert-butyl carbamate (I-3C)
  • the third step the synthesis of 1-cyclobutyl-N-methylmethylamine hydrochloride (I-3D)
  • Embodiment 4 the preparation of target compound 1-4
  • the first step the synthesis of (R)-(1-cyclopropylethyl) tert-butyl carbamate (I-4B)
  • the second step the synthesis of (R)-(1-cyclopropylethyl) (methyl) tert-butyl carbamate (I-4C)
  • the third step the synthesis of (R)-1-cyclopropyl-N-methylethane-1-amine hydrochloride (I-4D)
  • Embodiment 5 the preparation of target compound 1-5
  • the synthetic route of target compound 1-5 is as follows:
  • Embodiment 6 the preparation of target compound 1-6
  • the first step the synthesis of 4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate (I-6B)
  • the second step the synthesis of tert-butyl (4-fluorobutyl)(methyl)carbamate (I-6C)
  • the third step the synthesis of 4-fluoro-N-methylbutan-1-amine hydrochloride (I-6D)
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Embodiment 7 the preparation of target compound 1-7
  • the synthetic route of target compound 1-7 is as follows:
  • Embodiment 8 the preparation of target compound 1-8
  • the synthetic route of target compound 1-8 is as follows:
  • the first step the synthesis of (S)-(2-methylbutyl) tert-butyl carbamate (I-8B)
  • the second step the synthesis of (S)-(2-methylbutyl) tert-butyl carbamate (I-8C)
  • Embodiment 9 Preparation of target compound 1-9
  • the first step the synthesis of (4-nitrophenyl) butyl carbonate (I-9B)
  • Embodiment 10 Preparation of target compound I-10
  • the synthetic route of target compound 1-10 is as follows:
  • the first step the synthesis of 4-fluorobutyl carbonate (4-nitrophenyl) (I-10B)
  • Embodiment 11 Preparation of target compound I-11
  • Embodiment 12 Preparation of target compound 1-12
  • the synthetic route of target compound 1-12 is as follows:
  • Embodiment 13 Preparation of target compound 1-13
  • the synthetic route of target compound 1-13 is as follows:
  • the first step (1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)- 1-Methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-13B) synthesis
  • Embodiment 14 Preparation of Target Compound I-14
  • the synthetic route of target compound 1-14 is as follows:
  • the first step the synthesis of (S)-4-nitrophenyl carbonate pent-2-yl ester (I-14B)
  • Embodiment 15 Preparation of target compound I-15
  • the synthetic route of target compound 1-15 is as follows:
  • the first step 2-cyclobutyl-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-(((trimethylsilyl)methyl Synthesis of -1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-15B)
  • bromocyclobutane (1.00 g, 7.41 mmol) was added to a solution of elemental magnesium (360 mg, 14.8 mmol) in tetrahydrofuran (15.0 mL), and the reaction was stirred at 60°C for 3 hours.
  • the seventh step (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-cyclobutylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-15)
  • Embodiment 16 Preparation of Target Compound I-16
  • the synthetic route of target compound 1-16 is as follows:
  • Embodiment 17 Preparation of Target Compound I-17
  • the synthetic route of target compound 1-17 is as follows:
  • Embodiment 18 Preparation of target compound I-18
  • the synthetic route of target compound 1-18 is as follows:
  • Embodiment 19 Preparation of Target Compound I-19
  • the synthetic route of target compound 1-19 is as follows:
  • Embodiment 20 Preparation of Target Compound I-20
  • the synthetic route of target compound 1-20 is as follows:
  • the first step 2-(oxyethane-3-yl)-6-(5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilane Base)methyl)-1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-20A) synthesis
  • the second step 6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl )-2-(oxyl-3-yl)pyridin-3-ol (I-20B) synthesis
  • the seventh step (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)
  • Embodiment 21 Preparation of target compound I-21
  • the first step the synthesis of N-cyanocyclopropanamide (I-21B)
  • the second step the synthesis of 5-cyclopropyl-1,2,4-oxadiazol-3-amine (I-21C)
  • Embodiment 22 Preparation of Target Compound I-22
  • the first step the synthesis of (E)-4-ethoxy-1,1-difluorobut-3-en-2-one (I-22B)
  • Embodiment 23 Preparation of Target Compound I-23
  • the target compound I-23 can be synthesized with reference to compound I-18, replacing 3,3,3-trifluoro-N-methylpropan-1-amine with N-isopropylmethylamine.
  • Embodiment 24 Preparation of target compound I-24
  • the synthetic route of target compound 1-24 is as follows:
  • the first step Synthesis of 3-(1,3-dioxylideneisoindolin-2-yl)propionaldehyde (I-24B)
  • the second step Synthesis of 2-(3,3-difluoropropyl)isoindoline-1,3-dione (I-24C)
  • the third step the synthesis of tert-butyl (3,3-difluoropropyl) aminomethyl ester (I-24D)
  • the fourth step the synthesis of tert-butyl (3,3-difluoropropyl) (methyl) aminomethyl ester (I-24E)
  • the seventh step (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24)
  • Embodiment 25 Preparation of Target Compound I-25
  • the synthetic route of target compound 1-25 is as follows:
  • Embodiment 26 Preparation of Target Compound I-26
  • the first step the synthesis of N-vinyl-N-methylcarbamate tert-butyl ester (I-26B)
  • the second step the synthesis of tert-butyl N-(2,2-difluorocyclopropyl)-N-methylcarbamate (I-26D)
  • the third step the synthesis of 2,2-difluoro-N-methylcyclopropane-1-amine hydrochloride (I-26E)
  • Embodiment 27 Preparation of Target Compound I-27
  • the first step the synthesis of N-benzyl-3-fluoro-N-methylpropane-1-amine (compound I-27C)
  • Embodiment 28 Preparation of target compound I-28
  • the first step the synthesis of 1-(benzyl(methyl)amino)propan-2-ol (I-28B)
  • the second step the synthesis of N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C)
  • the third step the synthesis of 2-fluoro-N-methylpropane-1-amine hydrochloride (I-28D)
  • Embodiment 29 Preparation of Target Compound I-29

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Abstract

L'invention concerne un composé antagonisant efficacement le LPAR1. Ce 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/CN2022/139166 2021-12-15 2022-12-15 Antagoniste de lpar1 triazaspiro et son utilisation WO2023109878A1 (fr)

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CN117024409A (zh) * 2023-10-10 2023-11-10 药康众拓(北京)医药科技有限公司 氘代lpa1抑制剂化合物及其用途

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CN109963843A (zh) * 2016-06-21 2019-07-02 百时美施贵宝公司 作为lpa拮抗剂的氨甲酰基氧甲基三唑环己基酸
WO2020147739A1 (fr) * 2019-01-15 2020-07-23 武汉朗来科技发展有限公司 Antagonistes du récepteur de l'acide lysophosphatidique et procédé de préparation associé
WO2022100624A1 (fr) * 2020-11-10 2022-05-19 武汉人福创新药物研发中心有限公司 Composé à base de thiophène aminocarbonate oxy-substitué et son utilisation
WO2022100625A1 (fr) * 2020-11-10 2022-05-19 武汉人福创新药物研发中心有限公司 Composé aminocarbonate thiophène substitué par azote et son utilisation
WO2022100623A1 (fr) * 2020-11-10 2022-05-19 武汉人福创新药物研发中心有限公司 Composés thiophène hétérocycliques substitués par azote et leur utilisation
WO2022232459A1 (fr) * 2021-04-30 2022-11-03 Viva Star Biosciences (Suzhou) Co., Ltd. Nouveaux composés d'acide pyrrolidinyl et tétrahydro-2 h-pyranyl acétique à substitution par triazole-pyridine utilisés en tant qu'antagonistes de lpa

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Publication number Priority date Publication date Assignee Title
CN109963843A (zh) * 2016-06-21 2019-07-02 百时美施贵宝公司 作为lpa拮抗剂的氨甲酰基氧甲基三唑环己基酸
WO2020147739A1 (fr) * 2019-01-15 2020-07-23 武汉朗来科技发展有限公司 Antagonistes du récepteur de l'acide lysophosphatidique et procédé de préparation associé
WO2022100624A1 (fr) * 2020-11-10 2022-05-19 武汉人福创新药物研发中心有限公司 Composé à base de thiophène aminocarbonate oxy-substitué et son utilisation
WO2022100625A1 (fr) * 2020-11-10 2022-05-19 武汉人福创新药物研发中心有限公司 Composé aminocarbonate thiophène substitué par azote et son utilisation
WO2022100623A1 (fr) * 2020-11-10 2022-05-19 武汉人福创新药物研发中心有限公司 Composés thiophène hétérocycliques substitués par azote et leur utilisation
WO2022232459A1 (fr) * 2021-04-30 2022-11-03 Viva Star Biosciences (Suzhou) Co., Ltd. Nouveaux composés d'acide pyrrolidinyl et tétrahydro-2 h-pyranyl acétique à substitution par triazole-pyridine utilisés en tant qu'antagonistes de lpa

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117024409A (zh) * 2023-10-10 2023-11-10 药康众拓(北京)医药科技有限公司 氘代lpa1抑制剂化合物及其用途

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