WO2022100623A1 - Nitrogen-substituted heterocyclic thiophene compounds and use thereof - Google Patents

Nitrogen-substituted heterocyclic thiophene compounds and use thereof Download PDF

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WO2022100623A1
WO2022100623A1 PCT/CN2021/129863 CN2021129863W WO2022100623A1 WO 2022100623 A1 WO2022100623 A1 WO 2022100623A1 CN 2021129863 W CN2021129863 W CN 2021129863W WO 2022100623 A1 WO2022100623 A1 WO 2022100623A1
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och
methyl
alkyl
substituted
halogen
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张学军
常少华
雷四军
丁肖华
陈浩民
井真中
杨成兵
刘礼飞
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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    • 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
    • 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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • 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
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • 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
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention belongs to the field of medicinal chemistry, in particular, the present invention relates to nitrogen-substituted heterocyclic thiophenes, more particularly, the present invention relates to nitrogen-substituted heterocyclic 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., Worldjournal 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), certain central diseases and the like.
  • Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology characterized by diffuse alveolitis and alveolar structural disorders. The main manifestation is common interstitial pneumonia. IPF originates from repeated damage to the tissue of alveolar tissue, and this damage triggers a series of physiopathological events, including (I) disruption of homeostasis; (II) inflammatory response; (III) cell proliferation, migration and differentiation; ( IV) matrix and tissue remodeling; and (V) wound contracture and scarring, many of these events are controlled by the coordinated release of biochemical factors at and around the injury site, in which LPA plays an important role.
  • LPA extracellular matrix
  • LPA induces endothelial cell barrier dysfunction and vascular leakage.
  • increased vascular permeability can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated increased vascular permeability promotes fibrosis development.
  • bleomycin treatment resulted in a marked increase in LPA levels in bronchoalveolar lavage fluid following lung injury and caused pulmonary fibrosis, vascular leakage, and death, which Pathological changes were significantly attenuated in LPAR1 -/- mice; LPAR1 antagonist AM966 reduced total protein content and LDH activity in bronchoalveolar lavage fluid in a bleomycin model, suggesting that AM966 reduces LPA-mediated IPF and other interstitial Vascular leakage and epithelial cell death in sexual lung disease.
  • LPAR1 is a promising target for the treatment of IPF
  • BMS-986278 is undergoing Phase II clinical trials for the treatment of IPF (Swaney JS et al., Br J Pharmacol. 2010; 160(7): 1699-1713.).
  • Radiation pulmonary fibrosis is a common and serious complication of radiation therapy for lung cancer.
  • the LPAR1/LPAR3 antagonist VPC12249 inhibited the expression of the pro-fibrocytokines transforming growth factor ⁇ 1 and connective tissue growth factor in vivo, resulting in decreased fibroblast proliferation in mice and slowing the progression of radiation-induced pulmonary fibrosis, suggesting that LPAR1 antagonists are also therapeutic Potential for radiation pulmonary fibrosis (Xiang H et al, 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.
  • LPA-LPAR1 signaling plays a critical role in the initiation of neuropathic pain and that LPAR1 antagonists may hold promise as analgesics for the treatment of neuropathic pain (Inoue M et al., ERRATUM: Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling[J]. 2004, 10(7):755-755.).
  • Rheumatoid arthritis is a chronic autoimmune disease
  • LPAR1 signaling is related to the occurrence of RA.
  • LPAR1 and/or LPAR2 expression levels are increased in the synovium of patients with rheumatoid arthritis
  • preclinical studies have shown that gene knockout of LPAR1 completely abolished RA symptoms, and pharmacological antagonism of LPAR1 reduced the severity of the disease. Severity, inflammation and bone erosion were reduced (Kaffe E et al. Cancers(Basel). 2019; 11(11):1626. Published 2019 Oct 23.doi:10.3390/cancers11111626).
  • Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and sensitizes them to tumor necrosis factor (TNF)-mediated apoptosis, and LPA is also involved in interleukin (IL)- 6. Production of IL-8 and cyclooxygenase-2 (COX-2). These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals of the Rheumatic Diseases, 2014, 73(1):298-305.).
  • the present invention aims to at least to some extent solve one of the above technical problems or at least provide a useful business option.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):
  • R 1 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), -ZR a , C 1-6 alkyl unsubstituted or substituted by R b ⁇ the "C 1- 6 alkyl" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R b is one or more ( The number is subject to the substituted group conforming to the valence bond theory and stable existence.
  • halogen such as fluorine, chlorine, bromine or iodine
  • R b when there are multiple R b , the R b is the same or different ⁇ , unsubstituted or C 3-6 cycloalkyl substituted by R b (the "C 3-6 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or C 1 substituted by R b -6 alkylamino (the "C 1-6 alkylamino" such as wherein m1 and m2 are each independently selected from integers from 0 to 6, the sum of m1 and m2 does not exceed 6, and/or m1 and m2 are not both zero), 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 a single bond, -O-, -S- or -CO-;
  • 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 (e.g. 1, 2 or 3), when multiple halogens are present, the halogens are the same or different ⁇ , amino (eg -NH 2 ), C 1-3 alkylamino (eg );
  • 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 zero), unsubstituted or substituted 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);
  • Y is selected from a single bond, -O- or -S-;
  • R d is selected from C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1 substituted by halogen -6 alkyl
  • halogen is such as fluorine, chlorine, bromine or iodine
  • the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different ⁇ ;
  • R e is selected from -CN, halogen (eg fluorine, chlorine, bromine or iodine), C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) butyl, pentyl, hexyl), C 1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy, hexyloxy);
  • X 1 , X 2 , and X 3 are independently selected from C or N, and X 1 , X 2 , and X 3 are not N at the same time;
  • R g is selected from H, F, Cl, methyl
  • L 1 is selected from a single bond, -N(R 3 )- or -O-;
  • L 2 is selected from single bond, -O-, unsubstituted C 1-6 alkylene (for example ), C 1-6 alkylene substituted by C 1-3 alkyl (such as ), unsubstituted or cyclopropyl substituted by C 1-3 alkyl;
  • R 3 is selected from -H, C 1-3 alkyl (eg methyl, ethyl, propyl);
  • R 4 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), unsubstituted or substituted C 1-6 alkyl ⁇ 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 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 h when there are multiple R h , the R h is the same or different ⁇ , unsubstituted or substituted by R h C 3-8 cycloalkyl (the "C 3-6 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl);
  • R is selected from -H, halogen (eg fluorine, chlorine, bromine, iodine), C 1-6 alkyl (eg methyl, ethyl, n -propyl, isopropyl, n-butyl, n-pentyl), C1-6 alkyl substituted with halogen (eg trifluoromethyl), C1-6 alkoxy substituted with halogen (eg difluoromethoxy).
  • halogen eg fluorine, chlorine, bromine, iodine
  • C 1-6 alkyl eg methyl, ethyl, n -propyl, isopropyl, n-butyl, n-pentyl
  • C1-6 alkyl substituted with halogen eg trifluoromethyl
  • C1-6 alkoxy substituted with halogen eg difluoromethoxy
  • 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 -CO-NH 2 , -CO- NH- CH3 , -CO-N( CH3 ) 2 , -CO-NH- CH2 - CH3 , -CO-N( CH3 )( CH2CH3 ) ;
  • 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 or methyl.
  • R 4 is selected from methyl, ethyl, isopropyl , n-butyl.
  • R 4 is selected from cyclopropyl, cyclobutyl, cyclopropyl amyl.
  • R 4 is selected from -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -(CH 2 ) 2 Cl, -( CH2 )3Cl, -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, -CO- NH2 , -CO-NH- CH3 , -CO-N( CH3 ) 2 .
  • R 2 is selected from -H, -F, -Cl, -CH3 .
  • L 1 is selected from a single bond, -NH- or -O -.
  • R 4 is selected from -H, -F, methyl, Ethyl, isopropyl, cyclopropyl, n-butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
  • R 2 is selected from -H, -F, -Cl, -CH 3 ; selected from L 1 is selected from single bond, -NH- or -O-; L 2 is selected from single bond, -O-, R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
  • R 1 is methyl
  • R 2 is selected from halogen
  • selected from L 1 is selected from single bond, -NH- or -O-
  • L 2 is selected from single bond, -O-
  • R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F ;
  • R 1 is selected from methyl, -CO-NH 2 ;
  • R 2 is selected from -F, -Cl;
  • selected from L 1 is selected from -NH- or -O-;
  • L 2 is selected from -O-,
  • R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
  • 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), -CO-NH 2 -, -CO,
  • 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 g is selected from H, F, Cl, methyl
  • L 1 is selected from a single bond, -N(R 3 )- or -O-;
  • L 2 is selected from single bond, -O-, unsubstituted or C 1-6 alkylene substituted by C 1-3 alkyl;
  • R 3 is selected from H, C 1-3 alkyl
  • R 4 is selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -( CH 2 ) 2 Cl, -(CH 2 ) 3 Cl, -CH(CH 3 )(CH 2 Cl),
  • 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), -CO-NH 2 -, -CO,
  • 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),
  • 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, solvate, pharmaceutically acceptable salt or prodrug.
  • the compound represented by the formula (I), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) may be in a therapeutically effective dose.
  • the present invention also provides a compound represented by the above formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) in the preparation of therapeutic and Use in medicine for LPAR-related diseases.
  • the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  • said LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal brain volume water.
  • the present invention also provides a method of treating or preventing LPAR-related diseases.
  • the method comprises administering to the patient a pharmaceutically acceptable dose of the aforementioned compound, or the aforementioned pharmaceutical composition.
  • the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  • the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus .
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
  • a number from 1 to 10 should be understood as not only reciting each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also reciting at least that each integer is respectively associated with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • stereoisomers refers to isomers resulting from different arrangements of atoms in a molecule in space, including 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”, as 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, 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 compounds of the present invention have excellent pharmacokinetic properties and good druggability; the compounds of the present invention can significantly inhibit LPA-induced histamine release by antagonizing LPAR1, and at the same time significantly improve the symptoms of bleomycin-induced pulmonary fibrosis in mice.
  • the embodiments of the present invention provide compounds represented by formula (I), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs thereof, to prepare formula (I) ) of the compound or its pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs, methods and intermediates, pharmaceutical compositions, and compounds of the present invention and the use of the pharmaceutical composition in the preparation of medicine.
  • reaction solvent used in each reaction step of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention.
  • equivalent replacements, or equivalents to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • Liquid-mass spectrometry was determined by a Waters Acquity H-class Uplc-QDA mass spectrometer, monitored using an ACQUITY UPLC BEH C18, 2.1*50mm, 1.7 ⁇ m chromatographic column. Gradient elution conditions: flow rate of 1.0mL/min, 95-5% solvent A1 and 5-95% solvent B1, then 95% B1 and 5% A1 for 0.5min, the percentage is the volume percentage of a certain solvent in the total solvent volume . Wherein solvent A1: 0.1% formic acid in water; solvent B1: 0.1% formic acid in acetonitrile. The percentage is the volume percent of the solute in the solution.
  • IC 50 half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
  • M mol/L
  • N equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • PE petroleum ether
  • Comparative Example 1 Comparative Compound 1 and its preparation
  • Reference compound 1 was synthesized with reference to patent application WO2010141768A2.
  • Comparative Example 2 Comparative Compound 2 and its preparation
  • Reference compound 2 was synthesized with reference to patent application WO2017223016A1.
  • Comparative Example 3 Comparative Compound 3 and its preparation
  • Reference compound 3 was synthesized with reference to patent application WO2017223016A1.
  • Comparative Example 4 Comparative Compound 4 and its preparation
  • Control compound 4 was synthesized with reference to patent application WO2019126098A1.
  • Comparative Example 5 Comparative Compound 5 and its preparation
  • Reference compound 5 was synthesized with reference to patent application WO2019126084A1.
  • reaction solution was filtered through celite, concentrated, the residue was dissolved in methyl tert-butyl ether (100 mL), washed once with saturated sodium bicarbonate, once with saturated sodium sulfite, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid (1S,5R)-6-oxacyclo[3.2.1]octan-7-one (A-3) (3.88 g, 58.7% yield).
  • the first step the synthesis of 2-bromo-4-methylpyrimidin-5-ol (I-1B)
  • the second step the synthesis of methyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-1C) methyl( 1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1C)
  • Step 5 (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)- Synthesis of methyl 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-1F)
  • Step 6 (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)- Synthesis of 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-1)
  • the synthetic route of the target compound I-2 is as follows:
  • reaction solution was quenched with water (1 mL), and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was passed through a column to obtain compound (1S,3S)-3-((6-(5-chloro-3-((((4-isopropylpyrimidine- 2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2D) (0.26 g, yield 99.73%).
  • the synthetic route of the target compound I-3 is as follows:
  • the first step Synthesis of (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (I-3B)
  • reaction solution was extracted with ethyl acetate (20 mL ⁇ 2), and the organic layers were combined to obtain the compound 3-cyclopropylprop-1-ynyl(trimethyl)silane (I-3B) (1 g, yield 88.64%) . used directly in the next step.
  • reaction solution was extracted with ethyl acetate (10 mL ⁇ 2), and the organic layers were combined to obtain compound (1S,3S)-3-((6-(3-(azidomethyl)-5-chlorothiophen-2-yl) )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3D) (0.2 g, 94.37% yield).
  • the synthetic route of the target compound I-4 is as follows:
  • the synthetic route of the target compound I-6 is as follows:
  • the first step the synthesis of 4-isopropylpyrimidin-2-amine (I-6B)
  • the synthetic route of the target compound I-7 is as follows:
  • the synthetic route of the target compound I-8 is as follows:
  • the synthetic route of the target compound I-9 is as follows:
  • 2,2,2-Trifluoro-1-ol (1.158 g, 11.58 mmol) was added to 10 mL of tetrahydrofuran, sodium hydrogen (0.278 g, 11.58 mmol) was added at 0°C, and after stirring for 30 minutes, 4-chloropyrimidine was added -2-amine (1 g, 7.72 mmol), stirred at 70°C for 12 hours.
  • the synthetic route of the target compound I-11 is as follows:
  • the synthetic route of the target compound I-12 is as follows:
  • the first step Synthesis of 2-bromo-5-fluorothiophene-3-carbaldehyde (I-12B)
  • the first step Synthesis of (N-((2-bromo-5-fluorothiophen-3-yl)methyl)-4-isopropylpyrimidin-2-amine (I-13B)
  • Step 2 (1S,3S)-methyl 3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl) Synthesis of -2-methylpyridin-3-yloxy)cyclohexanecarboxylate (I-13C)
  • the synthetic route of the target compound I-15 is as follows:
  • the second step the synthesis of (1S,3S)-3-((2,4-dichloropyrimidin-5-yl)oxy) cyclohexanecarboxylic acid methyl ester (I-15C)
  • the third step the synthesis of (1S,3S)-3-((2-chloro-4-cyanopyrimidin-5-yl)oxy) cyclohexanecarboxylic acid methyl ester (I-15D)
  • Methyl (1S,3S)-3-((2-chloro-4-cyanopyrimidin-5-yl)oxy)cyclohexanecarboxylate 400 mg, 1.35 mmol
  • (3-formylthiophene-2 -yl)boronic acid 316.45 mg, 2.03 mmol
  • potassium fluoride 471.50 mg, 8.12 mmol
  • tetrahydrofuran 3 mL
  • bis(tri-tert-butylphosphine)palladium 69.13 mg, 135.26 ⁇ mol
  • the seventh step (1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazole- Synthesis of 3-yl)amino)methyl)thiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound 1-15).
  • the synthetic route of the target compound I-16 is as follows:
  • Step 2 (1S,3S)-methyl 3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl) Synthesis of -4-methylpyrimidin-5-yloxy)cyclohexanecarboxylate (I-16B)
  • the target compound I-17 was synthesized with reference to compound I-13, except that 4-isopropylpyrimidin-2-amine was replaced by 1-(cyclopropylmethyl)-1,4-dihydro-5H-tetrazole -5-keto.
  • the target compound I-18 was synthesized with reference to compound I-11, except that 5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-amine was replaced by 5-butyl-1,2,4 - oxadiazol-3-amine.
  • the target compound I-19 was synthesized with reference to compound I-8, except that 2,2-difluoroethanol was replaced by 3-fluoro-1-propanol.
  • Test Example 1 LPAR1 In Vitro Calcium Flux Assay
  • the antagonism of compounds on LPAR1 was determined in a CHO cell line stably expressing human LPAR1. 18 hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 ⁇ L of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours 20 ⁇ L/well of dye solution was added to each well of cells, placed back in a 37°C incubator for 30 min in the dark, and then incubated at room temperature for 10 min in the dark. Add 10 ⁇ L/well of compounds of different final concentrations into the cells, and equilibrate.
  • test compound IC50 (nM) Control compound 1 117.9 Control compound 2 243.8 Control compound 3 251.6 Control compound 4 243.3 Control compound 5 109.5 I-1 93.63 I-2 27.82 I-3 33.92 I-4 69.2 I-5 39.75 I-6 46.32 I-7 1697 I-8 82.06 I-9 47.49 I-10 288.1 I-11 35.18 I-12 11.29 I-13 22.16 I-14 49.29 I-16 91.3
  • the results of the LPAR1 calcium flux test showed that the compounds of the present invention had a good antagonistic effect on LPAR1. Compared with the control compounds, most of the inventive compounds showed more excellent antagonistic effects on LPAR1.
  • Test Example 2 LPAR3 In Vitro Calcium Flux Assay
  • the antagonism of compounds on LPAR3 was determined in a CHO cell line stably expressing human LPAR3. Eighteen hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 ⁇ L of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours. 20 ⁇ L/well of dye solution was added to each well of cells, placed back in a 37°C incubator for 30 min in the dark, then incubated at room temperature for 10 min in the dark, and 10 ⁇ L/well of different final concentrations of compounds were added to the cells and equilibrated.
  • the results of the LPAR3 calcium flux assay showed that the compounds of the present invention had a weak antagonistic effect on LPAR3, and compared with the control compounds, the compounds of the present invention showed better selective inhibition of LPAR1.
  • Test Example 3 Test test for the inhibitory effect of compounds on bile efflux transporters
  • NC negative control
  • PC positive control
  • the assay was terminated with pre-chilled Buffer B1 (10 ⁇ Buffer B1 (Stopping and Washing Buffer): 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose). Transfer the test sample to a 96-well filter plate, filter it with a vacuum pump, and then repeatedly wash it with 0.2 mL of pre-cooled Buffer B1 for 5 times, dissolve the vesicles on the filter plate with 50 ⁇ L of 80% methanol, and centrifuge at 2000 rpm for 2 minutes after collection. The filtrate was collected and repeated once. The two filtrates were combined and mixed to obtain about 100 ⁇ L of the filtrate.
  • Buffer B1 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose.
  • mice pharmacokinetic test show that, compared with the control compound, the compound of the present invention exhibits better pharmacokinetic properties and better drug-forming properties.
  • LPA-induced mouse histamine release assays were performed with 20-25 g female Balb/c mice. Compounds and positive control groups were set up in three administration groups, each group of 6 mice, orally administered 1, 3, 10mpk, respectively, blank group and negative control group were given the same volume of vehicle (5% DMSO + 5% Solutol+90%Saline). After 2 hours of administration, mice in each administration group were injected with 300 ⁇ g/mouse LPA through the tail vein, while the blank group and the negative control group were injected with an equal volume of vehicle (4 mg/ml BSA/PBS) through the tail vein.
  • vehicle 5% DMSO + 5% Solutol+90%Saline
  • the samples were stored at 2-8 degrees, centrifuged at 5000 rpm for 5 min within 20 min, and the plasma was collected, and the histamine concentration in the plasma was detected using the HTRF kit (Cisbio, 62HTMDPEG).
  • the inhibition rates of different concentrations of compounds on LPA-induced histamine release were calculated using the histamine concentration data in plasma.
  • Test Example 6 Efficacy test of bleomycin-induced pulmonary fibrosis
  • mice were reared adaptively for 1 week, and after reaching the target body weight, they were randomly divided into the control group, the model group and the administration group according to the body weight of the animals.
  • the model group and the administration group were evenly given 50 ⁇ L of bleomycin in the lungs to establish a mouse pulmonary fibrosis model, while the control group was evenly given 50 ⁇ L of normal saline in the lungs;
  • the animals were deeply anesthetized with sodium pentobarbital, and the bronchoalveolar lavage fluid (BALF) was collected and temporarily stored in a wet ice box for subsequent index detection; some animal lungs were placed in 10% neutral fortification.
  • BALF bronchoalveolar lavage fluid

Abstract

Disclosed is a new class of compounds that effectively antagonize LPAR, which are compounds represented by the following formula, or a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compounds represented by the following formula:

Description

氮取代杂环噻吩类化合物及其用途Nitrogen-substituted heterocyclic thiophenes and their uses
优先权信息priority information
本申请请求2020年11月10日向中国国家知识产权局提交的、专利申请号为202011248266.X的专利申请的优先权和权益，并且通过参照将其全文并入此处。This application claims priority to and the benefit of the patent application No. 202011248266.X filed with the State Intellectual Property Office of China on November 10, 2020, which is hereby incorporated by reference in its entirety.
技术领域technical field
本发明属于药物化学领域，具体地，本发明涉及氮取代杂环噻吩类化合物，更具体地，本发明涉及氮取代杂环噻吩类化合物及其在制备药物中的用途。The present invention belongs to the field of medicinal chemistry, in particular, the present invention relates to nitrogen-substituted heterocyclic thiophenes, more particularly, the present invention relates to nitrogen-substituted heterocyclic thiophenes and their use in preparing medicines.
背景技术Background technique
溶血磷脂酸(LPA)是一类分子量为430-480Da的关键内源性脂质信号分子，其广泛存在于人体各组织中的胞内和胞外，如各种体液，唾液、尿液、脑脊液、血液、支气管肺泡灌洗液(BALF)等(Kaffe E等人，Cancers(Basel).2019；11(11):1626.)。LPA主要是以膜磷脂为原料通过以下两条途径产生的：(1)磷脂酶D(PLD)-磷脂酶A2(PLA2)途径；(2)PLA2-溶血磷脂酶D(LysoPLD)途径。Enpp2基因编码的自体趋化蛋白(ATX)是一种焦磷酸酶/磷酸二酯酶，其具有溶血磷脂酶D(LysoPLD)活性，能将胞外溶血磷脂酰胆碱(LPC)水解成相应的LPA和游离胆碱(Choi JW等人，AnnuRevPharmacolToxicol.2010；50:157186.)，这一反应是LPA的主要来源，抑制ATX活性能抑制全身80％以上LPA的产生(Kaffe E等人，Cancers(Basel).2019；11(11):1626.)。Lysophosphatidic acid (LPA) is a key endogenous lipid signaling molecule with a molecular weight of 430-480Da, which is widely present in various tissues of the human body intracellular and extracellular, such as various body fluids, saliva, urine, cerebrospinal fluid , blood, bronchoalveolar lavage fluid (BALF), etc. (Kaffe E et al. Cancers(Basel). 2019;11(11):1626.). LPA is mainly produced from membrane phospholipids through the following two pathways: (1) phospholipase D (PLD)-phospholipase A2 (PLA2) pathway; (2) PLA2-lysophospholipase D (LysoPLD) pathway. Autochemotactic protein (ATX) encoded by Enpp2 gene is a pyrophosphatase/phosphodiesterase, which has lysophospholipase D (LysoPLD) activity and can hydrolyze extracellular lysophosphatidylcholine (LPC) into the corresponding LPA and free choline (Choi JW et al., AnnuRev Pharmacol Toxicol. 2010;50:157186.), this response is the main source of LPA, and inhibition of ATX activity can inhibit LPA production in the body by more than 80% (Kaffe E et al. Cancers ( Basel). 2019;11(11):1626.).
LPA通过与G蛋白偶联受体作用介导多种功能，包括细胞存活、细胞增殖、细胞粘附、细胞迁移、细胞骨架改变、钙动员、增加血管通透性和血管形成、免疫功能和髓鞘形成等。LPA可与六种溶血磷脂酸受体(LPAR)结合并发挥功能，分别为：LPAR1-LPAR6。LPA通过与6种LPAR结合调节多种生理/病理过程，包括血管和神经发育、毛囊发育、淋巴细胞转运、骨发育、纤维化、脂肪量调节、胆汁淤积性瘙痒、神经性疼痛、胚胎植入、肥胖和葡萄糖稳态、***产生、慢性炎症、细胞增殖、细胞趋化、伤口愈合、肿瘤进展、胎儿脑积水等(FangYang等人，Worldjournal of gastroenterology,2018,24(36):4132.)。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., Worldjournal of gastroenterology, 2018, 24(36):4132.) .
LPAR1是最早被鉴定和分布最广的LPA受体，其是一个41kDa的膜蛋白，由364个氨基酸组成，在人体各组织器官中广泛表达，其中脑、心、结肠、小肠和胎盘的mRNA水平较高，而在其他器官和组织中的mRNA水平相对较低。LPAR1通过与GαI/o、GαQ/11 和Gα12/13偶联，激活Akt、Rho、丝裂原活化蛋白激酶和磷脂酶C等下游通路，虽然已证明LPA-LPAR1信号在神经***的发育阶段有重要作用，但成年个体的全身抑制未发现明显毒性。但LPAR3信号被抑制会产生显著的生殖毒性，因此化合物需避免对LPAR3信号的抑制。LPAR1 is the earliest identified and most widely distributed LPA receptor. It is a 41kDa membrane protein composed of 364 amino acids. It is widely expressed in various tissues and organs of the human body, among which the mRNA levels of brain, heart, colon, small intestine and placenta are high, while mRNA levels in other organs and tissues were relatively low. LPAR1 activates downstream pathways such as Akt, Rho, mitogen-activated protein kinase, and phospholipase C by coupling to GαI/o, GαQ/11, and Gα12/13, although LPA-LPAR1 signaling has been shown to play a role in the developmental stages of the nervous system. important effects, but no apparent toxicity was found for systemic inhibition in adults. However, inhibition of LPAR3 signaling can produce significant reproductive toxicity, so compounds need to avoid inhibition of LPAR3 signaling.
与LPAR1具有显著相关性的疾病主要是纤维化疾病、肿瘤、神经性疼痛、RA(类风湿性关节炎)、某些中枢性疾病等。The diseases that are significantly related to LPAR1 are mainly fibrotic diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), certain central diseases and the like.
特发性肺纤维化(idiopathic pulmonary fibrosis，IPF)是一种病因不明，以弥漫性肺泡炎和肺泡结构紊乱为特征的慢性、进行性、纤维化性间质性肺炎，在影像学和病理组织学中主要表现为普通型间质性肺炎。IPF起源于肺泡组织的组织的反复损伤，而这种损伤会引发一系列生理病理事件，包括(I)破坏内稳态；(II)引起炎症反应；(III)细胞增殖、迁移和分化；(IV)基质和组织重建；以及(V)伤口挛缩和瘢痕形成，这些事件中的许多是由损伤部位及其周围的生化因子的协调释放控制的，而LPA在其中起重要作用。病理升高的LPA浓度可能会继续激活肺细胞上的LPAR1受体，从而增强组织炎症并刺激过度的细胞外基质(ECM)产生。LPA是受损肺组织BALF中的成纤维细胞迁移的主要介质之一(TagerA M等人，Proceedings of the American Thoracic Society,2008.)，IPF患者的BALF(肺泡灌洗液)LPA水平高于正常对照组，抑制LPA信号显著降低成纤维细胞对IPF BALF的趋化反应。Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology characterized by diffuse alveolitis and alveolar structural disorders. The main manifestation is common interstitial pneumonia. IPF originates from repeated damage to the tissue of alveolar tissue, and this damage triggers a series of physiopathological events, including (I) disruption of homeostasis; (II) inflammatory response; (III) cell proliferation, migration and differentiation; ( IV) matrix and tissue remodeling; and (V) wound contracture and scarring, many of these events are controlled by the coordinated release of biochemical factors at and around the injury site, in which LPA plays an important role. Pathologically elevated LPA concentrations may continue to activate LPAR1 receptors on lung cells, thereby enhancing tissue inflammation and stimulating excessive extracellular matrix (ECM) production. LPA is one of the main mediators of fibroblast migration in the BALF of damaged lung tissue (TagerAM et al., Proceedings of the American Thoracic Society, 2008.), and BALF (alveolar lavage fluid) LPA levels in IPF patients are higher than normal In the control group, inhibition of LPA signaling significantly reduced the chemotactic response of fibroblasts to IPF BALF.
在临床前研究中，用博莱霉素处理LPAR1基因缺陷小鼠，结果发现LPAR1基因敲除对小鼠具有明显的保护作用，而且在LPAR1缺陷的小鼠中，博莱霉素处理后的成纤维细胞聚集明显减少。LPA诱导内皮细胞屏障功能障碍和血管渗漏，在组织损伤修复的早期阶段，血管通透性增加，能加快组织修复，但在IPF进程中，LPA-LPAR1介导的血管通透性增加促进纤维化发展。在另一项博来霉素诱导的IPF临床前模型中，博来霉素处理导致肺损伤后支气管肺泡灌洗液中LPA水平显著升高，并引起肺纤维化、血管渗漏和死亡，这些病理改变在LPAR1 -/-小鼠中明显减轻；LPAR1拮抗剂AM966降低了博来霉素模型中肺泡灌洗液中总蛋白质含量和LDH活性，表明AM966减少了LPA介导的IPF和其他间质性肺疾病中血管渗漏和上皮细胞死亡。这些内容表明LPAR1是治疗IPF有前途的靶点，在一项随机、双盲、安慰剂对照的临床试验中，LPAR1拮抗剂BMS-986020的使用显著减缓了特发性肺纤维化患者肺活量的下降，并减轻了临床症状，其二代化合物BMS-986278正在开展治疗IPF的II期临床试验(Swaney JS等人，Br J Pharmacol.2010；160(7):1699-1713.)。 In preclinical studies, LPAR1 gene-deficient mice were treated with bleomycin, and it was found that LPAR1 gene knockout had a significant protective effect in mice, and in LPAR1-deficient mice, the effect of bleomycin treatment Fibrocyte aggregation was significantly reduced. LPA induces endothelial cell barrier dysfunction and vascular leakage. In the early stages of tissue damage repair, increased vascular permeability can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated increased vascular permeability promotes fibrosis development. In another preclinical model of bleomycin-induced IPF, bleomycin treatment resulted in a marked increase in LPA levels in bronchoalveolar lavage fluid following lung injury and caused pulmonary fibrosis, vascular leakage, and death, which Pathological changes were significantly attenuated in LPAR1 -/- mice; LPAR1 antagonist AM966 reduced total protein content and LDH activity in bronchoalveolar lavage fluid in a bleomycin model, suggesting that AM966 reduces LPA-mediated IPF and other interstitial Vascular leakage and epithelial cell death in sexual lung disease. These findings suggest that LPAR1 is a promising target for the treatment of IPF, and the use of the LPAR1 antagonist BMS-986020 significantly slowed the decline in lung capacity in patients with idiopathic pulmonary fibrosis in a randomized, double-blind, placebo-controlled clinical trial , and alleviated clinical symptoms, and its second-generation compound BMS-986278 is undergoing Phase II clinical trials for the treatment of IPF (Swaney JS et al., Br J Pharmacol. 2010; 160(7): 1699-1713.).
放射性肺纤维化是肺癌放射治疗常见而严重的并发症。LPAR1/LPAR3拮抗剂VPC12249可在体内抑制促成纤维细胞因子转化生长因子β1和***生长因子的表达， 导致小鼠成纤维细胞增殖减少，减慢放射性肺纤维化进展，这说明LPAR1拮抗剂也有治疗放射性肺纤维化的潜力(Xiang H等人，J Cancer.2020；11(12):3519-3535.)。Radiation pulmonary fibrosis is a common and serious complication of radiation therapy for lung cancer. The LPAR1/LPAR3 antagonist VPC12249 inhibited the expression of the pro-fibrocytokines transforming growth factor β1 and connective tissue growth factor in vivo, resulting in decreased fibroblast proliferation in mice and slowing the progression of radiation-induced pulmonary fibrosis, suggesting that LPAR1 antagonists are also therapeutic Potential for radiation pulmonary fibrosis (Xiang H et al, J Cancer. 2020;11(12):3519-3535.).
LPAR1与肝纤维化的发生有密切关联。研究证明ATX-LPA信号轴激活PI3K并稳定缺氧诱导因子HIF-1的mRNA，从而促进丙型肝炎病毒的复制，抑制ATX-LPA信号则减少了丙型肝炎病毒的复制，这一过程可能与LPAR1和LPAR3有关，而肝炎是肝纤维化发生的关键因素，这表明拮抗LPAR1可能具有治疗肝纤维化的潜力(Farquhar MJ等人，J Hepatol.2017；66(5):919-929.)；在另一项研究中，下调LPAR1信号，降低了α-SMA、CTGF和TGF-β1表达，从而显著改善硫代乙酰胺诱导的肝纤维化，这更证明了LPAR1拮抗剂可以用于治疗肝纤维化。LPAR1 is closely related to the occurrence of liver fibrosis. Studies have shown that the ATX-LPA signaling axis activates PI3K and stabilizes the mRNA of hypoxia-inducible factor HIF-1, thereby promoting the replication of hepatitis C virus, and inhibiting ATX-LPA signaling reduces the replication of hepatitis C virus. This process may be related to LPAR1 and LPAR3 are related, and hepatitis is a key factor in the development of liver fibrosis, suggesting that antagonism of LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol. 2017;66(5):919-929.); In another study, down-regulation of LPAR1 signaling reduced α-SMA, CTGF, and TGF-β1 expression, thereby significantly improving thioacetamide-induced liver fibrosis, further demonstrating that LPAR1 antagonists can be used to treat liver fibrosis change.
LPA通过LPAR1促进肾纤维化的进展。在单侧输尿管梗阻(UUO)诱导的肾间质纤维化(TIF)小鼠中，ATX和LPA浓度升高，LPAR1显著上调，而LPAR3显著下调(Sakai N等人，FASEB J.2013；27(5):1830-1846.)。ATX-LPA-LPAR1信号可刺激成纤维细胞迁移和增殖，在LPAR1 -/-小鼠上或使用LPAR1/3拮抗剂Ki16425预处理后，UUO诱导的肾脏纤维化显著减轻，且当LPAR1信号被阻断时，促纤维化细胞因子的表达(***生长因子和转化生长因子-β)也显著下调。这表明LPAR1拮抗剂可能可以用于肾纤维化的治疗。 LPA promotes the progression of renal fibrosis through LPAR1. In mice with unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis (TIF), ATX and LPA concentrations were elevated, LPAR1 was significantly up-regulated, and LPAR3 was significantly down-regulated (Sakai N et al., FASEB J. 2013; 27( 5): 1830-1846.). ATX-LPA-LPAR1 signaling stimulates fibroblast migration and proliferation, and UUO-induced renal fibrosis is significantly attenuated on LPAR1 -/- mice or after pretreatment with the LPAR1/3 antagonist Ki16425, and when LPAR1 signaling is blocked The expression of pro-fibrotic cytokines (connective tissue growth factor and transforming growth factor-beta) was also significantly down-regulated upon interruption. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.
胎儿脑积水(FH)是新生儿常见的神经***疾病，其发生与LPAR1信号密切相关。在临床前的小鼠颅内出血模型中，通过将小鼠胚胎脑暴露在血液或LPA中，神经前体细胞(NPC)表达的LPAR1被过度激活，导致皮层破坏和变薄，最终导致FH。(YungYC等人，Sci Transl Med.2011；3(99):99ra87.)。在小鼠相关模型使用Ki16425(LPAR1/3拮抗剂)预处理，可降低出血性脑积水(PHH)产生的概率和严重程度，提示LPAR1拮抗剂可能用于治疗胎儿脑积水。Fetal hydrocephalus (FH) is a common neurological disease in neonates, and its occurrence is closely related to LPAR1 signaling. In a preclinical mouse model of intracranial hemorrhage, by exposing mouse embryonic brains to blood or LPA, LPAR1 expressed by neural precursor cells (NPCs) was hyperactivated, leading to cortical disruption and thinning, ultimately leading to FH. (YungYC et al. Sci Transl Med. 2011;3(99):99ra87.). Pretreatment with Ki16425 (an LPAR1/3 antagonist) in a mouse-related model can reduce the probability and severity of hemorrhagic hydrocephalus (PHH), suggesting that LPAR1 antagonists may be useful in the treatment of fetal hydrocephalus.
LPA-LPAR1信号具有显著的促肿瘤作用。LPA在体外促进肿瘤细胞存活、增殖、增加迁移和组织侵袭、激活血管内皮生长因子和激活金属基质蛋白酶，促进肿瘤细胞对顺铂耐药。LPAR1信号下调肝癌细胞中肿瘤抑制因子p53的表达；LPA通过LPAR1激活PI3K和P38MPAK信号通路，促进MMP-9的表达和HCC的侵袭；LPA-LPAR1也能通过GTPase RhoA和Rho相关蛋白激酶(ROCK)促进侵袭性；它还诱导蛋白激酶C(PKC)和核因子κB(NF-kB)促进上皮向间充质转化(EMT)；另外，LPA-LPAR1对血管生成的积极作用也能促进癌症的发展，因为新生血管对于实体肿瘤的发展是必不可少的。这些研究结果表明LPAR1拮抗剂在相关肿瘤的治疗方面具有巨大潜力(Xiang H等人，J Cancer.2020；11(12):3519-3535.)。LPA-LPAR1 signaling has a significant tumor-promoting effect. LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion, activates vascular endothelial growth factor and activates metalloproteinases, and promotes tumor cell resistance to cisplatin in vitro. LPAR1 signaling downregulates the expression of tumor suppressor p53 in hepatoma cells; LPA activates PI3K and P38MPAK signaling pathways through LPAR1 to promote MMP-9 expression and HCC invasion; LPA-LPAR1 can also activate GTPase RhoA and Rho-related protein kinase (ROCK) Promotes invasiveness; it also induces protein kinase C (PKC) and nuclear factor kappa B (NF-kB) to promote epithelial-to-mesenchymal transition (EMT); in addition, the positive effect of LPA-LPAR1 on angiogenesis also promotes cancer development , because neovascularization is essential for the development of solid tumors. These findings suggest that LPAR1 antagonists have great potential in the treatment of related tumors (Xiang H et al, J Cancer. 2020;11(12):3519-3535.).
人类周围神经损伤可导致一种称为神经病理性疼痛的疼痛状态，症状包括持续的烧灼 性疼痛和异常感觉，如超敏和痛觉过敏，LPAR1信号与神经性疼痛的发生有关。神经***受损导致损伤部位血清渗漏，使神经细胞大量暴露在LPA中可能是神经病理性疼痛的病因之一。Makoto Inoue等的研究表明神经损伤引起的行为异常和痛敏动物模型可通过LPAR1的拮抗剂预处理或靶向删除LPAR1来消除痛敏症状，并可通过鞘内注射LPA来模拟。另一项研究表明LPA可通过激活LPAR1，释放伤害性因子P物质而引起神经病理性疼痛，且LPAR1 -/-小鼠对部分坐骨神经结扎引起的神经病理性疼痛具有抵抗力。这些结果表明，LPA-LPAR1信号在神经病理性疼痛的启动中起关键作用，LPAR1拮抗剂可能有希望作为止痛剂用于神经病理性疼痛的治疗(Inoue M等人，ERRATUM:Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling[J].2004,10(7):755-755.)。 Peripheral nerve injury in humans can lead to a painful state called neuropathic pain, with symptoms including persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia, and LPAR1 signaling has been implicated in the development of neuropathic pain. Injury to the nervous system leads to serum leakage from the injury site, which exposes nerve cells to LPA and may be one of the causes of neuropathic pain. The study by Makoto Inoue et al. showed that the behavioral abnormalities and hyperalgesia induced by nerve injury in animal models can be eliminated by pretreatment with LPAR1 antagonists or targeted deletion of LPAR1, and can be simulated by intrathecal injection of LPA. Another study showed that LPA could induce neuropathic pain by activating LPAR1 to release the nociceptive factor substance P, and that LPAR1 -/- mice were resistant to neuropathic pain induced by partial sciatic nerve ligation. These results suggest that LPA-LPAR1 signaling plays a critical role in the initiation of neuropathic pain and 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.).
类风湿性关节炎(RA)是一种慢性自身免疫性的疾病，LPAR1信号与RA的发生有关。与骨关节炎患者相比，类风湿性关节炎患者滑膜中LPAR1和/或LPAR2表达水平升高，临床前研究表明LPAR1的基因敲除完全消除了RA症状，LPAR1的药理拮抗降低了疾病的严重程度，减轻了炎症和骨质侵蚀(Kaffe E等人，Cancers(Basel).2019；11(11):1626.Published 2019 Oct 23.doi:10.3390/cancers11111626)。拮抗LPAR1信号还减少RA患者FLS(滑膜成纤维细胞)的增殖，并使其对肿瘤坏死因子(TNF)介导的凋亡敏感，另外LPA还参与了RA FLS中白细胞介素(IL)-6、IL-8和环氧合酶-2(COX-2)的产生。这些结果显示LPAR1是治疗类风湿性关节炎的一个很有前途的靶点(Orosa B等人，Annals of the Rheumatic Diseases,2014,73(1):298-305.)。Rheumatoid arthritis (RA) is a chronic autoimmune disease, and LPAR1 signaling is related to the occurrence of RA. Compared with patients with osteoarthritis, LPAR1 and/or LPAR2 expression levels are increased in the synovium of patients with rheumatoid arthritis, preclinical studies have shown that gene knockout of LPAR1 completely abolished RA symptoms, and pharmacological antagonism of LPAR1 reduced the severity of the disease. Severity, inflammation and bone erosion were reduced (Kaffe E et al. Cancers(Basel). 2019; 11(11):1626. Published 2019 Oct 23.doi:10.3390/cancers11111626). Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and sensitizes them to tumor necrosis factor (TNF)-mediated apoptosis, and LPA is also involved in interleukin (IL)- 6. Production of IL-8 and cyclooxygenase-2 (COX-2). These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals of the Rheumatic Diseases, 2014, 73(1):298-305.).
发明内容SUMMARY OF THE INVENTION
本发明旨在至少在一定程度上解决上述技术问题之一或至少提供一种有用的商业选择。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.
本发明提出了一种如式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：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):
Figure PCTCN2021129863-appb-000001
Figure PCTCN2021129863-appb-000001
其中，R 1选自-H，-CN，卤素(例如氟、氯、溴或碘)，-Z-R a，无取代或被R b取代的C 1-6烷基{所述的“C 1-6烷基”例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；所述的R b的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个R b时，所述的R b相同或不同}，无取代或被R b取代的C 3-6环烷基(所述的“C 3-6环烷基”例如环丙基、环丁基、环戊基)、无取代或被R b取代的C 1-6烷氨基(所述的“C 1-6烷氨基”例如
Figure PCTCN2021129863-appb-000002
其中m1和m2各自独立地选自0-6的整数，m1和m2的和不超过6，和/或m1和m2不同时为零)，无取代或被R b取代的C 1-6烷氧基(所述的“C 1-6烷氧基”例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)； wherein, R 1 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), -ZR a , C 1-6 alkyl unsubstituted or substituted by R b {the "C 1- 6 alkyl" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R b is one or more ( The number is subject to the substituted group conforming to the valence bond theory and stable existence. For example, 1, 2 or 3), when there are multiple R b , the R b is the same or different}, unsubstituted or C 3-6 cycloalkyl substituted by R b (the "C 3-6 cycloalkyl group" such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or C 1 substituted by R b -6 alkylamino (the "C 1-6 alkylamino" such as
Figure PCTCN2021129863-appb-000002
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 zero), 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选自单键、-O-、-S-或-CO-；Z is selected from a single bond, -O-, -S- or -CO-;
R a选自C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，被卤素取代的C 1-6烷基{所述的“卤素”例如氟、氯、溴或碘；所述的卤素的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个卤素时，所述的卤素相同或不同}，氨基(例如-NH 2)，C 1-3烷氨基(例如
Figure PCTCN2021129863-appb-000003
)； R a is selected from C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1 substituted by halogen -6 alkyl {The "halogen" is such as fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as (e.g. 1, 2 or 3), when multiple halogens are present, the halogens are the same or different}, amino (eg -NH 2 ), C 1-3 alkylamino (eg
Figure PCTCN2021129863-appb-000003
);
R b选自-CN，卤素(例如氟、氯、溴或碘)，C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，C 1-6烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)； R b is selected from -CN, halogen (eg fluorine, chlorine, bromine or iodine), C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, pentyl, hexyl), C 1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy, hexyloxy);
R 2选自-H，-CN，卤素(例如氟、氯、溴或碘)，-Y-R d，无取代或被R e取代的C 1-6烷基{所述的“C 1-6烷基”例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；所述的R e的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个R e时，所述的R e相同或不同}、无取代或被R e取代的C 3-6环烷基(所述的“C 3-6环烷基”例如环丙基、环丁基、环戊基)、无取代或被R e取代的C 1-6烷氨基(所述的“C 1-6烷氨基”例如
Figure PCTCN2021129863-appb-000004
其中n1和n2各自独立地选自0-6的整数，n1和n2的和不超过6，和/或n1和n2不同时为零)、无取代或被R e取代的C 1-6烷氧基(所述的“C 1-6烷氧基”例如甲氧基、乙氧基、正丙氧基、异丙氧基、 正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)； R 2 is selected from -H, -CN, halogen (eg fluorine, chlorine, bromine or iodine), -YR d , unsubstituted or substituted C 1-6 alkyl {the "C 1-6 alkane""base" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the Re is one or more (the The number is subject to the substituted group conforming to the valence bond theory and stable existence. For example, 1, 2 or 3), when there are multiple Re , the Re is the same or different}, unsubstituted or by Re -substituted C 3-6 cycloalkyl (the "C 3-6 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or R substituted C 1-6 Alkylamino (the "C 1-6 alkylamino" such as
Figure PCTCN2021129863-appb-000004
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 zero), unsubstituted or substituted 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);
Y选自单键、-O-或-S-；Y is selected from a single bond, -O- or -S-;
R d选自C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，被卤素取代的C 1-6烷基{所述的“卤素”例如氟、氯、溴或碘；所述的卤素的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个卤素时，所述的卤素相同或不同}； R d is selected from C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1 substituted by halogen -6 alkyl {The "halogen" is such as fluorine, chlorine, bromine or iodine; the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different};
R e选自-CN，卤素(例如氟、氯、溴或碘)，C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基)，C 1-6烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基)； R 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、X 3分别独立地选自C或N，且X 1、X 2、X 3不同时为N； X 1 , X 2 , and X 3 are independently selected from C or N, and X 1 , X 2 , and X 3 are not N at the same time;
Figure PCTCN2021129863-appb-000005
选自被R 1取代的苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，例如
Figure PCTCN2021129863-appb-000006
Figure PCTCN2021129863-appb-000007
Figure PCTCN2021129863-appb-000005
Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R, such as
Figure PCTCN2021129863-appb-000006
Figure PCTCN2021129863-appb-000007
Figure PCTCN2021129863-appb-000008
选自无无取代或任选被1～3个R g取代的以下基团：
Figure PCTCN2021129863-appb-000009
Figure PCTCN2021129863-appb-000010
Figure PCTCN2021129863-appb-000008
Selected from the following groups that are unsubstituted or optionally substituted with 1 to 3 R g :
Figure PCTCN2021129863-appb-000009
Figure PCTCN2021129863-appb-000010
R g选自H、F、Cl、甲基； R g is selected from H, F, Cl, methyl;
L 1选自单键、-N(R 3)-或-O-； L 1 is selected from a single bond, -N(R 3 )- or -O-;
L 2选自单键、-O-、无取代的C 1-6亚烷基(例如
Figure PCTCN2021129863-appb-000011
Figure PCTCN2021129863-appb-000012
)、被C 1-3烷基取代的C 1-6亚烷基(例如
Figure PCTCN2021129863-appb-000013
)、无取代或被C 1-3烷基取代的环丙基； L 2 is selected from single bond, -O-, unsubstituted C 1-6 alkylene (for example
Figure PCTCN2021129863-appb-000011
Figure PCTCN2021129863-appb-000012
), C 1-6 alkylene substituted by C 1-3 alkyl (such as
Figure PCTCN2021129863-appb-000013
), unsubstituted or cyclopropyl substituted by C 1-3 alkyl;
R 3选自-H、C 1-3烷基(例如甲基、乙基、丙基)； R 3 is selected from -H, C 1-3 alkyl (eg methyl, ethyl, propyl);
R 4选自-H、-CN、卤素(例如氟、氯、溴或碘)、无取代或被R h取代的C 1-6烷基{所述的“C 1-6烷基”例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基；所述的R h的个数为一个或多个(其个数以取代后的基团符合价键理论、稳定存在为准。例如1个、2个或3个)，当存在多个R h时，所述的R h相同或不同}、无取代或被R h取代的C 3-8环烷基(所述的“C 3-6环烷基”例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基)； R 4 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), unsubstituted or substituted C 1-6 alkyl { 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 is one or more (the number is after the substitution The group conforms to the valence bond theory and is subject to stable existence. For example, 1, 2 or 3), when there are multiple R h , the R h is the same or different}, unsubstituted or substituted by R h C 3-8 cycloalkyl (the "C 3-6 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl);
R h选自-H、卤素(例如氟、氯、溴、碘)、C 1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、正戊基)、被卤素取代的C 1-6烷基(例如三氟甲基)、被卤素取代的C 1-6烷氧基(例如二氟甲氧基)。 R is selected from -H, halogen (eg fluorine, chlorine, bromine, iodine), C 1-6 alkyl (eg methyl, ethyl, n -propyl, isopropyl, n-butyl, n-pentyl), C1-6 alkyl substituted with halogen (eg trifluoromethyl), C1-6 alkoxy substituted with halogen (eg difluoromethoxy).
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自氟、氯或溴。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from fluorine, chlorine or bromine.
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -OCH 2 CH 2 F, -O(CH 2 ) 2 CH 2 F. -OCH( CH3 )( CH2F ).
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH 2 F, -SCH 2 CH 2 F, -S(CH 2 ) 2 CH 2 F, -SCH(CH 3 )(CH 2F ).
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-CO-NH 2、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)； In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from -CO-NH 2 , -CO- NH- CH3 , -CO-N( CH3 ) 2 , -CO-NH- CH2 - CH3 , -CO-N( CH3 )( CH2CH3 ) ;
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000014
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
Figure PCTCN2021129863-appb-000014
-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 .
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
Figure PCTCN2021129863-appb-000015
-NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、 -NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、-OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、
Figure PCTCN2021129863-appb-000016
-NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
Figure PCTCN2021129863-appb-000017
-NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
Figure PCTCN2021129863-appb-000018
Figure PCTCN2021129863-appb-000019
In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN),
Figure PCTCN2021129863-appb-000015
-NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F, -CH(CH 3 )(CH 2 F),
Figure PCTCN2021129863-appb-000016
-NH- CH2F , -N( CH3 )( CH2F ), -NH- CH2CH2CH2F , -NH-( CH2 ) 2CH2F , -NH- CH ( CH3 ) (CH 2 F), -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
Figure PCTCN2021129863-appb-000017
-NH- CH2Cl , -N( CH3 )( CH2Cl ), -NH- CH2CH2CH2Cl , -NH-( CH2 ) 2CH2Cl , -NH- CH ( CH3 ) (CH 2 Cl), -OCH 2 Cl, -OCH 2 CH 2 Cl, -O(CH 2 ) 2 CH 2 Cl, -OCH(CH 3 )(CH 2 Cl),
Figure PCTCN2021129863-appb-000018
Figure PCTCN2021129863-appb-000019
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自氟、氯或溴。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 2 is selected from fluorine, chlorine or bromine.
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 2 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -OCH 2 CH 2 F, -O(CH 2 ) 2 CH 2 F. -OCH( CH3 )( CH2F ).
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 2 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH 2 F, -SCH 2 CH 2 F, -S(CH 2 ) 2 CH 2 F, -SCH(CH 3 )(CH 2F ).
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000020
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2； In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 2 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
Figure PCTCN2021129863-appb-000020
-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 ;
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
Figure PCTCN2021129863-appb-000021
-NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、-NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、-OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、
Figure PCTCN2021129863-appb-000022
-NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
Figure PCTCN2021129863-appb-000023
-NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
Figure PCTCN2021129863-appb-000024
Figure PCTCN2021129863-appb-000025
In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 2 is selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN),
Figure PCTCN2021129863-appb-000021
-NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F, -CH(CH 3 )(CH 2 F),
Figure PCTCN2021129863-appb-000022
-NH- CH2F , -N( CH3 )( CH2F ), -NH- CH2CH2CH2F , -NH-( CH2 ) 2CH2F , -NH- CH ( CH3 ) (CH 2 F), -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
Figure PCTCN2021129863-appb-000023
-NH- CH2Cl , -N( CH3 )( CH2Cl ), -NH- CH2CH2CH2Cl , -NH-( CH2 ) 2CH2Cl , -NH- CH ( CH3 ) (CH 2 Cl), -OCH 2 Cl, -OCH 2 CH 2 Cl, -O(CH 2 ) 2 CH 2 Cl, -OCH(CH 3 )(CH 2 Cl),
Figure PCTCN2021129863-appb-000024
Figure PCTCN2021129863-appb-000025
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129863-appb-000026
选自
Figure PCTCN2021129863-appb-000027
Figure PCTCN2021129863-appb-000028
In a certain scheme, the definitions of some groups of the compound represented by the formula (I) are as follows, and the undefined groups are as described in any of the previous schemes:
Figure PCTCN2021129863-appb-000026
selected from
Figure PCTCN2021129863-appb-000027
Figure PCTCN2021129863-appb-000028
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 3选自-H或甲基。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 3 is selected from -H or methyl.
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：L 2选自单键、-O-、
Figure PCTCN2021129863-appb-000029
In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: L 2 is selected from a single bond, -O-,
Figure PCTCN2021129863-appb-000029
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4为氟。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 4 is fluorine.
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自甲基、乙基、异丙基、正丁基。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 4 is selected from methyl, ethyl, isopropyl , n-butyl.
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自环丙基、环丁基、环戊基。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 4 is selected from cyclopropyl, cyclobutyl, cyclopropyl amyl.
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-(CH 2) 2F、-(CH 2) 3F、-CH(CH 3)(CH 2F)、-(CH 2) 2Cl、-(CH 2) 3Cl、-CH(CH 3)(CH 2Cl)。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 4 is selected from -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -(CH 2 ) 2 Cl, -( CH2 )3Cl, -CH( CH3 ) ( CH2Cl ).
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自
Figure PCTCN2021129863-appb-000030
Figure PCTCN2021129863-appb-000031
In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 4 is selected from
Figure PCTCN2021129863-appb-000030
Figure PCTCN2021129863-appb-000031
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000032
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CO-NH 2、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)、
Figure PCTCN2021129863-appb-000033
Figure PCTCN2021129863-appb-000034
In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
Figure PCTCN2021129863-appb-000032
-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), -CO-NH 2 , -CO-NH-CH 3 , -CO-N(CH 3 ) 2 , -CO-NH-CH 2 -CH 3 , -CO-N(CH 3 )(CH 2 CH 3 ),
Figure PCTCN2021129863-appb-000033
Figure PCTCN2021129863-appb-000034
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000035
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、 -OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129863-appb-000036
Figure PCTCN2021129863-appb-000037
In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
Figure PCTCN2021129863-appb-000035
-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),
Figure PCTCN2021129863-appb-000036
Figure PCTCN2021129863-appb-000037
和/或，
Figure PCTCN2021129863-appb-000038
选自
Figure PCTCN2021129863-appb-000039
Figure PCTCN2021129863-appb-000040
and / or,
Figure PCTCN2021129863-appb-000038
selected from
Figure PCTCN2021129863-appb-000039
Figure PCTCN2021129863-appb-000040
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129863-appb-000041
选自
Figure PCTCN2021129863-appb-000042
In a certain scheme, the definitions of some groups of the compound represented by the formula (I) are as follows, and the undefined groups are as described in any of the previous schemes:
Figure PCTCN2021129863-appb-000041
selected from
Figure PCTCN2021129863-appb-000042
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 1选自-H、-F、甲基、环丙基、-CO-NH 2、-CO-NH-CH 3、-CO-N(CH 3) 2。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 1 is selected from -H, -F, methyl, Cyclopropyl, -CO- NH2 , -CO-NH- CH3 , -CO-N( CH3 ) 2 .
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 2选自-H、-F、-Cl、-CH 3。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 2 is selected from -H, -F, -Cl, -CH3 .
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前 任一方案所述：
Figure PCTCN2021129863-appb-000043
选自
Figure PCTCN2021129863-appb-000044
Figure PCTCN2021129863-appb-000045
In a certain scheme, the definitions of some groups of the compound represented by the formula (I) are as follows, and the undefined groups are as described in any of the previous schemes:
Figure PCTCN2021129863-appb-000043
selected from
Figure PCTCN2021129863-appb-000044
Figure PCTCN2021129863-appb-000045
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：L 1选自单键、-NH-或-O-。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: L 1 is selected from a single bond, -NH- or -O -.
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：L 2选自单键、-O-、
Figure PCTCN2021129863-appb-000046
In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: L 2 is selected from a single bond, -O-,
Figure PCTCN2021129863-appb-000046
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：R 4选自-H、-F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F。 In a certain scheme, some groups of the compound represented by the formula (I) are defined as follows, and the undefined groups are as described in any of the previous schemes: R 4 is selected from -H, -F, methyl, Ethyl, isopropyl, cyclopropyl, n-butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129863-appb-000047
选自
Figure PCTCN2021129863-appb-000048
其中R 1选自-F、甲基、-CO-NH 2； In a certain scheme, the definitions of some groups of the compound represented by the formula (I) are as follows, and the undefined groups are as described in any of the previous schemes:
Figure PCTCN2021129863-appb-000047
selected from
Figure PCTCN2021129863-appb-000048
wherein R 1 is selected from -F, methyl, -CO-NH 2 ;
R 2选自-H、-F、-Cl、-CH 3；
Figure PCTCN2021129863-appb-000049
选自
Figure PCTCN2021129863-appb-000050
Figure PCTCN2021129863-appb-000051
L 1选自单键、-NH-或-O-；L 2选自单键、-O-、
Figure PCTCN2021129863-appb-000052
R 4选自H、F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F。 R 2 is selected from -H, -F, -Cl, -CH 3 ;
Figure PCTCN2021129863-appb-000049
selected from
Figure PCTCN2021129863-appb-000050
Figure PCTCN2021129863-appb-000051
L 1 is selected from single bond, -NH- or -O-; L 2 is selected from single bond, -O-,
Figure PCTCN2021129863-appb-000052
R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前 任一方案所述：
Figure PCTCN2021129863-appb-000053
为
Figure PCTCN2021129863-appb-000054
R 1为甲基；R 2选自卤素；
Figure PCTCN2021129863-appb-000055
选自
Figure PCTCN2021129863-appb-000056
L 1选自单键、-NH-或-O-；L 2选自单键、-O-、
Figure PCTCN2021129863-appb-000057
Figure PCTCN2021129863-appb-000058
R 4选自H、F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F； In a certain scheme, the definitions of some groups of the compound represented by the formula (I) are as follows, and the undefined groups are as described in any of the previous schemes:
Figure PCTCN2021129863-appb-000053
for
Figure PCTCN2021129863-appb-000054
R 1 is methyl; R 2 is selected from halogen;
Figure PCTCN2021129863-appb-000055
selected from
Figure PCTCN2021129863-appb-000056
L 1 is selected from single bond, -NH- or -O-; L 2 is selected from single bond, -O-,
Figure PCTCN2021129863-appb-000057
Figure PCTCN2021129863-appb-000058
R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F ;
在某一方案中，所述的式(I)所示化合物的某些基团的定义如下，未定义的基团如前任一方案所述：
Figure PCTCN2021129863-appb-000059
为
Figure PCTCN2021129863-appb-000060
R 1选自甲基、-CO-NH 2；R 2选自-F、-Cl；
Figure PCTCN2021129863-appb-000061
选自
Figure PCTCN2021129863-appb-000062
L 1选自-NH-或-O-；L 2选自-O-、
Figure PCTCN2021129863-appb-000063
Figure PCTCN2021129863-appb-000064
R 4选自H、F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F。 In a certain scheme, the definitions of some groups of the compound represented by the formula (I) are as follows, and the undefined groups are as described in any of the previous schemes:
Figure PCTCN2021129863-appb-000059
for
Figure PCTCN2021129863-appb-000060
R 1 is selected from methyl, -CO-NH 2 ; R 2 is selected from -F, -Cl;
Figure PCTCN2021129863-appb-000061
selected from
Figure PCTCN2021129863-appb-000062
L 1 is selected from -NH- or -O-; L 2 is selected from -O-,
Figure PCTCN2021129863-appb-000063
Figure PCTCN2021129863-appb-000064
R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
在某一方案中，所述的式(I)所示化合物进一步为式(I-0)所示化合物：In a certain scheme, the compound represented by the formula (I) is further the compound represented by the formula (I-0):
Figure PCTCN2021129863-appb-000065
Figure PCTCN2021129863-appb-000065
其中，R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000066
Figure PCTCN2021129863-appb-000067
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CO-NH 2-、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)、
Figure PCTCN2021129863-appb-000068
Figure PCTCN2021129863-appb-000069
Wherein, R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
Figure PCTCN2021129863-appb-000066
Figure PCTCN2021129863-appb-000067
-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), -CO-NH 2 -, -CO-NH-CH 3 , -CO-N(CH 3 ) 2 , -CO-NH-CH 2 -CH 3 , -CO-N(CH 3 )(CH 2 CH 3 ),
Figure PCTCN2021129863-appb-000068
Figure PCTCN2021129863-appb-000069
R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000070
Figure PCTCN2021129863-appb-000071
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129863-appb-000072
Figure PCTCN2021129863-appb-000073
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 ,
Figure PCTCN2021129863-appb-000070
Figure PCTCN2021129863-appb-000071
-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),
Figure PCTCN2021129863-appb-000072
Figure PCTCN2021129863-appb-000073
Figure PCTCN2021129863-appb-000074
选自被R 1取代的苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
Figure PCTCN2021129863-appb-000074
Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R 1 ;
Figure PCTCN2021129863-appb-000075
选自无取代或任选被1～3个R g取代的以下基团：
Figure PCTCN2021129863-appb-000076
Figure PCTCN2021129863-appb-000077
其中R g选自H、F、Cl、甲基；
Figure PCTCN2021129863-appb-000075
Selected from the following groups unsubstituted or optionally substituted with 1 to 3 R g :
Figure PCTCN2021129863-appb-000076
Figure PCTCN2021129863-appb-000077
wherein R g is selected from H, F, Cl, methyl;
L 1选自单键、-N(R 3)-或-O-； L 1 is selected from a single bond, -N(R 3 )- or -O-;
L 2选自单键、-O-、无取代或被C 1-3烷基取代的C 1-6亚烷基； L 2 is selected from single bond, -O-, unsubstituted or C 1-6 alkylene substituted by C 1-3 alkyl;
R 3选自H、C 1-3烷基； R 3 is selected from H, C 1-3 alkyl;
R 4选自-H、-CN、-F、-Cl、-Br、甲基、乙基、异丙基、正丁基、环丙基、环丁基、环戊基、-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-(CH 2) 2F、-(CH 2) 3F、-CH(CH 3)(CH 2F)、-(CH 2) 2Cl、-(CH 2) 3Cl、-CH(CH 3)(CH 2Cl)、
Figure PCTCN2021129863-appb-000078
Figure PCTCN2021129863-appb-000079
R 4 is selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -( CH 2 ) 2 Cl, -(CH 2 ) 3 Cl, -CH(CH 3 )(CH 2 Cl),
Figure PCTCN2021129863-appb-000078
Figure PCTCN2021129863-appb-000079
在某一方案中，所述的式(I)所示化合物进一步为式(I-0)所示化合物：In a certain scheme, the compound represented by the formula (I) is further the compound represented by the formula (I-0):
Figure PCTCN2021129863-appb-000080
Figure PCTCN2021129863-appb-000080
其中，R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000081
Figure PCTCN2021129863-appb-000082
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、 -OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CO-NH 2-、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)、
Figure PCTCN2021129863-appb-000083
Figure PCTCN2021129863-appb-000084
Wherein, R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
Figure PCTCN2021129863-appb-000081
Figure PCTCN2021129863-appb-000082
-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), -CO-NH 2 -, -CO-NH-CH 3 , -CO-N(CH 3 ) 2 , -CO-NH-CH 2 -CH 3 , -CO-N(CH 3 )(CH 2 CH 3 ),
Figure PCTCN2021129863-appb-000083
Figure PCTCN2021129863-appb-000084
R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021129863-appb-000085
Figure PCTCN2021129863-appb-000086
-NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
Figure PCTCN2021129863-appb-000087
Figure PCTCN2021129863-appb-000088
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 ,
Figure PCTCN2021129863-appb-000085
Figure PCTCN2021129863-appb-000086
-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),
Figure PCTCN2021129863-appb-000087
Figure PCTCN2021129863-appb-000088
Figure PCTCN2021129863-appb-000089
选自被R 1取代的苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基；
Figure PCTCN2021129863-appb-000089
Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R 1 ;
Figure PCTCN2021129863-appb-000090
选自
Figure PCTCN2021129863-appb-000091
Figure PCTCN2021129863-appb-000092
Figure PCTCN2021129863-appb-000093
Figure PCTCN2021129863-appb-000090
selected from
Figure PCTCN2021129863-appb-000091
Figure PCTCN2021129863-appb-000092
Figure PCTCN2021129863-appb-000093
在某一方案中，所述的式(I)所示化合物可为如下任一化合物：In a certain scheme, the compound represented by the formula (I) can be any of the following compounds:
Figure PCTCN2021129863-appb-000094
Figure PCTCN2021129863-appb-000094
Figure PCTCN2021129863-appb-000095
Figure PCTCN2021129863-appb-000095
本发明还提供了一种药物组合物，其包含上述的式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。The present invention also provides a pharmaceutical composition comprising the above-mentioned compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.
在所述的药物组合物中，所述的式(I)所示化合物，或者式(I)所示化合物的立体异 构体、水合物、溶剂化物、药学上可接受的盐或前药的药物组合物可为治疗有效剂量。In the pharmaceutical composition, the compound represented by the formula (I), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) The pharmaceutical composition may be in a therapeutically effective dose.
本发明还提供了一种上述的式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与LPAR相关疾病的药物中的用途。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.
在所述的用途中，所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。In the use, the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
在所述的用途中，所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。In said use, said LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal brain volume water.
本发明还提供了一种治疗或预防LPAR相关疾病的方法。根据本发明的实施例，所述方法包括给与患者药学上可接受剂量的前面所述化合物，或前面所述的药物组合物。The present invention also provides a method of treating or preventing LPAR-related diseases. According to an embodiment of the present invention, the method comprises administering to the patient a pharmaceutically acceptable dose of the aforementioned compound, or the aforementioned pharmaceutical composition.
在所述方法中，所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。In the method, the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
在所述方法中，所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。In the method, the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus .
术语定义和说明Definition and Explanation of Terms
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise stated, definitions of groups and terms set forth in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations, group definitions and compound structures after the combination should fall within the scope described in the specification of the present application.
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms in this document, the definitions in this chapter shall prevail.
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳 定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。 Unless otherwise stated, conventional methods within the skill in the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in this application. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds. When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。The numerical range described in the specification and claims of the present application, when the numerical range is understood as an "integer", should be understood as describing the two endpoints of the range and each integer in the range. For example, "an integer of 1 to 6" should be understood as reciting each integer of 0, 1, 2, 3, 4, 5, and 6. When such a numerical range is read as a "number," it should be understood as reciting both endpoints of the range and each integer within the range and every decimal point within the range. For example, "a number from 1 to 10" should be understood as not only reciting each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also reciting at least that each integer is respectively associated with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。本发明使用的立体化学定义和惯例大体上按照S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，NewYork，1994来定义。The term "stereoisomers" refers to isomers resulting from different arrangements of atoms in a molecule in space, including 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”, as defined by John Wiley & Sons, Inc., New York, 1994.
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的 化合物中，且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of starting materials and methods, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers. A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane polarized light by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl group may be in the cis- or trans- (cis- or trans-) configuration.
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。When the bond to the chiral carbon in the formula of the present invention is depicted as a straight line, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of this formula. A schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge and dashed bonds are used to indicate the absolute configuration of a stereocenter.
旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的柱子上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本发明所描述化合物的任何对映体或非对映体。Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β- D and L forms of camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Selection of specific methods, elution conditions, and selection of chromatographic columns can be selected by those skilled in the art according to the structures of compounds and test results. Further, any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
针对药物或药理学活性剂而言，术语“有效剂量”、“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The terms "effective dose", "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refer to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。The term "solvate" means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound. The prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds. Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
术语“C 1- 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1-6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2 , 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the groups have 1, 2 or 3 carbon atoms (" C1 -C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.
术语“C 3- 6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环***。如环丙基、环丁基、环戊基、环己基。 The term "C3-6cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语“烷氨基”或“烷基氨基”是指氨基中的一个或两个氢原子被烷基取代，包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。合适的烷基氨基基团可以是单烷基氨基或二 烷基氨基，这样的实例包括，但并不限于，N-甲氨基(甲氨基)，N-乙氨基(乙氨基)，N,N-二甲氨基(二甲氨基)，N,N-二乙氨基(二乙氨基)等等。所述烷氨基基团任选地被一个或多个本发明所描述的取代基所取代。The term "alkylamino" or "alkylamino" refers to an amino group substituted with one or two hydrogen atoms by an alkyl group, including "N-alkylamino" and "N,N-dialkylamino", wherein the amino group The groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meanings as defined herein. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc. The alkylamino group is optionally substituted with one or more substituents described herein.
术语“C 1-6烷氨基”是指具有1至6个碳原子的“烷氨基”或“烷基氨基”。 The term "C 1-6 alkylamino" refers to "alkylamino" or "alkylamino" having 1 to 6 carbon atoms.
术语“C 1- 6烷氧基”应理解为-O-(C 1- 6烷基)，其中“C 1- 6烷基”具有上述定义。 The term "C 1-6 alkoxy" is to be understood as -O-(C 1-6 alkyl ) , wherein "C 1-6 alkyl " has the above definition.
术语“4-8元杂环基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的单环、二环或三环，其中1、2、3、4或5个环原子选自N、O和S，除非另有说明，其可通过碳或氮连接，其中-CH 2-基团任选被-C(O)-代替；及其中除非另有相反说明，环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化；其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代；及环任选被一个或多个卤素取代。应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为二环或三环，则至少一个环可任选为杂芳族环或芳族环，条件是至少一个环是非杂芳族的。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。 The term "4-8 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, of which 1, 2, 3, 4 or 5 rings Atoms are selected from N, O, and S, which, unless otherwise specified, may be attached through carbon or nitrogen, wherein the -CH2- group is optionally replaced by -C(O)-; and wherein, unless otherwise specified, the ring nitrogen Atoms or ring sulfur atoms are optionally oxidized to form N-oxides or S-oxides or ring nitrogen atoms are optionally quaternized; wherein -NH in the ring is optionally acetyl, formyl, methyl or methyl sulfonyl substitution; and the ring is optionally substituted with one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl group is monocyclic, it must not be aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indoline, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 -Dioximidazolidinyl.
术语“5-8元芳基”应理解为具有5-8个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；当所述5-8元芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。 The term "5-8 membered aryl" is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 5-8 carbon atoms, especially a ring having 6 carbon atoms (" C 6 aryl"), such as phenyl; when the 5-8 membered aryl is substituted, it may be mono- or poly-substituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
术语“5-8元杂芳基”应理解为具有5-8个环原子——特别是5或6个碳原子——且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。The term "5-8 membered heteroaryl" is to be understood as having 5-8 ring atoms - in particular 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S A monovalent monocyclic, bicyclic or tricyclic aromatic ring group. 1-3 monovalent monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and, in addition, in each case may be benzo-fused . In particular, heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; group, carbazolyl group, acridine group, phenazinyl group, phenothiazinyl group, phenoxazinyl group and the like.
术语“卤代基”或“卤素”为氟、氯、溴和碘。The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱 和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。"Haloalkyl" is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (eg -CvFw, where v=1 to 3, w=1 to (2v+ 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
有益效果beneficial effect
根据本发明的具体示例，本发明所述式(I)所示化合物，其立体异构体、水合物、溶剂化物、药学上可接受的盐或前药对LPAR1具有良好的拮抗作用。According to a specific example of the present invention, the compound represented by formula (I), its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the present invention has a good antagonistic effect on LPAR1.
根据本发明的具体示例，本发明化合物对LPAR1具有良好的拮抗作用，对LPAR3的拮抗作用很弱，亦即本发明化合物显示出优异的选择性；本发明化合物安全性更优，无胆汁淤积毒性风险；本发明化合物药代动力学性质优良，成药性好；本发明化合物能通过拮抗LPAR1显著抑制LPA诱导的组胺释，同时显著改善博来霉素诱导的小鼠肺纤维化症状。According to the specific example of the present invention, 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 compounds of the present invention have excellent pharmacokinetic properties and good druggability; the compounds of the present invention can significantly inhibit LPA-induced histamine release by antagonizing LPAR1, and at the same time significantly improve the symptoms of bleomycin-induced pulmonary fibrosis in mice.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be set forth, in part, from the following description, and in part will be apparent from the following description, or may be learned by practice of the invention.
具体实施方式Detailed ways
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The solution of the present invention will be explained below in conjunction with the embodiments. Those skilled in the art will understand that the following examples are only used to illustrate the present invention, and should not be construed as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used. The reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.
本发明的实施例提供了式(I)所示化合物，其药学上可接受的盐、互变异构体、立体异构体、水合物、溶剂化物、共晶或前药，制备式(I)所示化合物或其药学上可接受的盐、互变异构体、立体异构体、水合物、溶剂化物、共晶或前药的方法和中间体、药物组合物、以及本发明的化合物和药物组合物在制备药物中的用途。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.
本发明所述的各反应步骤所使用的反应溶剂没有特别限制，任何在一定程度上能溶解起始原料并且不抑制反应的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。The reaction solvent used in each reaction step of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications in the art, equivalent replacements, or equivalents to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10-6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
液质联用(LC-MS)由Waters Acquity H-class Uplc-QDA质谱仪测定，使用ACQUITY UPLC BEH C18，2.1*50mm，1.7μm色谱柱监测。梯度洗脱条件：以1.0mL/min流速，95—5％溶剂A1和5-95％溶剂B1，然后95％B1和5％A1保持0.5min，百分数为某一溶剂占总溶剂体积的体积百分数。其中溶剂A1：0.1％甲酸的水溶液；溶剂B1：0.1％甲酸的乙腈溶液。百分数为溶质占溶液的体积百分数。Liquid-mass spectrometry (LC-MS) was determined by a Waters Acquity H-class Uplc-QDA mass spectrometer, monitored using an ACQUITY UPLC BEH C18, 2.1*50mm, 1.7μm chromatographic column. Gradient elution conditions: flow rate of 1.0mL/min, 95-5% solvent A1 and 5-95% solvent B1, then 95% B1 and 5% A1 for 0.5min, the percentage is the volume percentage of a certain solvent in the total solvent volume . Wherein solvent A1: 0.1% formic acid in water; solvent B1: 0.1% formic acid in acetonitrile. The percentage is the volume percent of the solute in the solution.
本发明的缩写定义如下：Abbreviations of the present invention are defined as follows:
符号或单位：Symbol or unit:
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度 IC 50 : half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved
M：mol/L，例如正丁基锂(14.56mL，29.1mmol，2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液M: mol/L, for example n-butyllithium (14.56mL, 29.1mmol, 2.5M n-hexane solution) represents a molar concentration of 2.5mol/L n-butyllithium solution in n-hexane
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液N: equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
RT：保留时间RT: retention time
试剂：Reagents:
DCM：二氯甲烷DCM: dichloromethane
DIPEA：也可写为DIEA，二异丙基乙胺，亦即N,N-二异丙基乙胺DIPEA: can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
DMSO：二甲基亚砜DMSO: Dimethyl Sulfoxide
EA：乙酸乙酯EA: Ethyl acetate
Et 3N：三乙胺 Et 3 N: triethylamine
MeOH：甲醇MeOH: methanol
PE：石油醚PE: petroleum ether
THF：四氢呋喃THF: Tetrahydrofuran
试验或检测方法：Test or detection method:
HPLC：高效液相色谱HPLC: High Performance Liquid Chromatography
SFC：超临界流体色谱SFC: Supercritical Fluid Chromatography
除非作出相反的指示，本文例举的化合物使用ChemBioDraw Ultra 13.0命名和编号。Unless indicated to the contrary, compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.
对照例1：对照化合物1及其制备Comparative Example 1: Comparative Compound 1 and its preparation
Figure PCTCN2021129863-appb-000096
Figure PCTCN2021129863-appb-000096
对照化合物1参考专利申请WO2010141768A2合成。Reference compound 1 was synthesized with reference to patent application WO2010141768A2.
对照例2：对照化合物2及其制备Comparative Example 2: Comparative Compound 2 and its preparation
Figure PCTCN2021129863-appb-000097
Figure PCTCN2021129863-appb-000097
对照化合物2参考专利申请WO2017223016A1合成。Reference compound 2 was synthesized with reference to patent application WO2017223016A1.
对照例3：对照化合物3及其制备Comparative Example 3: Comparative Compound 3 and its preparation
Figure PCTCN2021129863-appb-000098
Figure PCTCN2021129863-appb-000098
对照化合物3参考专利申请WO2017223016A1合成。Reference compound 3 was synthesized with reference to patent application WO2017223016A1.
对照例4：对照化合物4及其制备Comparative Example 4: Comparative Compound 4 and its preparation
Figure PCTCN2021129863-appb-000099
Figure PCTCN2021129863-appb-000099
对照化合物4参考专利申请WO2019126098A1合成。Control compound 4 was synthesized with reference to patent application WO2019126098A1.
对照例5：对照化合物5及其制备Comparative Example 5: Comparative Compound 5 and its preparation
Figure PCTCN2021129863-appb-000100
Figure PCTCN2021129863-appb-000100
对照化合物5参考专利申请WO2019126084A1合成。Reference compound 5 was synthesized with reference to patent application WO2019126084A1.
制备例1：中间体A的合成Preparation Example 1: Synthesis of Intermediate A
(1S,3R)-3-羟基环己烷-1-甲酸甲酯(中间体A)的合成Synthesis of (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (intermediate A)
methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate(中间体A)methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate (Intermediate A)
Figure PCTCN2021129863-appb-000101
Figure PCTCN2021129863-appb-000101
中间体A的合成路线如下所示：The synthetic route of intermediate A is as follows:
Figure PCTCN2021129863-appb-000102
Figure PCTCN2021129863-appb-000102
第一步：(1S,5S)-4-碘-6-氧杂环[3.2.1]辛烷-7-酮(A-2)的合成The first step: Synthesis of (1S,5S)-4-iodo-6-oxacyclo[3.2.1]octan-7-one (A-2)
(1S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one(A-2)(1S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one(A-2)
Figure PCTCN2021129863-appb-000103
Figure PCTCN2021129863-appb-000103
将(S)-环己-3-烯-1-羧酸(8.1g)溶于DCM(135mL)和水(270mL)中，碳酸氢钠(10.79g，128.3mmol)，碘化钾(64.0g，385.5mmol)and碘(48.9g，192.6mmol)加入反应液。避光室温搅拌过夜。TLC监控反应完全，分液，水相用甲基叔丁基醚萃取(100mL×3)，合并有机相，无水硫酸钠干燥，浓缩得到产品(1S,5S)-4-碘-6-氧杂环[3.2.1]辛烷-7-酮(A-2)(13.6g，产率84％)，直接用于下一步反应。(S)-Cyclohex-3-ene-1-carboxylic acid (8.1 g) was dissolved in DCM (135 mL) and water (270 mL), sodium bicarbonate (10.79 g, 128.3 mmol), potassium iodide (64.0 g, 385.5 mmol) and iodine (48.9 g, 192.6 mmol) were added to the reaction. Stir overnight at room temperature in the dark. TLC monitored the completion of the reaction, the liquid was separated, the aqueous phase was extracted with methyl tert-butyl ether (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the product (1S,5S)-4-iodo-6-oxygen Heterocyclo[3.2.1]octan-7-one (A-2) (13.6 g, 84% yield) was used directly in the next reaction.
第二步：(1S,5R)-6-氧杂环[3.2.1]辛烷-7-酮(A-3)的合成Step 2: Synthesis of (1S,5R)-6-oxacyclo[3.2.1]octan-7-one (A-3)
(1S,5R)-6-oxabicyclo[3.2.1]octan-7-one(A-3)(1S,5R)-6-oxabicyclo[3.2.1]octan-7-one(A-3)
Figure PCTCN2021129863-appb-000104
Figure PCTCN2021129863-appb-000104
将(1S,5S)-4-碘-6-氧杂环[3.2.1]辛烷-7-酮(A-2)(13.2g，52.4mmol)溶于MeOH(150mL)中，加入乙酸钠(4.30g，52.4mmol)，氯化锂(2.22g，52.4mmol)和含量10％的干钯碳(1.11g)。氢气置换三次，氢气球室温搅拌反应过夜。反应液硅藻土过滤，浓缩，残余物加入甲基叔丁基醚(100mL)溶解，饱和碳酸氢钠洗涤一次，饱和亚硫酸钠洗涤一次，无水硫酸钠干燥，浓缩，柱层析分离得到白色固体(1S,5R)-6-氧杂环[3.2.1]辛烷-7-酮(A-3)(3.88g，产率58.7％)。(1S,5S)-4-iodo-6-oxacyclo[3.2.1]octan-7-one (A-2) (13.2 g, 52.4 mmol) was dissolved in MeOH (150 mL) and sodium acetate was added (4.30 g, 52.4 mmol), lithium chloride (2.22 g, 52.4 mmol) and 10% dry palladium on carbon (1.11 g). The hydrogen was replaced three times, and the reaction was stirred overnight with a hydrogen balloon at room temperature. The reaction solution was filtered through celite, concentrated, the residue was dissolved in methyl tert-butyl ether (100 mL), washed once with saturated sodium bicarbonate, once with saturated sodium sulfite, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid (1S,5R)-6-oxacyclo[3.2.1]octan-7-one (A-3) (3.88 g, 58.7% yield).
第三步：(1S,3R)-3-羟基环己烷-1-甲酸甲酯(中间体A)的合成The third step: the synthesis of (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (intermediate A)
methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate(中间体A)methyl(1S,3R)-3-hydroxycyclohexane-1-carboxylate (Intermediate A)
Figure PCTCN2021129863-appb-000105
Figure PCTCN2021129863-appb-000105
将(1S,5R)-6-氧杂环[3.2.1]辛烷-7-酮(A-3)(4.2g，33.3mmol)溶于MeOH(150mL)，反应液冷却至0-5℃，乙酰氯(7.5mL)滴加入反应液中，滴加完毕，升温至室温反应3h。TLC监测反应完毕，加入水(150mL)，二氯甲烷萃取(100mL×3)。有机相用无水硫酸钠干燥，浓缩至干，得到浅黄色油状物(1S,3R)-3-羟基环己烷-1-甲酸甲酯(中间体A)(4.63g，产率88％)。(1S,5R)-6-oxacyclo[3.2.1]octan-7-one (A-3) (4.2 g, 33.3 mmol) was dissolved in MeOH (150 mL), and the reaction solution was cooled to 0-5 °C , acetyl chloride (7.5 mL) was added dropwise to the reaction solution, the dropwise addition was completed, and the temperature was raised to room temperature for 3 h. The completion of the reaction was monitored by TLC, water (150 mL) was added, and the mixture was extracted with dichloromethane (100 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to give (1S,3R)-methyl 3-hydroxycyclohexane-1-carboxylate (Intermediate A) as a pale yellow oil (4.63 g, 88% yield) .
1H NMR(400MHz,CDCl 3)δ3.66(s,3H)，3.65-3.57(m,1H)，2.39-2.31(m,1H)，2.20-2.14(m,1H)，1.96-1.78(m,4H)，1.44-1.16(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ 3.66 (s, 3H), 3.65-3.57 (m, 1H), 2.39-2.31 (m, 1H), 2.20-2.14 (m, 1H), 1.96-1.78 (m ,4H), 1.44-1.16(m,4H).
制备例2：中间体B的合成Preparation Example 2: Synthesis of Intermediate B
(1S,3S)-3-((6-溴-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体B)Methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate B)
methyl(1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(中间体B)methyl(1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate B)
Figure PCTCN2021129863-appb-000106
Figure PCTCN2021129863-appb-000106
中间体B的合成路线如下所示：The synthetic route of intermediate B is shown below:
Figure PCTCN2021129863-appb-000107
Figure PCTCN2021129863-appb-000107
在0℃下，向(1S,3R)-3-羟基环己烷-1-甲酸甲酯(中间体A)(1.10g，6.95mmol)，6-溴-2-甲基-吡啶-3-醇(1.19g，6.31mmol)和三丁基膦(2.55g，12.6mmol)的甲苯(20.0mL)溶液中滴加偶氮二甲酰二哌啶(3.19g，10.7mmol)，然后将混合物在氮气下80℃搅拌反应10小时。反应完成后，将反应液浓缩得到粗品，用硅胶柱分离纯化(石油醚：乙酸乙酯(V/V)＝1:0-20:1)得到(1S,3S)-3-((6-溴-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体B)(0.580g，产率30.3％)。To (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (Intermediate A) (1.10 g, 6.95 mmol), 6-bromo-2-methyl-pyridine-3- at 0 °C To a solution of alcohol (1.19 g, 6.31 mmol) and tributylphosphine (2.55 g, 12.6 mmol) in toluene (20.0 mL) was added azodicarbonyldipiperidine (3.19 g, 10.7 mmol) dropwise, then the mixture was added to The reaction was stirred at 80°C for 10 hours under nitrogen. After the completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain (1S,3S)-3-((6- Bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (Intermediate B) (0.580 g, 30.3% yield).
制备例3：中间体C的合成Preparation Example 3: Synthesis of Intermediate C
(1S,3S)-3-((2-甲基-6-(三丁基锡烷基)吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体C)Methyl (1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate C)
methyl(1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(中间体C)methyl(1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate C)
Figure PCTCN2021129863-appb-000108
Figure PCTCN2021129863-appb-000108
中间体C的合成路线如下所示：The synthetic route of intermediate C is as follows:
Figure PCTCN2021129863-appb-000109
Figure PCTCN2021129863-appb-000109
向(1S,3S)-3-((6-溴-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体B)(0.5g，1.52mmol)的二甲苯(10mL)溶液中加入四三苯基磷钯(88.02mg，76.17μmol)，六正丁基二锡(5.30g，9.14mmol，4.57mL)，在氮气氛围下，加热到135℃搅拌2h。冷却到室温，然后加入饱和氟化钾溶液(10mL)淬灭，再用乙酸乙酯(10mL×2)萃取，合并有机层，无水硫酸钠干燥，浓缩得到化合物(1S,3S)-3-((2-甲基-6-(三丁基锡烷基)吡啶-3-基)氧基)环己烷-1-羧酸甲酯(中间体C)(0.82g，粗品)。To (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (Intermediate B) (0.5 g, 1.52 mmol) Add tetrakistriphenylphosphonium palladium (88.02mg, 76.17μmol), hexa-n-butylditin (5.30g, 9.14mmol, 4.57mL) to the xylene (10mL) solution, under nitrogen atmosphere, heat to 135 ℃ and stir 2h. Cool to room temperature, then add saturated potassium fluoride solution (10 mL) to quench, then extract with ethyl acetate (10 mL×2), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate to obtain compound (1S,3S)-3- Methyl ((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (Intermediate C) (0.82 g, crude).
实施例1：目标化合物I-1的合成Example 1: Synthesis of target compound I-1
(1S,3S)-3-((2-(5-氯-3-(((4-环丙氧基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-甲酸(目标化合物I-1)(1S,3S)-3-((2-(5-Chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methyl Pyrimidine-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-1)
(1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-1)(1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy )cyclohexane-1-carboxylic acid (target compound I-1)
Figure PCTCN2021129863-appb-000110
Figure PCTCN2021129863-appb-000110
目标化合物I-1合成路线如下所示：The synthetic route of target compound I-1 is as follows:
Figure PCTCN2021129863-appb-000111
Figure PCTCN2021129863-appb-000111
第一步：2-溴-4-甲基嘧啶-5-酚(I-1B)的合成The first step: the synthesis of 2-bromo-4-methylpyrimidin-5-ol (I-1B)
2-bromo-4-methylpyrimidin-5-ol(I-1B)2-bromo-4-methylpyrimidin-5-ol(I-1B)
Figure PCTCN2021129863-appb-000112
Figure PCTCN2021129863-appb-000112
在室温下，将2-氯-4-甲基嘧啶-5-酚(7g，48.42mmol)加入到33％溴化氢水溶液(104.30g，386.72mmol，70.00mL)中，然后在100℃下搅拌1小时。待反应液冷却到室温后，将反应液倒入冰水(100mL)中，然后用乙酸乙酯(100mL×3)萃取，合并有机层，旋干得到化合物2-溴-4-甲基嘧啶-5-酚(I-1B)(8.5g，产率92.87％)。直接用于下一步。2-Chloro-4-methylpyrimidin-5-ol (7 g, 48.42 mmol) was added to 33% aqueous hydrogen bromide (104.30 g, 386.72 mmol, 70.00 mL) at room temperature, followed by stirring at 100 °C 1 hour. After the reaction solution was cooled to room temperature, the reaction solution was poured into ice water (100 mL), then extracted with ethyl acetate (100 mL×3), the organic layers were combined, and spin-dried to obtain the compound 2-bromo-4-methylpyrimidine- 5-Phenol (I-1B) (8.5 g, 92.87% yield). used directly in the next step.
第二步：(1S,3S)-3-((2-溴-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-1C)的合成methyl(1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1C)The second step: the synthesis of methyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-1C) methyl( 1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1C)
Figure PCTCN2021129863-appb-000113
Figure PCTCN2021129863-appb-000113
在0℃氮气保护下，向2-溴-4-甲基嘧啶-5-酚(5g，26.45mmol)，(1S,3R)-3-羟基环己烷 -1-甲酸甲酯(中间体A)(8.37g，52.91mmol)和三苯基膦(13.88g，52.91mmol)的四氢呋喃(50mL)溶液中加入偶氮二羧酸二异丙酯(10.70g，52.91mmol)，然后反应液在室温下搅拌12小时。将反应液减压浓缩得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝5:1-1:1)得化合物(1S,3S)-3-((2-溴-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-1C)(6g，产率68.90％)。To 2-bromo-4-methylpyrimidin-5-ol (5 g, 26.45 mmol), (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (Intermediate A) under nitrogen protection at 0 °C ) (8.37 g, 52.91 mmol) and triphenylphosphine (13.88 g, 52.91 mmol) in tetrahydrofuran (50 mL) was added diisopropyl azodicarboxylate (10.70 g, 52.91 mmol), and then the reaction solution was cooled at room temperature under stirring for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate V/V)=5:1-1:1) to obtain compound (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl) )oxy)cyclohexane-1-carboxylic acid methyl ester (I-1C) (6 g, 68.90% yield).
第三步：(1S,3S)-3-((2-(3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-1D)的合成The third step: (1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl Synthesis of Esters (I-1D)
methyl(1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1D)methyl(1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1D)
Figure PCTCN2021129863-appb-000114
Figure PCTCN2021129863-appb-000114
在室温下，将(3-甲酰基噻吩-2-基)硼酸(2.13g，13.67mmol)，(1S,3S)-3-((2-溴-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(3g，9.11mmol)，三叔丁基磷烷钯(400mg，782.70μmol)和氟化钾(3.18g，54.68mmol)加入到四氢呋喃(50mL)溶液中，置换氮气，然后在室温下搅拌10小时。将反应液减压浓缩得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝10:1-5:1)得化合物(1S,3S)-3-((2-(3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-1D)(2.5g，产率76.11％)。At room temperature, (3-formylthiophen-2-yl)boronic acid (2.13 g, 13.67 mmol), (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy yl)cyclohexane-1-carboxylate (3 g, 9.11 mmol), palladium tri-tert-butylphosphine (400 mg, 782.70 μmol) and potassium fluoride (3.18 g, 54.68 mmol) were added to a solution of tetrahydrofuran (50 mL) was replaced with nitrogen, followed by stirring at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate V/V)=10:1-5:1) to obtain compound (1S,3S)-3-((2-(3-formylthiophen-2-yl) -4-Methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1D) (2.5 g, 76.11% yield).
第四步：(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-1E)的合成The fourth step: (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1 -Synthesis of methyl carboxylate (I-1E)
methyl(1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1E)methyl(1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1E)
Figure PCTCN2021129863-appb-000115
Figure PCTCN2021129863-appb-000115
在室温下，向(1S,3S)-3-((2-(3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(2.76g，7.66mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入N-氯代丁二酰亚胺(1.12g，8.42mmol)，然后反应液在40℃下搅拌1小时。反应液用乙酸乙酯(25mL×3)萃取，合并有机层，得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝15:1-1:1)得化合物(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-1E)(2.3g，产率76.06％)。To (1S,3S)-3-((2-(3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid at room temperature To a solution of methyl ester (2.76 g, 7.66 mmol) in N,N-dimethylformamide (20 mL) was added N-chlorosuccinimide (1.12 g, 8.42 mmol), then the reaction solution was stirred at 40°C 1 hour. The reaction solution was extracted with ethyl acetate (25 mL×3), and the organic layers were combined to obtain a crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate V/V)=15:1-1:1) to obtain compound (1S,3S)-3-((2-(5-chloro-3-formylthiophene- 2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1E) (2.3 g, 76.06% yield).
第五步：(1S,3S)-3-((2-(5-氯-3-(((4-环丙氧基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧)环己烷-1-羧酸甲酯(I-1F)的合成Step 5: (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)- Synthesis of methyl 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-1F)
methyl(1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1F)methyl(1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl) oxy)cyclohexane-1-carboxylate(I-1F)
Figure PCTCN2021129863-appb-000116
Figure PCTCN2021129863-appb-000116
在室温下，向(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(0.2g，506.49μmol)和4-环丙氧基嘧啶-2-胺(91.88mg，607.79μmol)的甲醇(2mL)溶液中加入醋酸(304.16μg，5.06μmol，0.29μL)，在室温下搅拌12小时后再加入氰基硼氢化钠(95.49mg，1.52mmol)，然后在室温下搅拌2小时。反应液直接过滤，滤液浓缩得粗产品。粗产品纯化通过制备分离得到化合物(1S,3S)-3-((2-(5-氯-3-(((4-环丙氧基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧)环己烷-1-羧酸甲酯(I-1F)(0.1g，产率37.25％)。To (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane- To a solution of methyl 1-carboxylate (0.2 g, 506.49 μmol) and 4-cyclopropoxypyrimidin-2-amine (91.88 mg, 607.79 μmol) in methanol (2 mL) was added acetic acid (304.16 μg, 5.06 μmol, 0.29 μL) ), stirred at room temperature for 12 hours and then added sodium cyanoborohydride (95.49 mg, 1.52 mmol), followed by stirring at room temperature for 2 hours. The reaction solution was directly filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative isolation to give compound (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophene-2 -yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-1F) (0.1 g, 37.25% yield).
第六步：(1S,3S)-3-((2-(5-氯-3-(((4-环丙氧基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-1)的合成Step 6: (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)- Synthesis of 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-1)
(1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-1)(1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy )cyclohexane-1-carboxylic acid (target compound I-1)
Figure PCTCN2021129863-appb-000117
Figure PCTCN2021129863-appb-000117
在室温下，向(1S,3S)-3-((2-(5-氯-3-(((4-环丙氧基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧)环己烷-1-羧酸甲酯(0.1g，188.67μmol)的四氢呋喃(2mL)溶液中加入一水合氢氧化锂(39mg，943.33μmol)，然后在室温下搅拌12小时。反应液用柠檬酸调节pH到中性，再用乙酸乙酯(15mL×2)萃取，合并有机层，得到粗产品。粗产品纯化通过制备分离(羧酸条件)得到化合物(1S,3S)-3-((2-(5-氯-3-(((4-环丙氧基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-1)(2mg，产率2.05％)。To (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl) at room temperature To a solution of methyl-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (0.1 g, 188.67 μmol) in tetrahydrofuran (2 mL) was added lithium hydroxide monohydrate (39 mg, 943.33 μmol), It was then stirred at room temperature for 12 hours. The reaction solution was adjusted to neutral pH with citric acid, extracted with ethyl acetate (15 mL×2), and the organic layers were combined to obtain a crude product. Purification of crude product by preparative isolation (carboxylic acid conditions) to give compound (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methan yl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-1) (2 mg, 2.05% yield).
1H NMR(400MHz,CDCl 3)δ8.32(s,1H),7.91(s,1H),7.06(s,1H),6.00(s,1H),4.69-4.93(m,3H),4.31(s,1H),2.76(s,1H),2.51(s,3H),1.79-1.96(m,4H),1.63(m,4H),0.84(s,4H). 1 H NMR (400MHz, CDCl 3 )δ8.32(s,1H), 7.91(s,1H), 7.06(s,1H), 6.00(s,1H), 4.69-4.93(m,3H), 4.31( s, 1H), 2.76(s, 1H), 2.51(s, 3H), 1.79-1.96(m, 4H), 1.63(m, 4H), 0.84(s, 4H).
LC-MS,M/Z(ESI):516.3[M+H] + LC-MS, M/Z(ESI): 516.3[M+H] +
实施例2：目标化合物I-2的合成Example 2: Synthesis of target compound I-2
(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-2)(1S,3S)-3-((6-(5-Chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)
(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-2)(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexane-1-carboxylic acid (target compound I-2)
Figure PCTCN2021129863-appb-000118
Figure PCTCN2021129863-appb-000118
目标化合物I-2的合成路线如下所示：The synthetic route of the target compound I-2 is as follows:
Figure PCTCN2021129863-appb-000119
Figure PCTCN2021129863-appb-000119
第一步：(1S,3S)-3-((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-2A)的合成The first step: (1S,3S)-3-((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl Synthesis of Esters (I-2A)
methyl(1S,3S)-3-((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2A)methyl(1S,3S)-3-((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2A)
Figure PCTCN2021129863-appb-000120
Figure PCTCN2021129863-appb-000120
在室温下，将(1S,3S)-3-((6-溴-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(2.2g，6.70mmol)(中间体B)，(3-甲酰基-2-噻嗯基)硼酸(2.09g，13.41mmol)和氟化钾(2.34g， 40.22mmol)加入到四氢呋喃(30mL)中，然后在氮气保护下加入双(三叔丁基膦)钯(274.06mg，536.26μmol)，在室温搅拌4小时，将反应液用水(30mL)稀释，然后用乙酸乙酯(30mL×2)萃取，合并有机层，得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝15:1-1:1)得黄色油状化合物(1S,3S)-3-((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-2A)(2.25g，产率93.38％)。Methyl (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (2.2 g, 6.70 mmol) ( Intermediate B), (3-formyl-2-thienyl)boronic acid (2.09 g, 13.41 mmol) and potassium fluoride (2.34 g, 40.22 mmol) were added to tetrahydrofuran (30 mL), then under nitrogen Bis(tri-tert-butylphosphine)palladium (274.06 mg, 536.26 μmol) was stirred at room temperature for 4 hours, the reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (30 mL×2), and the organic layers were combined to obtain a crude product . Separation and purification with silica gel column (petroleum ether:ethyl acetate V/V)=15:1-1:1) to obtain yellow oily compound (1S,3S)-3-((6-(3-formylthiophene-2- (1-2A) (2.25 g, 93.38% yield).
第二步：(1S,3S)-3-((6-(3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-2B)的合成The second step: (1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- Synthesis of Methyl Carboxylate (I-2B)
methyl(1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2B)methyl(1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2B)
Figure PCTCN2021129863-appb-000121
Figure PCTCN2021129863-appb-000121
在室温下，将(1S,3S)-3-(((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(3.8g，10.57mmol)加入到甲醇(20mL)溶液中，在0℃下加入硼氢化钠(599.95mg，15.86mmol)，然后将反应液在0℃下搅拌0.5小时。反应液用水(10mL)淬灭，然后用乙酸乙酯(15mL×2)萃取，合并有机层，得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝5:1-1:1)得化合物(1S,3S)-3-((6-(3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-2B)(3.28g，产率85.83％)。At room temperature, (1S,3S)-3-(((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxy Methyl acid (3.8 g, 10.57 mmol) was added to methanol (20 mL) solution, sodium borohydride (599.95 mg, 15.86 mmol) was added at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 hours. The reaction solution was water (10mL) quenched, then extracted with ethyl acetate (15mL×2), the organic layers were combined to obtain crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate V/V)=5:1-1:1) The compound (1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid was obtained Methyl ester (I-2B) (3.28 g, 85.83% yield).
第三步：(1S,3S)-3-((6-(5-氯-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-2C)的合成The third step: (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Synthesis of Methyl Alkane-1-Carboxylic Acid (I-2C)
methyl(1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2C)methyl(1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2C)
Figure PCTCN2021129863-appb-000122
Figure PCTCN2021129863-appb-000122
在室温下，向(1S,3S)-3-((6-(3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(3.28g，9.07mmol)的N,N-二甲基甲酰胺(18mL)溶液中加入N-氯代丁二酰亚胺(1.33g，9.98mmol)，然后在45℃下搅拌12小时。反应液用乙酸乙酯(20mL×2)萃取，合并有机层，得到粗品。用硅胶柱分离纯化(石油醚：乙酸乙酯V/V)＝15:1-1:1)得化合物(1S,3S)-3-((6-(5-氯-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-2C)(2.4g，产率66.80％)。To (1S,3S)-3-((6-(3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1 at room temperature - To a solution of methyl carboxylate (3.28 g, 9.07 mmol) in N,N-dimethylformamide (18 mL) was added N-chlorosuccinimide (1.33 g, 9.98 mmol), then at 45°C Stir for 12 hours. The reaction solution was extracted with ethyl acetate (20 mL×2), and the organic layers were combined to obtain a crude product. Separation and purification with silica gel column (petroleum ether: ethyl acetate V/V)=15:1-1:1) to obtain compound (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)) )thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2C) (2.4 g, 66.80% yield).
第四步：(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-2D)的合成Fourth step: (1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)- Synthesis of methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2D)
methyl(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylatemethyl(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl) oxy)cyclohexane-1-carboxylate
Figure PCTCN2021129863-appb-000123
Figure PCTCN2021129863-appb-000123
在室温下，将(1S,3S)-3-((6-(5-氯-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(0.2g，505.18μmol)加入到四氢呋喃(5mL)溶液中，在0℃下加入钠氢(18.19mg，454.66μmol，60％含量)，搅拌0.5小时后，加入2-氯-4-异丙基-嘧啶(118.68mg，757.77μmol)，然后反应液在室温下搅拌2小时。反应液用水(1mL)淬灭，反应液减压浓缩得粗品，过柱得到化合物(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-2D)(0.26g，产率99.73％)。At room temperature, the (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) ring Hexane-1-carboxylate methyl ester (0.2 g, 505.18 μmol) was added to tetrahydrofuran (5 mL) solution, and sodium hydrogen (18.19 mg, 454.66 μmol, 60% content) was added at 0° C. After stirring for 0.5 hours, the 2-Chloro-4-isopropyl-pyrimidine (118.68 mg, 757.77 μmol) and the reaction was stirred at room temperature for 2 hours. The reaction solution was quenched with water (1 mL), and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was passed through a column to obtain compound (1S,3S)-3-((6-(5-chloro-3-((((4-isopropylpyrimidine- 2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2D) (0.26 g, yield 99.73%).
第五步：(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(化合物I-2)的合成Fifth step: (1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)- Synthesis of 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (compound I-2)
(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(化合物I-2)(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexane-1-carboxylic acid (Compound I-2)
Figure PCTCN2021129863-appb-000124
Figure PCTCN2021129863-appb-000124
在室温下，向(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(0.26g，503.83μmol)的四氢呋喃(2mL)和水(0.2mL)溶液中加入一水合氢氧化锂(105.71mg，2.52mmol)，然后在室温下搅拌1小时。反应液用乙酸乙酯(10mL×3)萃取，合并有机层，得到粗品。用硅胶板纯化得化合物(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-2)(0.014g，产率5.14％)。To (1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl) at room temperature To a solution of methyl-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.26 g, 503.83 μmol) in tetrahydrofuran (2 mL) and water (0.2 mL) was added lithium hydroxide monohydrate ( 105.71 mg, 2.52 mmol), then stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (10 mL×3), and the organic layers were combined to obtain a crude product. The compound (1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl was purified by silica gel plate )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2) (0.014 g, 5.14% yield).
1H NMR(400MHz,CDCl 3)δ8.37(d,1H),7.42(d,1H),7.19-7.08(m,2H),6.81(d,1H),5.53(s,2H),4.61(br s,1H),2.96-2.89(m,1H),2.76(br t,1H),2.46(s,3H),2.06(br d,1H),1.98-1.78(m,3H),1.75-1.50(m,4H),1.26(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.37(d,1H), 7.42(d,1H), 7.19-7.08(m,2H), 6.81(d,1H), 5.53(s,2H), 4.61( br s,1H),2.96-2.89(m,1H),2.76(br t,1H),2.46(s,3H),2.06(br d,1H),1.98-1.78(m,3H),1.75-1.50 (m,4H),1.26(d,6H).
LC-MS,M/Z(ESI):502.1[M+H] +。 LC-MS, M/Z (ESI): 502.1 [M+H] + .
实施例3：目标化合物I-3的制备Example 3: Preparation of target compound I-3
(1S,3S)-3-((6-(5-氯-3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-3)(1S,3S)-3-((6-(5-Chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophene -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
(1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-3)(1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)- 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
Figure PCTCN2021129863-appb-000125
Figure PCTCN2021129863-appb-000125
目标化合物I-3的合成路线如下所示：The synthetic route of the target compound I-3 is as follows:
Figure PCTCN2021129863-appb-000126
Figure PCTCN2021129863-appb-000126
第一步：(3-环丙基丙-1-炔-1-基)三甲基硅烷(I-3B)的合成The first step: Synthesis of (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (I-3B)
(3-cyclopropylprop-1-yn-1-yl)trimethylsilane(I-3B)(3-cyclopropylprop-1-yn-1-yl)trimethylsilane(I-3B)
Figure PCTCN2021129863-appb-000127
Figure PCTCN2021129863-appb-000127
在-78℃，氮气保护下，向乙炔基(三甲基)硅烷(727.53mg，7.41mmol)的四氢呋喃(10mL)溶液中加入正丁基锂(2.5M，3.85mL)，在-78℃下搅拌30分钟，然后升到0℃搅 拌30分钟后再降到-78℃，将六甲基磷酰三胺(1.99g，11.11mmol)加入到反应液后搅拌30分钟后再加入溴甲基环丙烷(1g，7.41mmol，709.22μL)，然后在室温下搅拌12小时。将反应液用乙酸乙酯(20mL×2)萃取，合并有机层，得到化合物3-环丙基丙-1-炔基(三甲基)硅烷(I-3B)(1g，产率88.64％)。直接用于下一步。To a solution of ethynyl(trimethyl)silane (727.53 mg, 7.41 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M, 3.85 mL) at -78 °C under nitrogen protection, at -78 °C Stir for 30 minutes, then rise to 0 °C and stir for 30 minutes, then drop to -78 °C, add hexamethylphosphoric triamide (1.99 g, 11.11 mmol) to the reaction solution, stir for 30 minutes, and then add bromomethyl ring Propane (1 g, 7.41 mmol, 709.22 μL), then stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate (20 mL×2), and the organic layers were combined to obtain the compound 3-cyclopropylprop-1-ynyl(trimethyl)silane (I-3B) (1 g, yield 88.64%) . used directly in the next step.
第二步：(1S,3S)-3-((6-(3-(溴甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3C)的合成The second step: (1S,3S)-3-((6-(3-(bromomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Synthesis of Alkane-1-Carboxylic Acid Methyl (I-3C)
methyl(1S,3S)-3-((6-(3-(bromomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3C)methyl(1S,3S)-3-((6-(3-(bromomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3C)
Figure PCTCN2021129863-appb-000128
Figure PCTCN2021129863-appb-000128
在0℃下，向(1S,3S)-3-((6-(5-氯-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-2C)(0.2g，505.18μmol)的乙二醇二甲醚(5mL)溶液中加入三溴化磷(341.86mg，1.26mmol)，然后反应液在室温下搅拌12小时。反应液温度降到0℃后加入饱和碳酸氢钠溶液(3mL)，再用乙酸乙酯(15mL×2)萃取，合并有机层，得到化合物(1S,3S)-3-((6-(3-(溴甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3C)(0.231g，产率99.67％)。直接用于下一步。To (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) at 0 °C To a solution of methyl cyclohexane-1-carboxylate (I-2C) (0.2 g, 505.18 μmol) in ethylene glycol dimethyl ether (5 mL) was added phosphorus tribromide (341.86 mg, 1.26 mmol), and then the reaction solution Stir at room temperature for 12 hours. The temperature of the reaction solution dropped to 0 °C, and then saturated sodium bicarbonate solution (3 mL) was added, followed by extraction with ethyl acetate (15 mL×2), and the organic layers were combined to obtain compound (1S,3S)-3-((6-(3 -(Bromomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3C) (0.231 g, yield rate 99.67%). used directly in the next step.
第三步：(1S,3S)-3-((6-(3-(叠氮甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3D)的合成The third step: (1S,3S)-3-((6-(3-(azidomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy) ring Synthesis of hexane-1-carboxylate methyl ester (I-3D)
methyl(1S,3S)-3-((6-(3-(azidomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3D)methyl(1S,3S)-3-((6-(3-(azidomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3D)
Figure PCTCN2021129863-appb-000129
Figure PCTCN2021129863-appb-000129
在室温下，向(1S,3S)-3-((6-(3-(溴甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(0.231g，503.49μmol)的N,N-二甲基甲酰胺(5mL)溶液中加入叠氮钠(32.73mg，503.49μmol)然后在80℃下搅拌1小时。将反应液用乙酸乙酯(10mL×2)萃取，合并有机层，得到化合物(1S,3S)-3-((6-(3-(叠氮甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3D)(0.2g，产率94.37％)。To the (1S,3S)-3-((6-(3-(bromomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy) ring at room temperature To a solution of methyl hexane-1-carboxylate (0.231 g, 503.49 μmol) in N,N-dimethylformamide (5 mL) was added sodium azide (32.73 mg, 503.49 μmol) and stirred at 80°C for 1 hour . The reaction solution was extracted with ethyl acetate (10 mL×2), and the organic layers were combined to obtain compound (1S,3S)-3-((6-(3-(azidomethyl)-5-chlorothiophen-2-yl) )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3D) (0.2 g, 94.37% yield).
第四步：(1S,3S)-3-((6-(5-氯-3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3E)的合成The fourth step: (1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl) Synthesis of methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E)
methyl(1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3E)methyl(1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl) -2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3E)
Figure PCTCN2021129863-appb-000130
Figure PCTCN2021129863-appb-000130
在室温下，将(1S,3S)-3-((6-(3-(叠氮甲基)-5-氯噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(0.1g，237.58μmol)，(3-环丙基丙-1-炔-1-基)三甲基硅烷(108.56mg，712.74μmol)，抗坏血酸钠(9.41mg，47.52μmol)和无水硫酸铜(7.58mg，47.52μmol)的四氢呋喃溶液中(2mL)和水(2mL)在20℃下搅拌2小时。反应完全后，将反应混合物用水(5mL)稀释，然后用乙酸乙酯(10mL×2)萃取，合并有机层浓缩得粗品，粗品用硅胶板纯化得化合物(1S,3S)-3-((6-(5-氯-3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-3E)(0.119g，产率99.97％)。(1S,3S)-3-((6-(3-(azidomethyl)-5-chlorothiophen-2-yl)-2-methylpyridin-3-yl)oxy) at room temperature Methyl cyclohexane-1-carboxylate (0.1 g, 237.58 μmol), (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (108.56 mg, 712.74 μmol), sodium ascorbate (9.41 mg, 47.52 μmol) and anhydrous copper sulfate (7.58 mg, 47.52 μmol) in tetrahydrofuran (2 mL) and water (2 mL) were stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (5 mL), then extracted with ethyl acetate (10 mL×2), the organic layers were combined and concentrated to obtain crude product, which was purified by silica gel plate to obtain compound (1S,3S)-3-((6 -(5-Chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3E) (0.119 g, 99.97% yield).
第五步：(1S,3S)-3-((6-(5-氯-3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-3)的合成The fifth step: (1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl) Synthesis of methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
(1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-3)(1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)- 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
Figure PCTCN2021129863-appb-000131
Figure PCTCN2021129863-appb-000131
室温下，向(1S,3S)-3-((6-(5-氯-3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(1.05g，2.65mmol)的四氢呋喃(2mL)中加入氢氧化锂水溶液(1.0M，498.96μL)，在室温搅拌2小时。反应完全后，将反应液倒入水(10mL)中,用乙酸乙酯(10mL×3)萃取，减压浓缩得化合物(1S,3S)-3-((6-(5-氯-3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-3)(0.16g，产率15.84％)。At room temperature, to (1S,3S)-3-((6-(5-chloro-3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl) Lithium hydroxide was added to methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (1.05 g, 2.65 mmol) in tetrahydrofuran (2 mL) Aqueous solution (1.0 M, 498.96 [mu]L), stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL×3), and concentrated under reduced pressure to obtain compound (1S,3S)-3-((6-(5-chloro-3- ((4-(Cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) Cyclohexane-1-carboxylic acid (target compound I-3) (0.16 g, yield 15.84%).
(160mg,产率15.84％)。(160 mg, 15.84% yield).
1H NMR(400MHz,CDCl 3)δ7.63(s,1H),7.25(s,1H),7.16(d,1H),6.78(s,1H),5.80(s,2H),4.70(br s,1H),2.93-2.80(m,1H),2.64(d,2H),2.51(s,3H),2.13(br s,1H),2.04-1.91(m,3H),1.85-1.64(m,4H),1.07-0.94(m,1H),0.57-0.45(m,2H),0.23-0.14(m,2H). 1 H NMR (400MHz, CDCl 3 )δ7.63(s,1H), 7.25(s,1H), 7.16(d,1H), 6.78(s,1H), 5.80(s,2H), 4.70(br s ,1H),2.93-2.80(m,1H),2.64(d,2H),2.51(s,3H),2.13(br s,1H),2.04-1.91(m,3H),1.85-1.64(m, 4H),1.07-0.94(m,1H),0.57-0.45(m,2H),0.23-0.14(m,2H).
LC-MS,M/Z(ESI):487.0[M+H] +。 LC-MS, M/Z (ESI): 487.0 [M+H] + .
实施例4：目标化合物I-4的合成Example 4: Synthesis of target compound I-4
(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二恶唑-5-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-4)(1S,3S)-3-((6-(5-Chloro-3-(((2,2-difluorobenzo[d][1,3]bisoxazol-5-yl)amino)methyl )thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)
(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-4)(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)
Figure PCTCN2021129863-appb-000132
Figure PCTCN2021129863-appb-000132
目标化合物I-4的合成路线如下所示：The synthetic route of the target compound I-4 is as follows:
Figure PCTCN2021129863-appb-000133
Figure PCTCN2021129863-appb-000133
第一步：(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-4B)的合成The first step: (1S,3S)-3-((6-(5-chloro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1 -Synthesis of methyl carboxylate (I-4B)
methyl(1S,3S)-3-((6-(5-chloro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-4B)methyl(1S,3S)-3-((6-(5-chloro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-4B)
Figure PCTCN2021129863-appb-000134
Figure PCTCN2021129863-appb-000134
室温下，向(1S,3S)-3-((6-(3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(1.61g，4.5mmol)的DMF(10mL)溶液中加入N-氯代丁二酰亚胺(0.89g，5.0mmol)，然后在45℃下搅拌12小时。反应液用乙酸乙酯(10mL×2)萃取，合并有机层，得到粗品。 用硅胶柱分离纯化(石油醚：乙酸乙酯(V/V)＝15:1-1:1)得化合物(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-4B)(1.1g，产率60％)。To (1S,3S)-3-((6-(3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl at room temperature To a solution of the ester (1.61 g, 4.5 mmol) in DMF (10 mL) was added N-chlorosuccinimide (0.89 g, 5.0 mmol), followed by stirring at 45°C for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL×2), and the organic layers were combined to obtain a crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=15:1-1:1) to obtain compound (1S,3S)-3-((6-(5-chloro-3-formylthiophene) Methyl -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-4B) (1.1 g, 60% yield).
第二步：(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧-5-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-4C)的合成The second step: (1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxo-5-yl)amino) )methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate methyl ester (I-4C)
methyl(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-4C)methyl(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)methyl)thiophen-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-4C)
Figure PCTCN2021129863-appb-000135
Figure PCTCN2021129863-appb-000135
室温下，将(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-4B)(0.1g，0.254mmol)加至3mL甲醇中，再加入2,2-二氟苯并[d][1,3]二氧-5-胺(0.13g，0.762mmol)，氮气保护下搅拌过夜，后加入硼氢化钠(0.096g，2.54mmol)，室温反应2h，TLC(PE:EA＝5:1)显示原料反应完，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得无色油状化合物(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧-5-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-4C)(0.12g，产率86％)。At room temperature, (1S,3S)-3-((6-(5-chloro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1 -Methyl carboxylate (I-4B) (0.1 g, 0.254 mmol) was added to 3 mL of methanol followed by 2,2-difluorobenzo[d][1,3]dioxo-5-amine (0.13 g , 0.762 mmol), stirred overnight under nitrogen protection, then added sodium borohydride (0.096 g, 2.54 mmol), reacted at room temperature for 2 h, TLC (PE:EA=5:1) showed that the reaction of the raw materials was completed, concentrated, and the residue was washed with silica gel column Separation and purification (petroleum ether:ethyl acetate (V/V)=5:1) gave colorless oily compound (1S,3S)-3-((6-(5-chloro-3-((((2,2-) Difluorobenzo[d][1,3]dioxo-5-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- Methyl carboxylate (I-4C) (0.12 g, 86% yield).
第三步：(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二恶唑-5-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-4)的合成The third step: (1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]bisoxazol-5-yl)) Synthesis of Amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)
(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid(目标化合物I-4)(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid (target compound I-4)
Figure PCTCN2021129863-appb-000136
Figure PCTCN2021129863-appb-000136
室温下，(1S,3S)-3-((6-(5-氯-3-((2,2-二氟苯并[d][1,3]二氧-5-基)氨基)甲基)噻吩-2-基)-2- 甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(024B)(0.12g，0.218mmol)加至2mL的四氢呋喃溶液中，再加入0.2mL水，一水合氢氧化锂(0.061g，2.54mmol)，室温反应4h，用4.0M氯化氢的1,4-二氧六环溶液调节pH到7，浓缩干，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:2)得白色固体化合物(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二恶唑-5-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-4)(40mg，产率34.5％)。(1S,3S)-3-((6-(5-Chloro-3-((2,2-difluorobenzo[d][1,3]dioxo-5-yl)amino)methane at room temperature methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (024B) (0.12 g, 0.218 mmol) was added to 2 mL of a solution in tetrahydrofuran, Then add 0.2 mL of water, lithium hydroxide monohydrate (0.061 g, 2.54 mmol), react at room temperature for 4 h, adjust the pH to 7 with 4.0 M hydrogen chloride solution in 1,4-dioxane, concentrate to dryness, and use a silica gel column for the residue. Separation and purification (petroleum ether:ethyl acetate (V/V)=1:2) gave white solid compound (1S,3S)-3-((6-(5-chloro-3-((((2,2-di) Fluorobenzo[d][1,3]bisoxazol-5-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1- Carboxylic acid (target compound I-4) (40 mg, 34.5% yield).
1H NMR(400MHz,DMSO-d 6)δ12.17(s,1H),7.43-7.36(dd,2H),7.05(t,2H),6.65(d,1H),6.38-6.32(m,2H),4.75(s,1H),4.31(d,2H),2.62-2.57(m,1H),2.39(s,3H),2.00-1.45(m,7H). 1 H NMR (400MHz, DMSO-d 6 ) δ 12.17(s, 1H), 7.43-7.36(dd, 2H), 7.05(t, 2H), 6.65(d, 1H), 6.38-6.32(m, 2H) ), 4.75(s, 1H), 4.31(d, 2H), 2.62-2.57(m, 1H), 2.39(s, 3H), 2.00-1.45(m, 7H).
LC-MS,M/Z(ESI):537.1[M+H] +。 LC-MS, M/Z (ESI): 537.1 [M+H] + .
实施例5：目标化合物I-5的合成Example 5: Synthesis of target compound I-5
(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧杂-5-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-5)的合成(1S,3S)-3-((6-(5-Chloro-3-(((2,2-difluorobenzo[d][1,3]dioxan-5-yl)oxy)methan Synthesis of thiophene-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-5)(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)oxy)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
Figure PCTCN2021129863-appb-000137
Figure PCTCN2021129863-appb-000137
目标化合物I-5合成路线如下所示：The synthetic route of target compound I-5 is as follows:
Figure PCTCN2021129863-appb-000138
Figure PCTCN2021129863-appb-000138
第一步：(1S,3S)-3-((6-(5-氯-3-(氯甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-5A)的合成The first step: (1S,3S)-3-((6-(5-chloro-3-(chloromethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Synthesis of Methyl Alkane-1-carboxylate (I-5A)
methyl(1S,3S)-3-((6-(5-chloro-3-(chloromethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5A)methyl(1S,3S)-3-((6-(5-chloro-3-(chloromethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5A)
Figure PCTCN2021129863-appb-000139
Figure PCTCN2021129863-appb-000139
在0℃下，向(1S,3S)-3-((6-(5-氯-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(0.2g，505.18μmol)(I-2C)的二氯甲烷(5mL)溶液中加入二氯亚砜(301.0mg，2.53mmol)，然后反应液在室温下搅拌2小时。浓缩干得(1S,3S)-3-((6-(5-氯-3-(氯甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-5A)(0.2g，产率96.0％)。直接用于下一步。To (1S,3S)-3-((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) at 0 °C To a solution of methyl cyclohexane-1-carboxylate (0.2 g, 505.18 μmol) (I-2C) in dichloromethane (5 mL) was added thionyl chloride (301.0 mg, 2.53 mmol), then the reaction solution was cooled at room temperature Stir for 2 hours. Concentrate to dryness to give (1S,3S)-3-((6-(5-chloro-3-(chloromethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane -Methyl 1-carboxylate (I-5A) (0.2 g, 96.0% yield). used directly in the next step.
第二步：(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧杂-5-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-5B)的合成The second step: (1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxan-5-yl)) Synthesis of Methyl Oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5B)
methyl(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)oxy)methyl)thiophen-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5B)methyl(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)oxy)methyl)thiophen-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5B)
Figure PCTCN2021129863-appb-000140
Figure PCTCN2021129863-appb-000140
在0℃下，向(1S,3S)-3-((6-(5-氯-3-(氯甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(0.2g，483μmol)的四氢呋喃(5mL)溶液中加入2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-醇(0.1g，580μmol)，再加入碳酸铯(236mg，725μmol)，然后反应液在室温下搅拌过夜。过滤，浓缩干得(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧杂-5-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-5B)(0.2g，产率74.9％)。直接用于下一步。To (1S,3S)-3-((6-(5-chloro-3-(chloromethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) at 0 °C To a solution of methyl cyclohexane-1-carboxylate (0.2 g, 483 μmol) in tetrahydrofuran (5 mL) was added 2,2-difluorobenzo[d][1,3]dioxol-5-ol (0.1 g, 580 μmol), cesium carbonate (236 mg, 725 μmol) was added, and the reaction was stirred at room temperature overnight. Filtration and concentration to give (1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxan-5-yl )oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5B) (0.2 g, 74.9% yield) ). used directly in the next step.
第三步：(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧杂-5-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-5)的合成The third step: (1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxan-5-yl)) Synthesis of oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound 1-5)
(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-5)(1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)oxy)methyl)thiophen-2-yl )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
Figure PCTCN2021129863-appb-000141
Figure PCTCN2021129863-appb-000141
室温下，向(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧杂-5-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(0.2g，362μmol)的四氢呋喃(1mL)和水(2mL)的混合液中加入氢氧化锂(17.4mg，725μmol)，在室温搅拌36小时。反应完全后，将反应液倒入水(5mL)中，减压浓缩掉四氢呋喃，用1M盐酸调节pH值至5-6，过滤收集固体干燥得化合物(1S,3S)-3-((6-(5-氯-3-(((2,2-二氟苯并[d][1,3]二氧杂-5-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-5)(153mg，产率78％)。At room temperature, to (1S,3S)-3-((6-(5-chloro-3-(((2,2-difluorobenzo[d][1,3]dioxan-5-yl) oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.2 g, 362 μmol) in tetrahydrofuran (1 mL) and water ( Lithium hydroxide (17.4 mg, 725 μmol) was added to the mixture of 2 mL), and the mixture was stirred at room temperature for 36 hours. After the reaction was completed, the reaction solution was poured into water (5 mL), the tetrahydrofuran was concentrated under reduced pressure, the pH was adjusted to 5-6 with 1M hydrochloric acid, and the solid was collected by filtration and dried to obtain compound (1S,3S)-3-((6- (5-Chloro-3-(((2,2-difluorobenzo[d][1,3]dioxan-5-yl)oxy)methyl)thiophen-2-yl)-2-methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound 1-5) (153 mg, 78% yield).
1H NMR(400MHz,DMSO-d 6)δ7.47(d,1H),7.35(d,1H),7.31(d,1H),7.25(d,1H),7.21(s,1H),6.83(dd,1H),5.17(s,2H),4.71(b,1H),2.52(s,1H),2.36(s,3H),1.84-1.72(m,4H),1.61-1.50(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ7.47(d,1H), 7.35(d,1H), 7.31(d,1H), 7.25(d,1H), 7.21(s,1H), 6.83( dd, 1H), 5.17(s, 2H), 4.71(b, 1H), 2.52(s, 1H), 2.36(s, 3H), 1.84-1.72(m, 4H), 1.61-1.50(m, 4H) .
LC-MS,M/Z(ESI):538.1[M+1] +。 LC-MS, M/Z (ESI): 538.1 [M+1] + .
实施例6：目标化合物I-6的合成Example 6: Synthesis of target compound I-6
(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-6)(1S,3S)-3-((6-(5-Chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6)
(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-6)(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexane-1-carboxylic acid (target compound I-6)
Figure PCTCN2021129863-appb-000142
Figure PCTCN2021129863-appb-000142
目标化合物I-6的合成路线如下所示：The synthetic route of the target compound I-6 is as follows:
Figure PCTCN2021129863-appb-000143
Figure PCTCN2021129863-appb-000143
第一步：4-异丙基嘧啶-2-胺(I-6B)的合成The first step: the synthesis of 4-isopropylpyrimidin-2-amine (I-6B)
4-isopropylpyrimidin-2-amine(I-6B)4-isopropylpyrimidin-2-amine(I-6B)
Figure PCTCN2021129863-appb-000144
Figure PCTCN2021129863-appb-000144
在室温下，将2-氯-4-异丙基嘧啶(500mg，3.19mmol)加入到氨水(5mL，含量30％)溶液中，然后在85℃下搅拌10小时。反应完全后，将反应液冷却到室温后过滤，收集滤饼得化合物4-异丙基嘧啶-2-胺(I-6B)(200mg，产率45.67％)。2-Chloro-4-isopropylpyrimidine (500 mg, 3.19 mmol) was added to a solution of aqueous ammonia (5 mL, content 30%) at room temperature, followed by stirring at 85°C for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and the filter cake was collected to obtain compound 4-isopropylpyrimidin-2-amine (I-6B) (200 mg, yield 45.67%).
第二步：(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-6C)的合成The second step: (1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-6C)
methyl(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-6C)methyl(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl) oxy)cyclohexane-1-carboxylate(I-6C)
Figure PCTCN2021129863-appb-000145
Figure PCTCN2021129863-appb-000145
在室温下，向(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-4B)(0.1g，253.88μmol)和4-异丙基嘧啶-2-胺(38.31mg，279.27μmol)的甲醇(10mL)溶液中，加入醋酸(1.52mg，25.39μmol，1.45μL)，在室温下搅拌2小时后，将氰基硼氢化钠(47.86mg，761.65μmol)加入到反应液中，然后在室温下搅拌1小时。将反应液减压浓缩得化合物(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(I-6C)(0.1g，产率76.47％)。To (1S,3S)-3-((6-(5-chloro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane- To a solution of methyl 1-carboxylate (I-4B) (0.1 g, 253.88 μmol) and 4-isopropylpyrimidin-2-amine (38.31 mg, 279.27 μmol) in methanol (10 mL) was added acetic acid (1.52 mg, 25.39 μmol, 1.45 μL), after stirring at room temperature for 2 hours, sodium cyanoborohydride (47.86 mg, 761.65 μmol) was added to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound (1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophene-2- (1-6C) (0.1 g, 76.47% yield).
第三步：(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-6)的合成The third step: (1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-6)
(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-6)(1S,3S)-3-((6-(5-chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexane-1-carboxylic acid (target compound I-6)
Figure PCTCN2021129863-appb-000146
Figure PCTCN2021129863-appb-000146
室温下，向(1S,3S)-3-((6-(5-氯-3-((((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧)环己烷-1-羧酸甲酯(0.1g，194.15μmol)的四氢呋喃(2mL)中，再加入一水合氢氧化锂溶液(1M，2mL)，在室温搅拌1小时。将反应液用1.0M盐酸调至pH＝6，加入水(10mL)，用乙酸乙酯(30mL×2)萃取减压浓缩得粗品，粗品经过硅胶板分离得白色固体状化合物(1S,3S)-3-((6-(5-氯-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧 代)环己羧酸(目标化合物I-6)(5mg，产率4.55％)。To (1S,3S)-3-((6-(5-chloro-3-((((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)- To methyl 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (0.1 g, 194.15 μmol) in tetrahydrofuran (2 mL) was added lithium hydroxide monohydrate solution (1 M, 2 mL), Stir at room temperature for 1 hour. The reaction solution was adjusted to pH=6 with 1.0M hydrochloric acid, added with water (10 mL), extracted with ethyl acetate (30 mL×2) and concentrated under reduced pressure to obtain a crude product, which was separated into a white solid through silica gel plate Compound (1S,3S)-3-((6-(5-Chloro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxo)cyclohexanecarboxylic acid (target compound 1-6) (5 mg, 4.55% yield).
1H NMR(400MHz,CDCl 3)δ8.18(s,1H),7.24(s,1H),7.00-7.15(m,3H),6.45(d,1H),4.68-4.70(m,3H),2.82-2.87(m,2H),2.59(s,3H),2.05-2.15(m,1H),1.85-2.04(m,4H),1.59-1.81(m,3H),1.28(d,6H). 1 H NMR (400MHz, CDCl 3 ) δ 8.18(s, 1H), 7.24(s, 1H), 7.00-7.15(m, 3H), 6.45(d, 1H), 4.68-4.70(m, 3H), 2.82-2.87(m, 2H), 2.59(s, 3H), 2.05-2.15(m, 1H), 1.85-2.04(m, 4H), 1.59-1.81(m, 3H), 1.28(d, 6H).
LC-MS,M/Z(ESI):501.2[M+H] +。 LC-MS, M/Z (ESI): 501.2 [M+H] + .
实施例7：目标化合物I-7的合成Example 7: Synthesis of target compound I-7
(1S,3S)-3-((6-(5-氯-3-(((5-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-7)(1S,3S)-3-((6-(5-Chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-7)
(1S,3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-7)(1S,3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexane-1-carboxylic acid (target compound I-7)
Figure PCTCN2021129863-appb-000147
Figure PCTCN2021129863-appb-000147
目标化合物I-7的合成路线如下所示：The synthetic route of the target compound I-7 is as follows:
Figure PCTCN2021129863-appb-000148
Figure PCTCN2021129863-appb-000148
第一步：(3S)-3-((6-(5-氯-3-(((5-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(I-7A)的合成The first step: (3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2- Synthesis of Methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-7A)
(3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(I-7A)(3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane -1-carboxylic acid(I-7A)
Figure PCTCN2021129863-appb-000149
Figure PCTCN2021129863-appb-000149
在0℃下，向(1S,3S)-3-(((6-(5-氯-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(100mg，252μmol)(I-2C)的四氢呋喃(1.00mL)溶液中加入氢化钠(9.09mg，227μmol，60％含量)，反应液在0℃下搅拌1.5小时后加入2-氯-5-异丙基嘧啶(47.4mg，303μmol)。反应液温度升至25℃搅拌2小时。反应完成后，向反应液中滴加饱和的氯化铵水溶液淬灭，淬灭完成后加入乙酸乙酯萃取(5.00mL)，有机相用饱和氯化钠水溶液洗涤(5.00mL)，无水硫酸钠干燥，过滤浓缩后制备分离(分离方法：柱子:Phenomenex luna C 18150*25mm*10um；流动相：A＝水+0.225体积％甲酸(99％)，B＝乙腈；梯度洗脱：43％-73％B，10分钟)得到目标产物(3S)-3-((6-(5-氯-3-(((5-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(32.0mg，产率25.1％)。 To (1S,3S)-3-((((6-(5-chloro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy at 0 °C ) methyl cyclohexane-1-carboxylate (100 mg, 252 μmol) (I-2C) in tetrahydrofuran (1.00 mL) was added sodium hydride (9.09 mg, 227 μmol, 60% content), and the reaction solution was stirred at 0°C After 1.5 hours, 2-chloro-5-isopropylpyrimidine (47.4 mg, 303 μmol) was added. The temperature of the reaction solution was raised to 25° C. and stirred for 2 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution was added dropwise to the reaction solution to quench After quenching, ethyl acetate was added for extraction (5.00 mL), the organic phase was washed with saturated aqueous sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated to prepare and separate (separation method: column: Phenomenex luna C 18 150*25mm*10um; mobile phase: A=water+0.225 vol% formic acid (99%), B=acetonitrile; gradient elution: 43%-73%B, 10 minutes) to obtain the target product (3S)-3-( (6-(5-Chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) Cyclohexane-1-carboxylic acid (32.0 mg, 25.1% yield).
第二步：(1S,3S)-3-((6-(5-氯-3-(((5-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-7)的合成Second step: (1S,3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)- Synthesis of 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-7)
(1S,3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-7)(1S,3S)-3-((6-(5-chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexane-1-carboxylic acid (target compound I-7)
Figure PCTCN2021129863-appb-000150
Figure PCTCN2021129863-appb-000150
化合物(3S)-3-((6-(5-氯-3-(((5-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(6)(32.0mg，63.4μmol)经过手性分离(分离方法：柱子：DAICEL CHIRALPAKAD(250mm*30mm,10μm)，流动相：A＝水+0.1％氨水，B＝乙醇；梯度：40％-40％B，1.80分钟，90分钟)得到目标产物(1S,3S)-3-((6-(5-氯-3-(((5-异丙基嘧啶-2-基)氧基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-7)(13.0mg，产率42.4％)。Compound (3S)-3-((6-(5-Chloro-3-(((5-isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (6) (32.0mg, 63.4μmol) was subjected to chiral separation (separation method: column: DAICEL CHIRALPAKAD (250mm*30mm, 10μm), mobile phase: A = water + 0.1% ammonia, B = ethanol; gradient: 40%-40% B, 1.80 min, 90 min) to give the desired product (1S,3S)-3-((6-(5-chloro-3-(( (5-Isopropylpyrimidin-2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I -7) (13.0 mg, 42.4% yield).
1H NMR(400MHz,CDCl 3)δ8.42-8.34(m,2H),7.45-7.37(m,1H),7.16-7.04(m,2H), 5.55-5.44(m,2H),4.64-4.52(m,1H),2.95-2.80(m,2H),2.77-2.72(m,1H),2.44(br s,3H),2.09-2.00(m,1H),1.97-1.80(m,3H),1.55(m,3H),1.26(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.42-8.34 (m, 2H), 7.45-7.37 (m, 1H), 7.16-7.04 (m, 2H), 5.55-5.44 (m, 2H), 4.64-4.52 (m,1H),2.95-2.80(m,2H),2.77-2.72(m,1H),2.44(br s,3H),2.09-2.00(m,1H),1.97-1.80(m,3H), 1.55(m, 3H), 1.26(s, 6H).
LC-MS,M/Z(ESI):502.1[M+H] +。 LC-MS, M/Z (ESI): 502.1 [M+H] + .
实施例8：目标化合物I-8的合成Example 8: Synthesis of target compound I-8
(1S,3S)-3-((6-(5-氯-3-(((4-(2,2-二氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-8)(1S,3S)-3-((6-(5-Chloro-3-((((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophene-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8)
(1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-8)(1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8)
Figure PCTCN2021129863-appb-000151
Figure PCTCN2021129863-appb-000151
目标化合物I-8的合成路线如下所示：The synthetic route of the target compound I-8 is as follows:
Figure PCTCN2021129863-appb-000152
Figure PCTCN2021129863-appb-000152
第一步：4-(2,2-二氟乙氧基)嘧啶-2-胺(I-8B)的合成Step 1: Synthesis of 4-(2,2-difluoroethoxy)pyrimidin-2-amine (I-8B)
4-(2,2-difluoroethoxy)pyrimidin-2-amine(I-8B)4-(2,2-difluoroethoxy)pyrimidin-2-amine(I-8B)
Figure PCTCN2021129863-appb-000153
Figure PCTCN2021129863-appb-000153
在0℃下，向氢化钠(583mg，14.5mmol)的N,N-二甲基甲酰胺(15.0mL)溶液中缓慢滴加2,2-二氟乙醇(1.15g，14.0mmol)，在25℃搅拌0.5小时后，向反应液中滴加4-氯嘧啶-2-胺(1.40g，10.8mmol)的N,N-二甲基甲酰胺(5.00mL)溶液。混合溶液在25℃下搅拌2小时。反应完成后，往反应液中滴加1M的稀盐酸溶液淬灭，乙酸乙酯(20.0mL)萃取。萃取的有机相用饱和的氯化钠水溶液洗涤(20.0mL)，无水硫酸钠干燥后过滤浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚：乙酸乙酯(V/V)＝10:0-2:1)得到4-(2,2-二氟乙氧基)嘧啶-2-胺(I-8B)(945mg，产率49.9％)。To a solution of sodium hydride (583 mg, 14.5 mmol) in N,N-dimethylformamide (15.0 mL) was slowly added dropwise 2,2-difluoroethanol (1.15 g, 14.0 mmol) at 0 °C, over 25 After stirring at °C for 0.5 hours, a solution of 4-chloropyrimidin-2-amine (1.40 g, 10.8 mmol) in N,N-dimethylformamide (5.00 mL) was added dropwise to the reaction solution. The mixed solution was stirred at 25°C for 2 hours. After the completion of the reaction, 1M dilute hydrochloric acid solution was added dropwise to the reaction solution to quench, and ethyl acetate (20.0 mL) was used for extraction. The extracted organic phase was washed with saturated aqueous sodium chloride solution (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:0-2:1) to obtain 4-(2,2-difluoroethoxy)pyrimidin-2-amine (I-8B ) (945 mg, 49.9% yield).
第二步：(1S,3S)-3-((6-(5-氯-3-(((4-(2,2-二氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-8C)的合成The second step: (1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl) Synthesis of Thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-8C)
methyl(1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-8C)methyl(1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2 -methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-8C)
Figure PCTCN2021129863-appb-000154
Figure PCTCN2021129863-appb-000154
在室温下，向(1S,3S)-3-((6-(5-氯-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(100mg，253.8μmol)(I-4B)和4-(2,2-二氟乙氧基)嘧啶-2-胺(88.9mg，507.7mmol)的甲醇(2mL)溶液中，加入氰基硼氢化钠(31.9mg，2.53mmol)，在室温下搅拌2小时。反应完成后，将反应减压浓缩，加入乙酸乙酯(5.00mL)稀释，有机相用水(5.00mL)和饱和氯化钠水溶液(5.00mL)洗涤，无水硫酸钠干燥，过滤浓缩得到(1S,3S)-3-((6-(5-氯-3-(((4-(2,2-二氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(I-8C)(100mg，180.8μmol，粗品)。粗产品直接用于下一步。To (1S,3S)-3-((6-(5-chloro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane- Methyl 1-carboxylate (100 mg, 253.8 μmol) (I-4B) and 4-(2,2-difluoroethoxy)pyrimidin-2-amine (88.9 mg, 507.7 mmol) in methanol (2 mL) , sodium cyanoborohydride (31.9 mg, 2.53 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, diluted with ethyl acetate (5.00 mL), the organic phase was washed with water (5.00 mL) and saturated aqueous sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain (1S ,3S)-3-((6-(5-Chloro-3-((((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl) -2-Methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-8C) (100 mg, 180.8 μmol, crude). The crude product was used directly in the next step.
第三步：(1S,3S)-3-((6-(5-氯-3-(((4-(2,2-二氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-8)的合成The third step: (1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl) Synthesis of Thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8)
(1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-8)(1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-8)
Figure PCTCN2021129863-appb-000155
Figure PCTCN2021129863-appb-000155
室温下，向(1S,3S)-3-((6-(5-氯-3-(((4-(2,2-二氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸甲酯(100mg，180.8μmol，粗品)的水(2mL)和四氢呋喃(2mL)中加入一水合氢氧化锂(21.6mg，0.90mmol)，在室温搅拌12小时。反应完成后将反应液用1M的盐酸溶液调至pH＝3～4，然后减压浓缩得粗品。粗品经过制备分离(分离方法：柱子：Phenomenex Luna C18 150*25mm*10μm；溶剂：A＝水+0.225体积％甲酸(99％)，B＝乙腈；梯度：42％-62％B,10分钟)，冻干得白色固体状化合物(1S,3S)-3-((6-(5-氯-3-(((4-(2,2-二氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧代)环己甲酸(目标化合物I-8)(1.93mg，产率1.98％)。To (1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino)methyl) at room temperature Thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (100 mg, 180.8 μmol, crude) in water (2 mL) and tetrahydrofuran (2 mL) was added Lithium hydroxide monohydrate (21.6 mg, 0.90 mmol) was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction solution was adjusted to pH=3-4 with 1M hydrochloric acid solution, and then concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative (separation method: column: Phenomenex Luna C18 150*25mm*10μm; solvent: A=water+0.225vol% formic acid (99%), B=acetonitrile; gradient: 42%-62%B, 10 minutes) , lyophilized to give white solid compound (1S,3S)-3-((6-(5-chloro-3-(((4-(2,2-difluoroethoxy)pyrimidin-2-yl)amino) )methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxo)cyclohexanecarboxylic acid (target compound 1-8) (1.93 mg, 1.98% yield).
1H NMR(400MHz,CDCl 3)δ10.79(s,1H),7.87(d,1H),7.38-7.33(m,2H),6.91(s,1H),6.26(d,1H),6.27-5.87(m,1H),4.83(s,2H),4.72(s,1H),4.46-4.39(m,2H),2.93-2.88(m,1H),2.57(s,3H),2.17-1.18(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ 10.79(s, 1H), 7.87(d, 1H), 7.38-7.33(m, 2H), 6.91(s, 1H), 6.26(d, 1H), 6.27- 5.87(m, 1H), 4.83(s, 2H), 4.72(s, 1H), 4.46-4.39(m, 2H), 2.93-2.88(m, 1H), 2.57(s, 3H), 2.17-1.18( m, 9H).
LC-MS,M/Z(ESI):539.1[M+H] +。 LC-MS, M/Z (ESI): 539.1 [M+H] + .
实施例9：目标化合物I-9的合成Example 9: Synthesis of target compound I-9
(1S,3S)-3-((2-(5-氯-3-(((4-(2,2,2-三氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-9)(1S,3S)-3-((2-(5-Chloro-3-((((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophene- 2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-9)
(1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-9)(1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)- 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-9)
Figure PCTCN2021129863-appb-000156
Figure PCTCN2021129863-appb-000156
目标化合物I-9的合成路线如下所示：The synthetic route of the target compound I-9 is as follows:
Figure PCTCN2021129863-appb-000157
Figure PCTCN2021129863-appb-000157
第一步：4-(2,2,2-三氟乙氧基)嘧啶-2-胺(I-9B)的合成Step 1: Synthesis of 4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine (I-9B)
4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine(I-9B)4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine(I-9B)
Figure PCTCN2021129863-appb-000158
Figure PCTCN2021129863-appb-000158
将2,2,2-三氟-1-醇(1.158g，11.58mmol)加入到10mL四氢呋喃中，0℃下加入钠氢(0.278g，11.58mmol)，搅拌30分钟后，加入4-氯嘧啶-2-胺(1g，7.72mmol)，70℃搅拌12小时。加入水(50mL)淬灭，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，浓缩物经柱层析(石油醚：乙酸乙酯(V:V)＝10:1)纯化得化合物白色固体4-(2,2,2-三氟乙氧基)嘧啶-2-胺(I-9B)(1g，产率67.1％)。2,2,2-Trifluoro-1-ol (1.158 g, 11.58 mmol) was added to 10 mL of tetrahydrofuran, sodium hydrogen (0.278 g, 11.58 mmol) was added at 0°C, and after stirring for 30 minutes, 4-chloropyrimidine was added -2-amine (1 g, 7.72 mmol), stirred at 70°C for 12 hours. Water (50 mL) was added to quench, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was subjected to column chromatography (petroleum ether: ethyl acetate (V: V)=10:1) was purified to give the compound 4-(2,2,2-trifluoroethoxy)pyrimidin-2-amine (I-9B) (1 g, 67.1% yield) as a white solid.
第二步：(1S,3S)-3-((2-(5-氯-3-(((4-(2,2,2-三氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-9C)的合成The second step: (1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methane Synthesis of methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-9C)
methyl(1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-9C)methyl(1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl) -4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-9C)
Figure PCTCN2021129863-appb-000159
Figure PCTCN2021129863-appb-000159
将4-(2,2,2-三氟乙氧基)嘧啶-2-胺(176mg，0.912mmol)，(1S,3S)-3-((2-(5-氯-3-甲酰 基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(180mg，0.456mmol)(I-1E)加入到4mL甲醇中，加入醋酸(0.3mg，4.56μmol)，室温搅拌12小时，加入氰基硼氢化钠(86mg，1.368mmol)，继续室温搅拌12小时。旋干，加入水(30mL)溶解，用乙酸乙酯(30mL×3)萃取，合并有机相，过滤，浓缩，浓缩物经柱层析(石油醚：乙酸乙酯(V:V)＝3:1)纯化得化合物(1S,3S)-3-((2-(5-氯-3-(((4-(2,2,2-三氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-9C)(110mg，产率42.2％)。4-(2,2,2-Trifluoroethoxy)pyrimidin-2-amine (176 mg, 0.912 mmol), (1S,3S)-3-((2-(5-chloro-3-formylthiophene) -2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester (180 mg, 0.456 mmol) (I-1E) was added to 4 mL of methanol, acetic acid (0.3 mg, 4.56 μmol), stirred at room temperature for 12 hours, added sodium cyanoborohydride (86 mg, 1.368 mmol), and continued stirring at room temperature for 12 hours. Spin dry, add water (30 mL) to dissolve, extract with ethyl acetate (30 mL×3), combine the organic phases, filter, concentrate, and the concentrate is subjected to column chromatography (petroleum ether:ethyl acetate (V:V)=3: 1) Purified compound (1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino) Methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-9C) (110 mg, 42.2% yield).
第三步：(1S,3S)-3-((2-(5-氯-3-(((4-(2,2,2-三氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-9)的合成The third step: (1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methane Synthesis of thiophene-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-9)
(1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-9)(1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)- 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-9)
Figure PCTCN2021129863-appb-000160
Figure PCTCN2021129863-appb-000160
将(1S,3S)-3-((2-(5-氯-3-(((4-(2,2,2-三氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(110mg，0.192mmol)加入到2mL四氢呋喃，2mL甲醇和0.5mL水的混合溶剂中，加入氢氧化锂(23.03mg，0.962mmol)，室温搅拌过夜。旋干，加入水(10mL)溶解，用2.0M盐酸调pH至2，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩。浓缩物经制备板(石油醚：乙酸乙酯(V:V)＝1:1)纯化得化合物(1S,3S)-3-((2-(5-氯-3-(((4-(2,2,2-三氟乙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-9)(24.7mg，产率23.0％)。(1S,3S)-3-((2-(5-chloro-3-(((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophene Methyl -2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (110 mg, 0.192 mmol) was added to a mixed solvent of 2 mL of tetrahydrofuran, 2 mL of methanol and 0.5 mL of water , Lithium hydroxide (23.03 mg, 0.962 mmol) was added, and the mixture was stirred at room temperature overnight. Spin dry, add water (10 mL) to dissolve, adjust pH to 2 with 2.0 M hydrochloric acid, extract with ethyl acetate (10 mL×3), combine organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The concentrate was purified by preparative plate (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound (1S,3S)-3-((2-(5-chloro-3-((((4-( 2,2,2-Trifluoroethoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxy Acid (target compound I-9) (24.7 mg, 23.0% yield).
1H NMR(400MHz,CDCl 3)δ8.28(s,1H),8.00(s,1H),6.90(s,1H),6.10(d,1H),4.80-4.77(m,4H),2.82-2.80(m,1H),2.52(s,3H),2.16-2.14(m,1H),2.02-1.98(m,3H),1.67-1.64(m,4H),1.32-1.30(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.28(s, 1H), 8.00(s, 1H), 6.90(s, 1H), 6.10(d, 1H), 4.80-4.77(m, 4H), 2.82- 2.80(m, 1H), 2.52(s, 3H), 2.16-2.14(m, 1H), 2.02-1.98(m, 3H), 1.67-1.64(m, 4H), 1.32-1.30(m, 2H).
LC-MS,M/Z(ESI):558.1[M+H] +。 LC-MS, M/Z (ESI): 558.1 [M+H] + .
实施例10：目标化合物I-10的合成Example 10: Synthesis of target compound I-10
(1S,3S)-3-((2-(5-氯-3-(((5-(环丙基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基 嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-10)(1S,3S)-3-((2-(5-Chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl ) thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)
(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-10)(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl) -4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)
Figure PCTCN2021129863-appb-000161
Figure PCTCN2021129863-appb-000161
目标化合物I-10合成路线如下所示：The synthetic route of target compound I-10 is as follows:
Figure PCTCN2021129863-appb-000162
Figure PCTCN2021129863-appb-000162
第一步：(1S,3S)-3-((2-(5-氯-3-(((5-(环丙基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-10A)的合成The first step: (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl) Synthesis of methyl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-10A)
methyl(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-10A)methyl(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl )-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-10A)
Figure PCTCN2021129863-appb-000163
Figure PCTCN2021129863-appb-000163
在室温下，向(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(100mg，0.254mmol)和5-(环丙基甲基)-1,2,4-恶二唑-3-胺(65.8mg，0.473mmol) 的乙醇(5mL)溶液中加入醋酸(142mg，2.364μmol)，然后在室温下搅拌1小时后加入氰基硼氢化钠(44.6mg，0.709mmol)，将反应液在室温下搅拌2小时。反应液用乙酸乙酯(15mL×2)萃取，合并有机层，浓缩得到化合物异丙基(1S,3S)-3-((2-(5-氯-3-(((5-(环丙基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-10A)(60mg，产率46.5％)。To (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane- Methyl 1-carboxylate (100 mg, 0.254 mmol) and 5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-amine (65.8 mg, 0.473 mmol) in ethanol (5 mL) Acetic acid (142 mg, 2.364 μmol) was added, followed by stirring at room temperature for 1 hour. After adding sodium cyanoborohydride (44.6 mg, 0.709 mmol), the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (15 mL×2), and the organic layers were combined and concentrated to obtain the compound isopropyl (1S,3S)-3-((2-(5-chloro-3-((((5-(cyclopropyl) (ylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1- Methyl formate (I-10A) (60 mg, 46.5% yield).
第二步：(1S,3S)-3-((2-(5-氯-3-(((5-(环丙基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-10)的合成The second step: (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl) Synthesis of Amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)
(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-10)(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl) -4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)
Figure PCTCN2021129863-appb-000164
Figure PCTCN2021129863-appb-000164
在室温下，向(1S,3S)-3-((2-(5-氯-3-(((5-(环丙基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(60mg，0.12mmol)的四氢呋喃(5mL)和甲醇(2mL)溶液中加入一水合氢氧化锂(50mg，1.2mmol)，然后在室温下搅拌2小时。反应液用乙酸乙酯(15mL×2)萃取，合并有机层，得到粗产品。粗产品纯化通过硅胶板得到化合物(1S,3S)-3-((2-(5-氯-3-(((5-(环丙基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-10)(30mg，产率54％)。At room temperature, to (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl )amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (60 mg, 0.12 mmol) in tetrahydrofuran (5 mL) and methanol (2 mL) ) solution was added lithium hydroxide monohydrate (50 mg, 1.2 mmol), followed by stirring at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (15 mL×2), and the organic layers were combined to obtain a crude product. The crude product was purified by silica gel plate to give compound (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclopropylmethyl)-1,2,4-oxadiazole- 3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10) (30 mg, yield 54 %).
1H NMR(400MHz,CDCl 3)δ12.30(s,1H),8.50(s,1H),7.20(t,1H),7.02(s,1H),4.80(s,1H),4.75(d,2H),2.58(d,3H),2.48(s,3H),1.98-2.02(m,1H),1.70-1.78(m,3H),1.48-1.60(m,4H),1.00-1.05(m,1H),0.48-0.51(m,2H),0.23-0.25(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 12.30(s, 1H), 8.50(s, 1H), 7.20(t, 1H), 7.02(s, 1H), 4.80(s, 1H), 4.75(d, 2H), 2.58(d, 3H), 2.48(s, 3H), 1.98-2.02(m, 1H), 1.70-1.78(m, 3H), 1.48-1.60(m, 4H), 1.00-1.05(m, 1H), 0.48-0.51(m, 2H), 0.23-0.25(m, 2H).
LC-MS,M/Z(ESI):504.1[M+H] +。 LC-MS, M/Z (ESI): 504.1 [M+H] + .
实施例11：目标化合物I-11的合成Example 11: Synthesis of target compound I-11
(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-11)(1S,3S)-3-((2-(5-Chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophene -2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-11)
(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-11)(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl) -4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-11)
Figure PCTCN2021129863-appb-000165
Figure PCTCN2021129863-appb-000165
目标化合物I-11的合成路线如下所示：The synthetic route of the target compound I-11 is as follows:
Figure PCTCN2021129863-appb-000166
Figure PCTCN2021129863-appb-000166
第一步：(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-11A)的合成The first step: (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino) Synthesis of methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-11A)
methyl(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-11A)methyl(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl )-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-11A)
Figure PCTCN2021129863-appb-000167
Figure PCTCN2021129863-appb-000167
在室温下，向(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(0.5g，1.27mmol)和5-(环丁基甲基)-1,2,4-噁二唑-3-胺(387.93mg，2.53mmol)的甲醇(5mL)溶液中加入醋酸(760.40μg，12.66μmol)，然后在室温下搅拌1小时后加入氰基硼氢化钠(238.72mg，3.80mmol)，将反应液在室温下搅拌2小时。反应液用乙酸乙酯(15mL×2)萃取，合并有机层，浓缩得到化合物(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(I-11A)(0.673g， 产率99.90％)。To (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane- To a solution of methyl 1-carboxylate (0.5 g, 1.27 mmol) and 5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-amine (387.93 mg, 2.53 mmol) in methanol (5 mL) was added Acetic acid (760.40 μg, 12.66 μmol) was then stirred at room temperature for 1 hour, sodium cyanoborohydride (238.72 mg, 3.80 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (15 mL×2), the organic layers were combined and concentrated to obtain compound (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-) 1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate methyl ester ( 1-11A) (0.673 g, 99.90% yield).
第二步：(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-11)的合成The second step: (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino) Synthesis of methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-11)
(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-11)(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl) -4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-11)
Figure PCTCN2021129863-appb-000168
Figure PCTCN2021129863-appb-000168
在室温下，向(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸甲酯(0.3g，563.85μmol)的四氢呋喃(5mL)溶液中加入一水合氢氧化锂(230mg，5.63mmol)，然后在室温下搅拌2小时。反应液用乙酸乙酯(15mL×2)萃取，合并有机层，得到粗产品。粗产品纯化通过硅胶板得到化合物(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-11)(65mg，产率21.88％)。To (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino at room temperature ) methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (0.3 g, 563.85 μmol) in tetrahydrofuran (5 mL) was added a Hydrate lithium hydroxide (230 mg, 5.63 mmol), then stir at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (15 mL×2), and the organic layers were combined to obtain a crude product. The crude product was purified by silica gel plate to give compound (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazole-3- yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-11) (65 mg, 21.88% yield) .
1H NMR(400MHz,CDCl 3)δ8.24(s,1H),7.01(s,1H),6.14(br t,1H),4.76(br s,1H),4.60(d,2H),2.93-2.79(m,3H),2.74(dt,1H),2.50(s,3H),2.23-2.09(m,3H),2.05-1.82(m,5H),1.81-1.61(m,6H). 1 H NMR (400MHz, CDCl 3 )δ8.24(s,1H),7.01(s,1H),6.14(br t,1H),4.76(br s,1H),4.60(d,2H),2.93- 2.79(m,3H),2.74(dt,1H),2.50(s,3H),2.23-2.09(m,3H),2.05-1.82(m,5H),1.81-1.61(m,6H).
LC-MS,M/Z(ESI):518.2[M+H] +。 LC-MS, M/Z (ESI): 518.2 [M+H] + .
实施例12：目标化合物I-12的合成Example 12: Synthesis of target compound I-12
(1S,3S)-3-((6-(3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-12)(1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophene -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12)
(1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-12)(1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophen-2-yl)- 2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12)
Figure PCTCN2021129863-appb-000169
Figure PCTCN2021129863-appb-000169
目标化合物I-12的合成路线如下所示：The synthetic route of the target compound I-12 is as follows:
Figure PCTCN2021129863-appb-000170
Figure PCTCN2021129863-appb-000170
第一步：2-溴-5-氟噻吩-3-甲醛(I-12B)的合成The first step: Synthesis of 2-bromo-5-fluorothiophene-3-carbaldehyde (I-12B)
2-bromo-5-fluorothiophene-3-carbaldehyde(I-12B)2-bromo-5-fluorothiophene-3-carbaldehyde(I-12B)
Figure PCTCN2021129863-appb-000171
Figure PCTCN2021129863-appb-000171
在0℃下，向(2-溴-5-氟噻吩-3-基)甲醇(2.50g，11.8mmol)的二氯甲烷(30.0mL)溶液中加入戴斯-马丁氧化剂(10.0g，23.6mmol)，反应液在室温下搅拌过夜。反应完成后，将反应液过滤浓缩得到粗品。粗品通过柱层析分离得到目标产物2-溴-5-氟噻吩-3-甲醛(I-12B)(2.20g，10.5mmol，产率88.8％)。To a solution of (2-bromo-5-fluorothiophen-3-yl)methanol (2.50 g, 11.8 mmol) in dichloromethane (30.0 mL) was added Dess-Martin oxidant (10.0 g, 23.6 mmol) at 0 °C ), the reaction solution was stirred at room temperature overnight. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude product. The crude product was separated by column chromatography to obtain the target product 2-bromo-5-fluorothiophene-3-carbaldehyde (I-12B) (2.20 g, 10.5 mmol, 88.8% yield).
第二步：(1S,3S)-3-((6-(5-氟-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(I-12C)的合成The second step: (1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid methyl Synthesis of Esters (I-12C)
(1S,3S)-methyl3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-12C)(1S,3S)-methyl3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-12C)
Figure PCTCN2021129863-appb-000172
Figure PCTCN2021129863-appb-000172
在室温下，向2-溴-5-氟噻吩-3-甲醛(400mg,1.91mmol)和(1S,3S)-3-((2-甲基-6-(三丁基锡烷基)吡啶-3-基)氧基)环己烷甲酸甲酯(1.55g，2.87mmol)的1,4-二氧六环(10.0mL)溶液中加入四三苯基膦钯(221mg,191μmol)，反应液在100℃下搅拌过夜。反应完成后，将反应液浓缩得到粗品，粗品用层析硅胶板分离(分离方法：石油醚/乙酸乙酯＝5:1(V/V))得到目标产物(1S,3S)-3-((6-(5-氟-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(I-12C)(456mg，产率41.2％)。To 2-bromo-5-fluorothiophene-3-carbaldehyde (400 mg, 1.91 mmol) and (1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridine-3 at room temperature -yl)oxy)cyclohexanecarboxylate (1.55g, 2.87mmol) in 1,4-dioxane (10.0mL) solution was added tetrakistriphenylphosphine palladium (221mg, 191μmol), the reaction solution was Stir overnight at 100°C. After the completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was separated by a silica gel plate (separation method: petroleum ether/ethyl acetate=5:1 (V/V)) to obtain the target product (1S,3S)-3-( Methyl (6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate (I-12C) (456 mg, 41.2% yield ).
第三步：(1S,3S)-3-((6-(3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(I-12D)的合成The third step: (1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)- Synthesis of methyl 5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate (I-12D)
(1S,3S)-methyl3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-12D)(1S,3S)-methyl3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophen-2-yl)- 2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-12D)
Figure PCTCN2021129863-appb-000173
Figure PCTCN2021129863-appb-000173
在室温下，向(1S,3S)-3-((6-(5-氟-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(400mg，1.06mmol)和5-(环丁基甲基)-1,2,4-恶二唑-3-胺(162mg，1.06mmol)的乙醇(5.00mL)溶液中加入冰醋酸(127mg，2.12mmol)，反应液在60℃下搅拌6小时后降温之25℃加入氰基硼氢化钠(133mg，2.12mmol)，反应液在室温下继续搅拌6小时。反应完成后，将反应液浓缩得到粗品，粗品用层析硅胶制备板分离(分离方法：石油醚/乙酸乙酯(V/V)＝2:1)得到目标产物(1S,3S)-3-((6-(3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(150mg，产率74.6％)。To (1S,3S)-3-((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid at room temperature To a solution of methyl ester (400 mg, 1.06 mmol) and 5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-amine (162 mg, 1.06 mmol) in ethanol (5.00 mL) was added glacial acetic acid (127 mg, 2.12 mmol), the reaction solution was stirred at 60° C. for 6 hours, then cooled at 25° C. and sodium cyanoborohydride (133 mg, 2.12 mmol) was added, and the reaction solution was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated by a silica gel preparative plate (separation method: petroleum ether/ethyl acetate (V/V)=2:1) to obtain the target product (1S, 3S)-3- ((6-(3-(((5-(Cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophen-2-yl)-2- Methylpyridin-3-yl)oxy)cyclohexanecarboxylate (150 mg, 74.6% yield).
第四步：(1S,3S)-3-((6-(3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-12)的合成Fourth step: (1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)- Synthesis of 5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12)
(1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-12)(1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-5-fluorothiophen-2-yl)- 2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12)
Figure PCTCN2021129863-appb-000174
Figure PCTCN2021129863-appb-000174
在室温下，向(1S,3S)-甲基3-((6-(3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(80.0mg，155μmol)的四氢呋喃(1.50mL)和水(0.50mL)溶液中加入一水合氢氧化锂(65.2mg，1.55mmol)，反应液在室温下搅拌过夜。反应完成后，将反应液浓缩得到粗品，粗品通过制备分离(分离方法：色谱柱：Phenomenex luna C18 150*25mm*10μm；流动相A：0.225％甲酸水溶液，B＝乙腈；梯度洗脱：56％-86％B，10min)得到(1S,3S)-3-((6-(3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-12)(21.0mg，产率26.8％)。To (1S,3S)-methyl 3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methane at room temperature yl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (80.0 mg, 155 μmol) in tetrahydrofuran (1.50 mL) and water (0.50 mL) Lithium hydroxide monohydrate (65.2 mg, 1.55 mmol) was added and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was separated by preparation (separation method: chromatographic column: Phenomenex luna C18 150*25mm*10 μm; mobile phase A: 0.225% aqueous formic acid, B=acetonitrile; gradient elution: 56% -86%B, 10 min) to give (1S,3S)-3-((6-(3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino) Methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12) (21.0 mg, 26.8% yield).
1H NMR(400MHz,CDCl 3)δ7.24-7.16(m,1H),7.16-7.05(m,1H),6.57(d,J＝1.8Hz,1H),6.02(br s,1H),4.66(br s,1H),4.41(br d,J＝5.3Hz,2H),2.88(br s,1H),2.85-2.80(m,2H),2.76(td,J＝7.6,14.9Hz,1H),2.57-2.48(m,3H),2.19-2.12(m,2H),2.05-1.85(m,6H),1.83-1.75(m,3H),1.41-0.88(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.24-7.16 (m, 1H), 7.16-7.05 (m, 1H), 6.57 (d, J=1.8 Hz, 1H), 6.02 (br s, 1H), 4.66 (br s, 1H), 4.41 (br d, J=5.3Hz, 2H), 2.88 (br s, 1H), 2.85-2.80 (m, 2H), 2.76 (td, J=7.6, 14.9Hz, 1H) ,2.57-2.48(m,3H),2.19-2.12(m,2H),2.05-1.85(m,6H),1.83-1.75(m,3H),1.41-0.88(m,3H).
LC-MS,M/Z(ESI):501.3[M+H] +。 LC-MS, M/Z (ESI): 501.3 [M+H] + .
实施例13：目标化合物I-13的合成Example 13: Synthesis of target compound I-13
(1S,3S)-3-((6-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-13)(1S,3S)-3-((6-(5-Fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridine -3-yl)oxy)cyclohexanecarboxylic acid (target compound I-13)
(1S,3S)-3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-13)(1S,3S)-3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexanecarboxylic acid (target compound I-13)
Figure PCTCN2021129863-appb-000175
Figure PCTCN2021129863-appb-000175
目标化合物I-13合成路线如下所示：The synthetic route of target compound I-13 is as follows:
Figure PCTCN2021129863-appb-000176
Figure PCTCN2021129863-appb-000176
第一步：(N-((2-溴-5-氟噻吩-3-基)甲基)-4-异丙基嘧啶-2-胺(I-13B)的合成The first step: Synthesis of (N-((2-bromo-5-fluorothiophen-3-yl)methyl)-4-isopropylpyrimidin-2-amine (I-13B)
N-((2-bromo-5-fluorothiophen-3-yl)methyl)-4-isopropylpyrimidin-2-amine(I-13B)N-((2-bromo-5-fluorothiophen-3-yl)methyl)-4-isopropylpyrimidin-2-amine(I-13B)
Figure PCTCN2021129863-appb-000177
Figure PCTCN2021129863-appb-000177
在0℃下，往4-异丙基嘧啶-2-胺(I-6B)(59.77mg，435.73μmol)的四氢呋喃(2.00mL)溶液中加入钠氢(52.28mg，1.31mmol，60％含量)，反应液在室温下搅拌1小时后降温至0℃加入2-溴-3-(氯甲基)-5-氟噻吩(100mg，435.73μmol)，反应液继续在室温下搅拌1小时。反应完成后，缓慢滴加冰水淬灭反应，混合液用乙酸乙酯萃取(5.00mL)，有机相用饱和氯化钠水溶液(5.00mL)洗涤，无水硫酸钠干燥，过滤浓缩得到黄色油状物粗品(N-((2-溴-5-氟噻吩-3-基)甲基)-4-异丙基嘧啶-2-胺(I-13B)(120mg，粗品)。To a solution of 4-isopropylpyrimidin-2-amine (I-6B) (59.77 mg, 435.73 μmol) in tetrahydrofuran (2.00 mL) at 0 °C was added sodium hydrogen (52.28 mg, 1.31 mmol, 60% content) , the reaction solution was stirred at room temperature for 1 hour, then cooled to 0°C, and 2-bromo-3-(chloromethyl)-5-fluorothiophene (100 mg, 435.73 μmol) was added, and the reaction solution was further stirred at room temperature for 1 hour. After the reaction was completed, ice water was slowly added dropwise to quench the reaction, the mixture was extracted with ethyl acetate (5.00 mL), the organic phase was washed with saturated aqueous sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oil The crude product (N-((2-bromo-5-fluorothiophen-3-yl)methyl)-4-isopropylpyrimidin-2-amine (I-13B) (120 mg, crude).
第二步：(1S,3S)-甲基3-((6-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基氧)环己烷羧酸酯(I-13C)的合成Step 2: (1S,3S)-methyl 3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl) Synthesis of -2-methylpyridin-3-yloxy)cyclohexanecarboxylate (I-13C)
(1S,3S)-methyl3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-13C)(1S,3S)-methyl3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexanecarboxylate(I-13C)
Figure PCTCN2021129863-appb-000178
Figure PCTCN2021129863-appb-000178
在室温下，向(N-((2-溴-5-氟噻吩-3-基)甲基)-4-异丙基嘧啶-2-胺(130mg，393.68μmol)和(1S,3S)-3-((2-甲基-6-(三丁基锡烷基)吡啶-3-基)氧基)环己烷1-羧酸甲酯(中间体C)(317.90mg，590.52μmol)的二甲苯(0.5mL)溶液中加入四三苯基膦钯(45.49mg，39.37μmol)，反应液加热至100℃搅拌12小时。反应完成后，浓缩的到粗品，粗品通过制备层析板纯化(二氧化硅，石油醚：乙酸乙酯＝2∶1)得到黄色的油状物(1S,3S)-甲基3-((6-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基氧)环己烷羧酸酯(I-13C)(50.0mg，产率25.47％)。To (N-((2-bromo-5-fluorothiophen-3-yl)methyl)-4-isopropylpyrimidin-2-amine (130 mg, 393.68 μmol) and (1S,3S)- Methyl 3-((2-methyl-6-(tributylstannyl)pyridin-3-yl)oxy)cyclohexane 1-carboxylate (Intermediate C) (317.90 mg, 590.52 μmol) in xylene (0.5mL) solution was added tetrakistriphenylphosphine palladium (45.49mg, 39.37μmol), the reaction solution was heated to 100 ° C and stirred for 12 hours. After the reaction was completed, concentrated to the crude product, the crude product was purified by preparative chromatography (dioxide Silicon, petroleum ether: ethyl acetate = 2:1) to give a yellow oil (1S,3S)-methyl 3-((6-(5-fluoro-3-(((4-isopropylpyrimidine-2) -yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yloxy)cyclohexanecarboxylate (I-13C) (50.0 mg, 25.47% yield).
第三步：(1S,3S)-3-((6-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-13)的合成The third step: (1S,3S)-3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2 Synthesis of -methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-13)
(1S,3S)-3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-13)(1S,3S)-3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy )cyclohexanecarboxylic acid (target compound I-13)
Figure PCTCN2021129863-appb-000179
Figure PCTCN2021129863-appb-000179
在室温下，往(1S,3S)-甲基3-((6-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基氧)环己烷羧酸酯(20.0mg，40.11μmol)的四氢呋喃(0.5mL)和水(0.2mL)溶液中加入一水合氢氧化锂(16.83mg，401.11μmol)，反应在室温下搅拌过夜。反应完成后，将反应液浓缩得到粗品，粗品用反相高效液相色谱法进行分离(分离方法为：色谱柱：Phenomenex Synergi C18 150*25mm*10μm；溶剂：A＝水+0.1％甲酸，B＝乙腈；梯度：36％-66％B，15分钟)得到白色固体(1S,3S)-3-((6-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-13)(7.07mg，产率35.43％)。To (1S,3S)-methyl 3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl at room temperature )-2-methylpyridin-3-yloxy)cyclohexanecarboxylate (20.0 mg, 40.11 μmol) in tetrahydrofuran (0.5 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (16.83 mg, 401.11 μmol), the reaction is stirred at room temperature overnight. After the reaction is completed, the reaction solution is concentrated to obtain a crude product, and the crude product is separated by reversed-phase high performance liquid chromatography (separation method is: chromatographic column: Phenomenex Synergi C18 150*25mm*10 μm; Solvent: A = water + 0.1% formic acid, B = acetonitrile; gradient: 36%-66% B, 15 minutes) to give (1S,3S)-3-(((6-(5-fluoro-3-(() as a white solid) (4-Isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-13) (7.07 mg, yield 35.43%).
1H NMR(400MHz，CDCl 3)δ8.35-8.07(m,1H),7.25-7.17(m,1H),7.17-7.00(m,1H),6.68-6.53(m,1H),6.44(br s,1H),4.68(br s,3H),2.82(br s,2H),2.55(br s,3H),2.04-1.84(m,4H),1.34(m,5H),0.92(br s,6H) 1 H NMR (400MHz, CDCl 3 ) δ 8.35-8.07(m,1H), 7.25-7.17(m,1H), 7.17-7.00(m,1H), 6.68-6.53(m,1H), 6.44(br s,1H),4.68(br s,3H),2.82(br s,2H),2.55(br s,3H),2.04-1.84(m,4H),1.34(m,5H),0.92(br s, 6H)
LC-MS,M/Z(ESI):485.3[M+H] +。 LC-MS, M/Z (ESI): 485.3 [M+H] + .
实施例14：目标化合物I-14的制备合成Example 14: Preparation and synthesis of target compound I-14
(1S,3S)-3-((6-(3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-14)(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophene -2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-14)
(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-14)(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2 -methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-14)
Figure PCTCN2021129863-appb-000180
Figure PCTCN2021129863-appb-000180
目标化合物I-14合成路线如下所示：The synthetic route of target compound I-14 is as follows:
Figure PCTCN2021129863-appb-000181
Figure PCTCN2021129863-appb-000181
第一步：(1S,3S)-3-((6-(5-氟-3-羟甲基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(I-14A)的合成The first step: (1S,3S)-3-((6-(5-fluoro-3-hydroxymethylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid Synthesis of methyl ester (I-14A)
methyl(1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-14A)methyl(1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-14A)
Figure PCTCN2021129863-appb-000182
Figure PCTCN2021129863-appb-000182
在室温下，向2-溴-5-氟噻吩-3-甲醇(400mg，1.91mmol)和(1S,3S)-3-((2-甲基-6-(三丁基锡烷基)吡啶-3-基)氧基)环己烷甲酸甲酯(1.55g，2.87mmol)的1,4-二氧六环(10.0mL)溶液中加入四三苯基膦钯(221mg，191μmol)，反应液在100℃下搅拌过夜。反应完成后，将反应液浓缩得到粗品，粗品用层析硅胶制备板分离(分离方法：石油醚/乙酸乙酯(V/V)＝5:1)得到目标产物(1S,3S)-3-((6-(5-氟-3-甲酰基噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(456mg，产率41.2％)。To 2-bromo-5-fluorothiophene-3-methanol (400 mg, 1.91 mmol) and (1S,3S)-3-((2-methyl-6-(tributylstannyl)pyridine-3 at room temperature -yl)oxy)cyclohexanecarboxylate (1.55g, 2.87mmol) in 1,4-dioxane (10.0mL) solution was added tetrakistriphenylphosphine palladium (221mg, 191μmol), the reaction solution was in Stir overnight at 100°C. After the completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was separated by a silica gel preparative plate (separation method: petroleum ether/ethyl acetate (V/V)=5:1) to obtain the target product (1S, 3S)-3- Methyl ((6-(5-fluoro-3-formylthiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate (456 mg, 41.2% yield).
第二步：(1S,3S)-3-((6-(5-氟-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(I-14B)的合成Step 2: (1S,3S)-3-((6-(5-Fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl Synthesis of Methyl Alkanecarboxylate (I-14B)
(1S,3S)-methyl3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-14B)(1S,3S)-methyl3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-14B)
Figure PCTCN2021129863-appb-000183
Figure PCTCN2021129863-appb-000183
在0℃下，往(1S,3S)-3-((6-(5-氟-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(140mg，368.96μmol)和叠氮磷酸二苯酯(203.08mg，737.92μmol，159.90μL)的甲苯(2.00mL)溶液中滴加1.8-二氮杂二环[5.4.0]十一烷-7-烯(112.34mg，737.92μmol，111.23 μL)，反应液在室温下搅拌过夜。反应完成后，加水稀释，用乙酸乙酯萃取(10.0mL)，有机相用饱和氯化钠水(10.0mL)溶液洗涤，无水硫酸钠干燥，过滤浓缩的到粗品化合物(1S,3S)-3-((6-(5-氟-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(200mg，粗品)。To (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy) at 0 °C 1.8-diazabicyclo[5.4.0 ]undecan-7-ene (112.34 mg, 737.92 μmol, 111.23 μL), the reaction solution was stirred at room temperature overnight. After the reaction was completed, diluted with water, extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated aqueous sodium chloride (10.0 mL) solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude compound (1S, 3S)- Methyl 3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate (200 mg, crude).
第三步：(1S,3S)-3-((6-(3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(I-14C)的合成The third step: (1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)- Synthesis of methyl 5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate (I-14C)
(1S,3S)-methyl3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-14C)(1S,3S)-methyl3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2 -methylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-14C)
Figure PCTCN2021129863-appb-000184
Figure PCTCN2021129863-appb-000184
室温下，向(1S,3S)-3-((6-(5-氟-3-(羟甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(150mg，370.87μmol)和(3-环丙基丙-1-炔-1-基)三甲基硅烷(282.43mg，1.85mmol)的四氢呋喃(3.00mL)和水(1.00mL)溶液中加入硫酸铜(17.76mg，111.26μmol)和L-抗坏血酸钠(22.04mg，111.26μmol)，反应液在室温下搅拌过夜。反应完成后，过滤，滤液加水稀释，用乙酸乙酯(5.00mL)萃取，有机相用饱和氯化钠水溶液(5.00mL)洗涤，无水硫酸钠干燥，过滤浓缩的到粗品。粗品通过制备层析板纯化(二氧化硅，石油醚：乙酸乙酯＝2∶1)得到黄色的油状物(1S，3S)-3-((6-(3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸甲酯(I-14C)(100mg，产率55.64％)。To (1S,3S)-3-((6-(5-fluoro-3-(hydroxymethyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexyl at room temperature Methyl alkanoate (150 mg, 370.87 μmol) and (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (282.43 mg, 1.85 mmol) in tetrahydrofuran (3.00 mL) and water (1.00 mL) Copper sulfate (17.76 mg, 111.26 μmol) and sodium L-ascorbate (22.04 mg, 111.26 μmol) were added to the solution, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, filtered, the filtrate was diluted with water, extracted with ethyl acetate (5.00 mL), the organic phase was washed with saturated aqueous sodium chloride solution (5.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by preparative chromatography (silica, petroleum ether:ethyl acetate = 2:1) to give (1S,3S)-3-((6-(3-((4-(cyclopropane) as a yellow oil) (ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane Methyl formate (I-14C) (100 mg, 55.64% yield).
第四步：(1S,3S)-3-((6-(3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-14)的合成Fourth step: (1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)- Synthesis of 5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-14)
(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-14)(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2 -methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-14)
Figure PCTCN2021129863-appb-000185
Figure PCTCN2021129863-appb-000185
在室温下，向(1S,3S)-甲基3-((6-(3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(100mg，206.36μmol)的四氢呋喃(3.00mL)和水(1.00mL)的溶液中加入一水合氢氧化锂(86.60mg，2.06mmol)，反应液在室温下搅拌过夜。反应完成后，将反应液浓缩得到粗品，粗品用反相高效液相色谱法进行分离(分离方法为：柱子:Phenomenex Synergi C18 150*25mm*10μm；溶剂：A＝水+0.1％甲酸，B＝乙腈；梯度：48％-678％B，10分钟)得到白色固体(1S,3S)-3-((6-(3-((4-(环丙基甲基)-1H-1,2,3-***-1-基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-14)(58.7mg，产率58.58％)。To (1S,3S)-methyl 3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methan at room temperature yl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (100 mg, 206.36 μmol) in tetrahydrofuran (3.00 mL) and water (1.00 mL) Lithium hydroxide monohydrate (86.60 mg, 2.06 mmol) was added, and the reaction solution was stirred at room temperature overnight. After the reaction is completed, the reaction solution is concentrated to obtain a crude product, and the crude product is separated by reversed-phase high performance liquid chromatography (separation method is: column: Phenomenex Synergi C18 150*25mm*10 μm; solvent: A=water+0.1% formic acid, B= Acetonitrile; Gradient: 48%-678% B, 10 min) gave (1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-1H-1,2, 3-Triazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-14) (58.7 mg , yield 58.58%).
1H NMR(400MHz,CDCl 3)δ7.65(s,1H),7.26-7.20(m,1H),7.20-7.11(m,1H),6.35(d,1H),5.78(br s,2H),4.70(br s,1H),2.95-2.82(m,1H),2.64(d,2H),2.57-2.41(m,3H),2.14(d,1H),2.07-1.86(m,3H),1.84-1.48(m,4H),1.07-0.93(m,1H),0.55-0.43(m,2H),0.24-0.09(m,2H) 1 H NMR (400MHz, CDCl 3 )δ7.65(s,1H), 7.26-7.20(m,1H), 7.20-7.11(m,1H), 6.35(d,1H), 5.78(br s,2H) ,4.70(br s,1H),2.95-2.82(m,1H),2.64(d,2H),2.57-2.41(m,3H),2.14(d,1H),2.07-1.86(m,3H), 1.84-1.48(m,4H),1.07-0.93(m,1H),0.55-0.43(m,2H),0.24-0.09(m,2H)
LC-MS,M/Z(ESI):471.2[M+H] +。 LC-MS, M/Z (ESI): 471.2 [M+H] + .
实施例15：目标化合物I-15的制备Example 15: Preparation of target compound I-15
(1S,3S)-3-((4-氨基甲酰基-2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基]噻吩-2-基)嘧啶-5-基)氧基)环己烷甲酸(目标化合物I-15)(1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)) Amino)methyl]thiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound I-15)
(1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-15)(1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen- 2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound I-15)
Figure PCTCN2021129863-appb-000186
Figure PCTCN2021129863-appb-000186
目标化合物I-15的合成路线如下所示：The synthetic route of the target compound I-15 is as follows:
Figure PCTCN2021129863-appb-000187
Figure PCTCN2021129863-appb-000187
第一步：2,4-二氯嘧啶-5-醇(I-15B)的合成Step 1: Synthesis of 2,4-dichloropyrimidin-5-ol (I-15B)
2,4-dichloropyrimidin-5-ol(I-15B)2,4-dichloropyrimidin-5-ol(I-15B)
Figure PCTCN2021129863-appb-000188
Figure PCTCN2021129863-appb-000188
在-76℃下，往2,4-二氯-5-甲氧基嘧啶(10.0g，55.8mmol)的二氯甲烷(50.0mL)的溶液中滴加三溴化硼(69.9g，279mmol)，反应液在室温下搅拌过夜。反应完成后，将反应液缓慢地滴加到饱和碳酸氢钠水溶液(500mL)中，充分搅拌后用二氯甲烷(100mL)萃取，有机相用无水硫酸钠干燥后过滤浓缩得到粗品2,4-二氯嘧啶-5-醇(I-15B)(8.50g，粗产物)。To a solution of 2,4-dichloro-5-methoxypyrimidine (10.0 g, 55.8 mmol) in dichloromethane (50.0 mL) was added dropwise boron tribromide (69.9 g, 279 mmol) at -76°C , the reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was slowly added dropwise to saturated aqueous sodium bicarbonate solution (500 mL), fully stirred and extracted with dichloromethane (100 mL). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude product 2,4. - Dichloropyrimidin-5-ol (I-15B) (8.50 g, crude).
第二步：(1S,3S)-3-((2,4-二氯嘧啶-5-基)氧基)环己烷甲酸甲酯(I-15C)的合成The second step: the synthesis of (1S,3S)-3-((2,4-dichloropyrimidin-5-yl)oxy) cyclohexanecarboxylic acid methyl ester (I-15C)
(1S,3S)-methyl 3-((2,4-dichloropyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-15C)(1S,3S)-methyl 3-((2,4-dichloropyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-15C)
Figure PCTCN2021129863-appb-000189
Figure PCTCN2021129863-appb-000189
把2,4-二氯嘧啶-5-醇(2.00g,12.12mmol)，(1S,3R)3-羟基环己烷-1-甲酸甲酯(中间体A)(2.88g，18.18mmol)和三苯基膦(6.36g，24.25mmol)溶解在四氢呋喃(50mL)中，在氮气保护和0℃下，向反应液中滴加偶氮二羧酸二异丙酯(4.90g，24.25mmol)，然后用氮气置换3次，在25℃反应12小时。反应完成后，反应液直接减压浓缩得到粗品。粗品经柱层析(硅胶，乙酸乙酯：石油醚＝10:1-5:1(V/V))纯化后得到无色油状化合物(1S,3S)-3-((2,4-二氯嘧啶-5-基)氧基)环己烷甲酸甲酯(I-15C)(1.50g，产率40.55％)。Combine 2,4-dichloropyrimidin-5-ol (2.00 g, 12.12 mmol), (1S,3R) methyl 3-hydroxycyclohexane-1-carboxylate (Intermediate A) (2.88 g, 18.18 mmol) and Triphenylphosphine (6.36 g, 24.25 mmol) was dissolved in tetrahydrofuran (50 mL), and under nitrogen protection at 0 °C, diisopropyl azodicarboxylate (4.90 g, 24.25 mmol) was added dropwise to the reaction solution, Then, it was replaced with nitrogen three times, and the reaction was carried out at 25°C for 12 hours. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=10:1-5:1 (V/V)) to obtain the colorless oily compound (1S,3S)-3-((2,4-di) Methyl chloropyrimidin-5-yl)oxy)cyclohexanecarboxylate (I-15C) (1.50 g, 40.55% yield).
第三步：(1S,3S)-3-((2-氯-4-氰基嘧啶丁-5-基)氧基)环己烷甲酸甲酯(I-15D)的合成The third step: the synthesis of (1S,3S)-3-((2-chloro-4-cyanopyrimidin-5-yl)oxy) cyclohexanecarboxylic acid methyl ester (I-15D)
(1S,3S)-methyl 3-((2-chloro-4-cyanopyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-15D)(1S,3S)-methyl 3-((2-chloro-4-cyanopyrimdin-5-yl)oxy)cyclohexanecarboxylate(I-15D)
Figure PCTCN2021129863-appb-000190
Figure PCTCN2021129863-appb-000190
把(1S,3S)-3-((2,4-二氯嘧啶-5-基)氧基)环己烷甲酸甲酯(1.5g，4.92mmol)和氰化锌(692.67mg，5.90mmol)溶解在N，N-二甲基甲酰胺(15mL)中，在氮气保护和0℃反应液中加入四三苯基膦钯(568.02mg，491.55μmol)，然后用氮气置换3次，在100℃反应12小时。反应完成后，向反应液中加入水(10mL)稀释，再用乙酸乙酯(10mL×3)萃取，合并有机层，用饱和食盐水(30mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。直接减压浓缩得到粗品。粗品经大板制备(硅胶，乙酸乙酯：石油醚＝3:1)纯化后得到黄色油状化合物(1S,3S)-3-((2-氯-4-氰基嘧啶丁-5-基)氧基)环己烷甲酸甲酯(I-15D)(400mg，产率27.52％)。Combine methyl (1S,3S)-3-((2,4-dichloropyrimidin-5-yl)oxy)cyclohexanecarboxylate (1.5 g, 4.92 mmol) and zinc cyanide (692.67 mg, 5.90 mmol) Dissolved in N,N-dimethylformamide (15 mL), tetrakistriphenylphosphine palladium (568.02 mg, 491.55 μmol) was added to the reaction solution under nitrogen protection and at 0 °C, and then replaced with nitrogen three times at 100 °C The reaction was carried out for 12 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to dilute, and then extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was directly concentrated under reduced pressure. The crude product was purified by large plate preparation (silica gel, ethyl acetate:petroleum ether=3:1) to give yellow oily compound (1S,3S)-3-((2-chloro-4-cyanopyrimidinebutan-5-yl) oxy)methylcyclohexanecarboxylate (I-15D) (400 mg, 27.52% yield).
第四步：(1S,3S)-3-((4-氰基-2-(3-甲酰基噻吩-2-基)嘧啶-5-基)氧基)环己烷甲酸甲酯(I-15E)的合成The fourth step: (1S,3S)-3-((4-cyano-2-(3-formylthiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid methyl ester (I- 15E) Synthesis
(1S,3S)-methyl-3-((4-cyano-2-(3-formylthiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-15E)(1S,3S)-methyl-3-((4-cyano-2-(3-formylthiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-15E)
Figure PCTCN2021129863-appb-000191
Figure PCTCN2021129863-appb-000191
把(1S,3S)-3-((2-氯-4-氰基嘧啶丁-5-基)氧基)环己烷甲酸甲酯(400mg，1.35mmol)，(3-甲酰基噻吩-2-基)硼酸(316.45mg，2.03mmol)和氟化钾(471.50mg，8.12mmol)溶于四氢呋喃(3mL)中，在氮气保护下，向反应液中加入双(三叔丁基膦)钯(69.13mg,135.26μmol)，然后用氮气置换3次，在40℃反应12小时。反应完成后，反应液直接经大板制备(硅胶，乙酸乙酯：石油醚＝3:1)纯化后得到黄色油状物(1S,3S)-3-((4-氰基-2-(3-甲酰基噻吩-2-基)嘧啶-5-基)氧基))环己烷甲酸甲酯(I-15E)(150mg，产率29.86％)。Methyl (1S,3S)-3-((2-chloro-4-cyanopyrimidin-5-yl)oxy)cyclohexanecarboxylate (400 mg, 1.35 mmol), (3-formylthiophene-2 -yl)boronic acid (316.45 mg, 2.03 mmol) and potassium fluoride (471.50 mg, 8.12 mmol) were dissolved in tetrahydrofuran (3 mL), and bis(tri-tert-butylphosphine)palladium ( 69.13 mg, 135.26 μmol), then replaced with nitrogen 3 times, and reacted at 40° C. for 12 hours. After the completion of the reaction, the reaction solution was directly purified by large plate preparation (silica gel, ethyl acetate: petroleum ether=3:1) to obtain a yellow oil (1S,3S)-3-((4-cyano-2-(3). -Formylthiophen-2-yl)pyrimidin-5-yl)oxy))cyclohexanecarboxylic acid methyl ester (I-15E) (150 mg, 29.86% yield).
第五步：(1S,3S)-3-((2-(5-氯-3-甲酰基噻吩-2-基)-4-氰基吡啶亚胺-5-基)氧基)环己烷甲酸甲酯(I-15F)的合成The fifth step: (1S,3S)-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-cyanopyridineimino-5-yl)oxy)cyclohexane Synthesis of methyl formate (I-15F)
(1S,3S)-methyl-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-cyanopyrimidin-5-yl)oxy)cyclohex anecarboxylate(I-15F)(1S,3S)-methyl-3-((2-(5-chloro-3-formylthiophen-2-yl)-4-cyanopyrimdin-5-yl)oxy)cyclohex anecarboxylate(I-15F)
Figure PCTCN2021129863-appb-000192
Figure PCTCN2021129863-appb-000192
把(1S,3S)-3-((4-氰基-2-(3-甲酰基噻吩-2-基)嘧啶-5-基)氧基)环己烷甲酸甲酯(150mg，403.87μmol)溶于N,N-二甲基甲酰胺(1.5mL)中，在氮气保护下，向反应液中加入1-氯吡咯烷-2,5-二酮(53.93mg，403.87μmol)，然后用氮气置换3次，在60℃反应2小时。反应完成后，反应液直接经大板制备(硅胶，乙酸乙酯：石油醚＝3:1(V/V))纯化后得到黄色油状化合物(1S,3S)-3-((4-氰基-2-(3-甲酰基噻吩-2-基)嘧啶-5-基)氧基)环己烷甲酸甲酯(I-15F)(100mg，产率61.01％)。Methyl (1S,3S)-3-((4-cyano-2-(3-formylthiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylate (150 mg, 403.87 μmol) Dissolved in N,N-dimethylformamide (1.5 mL), under nitrogen protection, 1-chloropyrrolidine-2,5-dione (53.93 mg, 403.87 μmol) was added to the reaction solution, followed by nitrogen Replaced 3 times and reacted at 60°C for 2 hours. After the reaction was completed, the reaction solution was directly purified by large plate preparation (silica gel, ethyl acetate: petroleum ether=3:1 (V/V)) to obtain a yellow oily compound (1S,3S)-3-((4-cyano) -Methyl 2-(3-formylthiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylate (I-15F) (100 mg, 61.01% yield).
第六步：(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-氰基嘧啶-5-基)氧基)环己烷甲酸甲酯(I-15G)的合成The sixth step: (1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino) Synthesis of methyl)thiophen-2-yl)-4-cyanopyrimidin-5-yl)oxy)cyclohexanecarboxylate (I-15G)
(1S,3S)-methyl-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-cyanopyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-15G)(1S,3S)-methyl-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2- yl)-4-cyanopyrimdin-5-yl)oxy)cyclohexanecarboxylate(I-15G)
Figure PCTCN2021129863-appb-000193
Figure PCTCN2021129863-appb-000193
在室温下，向(1S,3S)-3-((4-氰基-2-(3-甲酰基噻吩-2-基)嘧啶-5-基)氧基)环己烷甲酸甲酯(100mg，246μmol)和5-(环丁基甲基)-1,2,4-恶二唑-3-胺(45.2mg，295μmol)的乙醇溶液中加入冰醋酸(29.5mg，492μmol)，反应液在室温下搅拌6小时后加入氰基硼氢化钠(30.9mg，492μmol)，反应液在室温下搅拌6小时。反应完成后，将反应液浓缩得到粗品，粗品用层析硅胶制备板分离(分离方法：石油醚：乙酸乙酯(V/V)＝2:1)得到(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-氰基嘧啶-5-基)氧基)环己烷甲酸甲酯(I-15G)(63.0mg，产率47.0％)。To methyl (1S,3S)-3-((4-cyano-2-(3-formylthiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylate (100 mg) at room temperature , 246 μmol) and 5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-amine (45.2 mg, 295 μmol) in ethanol was added glacial acetic acid (29.5 mg, 492 μmol), the reaction solution was at room temperature After stirring for 6 hours, sodium cyanoborohydride (30.9 mg, 492 μmol) was added, and the reaction solution was stirred at room temperature for 6 hours. After the completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was separated by a silica gel preparative plate (separation method: petroleum ether: ethyl acetate (V/V)=2:1) to obtain (1S,3S)-3-(( 2-(5-Chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)-4-cyano Methyl pyrimidin-5-yl)oxy)cyclohexanecarboxylate (I-15G) (63.0 mg, 47.0% yield).
第七步：(1S,3S)-3-((4-氨基甲酰基-2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基) 噻吩-2-基)嘧啶-5-基)氧基)环己烷甲酸(目标化合物I-15)的合成。The seventh step: (1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazole- Synthesis of 3-yl)amino)methyl)thiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound 1-15).
(1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-15)(1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)thiophen- 2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound I-15)
Figure PCTCN2021129863-appb-000194
Figure PCTCN2021129863-appb-000194
将(1S,3S)-3-((2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)-4-氰基嘧啶-5-基)氧基)环己烷甲酸甲酯(63mg，116.01μmol)和一水合氢氧化锂(48.68mg，1.16mmol)溶解在四氢呋喃(1mL)和水(0.2mL)中，在25℃下搅拌反应12小时。反应完成后，将粗品通过反相高效液相色谱法进行分离，分离方法为：色谱柱：Phenomenex Synergi C18 150*25mm*10μm；流动相：A＝0.225％甲酸水溶液，B＝乙腈；梯度洗脱：43％-73％B，10min，得到浅黄色固体化合物(1S,3S)-3-((4-氨基甲酰基-2-(5-氯-3-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)噻吩-2-基)嘧啶-5-基)氧基)环己烷甲酸(目标化合物I-15)(4.33mg，产率12.50％)。(1S,3S)-3-((2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl) Thiophen-2-yl)-4-cyanopyrimidin-5-yl)oxy)cyclohexanecarboxylic acid methyl ester (63 mg, 116.01 μmol) and lithium hydroxide monohydrate (48.68 mg, 1.16 mmol) were dissolved in tetrahydrofuran (1 mL) ) and water (0.2 mL), and the reaction was stirred at 25°C for 12 hours. After the reaction was completed, the crude product was separated by reversed-phase high performance liquid chromatography. The separation method was as follows: chromatographic column: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: A=0.225% aqueous formic acid, B=acetonitrile; gradient elution : 43%-73% B, 10min, to obtain light yellow solid compound (1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl) -1,2,4-oxadiazol-3-yl)amino)methyl)thiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound I-15) (4.33 mg, yield 12.50%).
1H NMR(400MHz，CDCl 3)δ8.6(s,1H),7.6(s,1H),7.0(s,1H),6.6(s,1H),6.4(s,1H),4.8(s,1H),4.6-4.7(d,2H,J＝6.6Hz),2.9-3.0(m,1H),2.8-2.8(m,2H),2.7-2.8(m,1H),2.1-2.2(m,4H),1.9-2.1(m,4H),1.8-1.9(m,2H),1.7-1.8(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.6(s, 1H), 7.6(s, 1H), 7.0(s, 1H), 6.6(s, 1H), 6.4(s, 1H), 4.8(s, 1H), 4.6-4.7(d, 2H, J＝6.6Hz), 2.9-3.0(m, 1H), 2.8-2.8(m, 2H), 2.7-2.8(m, 1H), 2.1-2.2(m, 4H), 1.9-2.1(m, 4H), 1.8-1.9(m, 2H), 1.7-1.8(m, 4H).
LC-MS,M/Z(ESI):547.2[M+H] +。 LC-MS, M/Z (ESI): 547.2 [M+H] + .
实施例16：目标化合物I-16的制备Example 16: Preparation of target compound I-16
(1S,3S)-3-((2-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷甲酸(目标化合物I-16)(1S,3S)-3-((2-(5-Fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidine -5-yl)oxy)cyclohexanecarboxylic acid (target compound I-16)
(1S,3S)-3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-16)(1S,3S)-3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy )cyclohexanecarboxylic acid (target compound I-16)
Figure PCTCN2021129863-appb-000195
Figure PCTCN2021129863-appb-000195
目标化合物I-16的合成路线如下所示：The synthetic route of the target compound I-16 is as follows:
Figure PCTCN2021129863-appb-000196
Figure PCTCN2021129863-appb-000196
第一步：(1S,3S)-3-((2-(5-氟-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷甲酸甲酯(I-16A)的合成The first step: (1S,3S)-3-((2-(5-fluoro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylic acid methyl Synthesis of Ester (I-16A)
(1S,3S)-methyl3-((2-(5-fluoro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-16A)(1S,3S)-methyl3-((2-(5-fluoro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-16A)
Figure PCTCN2021129863-appb-000197
Figure PCTCN2021129863-appb-000197
在室温下，向2-溴-5-氟噻吩-3-甲醛(370mg，1.77mmol)，三乙胺(716.44mg，7.08mmol,985.47μL)和双三叔丁基膦钯(5.23mg，88.50μmol)的四氢呋喃(6.00mL)溶液中加入4,4,5,5- 四甲基-1,3,2-二氧杂硼烷(339.78mg，2.66mmol)，反应液在40℃搅拌1小时后加入氟化钾(617.00mg，10.62mmol)和(1S,3S)-3-((2-溴-4-甲基嘧啶-5-基)氧基)环己烷甲酸甲酯(407.87mg，1.24mmol)，反应液加热至60℃搅拌12小时。反应完成后，浓缩的到粗品，粗品制备层析板纯化(二氧化硅，石油醚：乙酸乙酯＝3∶1)得到黄色油状物(1S,3S)-3-((2-(5-氟-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷甲酸甲酯(I-16A)(50.0mg，产率7.46％)。To 2-bromo-5-fluorothiophene-3-carbaldehyde (370 mg, 1.77 mmol), triethylamine (716.44 mg, 7.08 mmol, 985.47 μL) and bistri-tert-butylphosphine palladium (5.23 mg, 88.50 μL) at room temperature μmol) in tetrahydrofuran (6.00 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborane (339.78 mg, 2.66 mmol), and the reaction solution was stirred at 40°C for 1 hour Potassium fluoride (617.00 mg, 10.62 mmol) and methyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylate (407.87 mg, 1.24 mmol), the reaction solution was heated to 60°C and stirred for 12 hours. After the completion of the reaction, the crude product was concentrated, and the crude product was purified by preparative chromatography (silica, petroleum ether:ethyl acetate=3:1) to give a yellow oil (1S,3S)-3-((2-(5- Methyl fluoro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylate (I-16A) (50.0 mg, 7.46% yield).
第二步：(1S,3S)-甲基3-((2-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基氧)环己烷羧酸酯(I-16B)的合成Step 2: (1S,3S)-methyl 3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl) Synthesis of -4-methylpyrimidin-5-yloxy)cyclohexanecarboxylate (I-16B)
(1S,3S)-methyl3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylate(I-16B)(1S,3S)-methyl3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy )cyclohexanecarboxylate(I-16B)
Figure PCTCN2021129863-appb-000198
Figure PCTCN2021129863-appb-000198
在室温下，向(1S,3S)-3-((2-(5-氟-3-甲酰基噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷甲酸甲酯(50.0mg，132.13μmol)和4-异丙基嘧啶-2-胺(36.25mg，264.26μmol)的甲醇(1.00mL)溶液中加入甲酸(15.87mg，264.26μmol)，反应液在室温下搅拌6小时后降温至0℃加入氰基硼氢化钠(16.61mg，264.26μmol)，反应继续在室温下搅拌6小时。反应完成后，将反应液浓缩的到粗品，粗品通过制备层析板纯化(二氧化硅，石油醚：乙酸乙酯＝2∶1(V/V))得到黄色的油状物(1S,3S)-甲基3-((2-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基氧)环己烷羧酸酯(I-16B)(25.0mg，产率37.87％)。To (1S,3S)-3-((2-(5-fluoro-3-formylthiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylic acid at room temperature To a solution of methyl ester (50.0 mg, 132.13 μmol) and 4-isopropylpyrimidin-2-amine (36.25 mg, 264.26 μmol) in methanol (1.00 mL) was added formic acid (15.87 mg, 264.26 μmol), and the reaction solution was kept at room temperature After stirring for 6 hours, the temperature was lowered to 0°C and sodium cyanoborohydride (16.61 mg, 264.26 μmol) was added, and the reaction was continued to stir at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated to a crude product, and the crude product was purified by preparative chromatography (silica, petroleum ether: ethyl acetate = 2:1 (V/V)) to obtain a yellow oil (1S, 3S) -Methyl 3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidine-5- oxy)cyclohexanecarboxylate (I-16B) (25.0 mg, 37.87% yield).
第三步：(1S,3S)-3-((2-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷甲酸(目标化合物I-16)的合成The third step: (1S,3S)-3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4 Synthesis of -methylpyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound I-16)
(1S,3S)-3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-16)(1S,3S)-3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy )cyclohexanecarboxylic acid (target compound I-16)
Figure PCTCN2021129863-appb-000199
Figure PCTCN2021129863-appb-000199
在室温下，向(1S,3S)-甲基3-((2-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基氧)环己烷羧酸酯(20.0mg，40.03μmol)的四氢呋喃(0.5mL)和水(0.2mL)溶液中加入一水合氢氧化锂(16.80mg，400.32μmol)，25℃下反应12h。反应完后，浓缩得到粗品。粗品用反相高效液相色谱法进行分离(分离方法为：柱子:Phenomenex Synergi C18 150*25mm*10μm；溶剂：A＝水+0.1％三氟乙酸酸，B＝乙腈；梯度：37％-67％B，10分钟)，得到白色固体化合物(1S,3S)-3-((2-(5-氟-3-(((4-异丙基嘧啶-2-基)氨基)甲基)噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷甲酸(目标化合物I-16)(1.02mg，产率4.80％)。To (1S,3S)-methyl 3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl at room temperature )-4-methylpyrimidin-5-yloxy)cyclohexanecarboxylate (20.0 mg, 40.03 μmol) in tetrahydrofuran (0.5 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (16.80 mg, 400.32 μmol), reacted 12h at 25 ℃.After the reaction, concentrated to obtain the crude product.The crude product is separated by reversed-phase high performance liquid chromatography (separation method is: post: Phenomenex Synergi C18 150*25mm*10 μm; Solvent: A=water + 0.1% trifluoroacetic acid, B=acetonitrile; gradient: 37%-67% B, 10 min) to give compound (1S,3S)-3-(((2-(5-fluoro-3-(() as a white solid) (4-Isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound I-16) (1.02 mg, 4.80% yield).
1H NMR(400MHz，CDCl 3)δ8.46-8.36(m,1H),8.14-7.88(m,1H),6.59(s,2H),4.99-4.89(m,3H),4.83-4.75(m,1H),3.23-3.14(m,1H),3.01(m,1H),2.94-2.82(m,2H),2.51-2.49(m,3H),2.04-2.02(m,3H),1.26(br s,4H),0.92-0.76(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.46-8.36 (m, 1H), 8.14-7.88 (m, 1H), 6.59 (s, 2H), 4.99-4.89 (m, 3H), 4.83-4.75 (m ,1H),3.23-3.14(m,1H),3.01(m,1H),2.94-2.82(m,2H),2.51-2.49(m,3H),2.04-2.02(m,3H),1.26(br s,4H),0.92-0.76(m,4H).
LC-MS,M/Z(ESI):486.1[M+H] +。 LC-MS, M/Z (ESI): 486.1 [M+H] + .
实施例17：目标化合物I-17的制备Example 17: Preparation of target compound I-17
(1S,3S)-3-((6-(3-((4-(环丙基甲基)-5-氧-4,5-二氢-1H-四唑-1-基)甲基)-5-氟噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-17)(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl) -5-Fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)
(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-5-fluorothiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(1S,3S)-3-((6-(3-((4-(cyclopropylmethyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-5-fluorothiophen-2- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
Figure PCTCN2021129863-appb-000200
Figure PCTCN2021129863-appb-000200
目标化合物I-17参考化合物I-13合成，不同之处在于将4-异丙基嘧啶-2-胺替换为1-(环丙基甲基)-1,4-二氢-5H-四唑-5-酮。The target compound I-17 was synthesized with reference to compound I-13, except that 4-isopropylpyrimidin-2-amine was replaced by 1-(cyclopropylmethyl)-1,4-dihydro-5H-tetrazole -5-keto.
LC-MS,M/Z(ESI):488.2[M+H] + LC-MS, M/Z(ESI): 488.2[M+H] +
实施例18：目标化合物I-18的制备Example 18: Preparation of target compound I-18
(1S,3S)-3-((2-(3-(((5-丁基-1,2,4-恶二唑-3-基)氨基)甲基)-5-氯噻吩-2-基)-4-甲基嘧啶-5-基)氧基)环己烷-1-羧酸(目标化合物I-18)(1S,3S)-3-((2-(3-(((5-butyl-1,2,4-oxadiazol-3-yl)amino)methyl)-5-chlorothiophene-2- yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-18)
(1S,3S)-3-((2-(3-(((5-butyl-1,2,4-oxadiazol-3-yl)amino)methyl)-5-chlorothiophen-2-yl)-4-me thylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(1S,3S)-3-((2-(3-(((5-butyl-1,2,4-oxadiazol-3-yl)amino)methyl)-5-chlorothiophen-2-yl)-4- me thylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid
Figure PCTCN2021129863-appb-000201
Figure PCTCN2021129863-appb-000201
目标化合物I-18参考化合物I-11合成，不同之处在于将5-(环丁基甲基)-1,2,4-噁二唑-3-胺替换为5-丁基-1,2,4-恶二唑-3-胺。The target compound I-18 was synthesized with reference to compound I-11, except that 5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-amine was replaced by 5-butyl-1,2,4 - oxadiazol-3-amine.
LC-MS,M/Z(ESI):506.2[M+H] + LC-MS, M/Z(ESI): 506.2[M+H] +
实施例19：目标化合物I-19的制备Example 19: Preparation of target compound I-19
(1S,3S)-3-((6-(5-氯-3-((4-(3-氟丙氧基)嘧啶-2-基)氨基)甲基)噻吩-2-基)-2-甲基吡啶-3-基)氧基)环己烷-1-羧酸(目标化合物I-19)(1S,3S)-3-((6-(5-Chloro-3-((4-(3-fluoropropoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2 -Methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-19)
(1S,3S)-3-((6-(5-chloro-3-(((4-(3-fluoropropoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(1S,3S)-3-((6-(5-chloro-3-(((4-(3-fluoropropoxy)pyrimidin-2-yl)amino)methyl)thiophen-2-yl)-2-methylpyridin- 3-yl)oxy)cyclohexane-1-carboxylic acid
Figure PCTCN2021129863-appb-000202
Figure PCTCN2021129863-appb-000202
目标化合物I-19参考化合物I-8合成，不同之处在于将2,2-二氟乙醇替换为3-氟-1-丙醇。The target compound I-19 was synthesized with reference to compound I-8, except that 2,2-difluoroethanol was replaced by 3-fluoro-1-propanol.
LC-MS,M/Z(ESI):535.2[M+H] + LC-MS, M/Z(ESI): 535.2[M+H] +
生物学活性及相关性质测试例Biological Activity and Related Properties Test Examples
测试例1：LPAR1体外钙流测定试验Test Example 1: LPAR1 In Vitro Calcium Flux Assay
化合物对LPAR1拮抗作用的测定在高表达人LPAR1的CHO稳转细胞株中进行。试验前18小时，将细胞以15,000细胞/孔的密度接种在含20μL DMEM/F12(1：1)培养基的384孔黑壁透明底板中，并保持在37℃/5％CO 2中孵育18小时，然后每孔细胞内加入20μL/孔 染料溶液，放回37℃培养箱中继续避光孵育30min，再在室温避光条件下孵育10min，细胞内加入10μL/孔不同终浓度的化合物，平衡20min，最后向细胞中加入12.5μL/孔的LPA溶液(终浓度5nM)，用FLIPR检测荧光信号值。以化合物浓度为X轴，荧光信号值为Y轴，通过软件Prism计算化合物的拮抗作用(IC 50值)。 The antagonism of compounds on LPAR1 was determined in a CHO cell line stably expressing human LPAR1. 18 hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 μL of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours 20 μL/well of dye solution was added to each well of cells, placed back in a 37°C incubator for 30 min in the dark, and then incubated at room temperature for 10 min in the dark. Add 10 μL/well of compounds of different final concentrations into the cells, and equilibrate. After 20 min, 12.5 μL/well of LPA solution (final concentration 5 nM) was finally added to the cells, and the fluorescence signal value was detected by FLIPR. Taking the compound concentration as the X-axis and the fluorescence signal value as the Y-axis, the antagonism (IC 50 value) of the compound was calculated by the software Prism.
表1 测试化合物对LPAR1的拮抗作用Table 1 Antagonism of test compounds on LPAR1
测试化合物test compound IC 50(nM) IC50 (nM)
对照化合物1Control compound 1 117.9117.9
对照化合物2Control compound 2 243.8243.8
对照化合物3Control compound 3 251.6251.6
对照化合物4Control compound 4 243.3243.3
对照化合物5Control compound 5 109.5109.5
I-1I-1 93.6393.63
I-2I-2 27.8227.82
I-3I-3 33.9233.92
I-4I-4 69.269.2
I-5I-5 39.7539.75
I-6I-6 46.3246.32
I-7I-7 16971697
I-8I-8 82.0682.06
I-9I-9 47.4947.49
I-10I-10 288.1288.1
I-11I-11 35.1835.18
I-12I-12 11.2911.29
I-13I-13 22.1622.16
I-14I-14 49.2949.29
I-16I-16 91.391.3
LPAR1钙流试验结果表明，本发明化合物对LPAR1具有良好的拮抗作用，与对照化合物相比，大多数发明化合物显示出更优异的LPAR1的拮抗作用。The results of the LPAR1 calcium flux test showed that the compounds of the present invention had a good antagonistic effect on LPAR1. Compared with the control compounds, most of the inventive compounds showed more excellent antagonistic effects on LPAR1.
测试例2：LPAR3体外钙流测定试验Test Example 2: LPAR3 In Vitro Calcium Flux Assay
化合物对LPAR3拮抗作用的测定在高表达人LPAR3的CHO稳转细胞株中进行。实验前18小时，将细胞以15,000细胞/孔的密度接种在含20μL DMEM/F12(1：1)培养基的384孔黑壁透明底板中，并保持在37℃/5％CO 2中孵育18小时，然后每孔细胞内加入20μL/孔染料溶液，放回37℃培养箱中继续避光孵育30min，再在室温避光条件下孵育10min，细胞内加入10μl/孔不同终浓度的化合物，平衡20min，最后向细胞中加入12.5μL/孔的LPA溶液(终浓度5nM)，用FLIPR检测荧光信号值。以化合物浓度为X轴，荧光信号值为Y轴，通过软件Prism计算化合物的拮抗作用(IC 50值)。 The antagonism of compounds on LPAR3 was determined in a CHO cell line stably expressing human LPAR3. Eighteen hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 μL of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours. 20 μL/well of dye solution was added to each well of cells, placed back in a 37°C incubator for 30 min in the dark, then incubated at room temperature for 10 min in the dark, and 10 μL/well of different final concentrations of compounds were added to the cells and equilibrated. After 20 min, 12.5 μL/well of LPA solution (final concentration 5 nM) was finally added to the cells, and the fluorescence signal value was detected by FLIPR. Taking the compound concentration as the X-axis and the fluorescence signal value as the Y-axis, the antagonism (IC 50 value) of the compound was calculated by the software Prism.
LPAR3钙流试实验结果表明，本发明化合物对LPAR3的拮抗作用很较弱，与对照化合物相比，本发明化合物显示出更优异的LPAR1选择抑制性。The results of the LPAR3 calcium flux assay showed that the compounds of the present invention had a weak antagonistic effect on LPAR3, and compared with the control compounds, the compounds of the present invention showed better selective inhibition of LPAR1.
测试例3：化合物物对胆汁外排转运体的抑制作用测试试验Test Example 3: Test test for the inhibitory effect of compounds on bile efflux transporters
化合物物对胆汁外排转运体的抑制作用测试试验使用表达人源性胆汁外排转运体的囊泡(GenoMembrane)来进行。不同浓度的化合物与囊泡预孵育5分钟，同时设置阴性对照(NC)组和阳性对照(PC)组：NC组为囊泡与空白缓冲液37℃预孵育5分钟，PC组为阳性抑制剂与囊泡37℃预孵育5分钟。随后在分别加入ATP或AMP的条件下，与探针底物在37℃孵育5分钟。用预冷的Buffer B1(10×Buffer B1(Stopping and Washing Buffer):100mM Hepes-Tris,1000mM KNO3,500mM Sucrose)终止试验。将试验样本转移到96孔滤板上，用真空泵抽滤，随后用0.2mL预冷的Buffer B1反复洗5次，用50μL 80％甲醇溶解滤板上的囊泡，收集后2000转离心2分钟收集滤液，重复一次，将两次的滤液合并在一起，混匀，得到大约100μL的滤液，加入含内标的预冷甲醇，于12,000转离心5min。取上清液用于LC-MS/MS定量检测被转运的底物的含量。以化合物浓度为X轴，相对活性(％ofNC)为Y轴，通过软件Prism计算化合物抑制胆汁外排转运体活性的IC 50值以及抑制率。 Inhibitory effects of compounds on bile efflux transporters were tested using vesicles (GenoMembrane) expressing human-derived bile efflux transporters. Compounds with different concentrations were pre-incubated with vesicles for 5 minutes, and a negative control (NC) group and a positive control (PC) group were set at the same time: NC group was pre-incubated for 5 minutes with vesicles and blank buffer at 37°C, and PC group was positive inhibitor Pre-incubate with vesicles at 37 °C for 5 min. This was followed by incubation with the probe substrate for 5 minutes at 37°C with the addition of ATP or AMP, respectively. The assay was terminated with pre-chilled Buffer B1 (10×Buffer B1 (Stopping and Washing Buffer): 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose). Transfer the test sample to a 96-well filter plate, filter it with a vacuum pump, and then repeatedly wash it with 0.2 mL of pre-cooled Buffer B1 for 5 times, dissolve the vesicles on the filter plate with 50 μL of 80% methanol, and centrifuge at 2000 rpm for 2 minutes after collection. The filtrate was collected and repeated once. The two filtrates were combined and mixed to obtain about 100 μL of the filtrate. Pre-cooled methanol containing the internal standard was added and centrifuged at 12,000 rpm for 5 min. The supernatant was taken for LC-MS/MS quantitative detection of the transported substrate content. Taking the compound concentration as the X-axis and the relative activity (% of NC) as the Y-axis, the IC50 value and the inhibition rate of the compound for inhibiting the activity of bile efflux transporter were calculated by the software Prism.
按以下公式计算不同条件下的转运速率(活性)和相对活性：The transport rate (activity) and relative activity under different conditions were calculated as follows:
底物主动转运速率(pmol/min/mg)＝Substrate active transport rate (pmol/min/mg) =
Figure PCTCN2021129863-appb-000203
Figure PCTCN2021129863-appb-000203
Figure PCTCN2021129863-appb-000204
Figure PCTCN2021129863-appb-000204
胆汁外排转运体的抑制试验实验结果表明，本发明化合物对胆汁外排转运体无明显抑制作用，无胆汁淤积毒性风险。The experimental results of the inhibition test of bile efflux transporter show that the compound of the present invention has no obvious inhibitory effect on bile efflux transporter, and has no risk of cholestasis toxicity.
测试例4：药代动力学试验Test Example 4: Pharmacokinetic Test
小鼠药代动力学试验，使用雄性ICR小鼠，20-25g，禁食过夜。取3只小鼠，口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量 含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Pharmacokinetic test in mice, using male ICR mice, 20-25 g, fasted overnight. Three mice were taken and administered orally orally at 10 mg/kg. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the volume of acetonitrile solution containing the internal standard to mix, vortex for 1 minute, centrifuge at 13,000 rpm for 10 minutes at 4°C, take the supernatant and add 3 times the volume of water to mix, take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
表4 小鼠口服灌胃给药药代动力学试验结果Table 4 Pharmacokinetic test results of oral gavage in mice
Figure PCTCN2021129863-appb-000205
Figure PCTCN2021129863-appb-000205
小鼠药代动力学试验结果表明，与对照化合物相比，本发明化合物表现出更优良的药代动力学性质，成药性好。The results of the mouse pharmacokinetic test show that, compared with the control compound, the compound of the present invention exhibits better pharmacokinetic properties and better drug-forming properties.
测试例5：LPA诱导的小鼠组胺释放试验Test Example 5: LPA-induced histamine release test in mice
LPA诱导的小鼠组胺释放试验用20-25g的雌性Balb/c小鼠开展。化合物与阳性对照分别设置三个给药组，每组6只小鼠，分别口服灌胃给药1，3，10mpk，空白组和阴性对照组则灌胃相同体积溶媒(5％DMSO+5％Solutol+90％Saline)。给药2h后，各给药组小鼠尾静脉注射300μg/mouse LPA，而空白组和阴性对照组则尾静脉注射等体积溶媒(4mg/ml BSA/PBS)，刺激2min后取血，湿冰上或2-8度保存，20min内5000rpm低温离心5min，取血浆，使用HTRF试剂盒(Cisbio，62HTMDPEG)检测血浆中histamine浓度。利用血浆中histamine浓度数据计算不同浓度化合物对LPA诱导的组胺释放的抑制率。LPA-induced mouse histamine release assays were performed with 20-25 g female Balb/c mice. Compounds and positive control groups were set up in three administration groups, each group of 6 mice, orally administered 1, 3, 10mpk, respectively, blank group and negative control group were given the same volume of vehicle (5% DMSO + 5% Solutol+90%Saline). After 2 hours of administration, mice in each administration group were injected with 300 μg/mouse LPA through the tail vein, while the blank group and the negative control group were injected with an equal volume of vehicle (4 mg/ml BSA/PBS) through the tail vein. The samples were stored at 2-8 degrees, centrifuged at 5000 rpm for 5 min within 20 min, and the plasma was collected, and the histamine concentration in the plasma was detected using the HTRF kit (Cisbio, 62HTMDPEG). The inhibition rates of different concentrations of compounds on LPA-induced histamine release were calculated using the histamine concentration data in plasma.
表5 LPA诱导的小鼠组胺释放试验Table 5 LPA-induced histamine release test in mice
Figure PCTCN2021129863-appb-000206
Figure PCTCN2021129863-appb-000206
组胺释放试验结果表明，与对照化合物相比，本发明化合物在3个浓度下都有显著高于对照化合物的抑制LPA诱导的组胺释放的效率。The results of the histamine release test showed that, compared with the control compound, the compounds of the present invention had significantly higher inhibition efficiency of LPA-induced histamine release than the control compound at three concentrations.
测试例6：博来霉素诱导的肺纤维化药效试验Test Example 6: Efficacy test of bleomycin-induced pulmonary fibrosis
雄性小鼠适应性饲养1周，并体重达标后，根据动物体重随机分为对照组组，模型组和给药组。异氟烷麻醉后：模型组和给药组肺内均匀给予50μL的博来霉素以建立小鼠肺纤维化模型，而对照组肺内均匀给予50μL生理盐水；7天后连续给药15天，给药完成后，动物经戊巴比妥钠深度麻醉，收集肺泡灌洗液(BALF)，并立即放到湿冰盒暂存，用于后续指标检测；部分动物肺放入10％中性***缓冲液固定，用于制备病理组织切片；另一部分动物肺准确称取重量并记录后，置于冻存管，立即放入液氮，和收集的BALF上清一并转移至超低温-80℃冰箱保存，用于后续检测肺泡灌洗液和肺组织羟脯氨酸水平、Collagen I表达情况等指标。The male mice were reared adaptively for 1 week, and after reaching the target body weight, they were randomly divided into the control group, the model group and the administration group according to the body weight of the animals. After isoflurane anesthesia: the model group and the administration group were evenly given 50 μL of bleomycin in the lungs to establish a mouse pulmonary fibrosis model, while the control group was evenly given 50 μL of normal saline in the lungs; After the administration was completed, the animals were deeply anesthetized with sodium pentobarbital, and the bronchoalveolar lavage fluid (BALF) was collected and temporarily stored in a wet ice box for subsequent index detection; some animal lungs were placed in 10% neutral fortification. It was fixed with formalin buffer and used to prepare pathological tissue sections; another part of the animal lung was accurately weighed and recorded, placed in a cryopreservation tube, immediately placed in liquid nitrogen, and transferred to ultra-low temperature- Stored in a refrigerator at 80 °C for subsequent detection of hydroxyproline levels in bronchoalveolar lavage fluid and lung tissue, Collagen I expression and other indicators.
博来霉素诱导的肺纤维化药效试验结果表明，本发明化合物能通过拮抗LPAR1显著改善博来霉素诱导的小鼠肺纤维化症状。The results of the efficacy test on bleomycin-induced pulmonary fibrosis show that the compounds of the present invention can significantly improve the symptoms of bleomycin-induced pulmonary fibrosis in mice by antagonizing LPAR1.

Claims (18)

  1. 一种化合物，其为式(I)所示化合物，或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：A compound, which is a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):
    Figure PCTCN2021129863-appb-100001
    Figure PCTCN2021129863-appb-100001
    其中：in:
    R 1选自-H，-CN，卤素，-Z-R a，无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基； R 1 is selected from -H, -CN, halogen, -ZR a , the following groups unsubstituted or substituted by R b : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy;
    Z选自单键、-O-、-S-或-CO-；Z is selected from a single bond, -O-, -S- or -CO-;
    R a选自C 1-6烷基，被卤素取代的C 1-6烷基，氨基，C 1-3烷氨基； R a is selected from C 1-6 alkyl, C 1-6 alkyl substituted by halogen, amino, C 1-3 alkylamino;
    R b选自-CN，卤素，C 1-6烷基，C 1-6烷氧基； R b is selected from -CN, halogen, C 1-6 alkyl, C 1-6 alkoxy;
    R 2选自-H，-CN，卤素，-Y-R d，无取代或被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基； R 2 is selected from -H, -CN, halogen, -YR d , the following groups unsubstituted or substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy;
    Y选自单键或-O-、-S-；Y is selected from single bond or -O-, -S-;
    R d选自C 1-6烷基，被卤素取代的C 1-6烷基； R d is selected from C 1-6 alkyl, C 1-6 alkyl substituted by halogen;
    R e选自-CN，卤素，C 1-6烷基，C 1-6烷氧基； R e is selected from -CN, halogen, C 1-6 alkyl, C 1-6 alkoxy;
    X 1、X 2、X 3分别独立地选自C或N，且X 1、X 2、X 3不同时为N； X 1 , X 2 , and X 3 are independently selected from C or N, and X 1 , X 2 , and X 3 are not N at the same time;
    Figure PCTCN2021129863-appb-100002
    选自无无取代或任选被1～3个R g取代的以下基团：
    Figure PCTCN2021129863-appb-100003
    Figure PCTCN2021129863-appb-100004
    Figure PCTCN2021129863-appb-100002
    Selected from the following groups that are unsubstituted or optionally substituted with 1 to 3 R g :
    Figure PCTCN2021129863-appb-100003
    Figure PCTCN2021129863-appb-100004
    R g选自H、F、Cl、甲基； R g is selected from H, F, Cl, methyl;
    L 1选自单键、-N(R 3)-或-O-； L 1 is selected from a single bond, -N(R 3 )- or -O-;
    L 2选自单键、-O-、无取代或被C 1-3烷基取代的C 1-6亚烷基、无取代或被C 1-3烷基取代的环丙基； L 2 is selected from single bond, -O-, unsubstituted or C 1-3 alkyl substituted C 1-6 alkylene, unsubstituted or C 1-3 alkyl substituted cyclopropyl;
    R 3选自-H、C 1-3烷基； R 3 is selected from -H, C 1-3 alkyl;
    R 4选自-H、-CN、卤素、无取代或被R h取代的以下基团：C 1-6烷基、C 3-8环烷基； R 4 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R h : C 1-6 alkyl, C 3-8 cycloalkyl;
    R h选自-H、卤素、C 1-6烷基、被卤素取代的C 1-6烷基、被卤素取代的C 1-6烷氧基。 R h is selected from -H, halogen, C 1-6 alkyl, C 1-6 alkyl substituted by halogen, C 1-6 alkoxy substituted by halogen.
  2. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129863-appb-100005
    选自被R 1取代的苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基。     The compound of claim 1, wherein
    Figure PCTCN2021129863-appb-100005
    Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl substituted by R1.
  3. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129863-appb-100006
    选自
    Figure PCTCN2021129863-appb-100007
    Figure PCTCN2021129863-appb-100008
    The compound of claim 1, wherein
    Figure PCTCN2021129863-appb-100006
    selected from
    Figure PCTCN2021129863-appb-100007
    Figure PCTCN2021129863-appb-100008
    和/或，当R 1为卤素时，所述卤素为氟、氯、溴或碘； and/or, when R 1 is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 1为-Z-R a、R a为C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基； And/or, when R 1 is -ZR a and R a is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, pentyl, hexyl;
    和/或，当R 1为-Z-R a、R a为被卤素取代的C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基； And/or, when R 1 is -ZR a and R a is C 1-6 alkyl substituted by halogen, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, pentyl, hexyl;
    和/或，当R 1为-Z-R a、R a为被卤素取代的C 1-6烷基时，所述的卤素的个数为一个或多个，当存在多个卤素时，所述的卤素相同或不同； And/or, when R 1 is -ZR a and R a is a C 1-6 alkyl group substituted by halogen, the number of the halogen is one or more, and when there are multiple halogens, the halogen The halogens are the same or different;
    和/或，当R 1为-Z-R a、R a为被卤素取代的C 1-6烷基时，所述的卤素为氟、氯、溴或碘； And/or, when R 1 is -ZR a and R a is C 1-6 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 1为-Z-R a、R a为C 1-3烷氨基时，所述的C 1-3烷氨基为
    Figure PCTCN2021129863-appb-100009
    Figure PCTCN2021129863-appb-100010
    And/or, when R 1 is -ZR a and R a is C 1-3 alkylamino, the C 1-3 alkylamino is
    Figure PCTCN2021129863-appb-100009
    Figure PCTCN2021129863-appb-100010
    和/或，当R 1为无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R b的个数为一个或多个，当存在多个R b时，所述R b相同或不同； And/or, when R 1 is unsubstituted or substituted by R b the following groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the R b is one or more, and when there are multiple R b , the R b is the same or different;
    和/或，当R 1为无取代或被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R b的个数为一个或多个，所述R b选自-CN，氟、氯、溴、碘，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基； And/or, when R 1 is unsubstituted or substituted by R b the following groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the R b is one or more, the R b is selected from -CN, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyl Oxygen;
    和/或，当R 1为无取代或被R b取代的C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基； And/or, when R 1 is an unsubstituted or R b substituted C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, pentyl, hexyl;
    和/或，当R 1为无取代或被R b取代的C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基； And/or, when R 1 is an unsubstituted or R b substituted C 3-6 cycloalkyl group, the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, and cyclopentyl;
    和/或，当R 1为无取代或被R b取代的C 1-6烷氨基时，所述的C 1-6烷氨基为
    Figure PCTCN2021129863-appb-100011
    其中m1和m2各自独立地选自0-6的整数，且m1和m2不同时为零，且m1和m2的和不超过6；     And/or, when R 1 is C 1-6 alkylamino unsubstituted or substituted by R b , the C 1-6 alkylamino group is
    Figure PCTCN2021129863-appb-100011
    wherein m1 and m2 are independently selected from integers from 0 to 6, and m1 and m2 are not zero at the same time, and the sum of m1 and m2 does not exceed 6;
    和/或，当R 1为无取代或被R b取代的C 1-6烷氧基时，所述的C 1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基； And/or, when R 1 is unsubstituted or C 1-6 alkoxy substituted by R b , the C 1-6 alkoxy is methoxy, ethoxy, n-propoxy, iso- Propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy;
    和/或，当R 2为卤素时，所述卤素为氟、氯、溴或碘； and/or, when R 2 is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 2为-Y-R d、R d为C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基； And/or, when R 2 is -YR d and R d is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, pentyl, hexyl;
    和/或，当R 2为-Y-R d、R d为被卤素取代的C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基； And/or, when R 2 is -YR d and R d is C 1-6 alkyl substituted by halogen, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, pentyl, hexyl;
    和/或，当R 2为-Y-R d、R d为被卤素取代的C 1-6烷基时，所述的卤素的个数为一个或多个，当存在多个卤素时，所述的卤素相同或不同； And/or, when R 2 is -YR d and R d is C 1-6 alkyl substituted by halogen, the number of the halogen is one or more, and when there are multiple halogens, the halogen The halogens are the same or different;
    和/或，当R 2为-Y-R d、R d为被卤素取代的C 1-6烷基时，所述的卤素为氟、氯、溴或碘； And/or, when R 2 is -YR d and R d is C 1-6 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 2为无取代或被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R e的个数为一个或多个，当存在多个R e时，所述R e相同或不同； And/or, when R 2 is the following groups unsubstituted or substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the Re is one or more, and when there are multiple Re , the Re is the same or different;
    和/或，当R 2为无取代或被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，所述R e的个数为一个或多个，所述R e选自-CN，氟、氯、溴、碘，甲基、 乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基； And/or, when R 2 is the following groups unsubstituted or substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy , the number of the Re is one or more, and the Re is selected from -CN, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyl Oxygen;
    和/或，当R 2为无取代或被R e取代的C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基； And/or, when R 2 is unsubstituted or C 1-6 alkyl substituted by Re , the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, pentyl, hexyl;
    和/或，当R 2为无取代或被R e取代的C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基； And/or, when R 2 is unsubstituted or C 3-6 cycloalkyl substituted by R e , the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, and cyclopentyl;
    和/或，当R 2为无取代或被R e取代的C 1-6烷氨基时，所述的C 1-6烷氨基为
    Figure PCTCN2021129863-appb-100012
    其中n1和n2各自独立地选自0-6的整数，且n1和n2不同时为零，且n1和n2的和不超过6；     And/or, when R 2 is unsubstituted or substituted C 1-6 alkylamino group by Re , the C 1-6 alkylamino group is
    Figure PCTCN2021129863-appb-100012
    wherein n1 and n2 are each independently selected from an integer from 0 to 6, and n1 and n2 are not zero at the same time, and the sum of n1 and n2 does not exceed 6;
    和/或，当R 2为无取代或被R e取代的C 1-6烷氧基时，所述的C 1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基； And/or, when R 2 is unsubstituted or C 1-6 alkoxy substituted by Re , the C 1-6 alkoxy is methoxy, ethoxy, n-propoxy, isopropyl Propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy;
    和/或，
    Figure PCTCN2021129863-appb-100013
    选自
    Figure PCTCN2021129863-appb-100014
    Figure PCTCN2021129863-appb-100015
    其中R g选自H、F、Cl、甲基；     and / or,
    Figure PCTCN2021129863-appb-100013
    selected from
    Figure PCTCN2021129863-appb-100014
    Figure PCTCN2021129863-appb-100015
    wherein R g is selected from H, F, Cl, methyl;
    和/或，当L 1为-N(R 3)-时，所述R 3选自-H、甲基、乙基、丙基； And/or, when L 1 is -N(R 3 )-, said R 3 is selected from -H, methyl, ethyl, propyl;
    和/或，L 2选自单键、-O-、
    Figure PCTCN2021129863-appb-100016
    And/or, L 2 is selected from single bond, -O-,
    Figure PCTCN2021129863-appb-100016
    和/或，当R 4为卤素时，所述卤素为氟、氯、溴或碘； and/or, when R4 is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 4为无取代或被R h取代的以下基团：C 1-6烷基、C 3-8环烷基时，所述R h的个数为一个或多个，当存在多个R h时，所述R h相同或不同； And/or, when R 4 is the following groups unsubstituted or substituted by R h : C 1-6 alkyl group, C 3-8 cycloalkyl group, the number of said R h is one or more, when When there are multiple R h , the R h is the same or different;
    和/或，当R 4为无取代或被R h取代的以下基团：C 1-6烷基、C 3-8环烷基时，所述R h的个数为一个或多个，所述R h选自-H，氟、氯、溴、碘，甲基、乙基、正丙基、异丙基、正丁基、正戊基、氟代烷烃、三氟甲基、二氟甲氧基； And/or, when R 4 is the following group unsubstituted or substituted by R h : C 1-6 alkyl group, C 3-8 cycloalkyl group, the number of said R h is one or more, so Said R is selected from -H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n -propyl, isopropyl, n-butyl, n-pentyl, fluoroalkane, trifluoromethyl, difluoromethyl Oxygen;
    和/或，当R 4为无取代或被R h取代的C 1-6烷基时，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基； And/or, when R 4 is an unsubstituted or R substituted C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n -propyl, isopropyl, n-butyl , isobutyl, tert-butyl, pentyl, hexyl;
    和/或，当R 4为无取代或被R h取代的C 3-8环烷基时，所述的C 3-8环烷基为环丙基、环丁 基、环戊基、环己基、环庚基、环辛基。 And/or, when R 4 is an unsubstituted or R substituted C 3-8 cycloalkyl group, the C 3-8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl.
  4. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129863-appb-100017
    选自
    Figure PCTCN2021129863-appb-100018
    Figure PCTCN2021129863-appb-100019
    The compound of claim 1, wherein
    Figure PCTCN2021129863-appb-100017
    selected from
    Figure PCTCN2021129863-appb-100018
    Figure PCTCN2021129863-appb-100019
    和/或，当R 1为卤素时，所述卤素为氟、氯或溴； and/or, when R 1 is halogen, the halogen is fluorine, chlorine or bromine;
    和/或，当R 1为-Z-R a，Z为-O-时，R 1选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)； And/or, when R 1 is -ZR a and Z is -O-, R 1 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -OCH 2 CH 2 F, -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F);
    和/或，当R 1为-Z-R a，Z为-S-时，R 1选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)； And/or, when R 1 is -ZR a and Z is -S-, R 1 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH 2 F, -SCH 2 CH 2 F, -S(CH 2 ) 2 CH 2 F, -SCH(CH 3 )(CH 2 F);
    和/或，当R 1为-Z-R a，Z为-CO-时，R 1选自-CO-NH 2、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)； And/or, when R 1 is -ZR a and Z is -CO-, R 1 is selected from -CO-NH 2 , -CO-NH-CH 3 , -CO-N(CH 3 ) 2 , -CO- NH-CH 2 -CH 3 , -CO-N(CH 3 )(CH 2 CH 3 );
    和/或，当R 1为无取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基、C 1-6烷氧基，R b为-CN，卤素，C 1-6烷基或C 1-6烷氧基时，R 1选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100020
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2；     And/or, when R 1 is the following unsubstituted groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R b is -CN , halogen, C 1-6 alkyl or C 1-6 alkoxy, R 1 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
    Figure PCTCN2021129863-appb-100020
    -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 ;
    和/或，当R 1为被R b取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，R 1选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
    Figure PCTCN2021129863-appb-100021
    Figure PCTCN2021129863-appb-100022
    -NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、-NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、-OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、 -CH(CH 3)(CH 2F)、
    Figure PCTCN2021129863-appb-100023
    -NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129863-appb-100024
    -NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129863-appb-100025
    Figure PCTCN2021129863-appb-100026
    And/or, when R 1 is the following group substituted by R b : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R 1 Selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN),
    Figure PCTCN2021129863-appb-100021
    Figure PCTCN2021129863-appb-100022
    -NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F, -CH(CH 3 )(CH 2 F),
    Figure PCTCN2021129863-appb-100023
    -NH- CH2F , -N( CH3 )( CH2F ), -NH- CH2CH2CH2F , -NH-( CH2 ) 2CH2F , -NH- CH ( CH3 ) (CH 2 F), -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
    Figure PCTCN2021129863-appb-100024
    -NH- CH2Cl , -N( CH3 )( CH2Cl ), -NH- CH2CH2CH2Cl , -NH-( CH2 ) 2CH2Cl , -NH- CH ( CH3 ) (CH 2 Cl), -OCH 2 Cl, -OCH 2 CH 2 Cl, -O(CH 2 ) 2 CH 2 Cl, -OCH(CH 3 )(CH 2 Cl),
    Figure PCTCN2021129863-appb-100025
    Figure PCTCN2021129863-appb-100026
    和/或，当R 2为卤素时，所述卤素为氟、氯或溴； and/or, when R 2 is halogen, the halogen is fluorine, chlorine or bromine;
    和/或，当R 2为-Y-R d，Y为-O-时，R 2选自-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-O(CH 2) 2OCH 3、-OCH 2F、-OCH 2CH 2F、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)； And/or, when R 2 is -YR d and Y is -O-, R 2 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -OCH 2 CH 2 F, -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F);
    和/或，当R 2为Y-R d，Y为-O-时，R 2选自-SCH 3、-SCH 2CH 3、-S(CH 2) 2CH 3、-SCH(CH 3) 2、-SCH 2F、-SCH 2CH 2F、-S(CH 2) 2CH 2F、-SCH(CH 3)(CH 2F)； And/or, when R 2 is YR d and Y is -O-, R 2 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH2F, -SCH2CH2F, -S( CH2 ) 2CH2F , -SCH ( CH3 ) ( CH2F ) ;
    和/或，当R 2为无取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基、C 1-6烷氧基，R b为-CN，卤素，C 1-6烷基或C 1-6烷氧基时，R 2选自-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100027
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3、-NH-(CH 2) 2CH 3、-NH-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2；     And/or, when R 2 is the following unsubstituted groups: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R b is -CN , halogen, C 1-6 alkyl or C 1-6 alkoxy, R 2 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
    Figure PCTCN2021129863-appb-100027
    -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 ;
    和/或，当R 2为被R e取代的以下基团：C 1-6烷基、C 3-6环烷基、C 1-6烷氨基，C 1-6烷氧基时，R 2选自-CH 2CN、-CH 2CH 2CN、-(CH 2) 2CH 2CN、-CH(CH 3)(CH 2CN)、
    Figure PCTCN2021129863-appb-100028
    Figure PCTCN2021129863-appb-100029
    -NH-CH 2CN、-N(CH 3)(CH 2CN)、-NH-CH 2CH 2CH 2CN、-NH-(CH 2) 2CH 2CN、-NH-CH(CH 3)(CH 2CN)、-OCH 2CN、-OCH 2CH 2CN、-O(CH 2) 2CH 2CN、 -OCH(CH 3)(CH 2CN)、-CH 2F、-CHF 2、CF 3、-CF 2CH 3、-CH 2CF 3、-CH 2CH 2F、-(CH 2) 2CH 2F、-CH(CH 3)(CH 2F)、
    Figure PCTCN2021129863-appb-100030
    -NH-CH 2F、-N(CH 3)(CH 2F)、-NH-CH 2CH 2CH 2F、-NH-(CH 2) 2CH 2F、-NH-CH(CH 3)(CH 2F)、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CH 2CH 2Cl、-(CH 2) 2CH 2Cl、-CH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129863-appb-100031
    -NH-CH 2Cl、-N(CH 3)(CH 2Cl)、-NH-CH 2CH 2CH 2Cl、-NH-(CH 2) 2CH 2Cl、-NH-CH(CH 3)(CH 2Cl)、-OCH 2Cl、-OCH 2CH 2Cl、-O(CH 2) 2CH 2Cl、-OCH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129863-appb-100032
    Figure PCTCN2021129863-appb-100033
    And/or, when R 2 is the following groups substituted by Re : C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, R 2 Selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN),
    Figure PCTCN2021129863-appb-100028
    Figure PCTCN2021129863-appb-100029
    -NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F, -CH(CH 3 )(CH 2 F),
    Figure PCTCN2021129863-appb-100030
    -NH- CH2F , -N( CH3 )( CH2F ), -NH- CH2CH2CH2F , -NH-( CH2 ) 2CH2F , -NH- CH ( CH3 ) (CH 2 F), -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )( CH2F ), -CH2CH2Cl , -( CH2 ) 2CH2Cl, -CH( CH3 ) ( CH2Cl ),
    Figure PCTCN2021129863-appb-100031
    -NH- CH2Cl , -N( CH3 )( CH2Cl ), -NH- CH2CH2CH2Cl , -NH-( CH2 ) 2CH2Cl , -NH- CH ( CH3 ) (CH 2 Cl), -OCH 2 Cl, -OCH 2 CH 2 Cl, -O(CH 2 ) 2 CH 2 Cl, -OCH(CH 3 )(CH 2 Cl),
    Figure PCTCN2021129863-appb-100032
    Figure PCTCN2021129863-appb-100033
    和/或，
    Figure PCTCN2021129863-appb-100034
    选自
    Figure PCTCN2021129863-appb-100035
    Figure PCTCN2021129863-appb-100036
    and / or,
    Figure PCTCN2021129863-appb-100034
    selected from
    Figure PCTCN2021129863-appb-100035
    Figure PCTCN2021129863-appb-100036
    和/或，当L 1为-N(R 3)-时，所述R 3选自-H或甲基； and/or, when L 1 is -N(R 3 )-, said R 3 is selected from -H or methyl;
    和/或，L 2选自单键、-O-、
    Figure PCTCN2021129863-appb-100037
    And/or, L 2 is selected from single bond, -O-,
    Figure PCTCN2021129863-appb-100037
    和/或，当R 4为卤素时，所述卤素为氟； and/or, when R4 is halogen, the halogen is fluorine;
    和/或，当R 4为无取代的C 1-6烷基时，R 4选自甲基、乙基、异丙基、正丁基； And/or, when R 4 is unsubstituted C 1-6 alkyl, R 4 is selected from methyl, ethyl, isopropyl, n-butyl;
    和/或，当R 4为无取代的C 3-8环烷基时，R 4选自环丙基、环丁基、环戊基； And/or, when R 4 is unsubstituted C 3-8 cycloalkyl, R 4 is selected from cyclopropyl, cyclobutyl, and cyclopentyl;
    和/或，当R 4为被R h取代的C 1-6烷基时，R 4选自-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-(CH 2) 2F、-(CH 2) 3F、-CH(CH 3)(CH 2F)、-(CH 2) 2Cl、-(CH 2) 3Cl、-CH(CH 3)(CH 2Cl)； And/or, when R 4 is C 1-6 alkyl substituted by Rh , R 4 is selected from -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -(CH 2 ) 2 Cl, -(CH 2 ) 3 Cl, -CH(CH 3 ) (CH 2 Cl);
    和/或，当R 4为被R h取代的C 3-8环烷基时，R 4选自
    Figure PCTCN2021129863-appb-100038
    And/or, when R 4 is C 3-8 cycloalkyl substituted by R h , R 4 is selected from
    Figure PCTCN2021129863-appb-100038
    Figure PCTCN2021129863-appb-100039
    Figure PCTCN2021129863-appb-100039
  5. 根据权利要求1所述的化合物，其特征在于，R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100040
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CO-NH 2、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)、
    Figure PCTCN2021129863-appb-100041
    Figure PCTCN2021129863-appb-100042
    The compound of claim 1, wherein R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
    Figure PCTCN2021129863-appb-100040
    -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), -CO-NH 2 , -CO-NH-CH 3 , -CO-N(CH 3 ) 2 , -CO-NH-CH 2 -CH 3 , -CO-N(CH 3 )(CH 2 CH 3 ),
    Figure PCTCN2021129863-appb-100041
    Figure PCTCN2021129863-appb-100042
    和/或，R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100043
    Figure PCTCN2021129863-appb-100044
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129863-appb-100045
    Figure PCTCN2021129863-appb-100046
    And/or, R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 ,
    Figure PCTCN2021129863-appb-100043
    Figure PCTCN2021129863-appb-100044
    -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),
    Figure PCTCN2021129863-appb-100045
    Figure PCTCN2021129863-appb-100046
    和/或，
    Figure PCTCN2021129863-appb-100047
    选自
    Figure PCTCN2021129863-appb-100048
    and / or,
    Figure PCTCN2021129863-appb-100047
    selected from
    Figure PCTCN2021129863-appb-100048
    Figure PCTCN2021129863-appb-100049
    Figure PCTCN2021129863-appb-100049
  6. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129863-appb-100050
    选自
    Figure PCTCN2021129863-appb-100051
    Figure PCTCN2021129863-appb-100052
    The compound of claim 1, wherein
    Figure PCTCN2021129863-appb-100050
    selected from
    Figure PCTCN2021129863-appb-100051
    Figure PCTCN2021129863-appb-100052
    和/或，R 1选自-H、-F、甲基、环丙基、-CO-NH 2、-CO-NH-CH 3、-CO-N(CH 3) 2； and/or, R 1 is selected from -H, -F, methyl, cyclopropyl, -CO-NH 2 , -CO-NH-CH 3 , -CO-N(CH 3 ) 2 ;
    和/或，R 2选自-H、-F、-Cl、-CH 3； And/or, R 2 is selected from -H, -F, -Cl, -CH 3 ;
    和/或，
    Figure PCTCN2021129863-appb-100053
    选自
    Figure PCTCN2021129863-appb-100054
    Figure PCTCN2021129863-appb-100055
    and / or,
    Figure PCTCN2021129863-appb-100053
    selected from
    Figure PCTCN2021129863-appb-100054
    Figure PCTCN2021129863-appb-100055
    和/或，L 1选自单键、-NH-或-O-； And/or, L 1 is selected from single bond, -NH- or -O-;
    和/或，L 2选自单键、-O-、
    Figure PCTCN2021129863-appb-100056
    And/or, L 2 is selected from single bond, -O-,
    Figure PCTCN2021129863-appb-100056
    和/或，R 4选自-H、-F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F。 And/or, R 4 is selected from -H, -F, methyl, ethyl, isopropyl, cyclopropyl, n-butyl, cyclopropyl, cyclobutyl, -CHF 2 , -CF 3 , -( CH 2 ) 3 F.
  7. 根据权利要求1所述的化合物，其特征在于，
    Figure PCTCN2021129863-appb-100057
    选自
    Figure PCTCN2021129863-appb-100058
    Figure PCTCN2021129863-appb-100059
    其中R 1选自-F、甲基、-CO-NH 2；     The compound of claim 1, wherein
    Figure PCTCN2021129863-appb-100057
    selected from
    Figure PCTCN2021129863-appb-100058
    Figure PCTCN2021129863-appb-100059
    wherein R 1 is selected from -F, methyl, -CO-NH 2 ;
    R 2选自-H、-F、-Cl、-CH 3； R 2 is selected from -H, -F, -Cl, -CH 3 ;
    Figure PCTCN2021129863-appb-100060
    选自
    Figure PCTCN2021129863-appb-100061
    Figure PCTCN2021129863-appb-100062
    Figure PCTCN2021129863-appb-100060
    selected from
    Figure PCTCN2021129863-appb-100061
    Figure PCTCN2021129863-appb-100062
    L 1选自单键、-NH-或-O-； L 1 is selected from a single bond, -NH- or -O-;
    L 2选自单键、-O-、
    Figure PCTCN2021129863-appb-100063
    L 2 is selected from single bond, -O-,
    Figure PCTCN2021129863-appb-100063
    R 4选自H、F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F。 R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
  8. 根据权利要求1所述的化合物，其特征在于，所述的式I所示化合物的基团定义如下任一方案所述：The compound according to claim 1, wherein the group definition of the compound shown in the formula I is as described in any of the following schemes:
    方案一：
    Figure PCTCN2021129863-appb-100064
    为
    Figure PCTCN2021129863-appb-100065
    Option One:
    Figure PCTCN2021129863-appb-100064
    for
    Figure PCTCN2021129863-appb-100065
    R 1为甲基； R 1 is methyl;
    R 2选自卤素； R 2 is selected from halogen;
    Figure PCTCN2021129863-appb-100066
    选自
    Figure PCTCN2021129863-appb-100067
    Figure PCTCN2021129863-appb-100068
    Figure PCTCN2021129863-appb-100066
    selected from
    Figure PCTCN2021129863-appb-100067
    Figure PCTCN2021129863-appb-100068
    L 1选自单键、-NH-或-O-； L 1 is selected from a single bond, -NH- or -O-;
    L 2选自单键、-O-、
    Figure PCTCN2021129863-appb-100069
    L 2 is selected from single bond, -O-,
    Figure PCTCN2021129863-appb-100069
    R 4选自H、F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F； R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F ;
    方案二：
    Figure PCTCN2021129863-appb-100070
    为
    Figure PCTCN2021129863-appb-100071
    Option II:
    Figure PCTCN2021129863-appb-100070
    for
    Figure PCTCN2021129863-appb-100071
    R 1选自甲基、-CO-NH 2； R 1 is selected from methyl, -CO-NH 2 ;
    R 2选自-F、-Cl； R 2 is selected from -F, -Cl;
    Figure PCTCN2021129863-appb-100072
    选自
    Figure PCTCN2021129863-appb-100073
    Figure PCTCN2021129863-appb-100072
    selected from
    Figure PCTCN2021129863-appb-100073
    L 1选自-NH-或-O-； L 1 is selected from -NH- or -O-;
    L 2选自-O-、
    Figure PCTCN2021129863-appb-100074
    L 2 is selected from -O-,
    Figure PCTCN2021129863-appb-100074
    R 4选自H、F、甲基、乙基、异丙基、环丙基、正丁基、环丙基、环丁基、-CHF 2、-CF 3、-(CH 2) 3F。 R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
  9. 根据权利要求1所述的化合物，其特征在于，所述的式(I)所示化合物为式(I-0)所示化合物：The compound according to claim 1, wherein the compound represented by the formula (I) is the compound represented by the formula (I-0):
    Figure PCTCN2021129863-appb-100075
    Figure PCTCN2021129863-appb-100075
    其中：in:
    R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100076
    Figure PCTCN2021129863-appb-100077
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CO-NH 2-、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)、
    Figure PCTCN2021129863-appb-100078
    Figure PCTCN2021129863-appb-100079
    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 ,
    Figure PCTCN2021129863-appb-100076
    Figure PCTCN2021129863-appb-100077
    -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), -CO-NH 2 -, -CO-NH-CH 3 , -CO-N(CH 3 ) 2 , -CO-NH-CH 2 -CH 3 , -CO-N(CH 3 )(CH 2 CH 3 ),
    Figure PCTCN2021129863-appb-100078
    Figure PCTCN2021129863-appb-100079
    R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100080
    Figure PCTCN2021129863-appb-100081
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129863-appb-100082
    Figure PCTCN2021129863-appb-100083
    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 ,
    Figure PCTCN2021129863-appb-100080
    Figure PCTCN2021129863-appb-100081
    -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),
    Figure PCTCN2021129863-appb-100082
    Figure PCTCN2021129863-appb-100083
    X 1、X 2、X 3分别独立地选自C或N，且X 1、X 2、X 3不同时为N； X 1 , X 2 , and X 3 are independently selected from C or N, and X 1 , X 2 , and X 3 are not N at the same time;
    Figure PCTCN2021129863-appb-100084
    选自无取代或任选被1～3个R g取代的以下基团：
    Figure PCTCN2021129863-appb-100085
    Figure PCTCN2021129863-appb-100086
    其中R g选自H、F、Cl、甲基；
    Figure PCTCN2021129863-appb-100084
    Selected from the following groups unsubstituted or optionally substituted with 1 to 3 R g :
    Figure PCTCN2021129863-appb-100085
    Figure PCTCN2021129863-appb-100086
    wherein R g is selected from H, F, Cl, methyl;
    L 1选自单键、-N(R 3)-或-O-； L 1 is selected from a single bond, -N(R 3 )- or -O-;
    L 2选自单键、-O-、无取代或被C 1-3烷基取代的C 1-6亚烷基； L 2 is selected from single bond, -O-, unsubstituted or C 1-6 alkylene substituted by C 1-3 alkyl;
    R 3选自H、C 1-3烷基； R 3 is selected from H, C 1-3 alkyl;
    R 4选自-H、-CN、-F、-Cl、-Br、甲基、乙基、异丙基、正丁基、环丙基、环丁基、环戊基、-CH 2F、-CHF 2、-CF 3、-CF 2CH 3、-CH 2CF 3、-(CH 2) 2F、-(CH 2) 3F、-CH(CH 3)(CH 2F)、-(CH 2) 2Cl、-(CH 2) 3Cl、-CH(CH 3)(CH 2Cl)、
    Figure PCTCN2021129863-appb-100087
    Figure PCTCN2021129863-appb-100088
    R 4 is selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -( CH 2 ) 2 Cl, -(CH 2 ) 3 Cl, -CH(CH 3 )(CH 2 Cl),
    Figure PCTCN2021129863-appb-100087
    Figure PCTCN2021129863-appb-100088
  10. 根据权利要求1所述的化合物，其特征在于，所述的式(I)所示化合物为式(I-0)所示化合物：The compound according to claim 1, wherein the compound represented by the formula (I) is the compound represented by the formula (I-0):
    Figure PCTCN2021129863-appb-100089
    Figure PCTCN2021129863-appb-100089
    其中：in:
    R 1选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100090
    Figure PCTCN2021129863-appb-100091
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、-CO-NH 2-、-CO-NH-CH 3、-CO-N(CH 3) 2、-CO-NH-CH 2-CH 3、-CO-N(CH 3)(CH 2CH 3)、
    Figure PCTCN2021129863-appb-100092
    Figure PCTCN2021129863-appb-100093
    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 ,
    Figure PCTCN2021129863-appb-100090
    Figure PCTCN2021129863-appb-100091
    -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), -CO-NH 2 -, -CO-NH-CH 3 , -CO-N(CH 3 ) 2 , -CO-NH-CH 2 -CH 3 , -CO-N(CH 3 )(CH 2 CH 3 ),
    Figure PCTCN2021129863-appb-100092
    Figure PCTCN2021129863-appb-100093
    R 2选自-H、-CN、-F、-Cl、-Br、-CH 3、-CH 2CH 3、-(CH 2) 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021129863-appb-100094
    Figure PCTCN2021129863-appb-100095
    -NH 2、-NH-CH 3、-N(CH 3) 2、-NH-CH 2CH 3-OCH 3、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCH(CH 3) 2、-CH 2CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-OCH 2F、-OCHF 2、-OCF 3、-OCH 2CH 2F、-OCH 2CF 3、-O(CH 2) 2CH 2F、-OCH(CH 3)(CH 2F)、
    Figure PCTCN2021129863-appb-100096
    Figure PCTCN2021129863-appb-100097
    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 ,
    Figure PCTCN2021129863-appb-100094
    Figure PCTCN2021129863-appb-100095
    -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),
    Figure PCTCN2021129863-appb-100096
    Figure PCTCN2021129863-appb-100097
    X 1、X 2、X 3分别独立地选自C或N，且X 1、X 2、X 3不同时为N； X 1 , X 2 , and X 3 are independently selected from C or N, and X 1 , X 2 , and X 3 are not N at the same time;
    Figure PCTCN2021129863-appb-100098
    选自
    Figure PCTCN2021129863-appb-100099
    Figure PCTCN2021129863-appb-100100
    Figure PCTCN2021129863-appb-100098
    selected from
    Figure PCTCN2021129863-appb-100099
    Figure PCTCN2021129863-appb-100100
    Figure PCTCN2021129863-appb-100101
    Figure PCTCN2021129863-appb-100101
  11. 下式所示化合物，或其立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：A compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
    Figure PCTCN2021129863-appb-100102
    Figure PCTCN2021129863-appb-100102
    Figure PCTCN2021129863-appb-100103
    Figure PCTCN2021129863-appb-100103
  12. 一种药物组合物，其特征在于，包含有效剂量的权利要求1～11中任一项所述的化合物。A pharmaceutical composition, characterized by comprising an effective dose of the compound according to any one of claims 1 to 11.
  13. 权利要求1～11中任一项所述化合物，或权利要求12所述的药物组合物在制备治 疗与LPAR相关疾病的药物中的用途。Use of the compound according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 12, in the preparation of a medicament for the treatment of LPAR-related diseases.
  14. 根据权利要求13所述的用途，其中所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The use according to claim 13, wherein the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  15. 根据权利要求13所述的用途，其中所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The use according to claim 13, wherein the LPAR-related disease is selected from the group consisting of idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, Fetal hydrocephalus.
  16. 一种治疗或预防LPAR相关疾病的方法，其特征在于，给与患者药学上可接受剂量的权利要求1～11中任一项所述化合物，或权利要求16所述的药物组合物。A method for treating or preventing LPAR-related diseases, characterized by administering to a patient a pharmaceutically acceptable dose of the compound of any one of claims 1 to 11, or the pharmaceutical composition of claim 16.
  17. 根据权利要求16所述的方法，其特征在于，所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The method of claim 16, wherein the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
  18. 根据权利要求16所述的方法，其特征在于，所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The method according to claim 16, wherein the LPAR-related disease is selected from the group consisting of idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid Arthritis, fetal hydrocephalus.
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