WO2020001304A1 - Fxr受体激动剂 - Google Patents

Fxr受体激动剂 Download PDF

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WO2020001304A1
WO2020001304A1 PCT/CN2019/091482 CN2019091482W WO2020001304A1 WO 2020001304 A1 WO2020001304 A1 WO 2020001304A1 CN 2019091482 W CN2019091482 W CN 2019091482W WO 2020001304 A1 WO2020001304 A1 WO 2020001304A1
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group
membered
alkyl
alkoxy
amino
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PCT/CN2019/091482
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English (en)
French (fr)
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方文奎
王听中
程静
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轩竹（海南）医药科技有限公司
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Priority to CN201980039625.XA priority Critical patent/CN112334467B/zh
Publication of WO2020001304A1 publication Critical patent/WO2020001304A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to an FXR agonist, a pharmaceutically acceptable salt thereof, an ester thereof and a stereoisomer thereof, a pharmaceutical preparation containing these compounds, and the compound, a pharmaceutically acceptable salt thereof, and Esters and their stereoisomers in the preparation of drugs for the prevention and / or treatment of non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications, and malignant tumor-related diseases mediated by FXR Applications.
  • Farnesoid X receptor is a member of the nuclear receptor family of ligand-activated transcription factors. It has a typical nuclear receptor structure, namely a highly conserved amino-terminal DNA binding region (DBD), and a carboxyl-terminal ligand. Binding region (LBD), amino-terminal ligand-independent transcription activation domain (AF1), carboxy-terminal ligand-dependent transcription activation domain (AF2), and foot chain region. FXR can form a heterodimer with the retinol X receptor (RXR).
  • the conformation of FXR can change, and the DNA binding region binds to the FXR response element of the target gene promoter.
  • IR-1 releases co-inhibitory factors (such as NCOR), recruits co-activators, and thereby exerts transcriptional regulation.
  • FXR is expressed in many organs and tissues, including adipose tissue, liver, gastrointestinal tract, and kidneys. Among them, the liver is the most abundantly expressed.
  • the FXR signaling pathway can regulate the expression of multiple downstream genes, such as BSEP, SHP, CYP7A1, FGFR4, OST ⁇ / ⁇ , and SREBP-1C, and then regulate a variety of metabolic pathways, such as triglycerides, cholesterol, blood glucose, and energy Stable metabolism of bile acid has the function of treating cancer, non-alcoholic fatty liver (NAFLD), metabolic disorders, inflammation and other diseases.
  • NAFLD non-alcoholic fatty liver
  • FXR chenodeoxycholic acid
  • DCA deoxycholic acid
  • LCDA lithocholic acid
  • taurine taurine
  • FXR agonists currently developed internationally can be divided into two major categories, one is a steroid, represented by Intercept's obeticholic acid (OCA), in May 2016 Approved the indications for primary biliary cirrhosis, which is in the Phase III clinical trial for non-alcoholic steatohepatitis indications.
  • OCA Intercept's obeticholic acid
  • GS-9674 developed by Gilead, is in clinical stage II, and its indications are primary cholangiocirrhosis, primary sclerosing cholangitis, and non-alcoholic steatohepatitis. The structure is unknown.
  • LJN-452 is currently in clinical stage II, and the indication is primary Biliary cirrhosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis.
  • the invention relates to a compound having a novel molecular entity, which can effectively excite FXR, increase the expression levels of BSEP and SHP genes, and effectively inhibit the expression of CYP7A1 gene.
  • FXR receptor agonists in order to achieve better therapeutic effects and better meet market demand, it is also hoped that it can provide FXR receptor agonists with high efficiency, low toxicity and good stability.
  • the object of the present invention is to provide a novel structure of FXR agonist, which has physical and chemical properties superior to known FXR agonists, in vitro and in vivo pharmacodynamics, and / or excellent in vivo and in vitro kinetic properties.
  • FXR Agonists are used to treat non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, lipid metabolism disorders, diabetic complications and malignant tumors. possibility.
  • Another object of the present invention is to provide a method for preparing the FXR receptor agonist.
  • Another object of the present invention is to provide a pharmaceutical composition and a preparation containing the above-mentioned FXR receptor agonist.
  • Yet another object of the present invention is to provide the FXR receptor agonist prepared for the prevention and / or treatment of diseases such as non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications, and malignant tumors. Use in medicine.
  • the invention provides compounds that are FXR agonists.
  • the present invention provides a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein:
  • R 1 is selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, and C 1-6 Alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl, C 1-6 alkoxy C 1-6 alkyl, 3-8 membered cycloalkane 3-8 membered cycloalkyl C 1-6 alkyl, 3-8 membered cycloalkyl C 1-6 alkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyl C 1-6 Alkyl or 3-8 membered heterocyclyl C 1-6 alkoxy;
  • X 1 , X 2 , and X 3 are independently selected from N, NH, O, S, or CR 3 R 4 ;
  • R 3 and R 4 are independently selected from hydrogen, halogen atom, hydroxyl, amino, cyano, and C 1- 6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy or C 1-6 alkylamino;
  • R 2 is selected from-(CH 2 ) n -COOR 5 , and R 5 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered cycloalkyl C 1-6 alkyl, 3-8 membered heterocyclyl or 3-8 membered heterocyclyl C 1-6 alkyl;
  • M is selected from a C 1-6 alkylene group, and any carbon atom in the C 1-6 alkylene group is optionally replaced by a hetero atom or a group, and the hetero atom or group is selected from N, NH , O, CO, S, SO or SO 2 ;
  • Ring B is selected from a 6-10 membered aryl group, a 5-10 membered heteroaryl group, a 3-14 heterocyclic group, or a 3-8 membered cycloalkyl group optionally substituted with one or more Q 1 ;
  • Each Q 1 is independently selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, and a hydroxy C 1-6 alkyl group Amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylene Sulfonyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkyl C 1-6 alkyl, 3-8 membered cycloalkyl C 1-6 alkoxy, 3-8 membered heterocyclyl, 3- 8-membered heterocyclyl C 1-6 alkyl or 3-8-membered heterocyclyl C 1-6 alkoxy;
  • L is selected from the absence or C 1-6 alkylene group, and any carbon atom in the C 1-6 alkylene group is optionally replaced by a hetero atom or group, and the hetero atom or group is selected from N, NH, O, CO, S, SO or SO 2 ;
  • Ar is selected from a 6-10 membered aryl group optionally substituted with one or more Q 2 , a 6-10 membered aryl C 1-6 alkyl group, a 6-10 membered aryl C 1-6 alkoxy group, 5- 10 membered heteroaryl, 5 to 10 membered heteroaryl C 1-6 alkyl, 5 to 10 membered heteroaryl C 1-6 alkoxy, 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclic group ;
  • Each Q 2 is independently selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, and a hydroxy C 1-6 alkyl group Amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylcarbonyl, C 1 -6 alkylsulfonyl, C 1-6 alkylsulfinyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkyl C 1-6 alkyl, 3-8 membered cycloalkyl C 1-6 Alkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyl C 1-6 alkyl or 3-8 membered heterocyclyl C 1-6 alkoxy
  • n is selected from 0, 1, or 2.
  • the compound of the general formula (I) further has a structure represented by the general formula (I-1),
  • the compound of the general formula (I) further has a structure represented by the general formula (I-2),
  • the compound of the general formula (I) further has a structure represented by the general formula (I-3),
  • the compound of the general formula (I) further has a structure represented by the general formula (I-4),
  • the compound of the general formula (I) further has a structure represented by the general formula (I-5),
  • the compound of the general formula (I) further has a structure represented by the general formula (I-6),
  • the compound of the general formula (I) further has a structure represented by the general formula (I-7),
  • the compound of the general formula (I) further has a structure represented by the general formula (I-2),
  • R 1 is selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a hydroxy C 1-4 alkyl group, an amino C 1-4 alkyl group, and C 1-4 Alkoxy, halo C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylcarbonyl, C 1-4 alkoxy C 1-4 alkyl, 3-6 membered cycloalkane 3-6 membered cycloalkyl C 1-4 alkyl, 3-6 membered cycloalkyl C 1-4 alkoxy, 3-6 membered monoheterocyclyl, 3-6 membered monoheterocyclyl C 1 -4 alkyl or 3-6 membered monoheterocyclyl C 1-4 alkoxy;
  • X 1 and X 2 are each independently selected from NH, O, S or CR 3 R 4 ;
  • R 3 and R 4 are each independently selected from hydrogen, halogen atom, hydroxyl, amino, cyano, C 1-4 alkyl, halogen C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy or C 1-4 alkylamino;
  • R 2 is selected from-(CH 2 ) n -COOR 5 , R 5 is selected from hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C 1-4 alkyl, 3-6 membered heterocyclyl or 3-6 membered heterocyclyl C 1-4 alkyl;
  • M is selected from a C 1-4 alkylene group, and any carbon atom in the C 1-4 alkylene group is optionally replaced by a hetero atom or a group, and the hetero atom or group is selected from N, NH , O, CO, S, SO or SO 2 ;
  • Ring B is selected from optionally substituted with 1-2 Q 1 s 8-10 membered fused heteroaryl containing 1 to 3 hetero atoms or groups or 7-14 membered fused heterocyclic group, the hetero atom or a group
  • the group is independently selected from N, NH, O, S, SO or SO 2 ;
  • Each Q 1 is independently selected from a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, and a hydroxy C 1-4 alkyl group Amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylcarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylene Sulfonyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C 1-4 alkyl, 3-6 membered cycloalkyl C 1-4 alkoxy, 3-6 membered monoheterocyclyl, 3 6-membered mono-heterocyclyl C 1-4 alkyl or 3-6-membered mono-heterocyclyl C 1-4 alkoxy;
  • L is selected from the absence or C 1-4 alkylene group, and any carbon atom in the C 1-4 alkylene group is optionally replaced by a hetero atom or a group selected from the group consisting of NH, O, CO, S, SO or SO 2 ;
  • Ar is selected from 6-8 membered monocyclic aryl, 8-10 fused aryl, 6-8 membered monocyclic aryl C 1-4 alkyl, 8-10 membered fused optionally substituted with 1-3 Q 2
  • Each Q 2 is independently selected from a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, and a hydroxy C 1-4 alkyl group Amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylcarbonyl, C 1 -4 alkylsulfonyl, C 1-4 alkylsulfinyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C 1-4 alkyl, 3-6 membered cycloalkyl C 1-4 Alkoxy, 3-6 membered monoheterocyclyl, 3-6 membered monoheterocyclyl C 1-4 alkyl or 3-6 membered monoheterocyclyl C
  • n is selected from 0, 1, or 2.
  • M is selected from -CH 2- , -CH 2 -CH 2- , -CH 2 -CH 2 -CH 2- , -CH 2 -NH-, -CH 2 -CH 2 -O-, or -CH 2 -NH- CO-;
  • Ring B is selected from optionally substituted with 1-2 Q 1 s 9-10 membered fused heteroaryl group containing 1-2 hetero atom or group, a hetero atom or group independently selected from N, NH, O, S, SO, SO 2 ; preferably, ring B is connected to L or X 3 through a ring carbon atom;
  • Each Q 1 is independently selected from a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, and a C 1-4 alkoxy group 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C 1-4 alkyl, 3-6 membered cycloalkyl C 1-4 alkoxy, 3-6 membered monoheterocyclyl, 3- 6-membered monoheterocyclyl C 1-4 alkyl or 3-6 membered mono-heterocyclyl C 1-4 alkoxy;
  • L is selected from the absence or C 1-2 alkylene group, and any carbon atom in the C 1-2 alkylene group is optionally replaced by a hetero atom or group, and the hetero atom or group is selected from NH, O, S or CO.
  • Ring B is selected from optionally substituted with 1-2 Q 1 s 9 membered fused heteroaryl group containing 1-2 hetero atom or group, a hetero atom or group independently selected from N, NH, O, S, SO, SO 2 ; preferably, ring B is connected to L or X 3 through a ring carbon atom;
  • Each Q 1 is independently selected from a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, and a C 1-4 alkoxy group 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C 1-4 alkyl, 3-6 membered cycloalkyl C 1-4 alkoxy, 3-6 membered monoheterocyclyl, 3- 6-membered monoheterocyclyl C 1-4 alkyl or 3-6 membered mono-heterocyclyl C 1-4 alkoxy.
  • R 1 is selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a hydroxy C 1-4 alkyl group, an amino C 1-4 alkyl group, and C 1-4 Alkoxy, C 1-4 alkylamino, C 1-4 alkylcarbonyl, C 1-4 alkoxy C 1-4 alkyl, 3-4 membered cycloalkyl, 3-4 membered cycloalkyl C 1-4 alkyl, 3-4 membered cycloalkyl C 1-4 alkoxy, 3-4 membered mono-heterocyclyl, 3-4 membered mono-heterocyclyl C 1-4 alkyl or 3-4 membered mono Heterocyclyl C 1-4 alkoxy;
  • Ar is selected from phenyl, phenyl C 1-4 alkyl, phenyl C 1-4 alkoxy, 5-6 membered monocyclic heteroaryl, 5-6 membered optionally substituted with 1-2 Q 2 Monocyclic heteroaryl C 1-4 alkyl or 5-6 membered monocyclic heteroaryl C 1-4 alkoxy;
  • Each Q 2 is independently selected from a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a halogenated C 1-4 alkoxy group, and a hydroxy C 1-4 alkyl group Alkyl, amino C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, or C 1-4 alkylamino.
  • R 1 is selected from a halogen atom, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, Ethylamino, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl Methyl, cyclobutylethyl, cyclobutylmethoxy, epoxyethyl, epoxyethylmethyl, aziridine, aziridylmethyl, oxetanyl, or azetidinyl ;
  • R 2 is selected from-(CH 2 ) n -COOH
  • X 1 and X 2 are each independently selected from NH, O or S;
  • M is selected from -CH 2- , -CH 2 -CH 2 -or -CH 2 -CH 2 -CH 2- ;
  • Ring B is selected from the following groups optionally substituted with 1-2 Q 1 :
  • Each Q 1 is independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -Fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl , 3,3,3-trifluoropropyl, 1-trifluoromethylethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclo Propylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy,
  • L is selected from the absence
  • Ar is selected from phenyl, phenylmethyl, phenylethyl, phenylmethoxy, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridine, optionally substituted with 1-2 Q 2 group, pyrimidinyl group; each Q 2 is independently selected from fluoro, chloro, bromo, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, tris Fluoromethoxy, methoxy, ethoxy, propoxy, isopropyloxy, trifluoromethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl or ethyl Oxymethyl
  • n is selected from 0 or 1.
  • R 1 is selected from a halogen atom, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, Ethylamino, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl Methyl, cyclobutylethyl, cyclobutylmethoxy, epoxyethyl, epoxyethylmethyl, aziridine, aziridylmethyl, oxetanyl, or azetidinyl .
  • R 1 is selected from cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy, epoxyethyl , Epoxyethylmethyl, azetidinyl, azetidinylmethyl, oxetanyl or azetidinyl;
  • R 1 is selected from cyclopropyl or cyclobutyl.
  • X 1 and X 2 are each independently selected from NH, O or S;
  • X 1 and X 2 are both O.
  • M is selected from -CH 2- , -CH 2 -CH 2- , or -CH 2 -CH 2 -CH 2- .
  • Ring B is selected from the following groups optionally substituted with 1 Q 1 :
  • ring B is connected to L or X 3 through a ring carbon atom
  • ring B is selected from the following groups optionally substituted with 1 Q 1 :
  • ring B is connected to L or X 3 through a ring carbon atom
  • Q 1 is selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl Radical, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3 , 3-trifluoropropyl, 1-trifluoromethylethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclopropylmethyl , Cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy, cyclopenty
  • Q 1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and propoxy. Or isopropyloxy;
  • Q 1 is in the meta position of the carboxyl group in the general structure
  • L is selected from the absence.
  • Ar is selected from phenyl, phenylmethyl, phenylethyl, phenylmethoxy, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridine, optionally substituted with 1-2 Q 2 Or pyrimidinyl; each Q 2 is independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, tri Fluoromethoxy, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethylamino, methoxymethyl, methoxyethyl or ethoxymethyl.
  • Ar is selected from phenyl or 6-membered monocyclic heteroaryl optionally substituted with 1-2 Q 2 ;
  • Ar is selected from phenyl, pyridyl, and pyrimidinyl optionally substituted with 1-2 Q 2 ; each Q 2 is independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, Ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropyloxy, methylamino, ethyl Amino, methoxymethyl, methoxyethyl or ethoxymethyl;
  • each Q 2 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy, methoxy or ethoxy.
  • R 1 is selected from cyclopropyl or cyclobutyl
  • X 1 and X 2 are both O;
  • Ar is selected from phenyl optionally substituted with 1-2 Q 2 ; each Q 2 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, tri Fluoromethoxy, methoxy or ethoxy.
  • the present invention also provides a compound represented by (I '), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
  • R 1 , X 1 , X 2 , X 3 , M, and Ar have the meanings defined in some of the above schemes.
  • the invention relates to a formula comprising the general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or A pharmaceutical preparation of the compound represented by (I-7), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and / or diluents, which can be made into a pharmacy Any one of the acceptable dosage forms. It is administered orally, parenterally, rectally or pulmonary to patients in need of such treatment. When used for oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc .; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc.
  • suitable fillers, binders, disintegrating agents, lubricants, and the like can be added.
  • parenteral administration it can be made into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection.
  • injection When it is made into injection, it can be produced by the conventional method in the existing pharmaceutical field.
  • formulating an injection it is not necessary to add an additional agent, or a suitable additional agent may be added according to the properties of the drug.
  • rectal administration it can be made into suppositories.
  • pulmonary administration it can be made into an inhalant or a spray.
  • the present invention also relates to the general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or Use of the compound represented by (I-7), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof for the manufacture of a medicament for the prevention and / or treatment of FXR-mediated diseases and related diseases.
  • the diseases described include:
  • Lipid or lipoprotein disorders such as atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fibrosis-related diseases, fatty liver (alcoholic fatty liver, non-alcoholic fatty liver, etc.) ), Cirrhosis (primary biliary cirrhosis, primary biliary cirrhosis, etc.), hepatitis (chronic hepatitis, nonviral hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, etc.), liver failure, bile Stasis (benign intrahepatic cholestasis, progressive familial intrahepatic cholestasis, extrahepatic cholestasis, etc.), gallstone disease, myocardial infarction, stroke, thrombosis, etc .; acute liver failure, gallstone disease, and / or inflammatory bowel disease.
  • atherosclerosis such as atherosclerosis, bile
  • Non-malignant hyperproliferative or hyperproliferative diseases including hepatocellular carcinoma, colon adenoma and polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, esophageal cancer, and other forms of gastrointestinal and liver tumorigenicity disease.
  • halo in the present invention means being replaced by a “halogen atom”, and the “halogen atom” in the present invention includes fluorine, chlorine, bromine and iodine.
  • C 1-6 alkyl in the present invention refers to a straight or branched alkyl group containing 1-6 carbon atoms, and includes, for example, “C 1-5 alkyl”, “C 1-4 alkyl” ",” C 1-3 alkyl “,” C 1-2 alkyl “,” C 2-4 alkyl “,” C 2-3 alkyl “,” C 3-4 alkyl “, etc., specific examples Including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-di
  • halogenated C 1-6 alkyl group in the present invention refers to a group derived by replacing one or more hydrogen atoms on a C 1-6 alkyl group with one or more halogen atom atoms, and the "halogen atom "And” C 1-6 alkyl "are as defined above.
  • the "halo C 1-4 alkyl group” in the present invention refers to a specific example of a halogenated C 1-6 alkyl group containing 1-4 carbon atoms.
  • hydroxy C 1-6 alkyl group in the present invention refers to a group derived by substituting one or more hydroxyl groups with one or more hydrogen atoms on the C 1-6 alkyl group, and the “C 1-6 alkyl group” "Base” is as defined above.
  • the “hydroxy C 1-4 alkyl group” in the present invention refers to a specific example of a hydroxy C 1-6 alkyl group containing 1-4 carbon atoms.
  • amino C 1-6 alkyl group in the present invention refers to a group derived by substituting one or more amino groups with one or more hydrogen atoms on the C 1-6 alkyl group.
  • the “C 1-6 alkyl group” "Base” is as defined above.
  • the “amino C 1-4 alkyl group” in the present invention refers to a specific example of an amino C 1-6 alkyl group containing 1-4 carbon atoms.
  • C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl is Refers to C 1-6 alkyl-O-, C 1-6 alkyl-NH-, C 1-6 alkyl-C (O)-, C 1-6 alkyl-S (O) 2- , C 1-6 alkyl group -S (O) - group is connected, wherein "C 1-6 alkyl" is as defined above.
  • C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylcarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl is Refers to specific examples of the above-mentioned alkyl groups containing 1 to 4 carbon atoms.
  • halo C 1-6 alkoxy group in the present invention refers to a group derived from the substitution of one or more halogen atom atoms with one or more hydrogen atoms on the C 1-6 alkoxy group.
  • "Atom” and “C 1-6 alkoxy” are as defined above.
  • the "haloC 1-4 alkoxy group” in the present invention refers to a specific example of a halogenated C 1-6 alkoxy group containing 1-4 carbon atoms.
  • the “C 1-6 alkoxy C 1-6 alkyl group” in the present invention refers to one or more C 1-6 alkoxy groups substituted by one or more hydrogen atoms on the C 1-6 alkyl group.
  • the “C 1-6 alkyl” is as defined above.
  • the “C 1-4 alkoxy C 1-4 alkyl group” in the present invention refers to a specific example of a C 1-6 alkoxy C 1-6 alkyl group containing 1-4 carbon atoms.
  • CR 3 R 4 in the present invention refers to a group formed by R 3 and R 4 substituting two hydrogen atoms on a methylene group, and the specific connection mode is
  • the “C 1-6 alkylene group” in the present invention refers to a group derived by removing a linear alkane containing 1-6 carbon atoms by removing two hydrogens that are not on the same carbon atom, and includes “C 1-5 alkylene group” "Alkyl”, “C 1-4 alkylene”, “C 1-3 alkylene", “C 1-2 alkylene”, specific examples include, but are not limited to: -CH 2- , -CH 2 CH 2- , -CH 2 CH 2 CH 2- , -CH 2 CH 2 CH 2 CH 2- , -CH 2 CH 2 CH 2 CH 2- , -CH 2 CH 2 CH 2 CH 2- , -CH 2 CH 2 CH 2 CH 2 CH 2- Wait.
  • any carbon atom in a C 1-6 alkylene group is optionally replaced with a hetero atom or a group
  • any carbon atom in the "C 1-6 alkylene group” may be optionally Is replaced by a heteroatom or group, which may be a carbon atom in a C 1-6 alkylene group not being replaced by any heteroatom or group; or a carbon atom in a C 1-6 alkylene group may be replaced A heteroatom or group is substituted; or any two carbon atoms in a C 1-6 alkylene group are replaced by two heteroatoms or groups that are the same or different; or a C 1-6 alkylene group any number of carbon atoms in the group is replaced by a corresponding plurality of identical or different hetero atoms or groups; said hetero atom or group selected from N, NH, O, CO, S, SO , or SO 2.
  • the "3-8-membered cycloalkyl group” in the present invention refers to a monocyclic saturated cyclic alkyl group containing 3-8 carbon atoms, and includes, for example, "3-6-membered cycloalkyl group", "3-5 membered “Cycloalkyl”, “3-4 membered cycloalkyl”, “4-5 membered cycloalkyl”, “4-6 membered cycloalkyl”, “4-7 membered cycloalkyl”, “4-8 membered "Cycloalkyl” and the like.
  • cyclopropanyl cyclobutyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, and the like.
  • 3-6 membered cycloalkyl refers to a saturated cyclic alkyl group containing 3-6 carbon atoms.
  • 3-4 membered cycloalkyl refers to a saturated cyclic alkyl group containing 3-4 carbon atoms.
  • the "3-14 membered heterocyclic group” in the present invention refers to a group containing 3 to 14 ring atoms and containing at least one heteroatom and / or group (e.g., 1, 2, 3, 4 or 5 heteroatoms and And / or group) A group obtained by removing a hydrogen atom from a saturated or partially saturated monocyclic or fused ring compound.
  • the heteroatom and / or group is selected from N, NH, O, S, CO, SO or SO 2 ; the "fused ring" means that two or more cyclic structures share two phases with each other A group formed by adjacent atoms.
  • a 3-14 member partially saturated heterocyclic group refers to a cyclic group containing a double bond and a heteroatom.
  • a 3-14 membered saturated heterocyclic group refers to a heteroatom-containing cyclic group that is all saturated bonds.
  • ethylene oxide azetidinyl, diazacyclopropyl, oxetanyl, azetidinyl, 1,4-dioxane, 1 , 3-dioxane, 1,3-dioxolyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, piperazinyl, morpholine Base, benzodihydrofuryl, benzodihydropyranyl, benzo 1,4-dioxelenyl, benzo 1,3-dioxelenyl, benzotetrahydropyridine Base, benzodihydrooxazinyl, benzotetrahydropyrazinyl, 1,2,3,4-tetrahydroquinazolinyl, 1,2,3,4-tetrahydrofluorinyl or t
  • the "3-6 membered heterocyclic group” refers to a specific example of a 3-14 membered heterocyclic group containing 3-6 ring atoms.
  • the "3-4 membered monocyclic heterocyclic group” refers to a specific example of a monocyclic heterocyclic group containing 3 to 4 ring atoms in a 3 to 14 membered heterocyclic group.
  • the “3-8-membered cycloalkyl C 1-6 alkyl, 3-8-membered cycloalkyl C 1-6 alkoxy” in the present invention means a 3-8-membered cycloalkyl substituted C 1-6 alkane Radical derived from a hydrogen atom in a C 1-6 alkoxy group, the "3-8 membered cycloalkyl group", "C 1-6 alkyl group”, “C 1-6 alkoxy group” As defined above.
  • the “3-8-membered heterocyclyl C 1-6 alkyl, 3-8-membered heterocyclyl C 1-6 alkoxy” in the present invention means a 3-8-membered heterocyclyl substituted C 1-6 alkane Radical derived from a hydrogen atom in a C 1-6 alkoxy group, the "3-8 membered heterocyclic group", “C 1-6 alkyl group”, “C 1-6 alkoxy group” As defined above.
  • 3-6 membered cycloalkyl C 1-4 alkyl, 3-4 membered cycloalkyl C 1-4 alkyl, 3-6 membered monoheterocyclyl C 1-4 alkyl, 3 "4-membered monoheterocyclyl C 1-4 alkyl” means 3-6 membered cycloalkyl, 3-4 membered cycloalkyl, 3-6 membered monoheterocyclyl, 3-4 membered monoheterocyclyl substituted
  • a group derived from a hydrogen atom in a C 1-4 alkyl group, the "3-6 membered cycloalkyl group", "3-4 membered cycloalkyl group”, "3-6 membered monocyclic heterocyclic group”, "3-4 membered monoheterocyclyl” and " C1-4 alkyl” are as defined above.
  • 3-6 membered cycloalkyl C 1-4 alkoxy, 3-4 membered cycloalkyl, C 1-4 alkoxy, 3-6 membered monocyclic heterocyclyl C 1-4 alkoxy group of the present invention ", 3-4 membered monoheterocyclyl C 1-4 alkoxy” means 3-6 membered cycloalkyl, 3-4 membered cycloalkyl, 3-6 membered monoheterocyclyl, 3-4 membered monocyclic Heterocyclyl is a group derived from the substitution of a hydrogen atom in a C 1-4 alkoxy group.
  • the “6- to 10-membered aryl group” in the present invention refers to a monocyclic or polycyclic group having aromaticity and containing 6 to 10 ring carbon atoms. Examples include “6-8-membered monocyclic aryl”, “6-7-membered monocyclic aryl”, “8-10-membered dense aryl”, and the like.
  • the “fused aryl group” refers to an aromatic group formed by two or more cyclic structures sharing two adjacent atoms with each other. Specific embodiments include, but are not limited to, phenyl, cyclooctatetraenyl, naphthyl, and the like.
  • the "6- to 8-membered monocyclic aryl group” refers to a specific example of a monocyclic ring containing 6 to 8 ring carbon atoms in a 6 to 10-membered aryl group.
  • the “6-7-membered monocyclic aryl group” refers to a specific example of a monocyclic ring containing 6-7 ring carbon atoms in a 6-10 membered aryl group.
  • the "8-10 member fused aryl group” is a specific example of a polycyclic ring containing 8-10 ring carbon atoms in a 6-10 member aryl group.
  • the "5- to 10-membered heteroaryl group” in the present invention refers to an aromatic monocyclic or polycyclic group containing 5-10 ring atoms and at least one ring atom is a heteroatom, and includes monoheteroaryl groups and Thick heteroaryl.
  • the hetero atom is a nitrogen atom, an oxygen atom, and / or a sulfur atom.
  • the "monocyclic heteroaryl” refers to a monocyclic aromatic group; the “fused ring heteroaryl” refers to two or more cyclic structures formed by sharing two adjacent atoms with each other Aromatic group.
  • the "5-6 membered monocyclic heteroaryl” refers to a specific example of a monocyclic ring containing 5-6 ring atoms in a 5-10 membered heteroaryl.
  • the "7-10 membered condensed heteroaryl group”, “8-10 membered condensed heteroaryl group” and “9-10 membered condensed heteroaryl group” mean that 5-10 membered condensed heteroaryl group contains 7-10 members Specific examples of polycyclic rings of 8-10, 9-10 ring atoms.
  • the "6- to 10-membered aryl C 1-6 alkyl and 5- to 10-membered heteroaryl C 1-6 alkyl" in the present invention means 6- to 10-membered aryl and 5- to 10-membered heteroaryl substituted.
  • the "6- to 10-membered aryl", “5- to 10-membered heteroaryl", and "C 1-6 alkyl" are as described above.
  • the "6- to 10-membered aryl C 1-6 alkoxy group and the 5- to 10-membered heteroaryl C 1-6 alkoxy group" in the present invention refer to a 6 to 10-membered aryl group and a 5- to 10-membered heteroaryl A group derived from a hydrogen atom in a C 1-6 alkoxy group.
  • the "6- to 10-membered aryl", “5 to 10-membered heteroaryl", and "C 1-6 alkoxy" are as described above.
  • the "6- to 8-membered monocyclic aryl C 1-4 alkyl, 8 to 10-membered fused aryl C 1-4 alkyl, 6-membered mono-cyclic aryl C 1-4 alkyl, 5- 7-membered monocyclic heteroaryl C 1-4 alkyl, 8-10 member fused heteroaryl C 1-4 alkyl "means 6-8 membered monocyclic aryl, 8-10 member fused aryl, 6 membered A group derived from a monocyclic aryl group, a 5- to 7-membered monocyclic heteroaryl group, and an 8 to 10-membered condensed heteroaryl group in place of a hydrogen atom in a C 1-4 alkyl group.
  • the "6- to 8-membered monocyclic aryl C 1-4 alkoxy group, the 8 to 10-membered fused aryl C 1-4 alkoxy group, and the 6-membered mono-cyclic aryl C 1-4 alkoxy group” 5-7 membered monocyclic heteroaryl C 1-4 alkoxy, 8-10 membered thick heteroaryl C 1-4 alkoxy "means 6-8 membered monocyclic aryl, 8-10 membered fused An aryl group, a 6-membered monocyclic aryl group, a 5- to 7-membered monocyclic heteroaryl group, and an 8 to 10-membered condensed heteroaryl group substituted with a hydrogen atom in a C1-4 alkoxy group.
  • L is selected from the absence
  • ring B and X 3 are directly connected through a chemical bond.
  • the virtual bond in the structural formula or group of the present invention refers to the presence or absence of, for example, a group, Means Two situations.
  • cis or “trans” shown in the structural formula of the compound of the present invention refers to a positional relationship between a bridge having no substituent in an 8-membered bridge ring and a substituent connected through X 2 in the structure.
  • compound 1 has a cis structure, and the specific structural formula is as follows:
  • the “ring B is selected from the group optionally substituted with one or more Q 1 ” in the present invention includes the case where the ring B is not substituted with any Q 1 , and the case where the ring B is substituted with one or more Q 1 .
  • partially saturated in the present invention means that the related group contains at least one double bond or one triple bond.
  • the invention also provides a method for preparing a compound of formula (I), which includes but is not limited to the following process routes:
  • DMF N, N-dimethylformamide
  • DMA N, N-dimethylacetamide
  • THF tetrahydrofuran
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • EA ethyl acetate
  • PE petroleum ether
  • MeOH methanol.
  • R 1 , R 2 , X 1 , X 2 , X 3 , L, M, ring B and Ar are independently selected from Cl or Br.
  • the organic solvent is preferably tetrahydrofuran.
  • the solution containing an acidic substance is preferably a hydrochloric acid ethanol solution, a trifluoroacetic acid-containing methylene chloride solution, and the like, and the alkaline solution is preferably a saturated sodium bicarbonate solution.
  • the organic solvent is preferably DMA or DMF.
  • intermediate 2 intermediate 3 'and cesium carbonate were added to an organic solvent, and the reaction was completed by microwave or heating. After the reaction was completed, intermediate 4 was purified by column chromatography.
  • the organic solvent is preferably DMA or DMF.
  • the intermediate 4 was added to an organic solvent, and then an aqueous solution containing a basic substance was added, and the reaction was heated. After the reaction is completed, the pH is adjusted to 4-6 with an acidic substance solution, the solvent is spin-dried, and the compound of formula (I) is purified by column chromatography.
  • the organic solvent is preferably a methanol / tetrahydrofuran mixed solution
  • the alkaline substance is preferably lithium hydroxide, sodium hydroxide, or the like
  • the acidic solution is preferably hydrochloric acid.
  • the raw material 1 and the raw material 2 according to the present invention may be homemade or commercially available.
  • the "pharmaceutically acceptable salt” of the compound represented by formula (I) of the present invention refers to a salt formed by an acidic functional group and a suitable inorganic or organic cation (base) in the compound of formula (I), and includes an alkali metal or alkaline earth salts of the basic functional group (e.g. -NH 2, etc.) present in the compound and the formula (I) are formed with the appropriate inorganic or organic anion (acid); salts, ammonium salts, and salts with nitrogen-containing organic base is formed of metal , Including with inorganic acids, and organic carboxylic acids.
  • ester of the compound represented by the formula (I) of the present invention refers to an ester that can be formed by an esterification reaction with an alcohol when a carboxyl group is present in the compound of the formula (I).
  • Stepoisomerism is divided into conformational isomerism and configurational isomerism.
  • Configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (that is, optical isomerism).
  • Conformation is a stereoisomerism in which organic molecules of a certain configuration have different arrangements in space due to the rotation or distortion of carbon and carbon single bonds.
  • Common examples are alkanes and rings. The structures of alkanes, such as the chair and boat conformations that occur in cyclohexane structures.
  • the compound contains a bridged ring or a bridged heterocyclic ring.
  • the cis or trans refers to a bridge without a substituent and X
  • the 2 linked group is on the same side or different side of the bridge ring (or bridge heterocyclic ring).
  • Optical isomers mean that when the compounds of the invention contain one or more asymmetric centers, they can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single Diastereomers.
  • the compounds of the present invention have asymmetric centers, and each asymmetric center produces two optical isomers.
  • the scope of the present invention includes all possible mixtures of optical isomers and diastereomers and pure or partially pure compounds .
  • the compounds according to the invention can exist in the form of tautomers, which have different points of attachment of hydrogen through one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • Each tautomer and mixtures thereof are included in the compounds of the present invention.
  • Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers of all compounds of formula (I) Structures and mixtures thereof are all included in the scope of the present invention.
  • the compound of the present invention, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof have excellent FXR receptor agonistic activity, and can be safely used for the treatment and / or prevention of non-alcoholic fatty liver, primary bile Related diseases such as liver cirrhosis, lipid metabolism disorder, diabetes complications and malignant tumors;
  • Test substance The compound of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound.
  • DMSO was used to dilute the test compound to 0.3 and 3 mM; 5 ⁇ L of the stock solution obtained in the previous dilution was added to 5 mL of the culture medium, respectively.
  • the obtained working solution concentrations were 0.3 and 3 ⁇ M, respectively.
  • the control medium was prepared with an equal volume of DMSO instead of the stock solution; the cell culture plate was removed from the incubator, the medium was removed, the working solution and control medium were added; the culture plate was returned to the incubator at 37 ° C, 5% Incubate for 24 hours under CO 2 conditions.
  • Cell lysis Prepare fresh RNA lysate (1 mL of lysate plus 10 ⁇ L of 2-mercaptoethanol); add 600 ⁇ L of lysate to the cell sample; vortex vigorously for 1-2 minutes to completely lyse the cells; place the cell lysate at 12,000 ⁇ g Centrifuge for 5 minutes; transfer the supernatant to an RNase-free 1.5 mL centrifuge tube.
  • RNA extraction and purification add an equal amount of 70% ethanol to the cell lysate; shake the centrifuge tube vigorously, mix thoroughly, and try to disperse the particulates that may form after adding ethanol; place the adsorption column on the collection tube, and transfer the mixture to the adsorption In the column. Transfer up to 700 ⁇ L at a time; centrifuge at 12,000 ⁇ g for 15 seconds at room temperature. Discard the solution in the collection tube and reposition the adsorption column on the collection tube; transfer all remaining mixture to the adsorption column. Add 700 ⁇ L of eluent I to the adsorption column; centrifuge at 12,000 ⁇ g for 15 seconds at room temperature.
  • adsorption column Place the adsorption column on a new collection tube; add 500 ⁇ L of eluent II to the adsorption column; centrifuge at 12,000 ⁇ g for 15 seconds at room temperature. Discard the solution in the collection tube, and reposition the adsorption column on the collection tube; add 500 ⁇ L of eluent II to the adsorption column; centrifuge at 12,000 ⁇ g at room temperature for 1-2 minutes, and place the adsorption column on the RNA collection tube; Add 50 ⁇ L of RNase-free water to the center of the adsorption column and incubate for 1 minute at room temperature; centrifuge at 14,000 ⁇ g for 2 minutes at room temperature to elute the RNA into the collection tube.
  • RNA was stored at -80 ° C.
  • RNA extracted in the previous step was incubated at 70 ° C for 5 minutes to denature the RNA. After processing, place the sample on ice; dilute the RNA sample to 200ng / ⁇ L with RNAse-free water; prepare 10 ⁇ L of the reverse transcription solution according to the following table, and mix with 10 ⁇ L of denatured RNA. The total amount of RNA in the reverse transcription reaction was 2 ⁇ g. During the experiment, all reagents were placed on ice.
  • Reverse transcription was performed on a G-Storm GS1 thermal cycler PCR thermal cycler.
  • the reverse transcription process is set as follows: 25 ° C for 10 minutes ⁇ 37 ° C for 120 minutes ⁇ 85 ° C for 5 minutes ⁇ 4 ° C ⁇ .
  • the reverse transcription product (cDNA) was stored at -20 ° C.
  • the appropriate cDNA concentration is selected for the qPCR experiment of the sample.
  • the cDNA sample obtained by reverse transcription was diluted by 7 times with 10 ⁇ L plus 60 ⁇ L Rnase-free water.
  • qPCR was performed on the ABI7500 real-time quantitative PCR instrument.
  • the program was set as follows: 50 ° C for 2 minutes ⁇ 95 ° C for 10 minutes ⁇ 95 ° C for 15 seconds ⁇ 60 ° C for 60 seconds, of which 40 cycles were set between 95 ° C for 15 seconds and 60 ° C for 60 seconds. .
  • the relative expression data are based on the expression of the control drug at 3uM as 100%, and the ratio of other expressions to the expression of the control drug at 3uM is the relative expression (%) of the compound at that concentration.
  • BSEP is a direct downstream gene of FXR, which regulates bile acid production and efflux It plays an important role in other aspects.
  • the expression of BSEP mRNA directly reflects the agonistic activity of FXR, which is a good indicator of the agonistic activity of preliminary screening compounds on FXR.
  • the study of FXR agonists is of great significance for the treatment of non-alcoholic fatty liver .
  • Test article Compounds 1, 1-1 and 3 of the present invention. For their chemical names and preparation methods, see the preparation examples of each compound.
  • Beagle dog mixed liver microsomes were purchased from XenoTech with a liver microsome protein concentration of 20 mg ⁇ mL -1 .
  • the experimental initiation factor ⁇ -NADPH was purchased from American Roche Company. Phosphate buffered saline (PBS) at pH 7.4 was made by our laboratory.
  • DMSO dimethyl sulfoxide
  • each compound was taken with 6 mL of 100 mM PBS, 0.6 mL of 20 mM MgCl 2 solution and 3.66 mL of H 2 O to prepare a mixed solution 1 (excluding microsomes) of the incubation system. , Test article and ⁇ -NADPH).
  • liver microsomes (20mg protein / mL) from the refrigerator at -80 °C, and pre-incubate for 3min on a 37 °C water bath thermostat.
  • Sample group (containing microsomes and ⁇ -NADPH): Take 616 ⁇ L of the incubation system mixed solution 2 and add 14 ⁇ L of the test solution with a concentration of 50 ⁇ M, and add 70 ⁇ L of 10 mM ⁇ -NADPH working solution. Mix well and duplicate. The sampling time points were 0min, 5min, 10min, 20min, 30min, 60min.
  • Control group (containing microsomes, without ⁇ -NADPH, replacing ⁇ -NADPH with water): 264 ⁇ L of incubation system mixed solution 2 was added, 6 ⁇ L of a test solution with a concentration of 50 ⁇ M was added and 30 ⁇ L of water was added. Mix well and duplicate. The sampling time points were 0min and 60min.
  • the ratio of the test sample to the internal standard peak area in the following formula is converted into the remaining percentage.
  • the compounds of the present invention especially the 15 specific compounds in the specific embodiment, have good liver microsome stability in canine liver microsomes, which is conducive to better exerting pharmacological effects in the body and canine
  • the degree of metabolic stability in microsomes was significantly better than the control.
  • Test article Compound 3 of the present invention is self-made.
  • Test animals male beagle dogs, 3 animals / route of administration / compound, body weight 8-12 kg / head.
  • HP- ⁇ -CD solution preparation method Weigh HP- ⁇ -CD (hydroxypropylbetacyclodextrin) (14g), add an appropriate amount of purified water, dissolve it with ultrasound, and then make up to 50mL with purified water. Vortex Spin and mix to obtain a 28% HP- ⁇ -CD solution.
  • IV administration group 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h after administration
  • PO administration group 0.167, 0.5, 1, 2, 4, 6, 8, 24 hours after administration
  • Protein precipitation method Take 20 ⁇ L of plasma, add 200 ⁇ L of internal standard (containing 50 g / mL acetonitrile solution of tolbutamide), vortex for 10 minutes, then centrifuge at 4,000 rpm for 20 minutes, take 100 ⁇ L of the supernatant, and add 100 ⁇ L of water, vortexed for 3 minutes, and analyzed by LC-MS / MS.
  • internal standard containing 50 g / mL acetonitrile solution of tolbutamide
  • AUC 0-24h represents the area under the drug curve 0 ⁇ 24h; CL represents the clearance rate; V ss represents the steady-state apparent volume of distribution; T max represents the peak concentration of blood drug; C max represents the peak concentration of blood drug; T 1/2 represents half-life; F% represents absolute bioavailability.
  • Phenyl) isoxazole (770 mg, 2.55 mmol) and potassium iodide (423 mg, 2.55 mmol) were reacted at 60 ° C for 2 hours.
  • the corresponding raw materials are selected to prepare the corresponding compounds 4 to 13.

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Abstract

属于医药技术领域，具体涉及式(I)所示的化合物、其药学上可接受的盐、酯或其立体异构体，R 1、R 2、X 1、X 2、X 3、M、Ar、环B和L如说明书中所定义；还涉及这些化合物的制备方法、药物制剂及在用于制备治疗和/或预防由FXR受体介导的酒精性脂肪肝、非酒精性脂肪肝、原发性胆汁性肝硬化、脂质代谢紊乱、糖尿病并发症及恶性肿瘤等相关疾病的药物中的应用。

Description

FXR受体激动剂 技术领域
本发明属于医药技术领域，具体涉及FXR激动剂、其药学上可接受的盐、其酯及其立体异构体，含有这些化合物的药物制剂，以及该化合物、其药学上可接受的盐、其酯及其立体异构体在制备预防和/或治疗由FXR介导的非酒精性脂肪肝、原发性胆汁性肝硬化、脂质代谢紊乱、糖尿病并发症及恶性肿瘤等相关疾病的药物中的应用。
背景技术
法尼醇X受体(farnesoid X receptor，FXR)属于配体激活转录因子核受体家族成员，具有典型的核受体结构，即氨基末端高度保守的DNA结合区(DBD)，羧基末端配体结合区(LBD)，氨基末端配体非依赖性转录激活功能区(AF1)，羧基末端配体依赖性转录激活功能区(AF2)和脚链区。FXR可与视黄醇类X受体(RXR)形成异二聚体，当配体与FXR的LBD区域结合后，FXR构象可发生改变，DNA的结合区结合到靶基因启动子的FXR反应元件(IR-1)上面，释放辅抑制因子(如NCOR)，招募了辅激活因子，从而发挥转录调控作用。
FXR在多个器官组织中均有表达，包括脂肪组织、肝脏、胃肠道、肾脏等，其中肝脏中表达量最为丰富。FXR信号通路，可调节多个下游基因的表达，如BSEP、SHP、CYP7A1、FGFR4、OSTα/β、SREBP-1C等基因，进而调节多种代谢途径，如：甘油三酯、胆固醇、血糖及能量稳定性代谢胆酸的代谢，具有治疗癌症、非酒精性脂肪肝(NAFLD)、代谢紊乱、炎症等疾病的功能。通过抑制胆酸的合成、结合及转运，调节其代谢，是体内胆酸平衡的主要调节者。
部分天然胆酸类化合物可激动FXR，如鹅去氧胆酸(CDCA)、脱氧胆酸(DCA)、石胆酸(LCA)及牛磺酸和这些胆酸的甘氨酸结合物。除去天然的化合物，目前国际上研发的FXR激动剂可主要分为两大类，一类是甾体类，以Intercept公司的奥贝胆酸为代表(obeticholic acid，OCA)，于2016年5月份批准原发性胆管性肝硬化适应症，针对非酒精性脂肪肝炎适应症，处于临床III期，该类产品在临床研发期间有皮肤瘙痒等不良反应；另一类是新型分子实体，早期研发的化合物如GW4604(WO2000/037077)，虽然具有较强的激动活性，但其对光不稳定性且生物利用度较低。Phenex公司的PX-104(WO2011020615A1)已转让给Gilead公司，目前处于临床II期研究阶段。
Figure PCTCN2019091482-appb-000001
另有Gilead公司研发的GS-9674处于临床II期，适应症为原发性胆管性肝硬化、原发性硬化性胆管炎、非酒精性脂肪肝炎，结构未知。
Tully等人公开了一类FXR激动剂(参见专利申请WO2012087519A1)，并具体公开了化合物30-70和1-1B(LJN-452)，LJN-452目前处于临床II期，适应症为原发性胆管性肝硬化、原发性硬化性胆管炎、非酒精性脂肪肝炎。
Figure PCTCN2019091482-appb-000002
目前开发出高效、低毒、且稳定性较好的新型FXR受体激动剂，丰富药品种类，具有重要的临床意义。
发明内容
本发明涉及具有新型分子实体的化合物，可有效激动FXR，提升BSEP及SHP基因表达水平，同时有效抑制CYP7A1基因的表达。另外，为了达到更好的治疗效果，更好的满足市场需求，还希望能够提供高效、低毒、且稳定性较好的FXR受体激动剂。
具体而言，本发明的目的在于提供一种新型结构的FXR激动剂，其具有优于已知FXR激动剂的物理化学性质，体内外药效和/或优异的体内外动力学特性，为FXR激动剂用于治疗非酒精性脂肪肝、非酒精性脂肪肝炎、肝纤维化、原发性胆管性肝硬化、原发性硬化性胆管炎、脂质代谢紊乱、糖尿病并发症及恶性肿瘤提供了可能性。
本发明的其他目的在于提供上述FXR受体激动剂的制备方法。
本发明的另一目的在于提供含有上述FXR受体激动剂的药物组合物和制剂。
本发明的再一目的在于提供上述FXR受体激动剂在制备用于预防和/或治疗非酒精性脂肪肝、原发性胆汁性肝硬化、脂质代谢紊乱、糖尿病并发症及恶性肿瘤等疾病的药物中的用途。
在一方面，本发明提供了作为FXR激动剂的化合物。
本发明提供了通式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
Figure PCTCN2019091482-appb-000003
R 1选自卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、C 1-6烷氧基C 1-6烷基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元环烷基C 1-6烷氧基、3-8元杂环基、3-8元杂环基C 1-6烷基或3-8元杂环基C 1-6烷氧基；
X 1、X 2、X 3分别独立选自N、NH、O、S或CR 3R 4；R 3、R 4分别独立的选自氢、卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基或C 1-6烷基氨基；
R 2选自-(CH 2) n-COOR 5，R 5选自氢、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元杂环基或3-8元杂环基C 1-6烷基；
M选自C 1-6亚烷基，所述的C 1-6亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自N、NH、O、CO、S、SO或SO 2；
环B选自任选被一个或多个Q 1取代的6-10元芳基、5-10元杂芳基，3-14杂环基或3-8元环烷基；
每个Q 1独立的选自卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、C 1-6烷基磺酰基、C 1-6烷基亚磺酰基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元环烷基C 1-6烷氧基、3-8元杂环基、3-8元杂环基C 1-6烷基或3-8元杂环基C 1-6烷氧基；
L选自不存在或C 1-6亚烷基，所述的C 1-6亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自N、NH、O、CO、S、SO或SO 2；
Ar选自任选被一个或多个Q 2取代的6-10元芳基、6-10元芳基C 1-6烷基、6-10元芳基C 1-6烷氧基、5-10元杂芳基、5-10元杂芳基C 1-6烷基、5-10元杂芳基C 1-6烷氧基、3-8元环烷基或3-8元杂环基；
每个Q 2独立的选自卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷基氨基、 C 1-6烷基羰基、C 1-6烷基磺酰基、C 1-6烷基亚磺酰基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元环烷基C 1-6烷氧基、3-8元杂环基、3-8元杂环基C 1-6烷基或3-8元杂环基C 1-6烷氧基；
n选自0、1或2。
在某些实施方案中，通式(I)化合物进一步具有通式(I-1)所示的结构，
Figure PCTCN2019091482-appb-000004
其药学上可接受的盐、其酯或其立体异构体。
在某些实施方案中，通式(I)化合物进一步具有通式(I-2)所示的结构，
Figure PCTCN2019091482-appb-000005
其药学上可接受的盐、其酯或其立体异构体。
在某些实施方案中，通式(I)化合物进一步具有通式(I-3)所示的结构，
Figure PCTCN2019091482-appb-000006
其药学上可接受的盐、其酯或其立体异构体。
在某些实施方案中，通式(I)化合物进一步具有通式(I-4)所示的结构，
Figure PCTCN2019091482-appb-000007
其药学上可接受的盐、其酯或其立体异构体。
在某些实施方案中，通式(I)化合物进一步具有通式(I-5)所示的结构，
Figure PCTCN2019091482-appb-000008
其药学上可接受的盐、其酯或其立体异构体。
在某些实施方案中，通式(I)化合物进一步具有通式(I-6)所示的结构，
Figure PCTCN2019091482-appb-000009
其药学上可接受的盐、其酯或其立体异构体。
在某些实施方案中，通式(I)化合物进一步具有通式(I-7)所示的结构，
Figure PCTCN2019091482-appb-000010
其药学上可接受的盐、其酯或其立体异构体。
在某些实施方案中，通式(I)化合物进一步具有通式(I-2)所示的结构，
Figure PCTCN2019091482-appb-000011
其药学上可接受的盐、其酯或其立体异构体。
在上述的某些实施方案中，
R 1选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷氧基C 1-4烷基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
X 1、X 2分别独立选自NH、O、S或CR 3R 4；R 3、R 4分别独立的选自氢、卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基或C 1-4烷基氨基；
R 2选自-(CH 2) n-COOR 5，R 5选自氢、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元杂环基或3-6元杂环基C 1-4烷基；
M选自C 1-4亚烷基，所述的C 1-4亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自N、NH、O、CO、S、SO或SO 2；
环B选自任选被1-2个Q 1取代的含有1-3个杂原子或基团的8-10元稠杂芳基或7-14元稠杂环基，所述杂原子或基团独立的选自N、NH、O、S、SO或SO 2；
每个Q 1独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷基磺酰基、C 1-4烷基亚磺酰基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
L选自不存在或C 1-4亚烷基，所述的C 1-4亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自NH、O、CO、S、SO或SO 2；
Ar选自任选被1-3个Q 2取代的6-8元单环芳基、8-10稠芳基、6-8元单环芳基C 1-4烷基、8-10元稠芳基C 1-4烷基、6-8元单环芳基C 1-4烷氧基、8-10元稠芳基C 1-4烷氧基、5-7元单环杂芳基、8-10元稠杂芳基、5-7元单环杂芳基C 1-4烷基、8-10元稠杂芳基C 1-4烷基、5-7元单环杂芳基C 1-4烷氧基、8-10元稠杂芳基C 1-4烷氧基、3-8元环烷基或3-8元杂环基；
每个Q 2独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷基磺酰基、C 1-4烷基亚磺酰基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
n选自0、1或2。
在上述的某些方案中，其中，
M选自-CH 2-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-、-CH 2-NH-、-CH 2-CH 2-O-或-CH 2-NH-CO-；
环B选自任选被1-2个Q 1取代的含有1-2个杂原子或基团的9-10元稠杂芳基，所述杂原子或基团独立的选自N、NH、O、S、SO、SO 2；优选的，环B通过环碳原子与L或X 3相连；
每个Q 1独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷氧基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
L选自不存在或C 1-2亚烷基，所述的C 1-2亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自NH、O、S或CO。
在上述的某些实施方案中，
环B选自任选被1-2个Q 1取代的含有1-2个杂原子或基团的9元稠杂芳基，所述杂原子或基团独立的选自N、NH、O、S、SO、SO 2；优选的，环B通过环碳原子与L或X 3相连；
每个Q 1独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷氧基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基。
在上述的某些方案中，其中，
R 1选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷氧基C 1-4烷基、3-4元环烷基、3-4元环烷基C 1-4烷基、3-4元环烷基C 1-4烷氧基、3-4元单杂环基、3-4元单杂环基C 1-4烷基或3-4元单杂环基C 1-4烷氧基；
Ar选自任选被1-2个Q 2取代的苯基、苯基C 1-4烷基、苯基C 1-4烷氧基、5-6元单环杂芳基、5-6元单环杂芳基C 1-4烷基或5-6元单环杂芳基C 1-4烷氧基；
每个Q 2独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基或C 1-4烷基氨基。
在上述的某些实施方案中，
R 1选自卤素原子、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲氨基、乙氨基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基或氮杂环丁基；
R 2选自-(CH 2) n-COOH；
X 1、X 2分别独立选自NH、O或S；
M选自-CH 2-、-CH 2-CH 2-或-CH 2-CH 2-CH 2-；
环B选自任选被1-2个Q 1取代的如下基团：
Figure PCTCN2019091482-appb-000012
每个Q 1独立的选自氟、氯、溴、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、氟代甲基、二氟甲基、三氟甲基、1-氟代乙基、2-氟代乙基、1,1-二氟乙基、1,2-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、3,3,3-三氟丙基、1-三氟甲基乙基、三氟甲氧基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环戊基、环己基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基、氮杂环丁基、四氢呋喃基、吡咯烷基、咪唑烷基、吡唑烷基、噻唑烷基、四氢吡喃基、四氢吡啶基、哌啶基、哌嗪基或吗啉基；
L选自不存在；
Ar选自任选被1-2个Q 2取代的苯基、苯基甲基、苯基乙基、苯基甲氧基、呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、吡啶基、嘧啶基；每个Q 2独立的选自氟、氯、溴、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、三氟甲氧基、甲氧基、乙氧基、丙氧基、异丙基氧基、三氟甲氧基、甲基氨基、乙基氨基、甲氧基甲基、甲氧基乙基或乙氧基甲基；
n选自0或1。
在上述的某些方案中，
R 1选自卤素原子、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲氨基、乙氨基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基或氮杂环丁基。
在上述的某些实施方案中，
R 1选自环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基或氮杂环丁基；
优选的，R 1选自环丙基或环丁基。
在上述的某些实施方案中，
X 1、X 2分别独立选自NH、O或S；
优选的，X 1、X 2均为O。
在上述的某些实施方案中，
M选自-CH 2-、-CH 2-CH 2-或-CH 2-CH 2-CH 2-。
在上述的某些实施方案中，通式(I)所示化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
环B选自任选被1个Q 1取代的如下基团：
Figure PCTCN2019091482-appb-000013
Figure PCTCN2019091482-appb-000014
优选的，环B通过环碳原子与L或X 3相连；
优选的，环B选自任选被1个Q 1取代的如下基团：
Figure PCTCN2019091482-appb-000015
优选的，环B通过环碳原子与L或X 3相连；
Q 1选自氟、氯、溴、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、氟代甲基、二氟甲基、三氟甲基、1-氟代乙基、2-氟代乙基、1,1-二氟乙基、1,2-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、3,3,3-三氟丙基、1-三氟甲基乙基、三氟甲氧基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环戊基、环己基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基、氮杂环丁基、四氢呋喃基、吡咯烷基、咪唑烷基、吡唑烷基、噻唑烷基、四氢吡喃基、四氢吡啶基、哌啶基、哌嗪基或吗啉基；
优选的，Q 1选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基、三氟甲基、三氟甲氧基、甲氧基、乙氧基、丙氧基或异丙基氧基；
更优选的，Q 1处于通式结构中羧基的间位；
L选自不存在。
在上述的某些实施方案中，
Ar选自任选被1-2个Q 2取代的苯基、苯基甲基、苯基乙基、苯基甲氧基、呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、吡啶基或嘧啶基；每个Q 2独立的选自氟、氯、溴、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、三氟甲氧基、甲氧基、乙氧基、丙氧基、异丙基氧基、甲基氨基、乙基氨基、甲氧基甲基、甲氧基乙基或乙氧基甲基。
在上述的某些实施方案中，
Ar选自任选被1-2个Q 2取代的苯基或6元单环杂芳基；
优选的，Ar选自任选被1-2个Q 2取代的苯基、吡啶基、嘧啶基；每个Q 2独立的选自氟、氯、溴、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、三氟甲氧基、甲氧基、乙氧基、丙氧基、异丙基氧基、甲基氨基、乙基氨基、甲氧基甲基、甲氧基乙基或乙氧基甲基；
优选的，每个Q 2独立的选自氟、氯、溴、甲基、乙基、丙基、异丙基、三氟甲基、三氟甲氧基、甲氧基或乙氧基。
在上述的某些实施方案中，
R 1选自环丙基或环丁基；
X 1、X 2均为O；
Ar选自任选被1-2个Q 2取代的苯基；每个Q 2独立的选自氟、氯、溴、甲基、乙基、丙基、异丙基、三氟甲基、三氟甲氧基、甲氧基或乙氧基。
本发明还提供了(I’)所示的化合物、其药学上可接受的盐、其酯或其立体异构体：
Figure PCTCN2019091482-appb-000016
其中，R 1、X 1、X 2、X 3、M、Ar具有上述某些方案所定义的含义。
上述各实施方案之间以及各实施方案所涉及的各特征之间可以任意组合，所得到的技术方案均记载于本文中，属于本发明的技术方案。
本发明的部分化合物
Figure PCTCN2019091482-appb-000017
Figure PCTCN2019091482-appb-000018
另一方面，本发明涉及包含通式(I)、(I-1)、(I-2)、(I-3)、(I-4)、(I-5)、(I-6)或(I-7)所示的化合物、其药学上可接受的盐或其立体异构体与一种或多种药学上可接受的载体和/或稀释剂的药物制剂，其可以制成药学上可接受的任一剂型。以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者。用于口服方式给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可 采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
另一方面，本发明还涉及通式(I)、(I-1)、(I-2)、(I-3)、(I-4)、(I-5)、(I-6)或(I-7)所示的化合物、其药学上可接受的盐或其立体异构体在制备用于预防和/或治疗FXR介导的疾病及相关疾病的药物中的用途。
所述的疾病包括：
(1)脂质或脂蛋白紊乱，如动脉粥样硬化、胆汁酸紊乱、原发性硬化性胆管炎、胆固醇结石、纤维化相关疾病、脂肪肝(酒精性脂肪肝、非酒精性脂肪肝等)、肝硬化(原发性胆汁性肝硬化、原发性胆管性肝硬化等)、肝炎(慢性肝炎、非病毒性肝炎、酒精性脂肪肝炎、非酒精性脂肪肝炎等)、肝脏衰竭、胆汁郁积(良性肝内胆汁淤积、进行性家族性肝内胆汁淤积、肝外胆汁郁积病症等)、胆石病、心肌梗塞、中风、血栓等；急性肝衰竭，胆石病，和/或炎性肠道疾病。
(2)I型或II型糖尿病的临床并发症，包括糖尿病性肾病、糖尿病性神经病变、糖尿病性视网膜病、及其临床显性长期糖尿病的其他观察到的结果。
(3)非恶性过度增殖性疾病或过度增殖性疾病，包括肝细胞癌、结肠腺瘤和息肉病、结肠腺癌、乳腺癌、胰腺癌、食管癌和其他形式的胃肠道和肝脏肿瘤性疾病。
在本申请的说明书和权利要求书中，化合物都是依据化学结构式而命名的，如果表示同一化合物时化合物的命名与化学结构式不符，以化学结构式或化学反应式为准。
在本申请中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
发明详述
本发明所述“卤代”是指被“卤素原子”取代，本发明所述的“卤素原子”包括氟、氯、溴和碘。
本发明所述的“C 1-6烷基”是指直链或支链的含有1-6个碳原子的烷基，包括例如“C 1-5烷基”、“C 1-4烷基”、“C 1-3烷基”、“C 1-2烷基”、“C 2-4烷基”、“C 2-3烷基”、“C 3-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、 1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C 1-4烷基”是指C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“卤代C 1-6烷基”是指一个或多个卤素原子原子取代C 1-6烷基上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C 1-6烷基”如前文所定义。本发明所述的“卤代C 1-4烷基”指卤代C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“羟基C 1-6烷基”是指一个或多个羟基取代C 1-6烷基上的一个或多个氢原子所衍生的基团，所述“C 1-6烷基”如前文所定义。本发明所述的“羟基C 1-4烷基”指羟基C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“氨基C 1-6烷基”是指一个或多个氨基取代C 1-6烷基上的一个或多个氢原子所衍生的基团，所述“C 1-6烷基”如前文所定义。本发明所述的“氨基C 1-4烷基”指氨基C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、C 1-6烷基磺酰基、C 1-6烷基亚磺酰基”是指以C 1-6烷基-O-，C 1-6烷基-NH-，C 1-6烷基-C(O)-，C 1-6烷基-S(O) 2-，C 1-6烷基-S(O)-方式连接的基团，其中“C 1-6烷基”如前文所定义。本发明所述的“C 1-4烷氧基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷基磺酰基、C 1-4烷基亚磺酰基”是指上述实例的烷基中含有1-4个碳原子的具体实例。
本发明所述的“卤代C 1-6烷氧基”指一个或多个卤素原子原子取代C 1-6烷氧基上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C 1-6烷氧基”如前文所定义。本发明所述的“卤代C 1-4烷氧基”指卤代C 1-6烷氧基中的含有1-4个碳原子的具体实例。
本发明所述的“C 1-6烷氧基C 1-6烷基”是指一个或多个C 1-6烷氧基取代C 1-6烷基上的一个或多个氢原子所衍生的基团，所述“C 1-6烷基”如前文所定义。本发明所述的“C 1-4烷氧基C 1-4烷基”指C 1-6烷氧基C 1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“CR 3R 4”是指R 3、R 4分别取代亚甲基上的两个氢原子形成的基团，具体的连接方式为
Figure PCTCN2019091482-appb-000019
本发明所述的“C 1-6亚烷基”是指直链含1-6个碳原子的烷烃去除两个不在同一碳原子上的氢所衍生的基团，包括“C 1-5亚烷基”、“C 1-4亚烷基”、“C 1-3亚烷基”、“C 1-2亚烷基”，具体实例包括但不限于：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2CH 2CH 2-等。
本发明所述的“C 1-6亚烷基中的任一碳原子任选被杂原子或基团所替代”是指“C 1-6亚烷基”中的任意一个碳原子可以任选被一个杂原子或基团所替代，可以是C 1-6亚烷基中的碳原子未被任何杂原子或基团所替代；也可以是C 1-6亚烷基中的一个碳原子被一个杂原子或基团所替代；也可以是C 1-6亚烷基中的任意两个碳原子被相同或不同的两个杂原子或基团所替代；也可以是C 1-6亚烷基中的任意多个碳原子被相应的相同或不同的多个杂原子或基团所替代；所述的杂原子或基团选自N、NH、O、CO、S、SO或SO 2。
本发明所述的“3-8元环烷基”是指含有3-8个碳原子的单环饱和的环状烷基，包括例如“3-6元环烷基”、“3-5元环烷基”、“3-4元环烷基”、“4-5元环烷基”、“4-6元环烷基”、“4-7元环烷基”、“4-8元环烷基”等。具体实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基等。“3-6元环烷基”是指含有3-6个碳原子的饱和环状烷基。“3-4元环烷基”是指含有3-4个碳原子的饱和环状烷基。
本发明所述的“3-14元杂环基”是指含有3-14个环原子、且含有至少一个杂原子和/或基团(例如1、2、3、4或5个杂原子和/或基团)的饱和或部分饱和的单环或稠环化合物除去一个氢原子得到的基团。所述的杂原子和/或基团选自N、NH、O、S、CO、SO或SO 2；所述的“稠环”是指两个或两个以上环状结构彼此共用两个相邻的原子所形成的基团。包括例如“3-12元杂环基”、“3-10元杂环基”、“3-8元杂环基”、“3-7元杂环基”、“3-6元单杂环基”、“3-4元单杂环基”、“4-7元单杂环基”、“4-6元单杂环基”、“5-6元单杂环基”、“7-10元稠杂环基”、“7-14元稠杂环基”等。具体可以为：“含1-2个N、O和/或S原子的5-12元杂环基”、“含1-2个N、O、S和/或SO 2原子的9-10元部分饱和稠杂环基”。3-14元部分饱和杂环基，是指含有双键、杂原子的环状基团。3-14元饱和杂环基，是指全部为饱和键的含有杂原子的环状基团。具体实例包括但不仅限于：环氧乙烷、氮杂环丙烷基、二氮杂环丙基、氧杂环丁基、氮杂环丁基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、咪唑烷基、吡唑烷基、哌嗪基、吗啉基、苯并二氢呋喃基、苯并二氢吡喃基、苯并1,4-二氧杂环己烯基、苯并1,3-二氧杂环己烯基、苯并四氢吡啶基、苯并二氢噁嗪基、苯并四氢吡嗪基、1,2,3,4-四氢喹唑啉基、1,2,3,4-四氢噌啉基或四氢萘基等。所述“3-6元杂环基”是指3-14元杂环基中含有3-6个环原子的具体实例。所述“3-4元单杂环基”是指3-14元杂环基中含有3-4个环原子的单环杂环基的具体实例。
本发明所述的“3-8元环烷基C 1-6烷基、3-8元环烷基C 1-6烷氧基”是指3-8元环烷基取代C 1-6烷基、C 1-6烷氧基中的氢原子所衍生的基团，所述的“3-8元环烷基”、“C 1-6烷基”、“C 1-6烷氧基”如前文所定义。
本发明所述的“3-8元杂环基C 1-6烷基、3-8元杂环基C 1-6烷氧基”是指3-8元杂环基取代C 1-6烷基、C 1-6烷氧基中的氢原子所衍生的基团，所述的“3-8元杂环基”、“C 1-6烷基”、“C 1-6烷氧基”如前文所定义。
本发明所述的“3-6元环烷基C 1-4烷基、3-4元环烷基C 1-4烷基、3-6元单杂环基C 1-4烷基、3-4元单杂环基C 1-4烷基”是指3-6元环烷基、3-4元环烷基、3-6元单杂环基、3-4元单杂环基取代C 1-4烷基中的氢原子所衍生的基团，所述的“3-6元环烷基”、“3-4元环烷基”、“3-6元单杂环基”、“3-4元单杂环基”、“C 1-4烷基”如前文所定义。
本发明所述的“3-6元环烷基C 1-4烷氧基、3-4元环烷基C 1-4烷氧基、3-6元单杂环基C 1-4烷氧基、3-4元单杂环基C 1-4烷氧基”是指3-6元环烷基、3-4元环烷基、3-6元单杂环基、3-4元单杂环基取代C 1-4烷氧基中的氢原子所衍生的基团，所述的“3-6元环烷基”、“3-4元环烷基”、“3-6元单杂环基”、“3-4元单杂环基”、“C 1-4烷氧基”如前文所定义。
本发明所述的“6-10元芳基”是指含有6-10个环碳原子的具有芳香性的单环或多环基团。例如包括“6-8元单环芳基”、“6-7元单环芳基”、“8-10元稠芳基”等。所述的“稠芳基”是指两个或两个以上环状结构彼此共用两个相邻的原子所形成的具有芳香性的基团。具体实施例包括但不限于：苯基、环辛四烯基、萘基等。所述的“6-8元单环芳基”是指6-10元芳基中含有6-8个环碳原子的单环的具体实例。所述的“6-7元单环芳基”是指6-10元芳基中含有6-7个环碳原子的单环的具体实例。所述的“8-10元稠芳基”是6-10元芳基中含有8-10个环碳原子的多环的具体实例。
本发明所述的“5-10元杂芳基”是指含有5-10个环原子且至少一个环原子为杂原子的具有芳香性的单环或多环基团，包括单杂芳基和稠杂芳基。所述杂原子为氮原子、氧原子和/或硫原子。所述的“单环杂芳基”是指单环芳香性基团；所述的“稠环杂芳基”是指两个或两个以上环状结构彼此共用两个相邻的原子所形成的具有芳香性的基团。包括例如“5-7元单环杂芳基”、“5-6元单环杂芳基”、“6元单杂芳基”、“7-10元稠杂芳基”、“8-10元稠杂芳基”、“9-10元稠杂芳基”。具体实施例包括但不限于：呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、异喹啉基等。所述的“5-6元单环杂芳基”是指5-10元杂芳基中含有5-6个环原子的单环的具体实例。所述的“7-10元稠杂芳基”、“8-10元稠杂芳基”、“9-10元稠杂芳基”是指5-10元杂芳基中含有7-10个、8-10个、9-10个环原子的多环的具体实例。
本发明所述的“6-10元芳基C 1-6烷基、5-10元杂芳基C 1-6烷基”是指6-10元芳基、5-10元杂芳基取代C 1-6烷基中的氢原子所衍生的基团。所述的“6-10元芳基”、“5-10元杂芳基”、“C 1-6烷基”如前文所述。
本发明所述的“6-10元芳基C 1-6烷氧基、5-10元杂芳基C 1-6烷氧基”是指6-10元芳基、5-10元杂芳基取代C 1-6烷氧基中的氢原子所衍生的基团。所述的“6-10元芳基”、“5-10元杂芳基”、“C 1-6烷氧基”如前文所述。
本发明所述的“6-8元单环芳基C 1-4烷基、8-10元稠芳基C 1-4烷基、6元单环芳基C 1-4烷基、5-7元单环杂芳基C 1-4烷基、8-10元稠杂芳基C 1-4烷基”是指6-8元单环芳基、8-10元稠芳基、6元单环芳基、5-7元单环杂芳基、8-10元稠杂芳基取代C 1-4烷基中氢原子所衍生出的基团。其中，“6-8元单环芳基”、“8-10元稠芳基”、“6元单环芳基”、“5-7元单环杂芳基”、“8-10元稠杂芳基”、“C 1-4烷基”如前文所定义。
本发明所述的“6-8元单环芳基C 1-4烷氧基、8-10元稠芳基C 1-4烷氧基、6元单环芳基C 1-4烷氧基、5-7元单环杂芳基C 1-4烷氧基、8-10元稠杂芳基C 1-4烷氧基”是指6-8元单环芳基、8-10元稠芳基、6元单环芳基、5-7元单环杂芳基、8-10元稠杂芳基取代C 1-4烷氧基中氢原子所衍生出的基团。其中，“6-8元单环芳基”、“8-10元稠芳基”、“6元单环芳基”、“5-7元单环杂芳基”、“8-10元稠杂芳基”、“C 1-4烷氧基”如前文所定义。
本发明所述的“L选自不存在”是指，当L为不存在时，环B与X 3通过化学键直接相连。本发明结构式或基团中虚键是指存在或不存在，例如基团，
Figure PCTCN2019091482-appb-000020
是指包括
Figure PCTCN2019091482-appb-000021
Figure PCTCN2019091482-appb-000022
两种情况。
本发明化合物结构式中所示的“顺式”或“反式”是指结构中8元桥环中无取代基的桥与通过X 2相连的取代基之间的位置关系。以化合物1为例，化合物1为顺式结构，具体结构式如下：
Figure PCTCN2019091482-appb-000023
其表示，化合物1为含有两个对映异构体的消旋体，该两个对映异构体结构式分别为：
Figure PCTCN2019091482-appb-000024
本发明化合物结构命名中，“(1RS,4RS,5SR)”表示其为含有两个对映异构体的消旋体，该两个对映异构体的绝对构型分别为“1R,4R,5S”和“1S,4S,5R”。
本发明所述的“任选”是指可以存在，也可以不存在。例如，本发明所述的“环B选自任选被一个或多个Q 1取代”包括环B未被任何Q 1取代的情况，也包括环B被一个或多个Q 1取代的情况。
本发明所述的“部分饱和”是指相关基团至少包含一个双键或一个三键。
本发明还提供了式(I)化合物的制备方法，其包括但不限于下述工艺路线：
各缩写所代表的定义如下：
DMF：N,N-二甲基甲酰胺；DMA：N,N-二甲基乙酰胺；THF：四氢呋喃；DCM：二氯甲烷；TFA：三氟乙酸；EA：乙酸乙酯；PE：石油醚；MeOH：甲醇。
Figure PCTCN2019091482-appb-000025
R 1、R 2、X 1、X 2、X 3、L、M、环B和Ar如前文所述，X、X’独立的选自Cl或者Br。
具体的示例性步骤如下：
1、中间体1的制备
将原料2、叔丁醇钾、18-冠-6和KI加入到有机溶剂中，再加入原料1，25-60℃下反应，反应完毕，反应液浓缩，柱层析纯化，得中间体1。其中，有机溶剂优选为四氢呋喃。
2、中间体2(式I’化合物)的制备
将中间体1缓慢加入到含有酸性物质的溶液中反应，待反应完全后，可用碱性溶液调节pH至7-8，旋干体系，浓缩得中间体2或者，反应完全后，直接浓缩，粗产品直接用于下一步反应。其中，含有酸性物质的溶液优选盐酸乙醇溶液、含有三氟乙酸的二氯甲烷溶液等，所述碱性溶液优选饱和碳酸氢钠溶液。
3、式(I)化合物的制备一
将中间体2、中间体3和碳酸铯加入到有机溶剂中，微波反应或加热反应，反应完毕，经柱层析纯化得式(I)化合物。其中，所述有机溶剂优选DMA或DMF。
4、式(I)化合物的制备二
将中间体2、中间体3’和碳酸铯加入到有机溶剂中，微波反应或加热反应，反应完毕，经柱层析纯化得中间体4。其中，所述有机溶剂优选DMA或DMF。
将中间体4加入到有机溶剂中，再加入含有碱性物质的水溶液，加热反应。反应结束后，用酸性物质溶液调解pH至4-6，旋干溶剂，经柱层析纯化得式(I)化合物。其中所述有机溶剂优选甲醇/四氢呋喃混合溶液，所述的碱性物质优选氢氧化锂、氢氧化钠等，所述酸性溶液优选盐酸。
本发明所述的原料1和原料2可以自制也可以市购。
本发明式(I)所示化合物的“药学上可接受的盐”是指式(I)化合物中存在的酸性官能团与适当的无机或者有机阳离子(碱)形成的盐，包括与碱金属或碱土金属形成的盐、铵盐，以及与含氮有机碱形成的盐；以及式(I)化合物中存在的碱性官能团(例如-NH 2等)与适当的无机或者有机阴离子(酸)形成的盐，包括与无机酸，与有机羧酸。
本发明式(I)所示化合物的“酯”是指，当式(I)化合物存在羧基时，可以与醇发生酯化反应而形成的酯，当式(I)化合物存在羟基时，可以与有机酸、无机酸、有机酸盐等发生酯化反应而形成的酯。酯在酸或者碱存在的条件下，可以发生水解反应生成相应的酸或醇。
“立体异构”分为构象异构和构型异构，构型异构还可分为顺反异构和旋光异构(即光学异构)。构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现的椅式构象和船式构象。“顺反异构体”是指当化合物含有如C＝C双键、C≡C叁键、C＝N双键、N＝N双键或脂环等不能自由旋转的官能团所产生的顺式或反式异构体，按照国际统一的“顺序规则”，当两个较优基团在π键或脂环的同侧为顺式异构体，当两个较优基团在π键或脂环的异侧为反式异构体，具体到本发明，化合物中含有桥环或桥杂环，顺式或反式是指桥环(或桥杂环)中无取代基的桥与X 2连接的基团处于桥环(或桥杂环)的同侧或者异侧。“光学异构体”是指当本发明化合物含有一个或多个不对称中 心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，每个不对称中心会产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在，其通过一个或多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。
本发明化合物具有以下优点：
(1)本发明化合物、其药学上可接受的盐及其立体异构体具有优异的FXR受体激动活性，能被安全的用于治疗和/或预防非酒精性脂肪肝、原发性胆汁性肝硬化、脂质代谢紊乱、糖尿病并发症及恶性肿瘤等相关疾病；
(2)本发明化合物、其药学上可接受的盐及其立体异构体显示出良好的代谢稳定性，作用更持久，生物利用度高。
(3)本发明化合物、其药学上可接受的盐及其立体异构体显示出较低的毒性，耐药性好，安全性高。
实验方案
以下提供本发明的部分化合物的示例性实验方案，以显示本发明化合物的有益活性和有益技术效果。但是应当理解，下述实验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。本领域技术人员在本说明书的教导下，能够对本发明的技术方案进行适当的修改或改变，而不背离本发明的精神和范围。
实验例1：本发明化合物对HepG2细胞BSEP mRNA相对表达量的影响
1、测试物：本发明化合物，其化学名称和制备方法见各个化合物的制备实施例。
对照品：化合物1-1B，按照现有技术方法制备，其结构见背景技术。
2、实验方法：
(1)细胞培养、化合物处理和细胞收集
使用胰酶消化、收集细胞，测定细胞浓度；根据计数结果，重悬细胞至7.5×10 5cell/mL密度；6孔细胞培养板，每孔接种2mL细胞；将培养板至于培养箱中，于37℃，5％CO 2条件培养24小时。
使用DMSO稀释待测化合物至0.3和3mM；取上一步稀释得到的储液5μL分别加到5mL培养基中。得到的工作液浓度分别为0.3和3μM。对照组培养基使用等体积的DMSO代替储液配制；从培养箱中取出细胞培养板，移除培养基，加入工作液和对照培养基；将培养板放回培养箱，于37℃，5％CO 2条件培养24小时。
处理24小时后，从培养箱中取出细胞培养板，移除培养基，用预冷(4℃)的PBS(磷酸盐缓冲液)润洗细胞3次；每孔加入200μL胰酶(预热至37℃)，轻轻晃动使得胰酶均匀覆盖板底。将培养板放回培养箱温育直至细胞脱离板底。加入1mL培养基终止消化。用移液器轻轻吹打几次后，将孔中所有物质吸入到1.5mL的Rnase-free的离心管中，200×g离心5分钟；移除上清，收集细胞样品。
(2)细胞RNA样本提取和纯化
细胞裂解：准备新鲜的RNA裂解液(1mL裂解液加10μL 2-巯基乙醇)；向细胞样品加入600μL裂解液；剧烈涡旋1-2分钟，使细胞完全裂解；将细胞裂解液于12,000×g离心5分钟；取上清转移至RNase-free的1.5mL离心管中。
RNA提取纯化：添加等量的70％的乙醇到细胞裂解液中；剧烈震荡离心管，充分混合，尽量分散加入乙醇后可能形成的微粒沉淀；将吸附柱置于收集管上，转移混合物至吸附柱中。每次最多转移700μL；室温12,000×g离心15秒。弃掉收集管中的溶液，并将吸附柱重新放置于收集管上；将剩余的混合物全部转移到吸附柱中。加700μL洗脱液I至吸附柱中；室温12,000×g离心15秒。将吸附柱放置于新的收集管上；加500μL洗脱液II到吸附柱中；室温12,000×g离心15秒。弃掉收集管中的溶液，并将吸附柱重新放置于收集管上；加500μL洗脱液II到吸附柱中；室温12,000×g离心1-2分钟，将吸附柱放置于RNA收集管上；加入50μL RNase-free水至吸附柱的中心位置，室温孵育1分钟；室温14,000×g离心2分钟，将RNA洗脱至收集管中。
测量提取的RNA的浓度和质量。RNA存储于-80℃。
(3)RNA逆转录为cDNA
将上一骤中提取的RNA在70℃孵育5分钟使RNA变性。处理后将样品置于冰上；使用RNAse-free水稀释RNA样品至200ng/μL；按照下表配制10μL的逆转录溶液，并和10μL变性RNA混合。逆转录反应中RNA的总量为2μg。实验过程中，所有试剂均放置于冰上。
Figure PCTCN2019091482-appb-000026
Figure PCTCN2019091482-appb-000027
逆转录在G-Storm GS1 thermal cycler PCR热循环仪上进行。逆转录过程设置如下：25℃10分钟→37℃120分钟→85℃5分钟→4℃∞。逆转录产物(cDNA)存储于-20℃。
(4)样品qPCR实验
根据qPCR扩增效率，选择合适的cDNA浓度进行样品的qPCR实验。第三步骤逆转录得到的cDNA样品，取10μL加60μL Rnase-free水稀释7倍。
按照下表准备80μL的反应混合物，用移液器取20μL到96孔PCR反应板中，3个重复(每个反应孔加7μL 100ng)cDNA样品。
Figure PCTCN2019091482-appb-000028
qPCR在ABI7500实时定量PCR仪上进行，程序设置如下：50℃2分钟→95℃10分钟→95℃15秒→60℃60秒，其中95℃15秒与60℃60秒之间设置40个循环。
(5)实验结果和结论：
表1本发明化合物对HepG2细胞中BSEP mRNA相对表达量的检测结果
Figure PCTCN2019091482-appb-000029
注：相对表达量数据均是以对照药在3uM时的表达量作为100％，其他表达量与对照药在3uM时的表达量的比值作为该化合物在该浓度下的相对表达量(％)。
结论：
由表1结果可知，本发明化合物尤其是具体实施方式部分的15个具体化合物，对HepG2细胞中BSEP mRNA有较好的激动作用，BSEP是FXR的直接下游基因，在调控胆汁酸生成、外排等方面起重要作用，BSEP mRNA的表达情况直接反应FXR的激动活性，是初筛化合物 对FXR的激动活性较好的一个指标，FXR激动剂的研究对于非酒精性脂肪肝的治疗具有重要的意义。
实验例2：本发明化合物在不同种属中的肝微粒体代谢稳定性实验
供试品：本发明化合物1，1-1和3，其化学名称和制备方法见各化合物的制备实施例。
对照品：化合物30-70，按照现有技术方法制备，其结构见背景技术。
实验材料：
Beagle犬的混合肝微粒体购自XenoTech，肝微粒体蛋白浓度为20mg·mL -1。
实验启动因子β-NADPH购于美国Roche公司。pH7.4的磷酸盐缓冲液(PBS)由本实验室自制。
供试品溶液制备：
精密称取供试品粉末适量，加入适量的二甲基亚砜(DMSO)溶解到1mM，再用甲醇稀释20倍到50μM的工作液。
实验方法:
表2.肝微粒体代谢稳定性实验温孵体系组成
Figure PCTCN2019091482-appb-000030
实验操作步骤：
(1)按照上面表2“实验温孵体系的构成”比例，每个化合物取100mM PBS 6mL，20mM MgCl 2溶液0.6mL及H 2O 3.66mL，制备温孵体系混合溶液1(不含微粒体、供试品和β-NADPH)。
(2)从-80℃冰箱中取出肝微粒体(20mg蛋白/mL)，置于37℃水浴恒温振荡器上预温孵3min。
(3)每个化合物每个种属取1.88mL温孵体系混合溶液1，加入55μL不同种属的微粒体，制备温孵体系混合溶液2(不含供试品和β-NADPH)。
(4)样品组(含微粒体和β-NADPH)：取616μL温孵体系混合溶液2，加入14μL浓度为50μM的供试品工作溶液，加入70μL 10mM的β-NADPH工作溶液。混匀，复样。取样时间点为0min，5min，10min，20min，30min，60min。
(5)对照组(含微粒体，不含β-NADPH，以水代替β-NADPH)：取264μL温孵体系混合溶液2，加入6μL浓度为50μM的供试品工作溶液，加入30μL水。混匀，复样。取样时间点为0min和60min。
(6)于各个预定时间点从孵育样品管中取样50μL，加入至终止样品管(内含300μL冷的终止剂，含内标甲苯磺丁脲50ng/mL的乙腈溶液)，涡旋，终止反应。
(7)涡旋10min后，离心5min(12000rpm)。
(8)取上清液100μL，加入100μL水，涡旋混匀，LC-MS/MS进样分析。
数据分析：
通过下面公式中供试品与内标峰面积的比值转化成剩余量百分比。
Figure PCTCN2019091482-appb-000031
实验结果：
表3本发明化合物肝微粒体稳定性结果
Figure PCTCN2019091482-appb-000032
实验结论：
由表3结果可知，本发明化合物尤其是具体实施方式部分的15个具体化合物，在犬肝微粒体中具有良好的肝微粒体稳定性，利于在体内更好的发挥药理作用，且在犬肝微粒体中的代谢稳定性程度明显优于对照品。
实验例3：本发明化合物的比格犬体内药代动力学实验
供试品：本发明化合物3，自制，其化学名称和制备方法见各化合物的制备实施例。
对照品：化合物1-1B，参考现有技术方法制备，其结构见背景技术。
受试动物：雄性比格犬，3只/给药途径/化合物，体重8-12kg/只。
供试品及对照品给药药液的制备：
溶解方案：
IV(静脉注射)给药：5％DMSO+5％PEG400+90％(28％HP-β-CD)
PO(口服)给药：2％HPC+0.1％吐温80
空白溶媒1的配制：
28％HP-β-CD溶液配制方法：称取HP-β-CD(羟丙基倍他环糊精)(14g)，加入适量纯化水，超声溶解，再用纯化水定容到50mL，涡旋混匀，得28％HP-β-CD的溶液。
空白溶媒2的配制：
2％HPC+0.1％吐温80的配制：称取HPC(羟丙基纤维素)(20g)，缓慢加入50mL搅拌着的纯化水中，再加入1mL吐温80，用纯化水定容到1000mL，搅拌至澄清透明，即得。
具体配制方法：
对照品：
①称取对照品(21.96mg)，加入DMSO(二甲基亚砜)(2.1mL)，涡旋，超声溶解，加入PEG400(聚乙二醇400)(2.1mL)，涡旋混匀，再加入空白溶媒1(37.9mL)，涡旋混匀，即得均匀溶液，作为对照品比格犬IV给药药液1。
②称取对照品(43.11mg)，置于组织研磨器中，加入空白溶媒2(20.7mL)，以1000rpm的转速研磨均匀得2mg/mL均匀混悬液，再用空白溶媒2稀释至终体积为207mL，即得终浓度为0.2mg/mL均匀混悬液，作为对照品比格犬PO给药药液2。
供试品：
①取化合物3(20.05mg)，加入DMSO(1.961mL)，涡旋、超声溶解，再加入PEG400(1.961ml)，涡旋均匀，最后加入空白溶媒1(35.296mL)，涡旋混匀，置于50℃恒温水浴中保温20min，即得均匀溶液，作为供试品比格犬IV给药药液1。
②取化合物3(20.24mg)，置于组织研磨器中，加入空白溶媒2(39.6mL)，以1000rpm的转速研磨均匀，即得0.5mg/mL的均匀混悬液母液；取出此混悬液母液(38.75mL)，加入到烧杯中，再加入空白溶媒2(155mL)，搅拌成均匀混悬液，即得0.1mg/mL的均匀混悬液，作为供试品比格犬PO给药药液2。
实验方法
给药：
将对照品及供试品药液按照下表方法给药：
Figure PCTCN2019091482-appb-000033
Figure PCTCN2019091482-appb-000034
采血时间点：
IV给药组：给药后0.083、0.25、0.5、1、2、4、6、8、24h
PO给药组：给药后0.167、0.5、1、2、4、6、8、24h
每个时间点通过前肢静脉采集400μL左右的全血，放置到含有EDTA-K 2抗凝剂的抗凝管中，全血样品在4℃条件下8000转/分钟离心6分钟得到血浆样品，置于-80℃冰箱冻存。血浆样品分析：
采用蛋白沉淀法：取血浆20μL，加入内标(含甲苯磺丁脲50ng/mL的乙腈溶液)200μL，涡旋10分钟后，然后4000转/分钟离心20分钟，取上清液100μL，再加入100μL水，涡旋混匀3分钟后，LC-MS/MS分析。
实验结果
表4比格犬PK评价结果(IV)
Figure PCTCN2019091482-appb-000035
表5比格犬PK评价结果(PO)
Figure PCTCN2019091482-appb-000036
AUC 0-24h代表药时曲线下面积0→24h；CL代表清除率；V ss表示稳态表观分布容积；T max代表血药浓度达峰时间；C max代表血药浓度达峰浓度；T 1/2代表半衰期；F％代表绝对生物利用度。
实验结论
由表4和表5的实验结果可知，本发明化合物的药代动力学性质良好，与对照品相比，在测试动物体内，半衰期更长，暴露量更高。PO给药后，生物利用度更高。
实施例4：NASH模型试验
以高脂喂养(HFD/DIO)模型为主要代表，考察本发明化合物对模型脂质改善的影响，具体考察指标包括血清LDL、肝脏TG和NASH活动评分等。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1：2-((1RS,4RS,5SR)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸的制备(化合物1)
Figure PCTCN2019091482-appb-000037
1.(1RS,4RS,5SR)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-甲酸叔丁酯的制备
Figure PCTCN2019091482-appb-000038
将(1RS,4RS,5SR)-5-羟基-2-氮杂双环[2.2.2]辛烷-2-甲酸叔丁酯(0.2g,0.88mmol)和叔丁醇钾(140mg,1.25mmol)，18-冠醚-6(330mg,1.25mmol)溶于THF(20mL)中，加入4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(300mg,0.99mmol)和KI(120mg,0.8mmol)，加热至25℃反应6小时，加水(50mL)和乙酸乙酯(20mL)分液，水层再用乙酸乙酯(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析(石油醚：乙酸乙酯＝3:1)纯化，得目标产物(260mg，产率60.5％)。
2. 4-((((1RS,4RS,5SR)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑的制备
Figure PCTCN2019091482-appb-000039
将((1RS,4RS,5SR)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-甲酸叔丁酯(0.25g,0.51mmol)加入到二氯甲烷(5mL)中，0℃加入三氟乙酸(1mL)，0℃反应16小时，浓缩得粗产物直接用于下一步反应。
3. 2-((1RS,4RS,5SR)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-甲酸甲酯的制备
Figure PCTCN2019091482-appb-000040
将4-((((1RS,4RS,5SR)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(粗品)，2-溴苯并[d]噻唑-6-羧酸甲酯(140mg,0.51mmol)和碳酸铯(0.6g,1.84mmol)加入到DMF(2mL)中，加热至80℃反应1小时，过滤，滤液浓缩，经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化，得目标产物(0.11g，两步产率37.2％)。
4. 2-((1RS,4RS,5SR)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸的制备
Figure PCTCN2019091482-appb-000041
将2-((1RS,4RS,5SR)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-甲酸甲酯(100mg,0.17mmol)，溶于甲醇(5mL)和四氢呋喃(5mL)的混合溶剂中，加入氢氧化钠水溶液(0.5mL,1mmol,2M)，25℃搅拌16小时，加入磷酸二氢钠调pH＝6，过滤，滤液浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝10:1)纯化，得目标产物(60mg，产率61.2％)。
分子式:C 28H 25Cl 2N 3O 4S        分子量:569.1        LC-MS(m/z):570.1(M+H +)
1H-NMR(400MHz,CDCl3)δ:8.29(s,1H),8.01(s,1H),7.36-7.44(m,3H),7.27-7.34(m,1H),4.24-4.35(m,2H),3.66-3.69(m,1H),3.50-3.66(m,1H),3.30-3.50(m,1H),2.01-2.3(m,3H),1.81-1.90(m,2H),1.50-1.70(m,1H),1.20-1.40(m,4H),1.10-1.20(m,2H),0.80-0.90(m,2H).
实施例2：2-((1S,4S,5R)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸的制备(化合物1-1)
Figure PCTCN2019091482-appb-000042
1.(1S,4S,5R)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-甲酸叔丁酯的制备
Figure PCTCN2019091482-appb-000043
将(1S,4S,5R)-5-羟基-2-氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯(387mg,1.7mmol)，18冠6(898mg,3.4mmol)，叔丁醇钾(381mg,3.4mmol)加入到THF(50mL)中，25℃下反应半小时，再加入4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(770mg,2.55mmol)和碘化钾(423mg,2.55mmol)，60℃下反应2小时。体系旋干经硅胶柱层析(PE:EA＝3:1)，得到产物(629mg,产率75.0％)。
2. 4-((((1S,4S,5R)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑的制备
Figure PCTCN2019091482-appb-000044
将(1S,4S,5R)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-甲酸叔丁酯(550mg,1.1mmol)加入到DCM(5mL)中，再加入TFA(2mL)，25℃反应2小时，体系旋干直接用于下一步。
3. 2-((1S,4S,5R)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸甲酯的制备
Figure PCTCN2019091482-appb-000045
将4-((((1S,4S,5R)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(粗品)，2-溴基苯并[d]噻唑-6-甲酸甲酯(370mg,1.36mmol)，碳酸铯(665mg,2.04mmol)加入到DMA(20mL)中，120℃下反应3小时。降至25℃，体系加入乙酸乙酯(100mL)和水(80mL)萃取分液，有机相旋干硅胶柱层析(PE:EA＝4:1)，得产物(410mg,两步产率63.8％)。
4. 2-((1S,4S,5R)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸的制备
Figure PCTCN2019091482-appb-000046
将2-((1S,4S,5R)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸甲酯(410mg,0.70mmol)加入到甲醇(5mL)和THF(5mL)中，然后加入含氢氧化锂一水合物(118mg,2.8mmol)的水溶液(2mL)，然后加热至50℃反应12小时。降至25℃，体系用1N HCl调节pH至4，旋干溶剂经硅胶柱层析(DCM:MeOH＝50:1)，得产物(370mg,产率92.6％)。
分子式：C 28H 25Cl 2N 3O 4S       分子量：569.1      LC-MS(m/z):569.8(M+H +)
1H-NMR(400MHz,CDCl 3)δ:8.35(s,1H),8.08-8.04(m,1H),7.52-7.48(m,1H),7.46-7.39(m,2H),7.37-7.34(m,1H),4.35-4.28(m,2H),3.71-3.68(m,1H),3.65-3.52(m,1H),3.45-3.38(m,1H),2.25-2.19(m,1H),2.15-2.08(m,2H),1.90-1.75(m,2H),1.68-1.58(m,1H),1.49-1.39(m,2H),1.33-1.25(m,2H),1.15-1.09(m,2H).
实施例3：2-((1R,4R,5S)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸的制备(化合物1-2)
Figure PCTCN2019091482-appb-000047
1.(1R,4R,5S)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯的制备
Figure PCTCN2019091482-appb-000048
将(1R,4R,5S)-5-羟基-2-氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯(500mg,2.2mmol)，18冠6(1.16mg,4.4mmol)，叔丁醇钾(493mg,4.4mmol)加入到THF(50mL)中，25℃下反应半小时，再加入4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(997mg,3.3mmol)和碘化钾(548mg,3.3mmol)，60℃下反应2小时。体系旋干经硅胶柱层析(PE:EA＝3:1)纯化，得到产物(800mg,产率73.7％)。
2. 4-((((1R,4R,5S)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑的制备
Figure PCTCN2019091482-appb-000049
将(1R,4R,5S)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯(800mg,1.6mmol)加入到DCM(8mL)中，再加入TFA(3mL)，25℃反应2小时，体系旋干直接用于下一步。
3. 2-((1R,4R,5S)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸甲酯的制备
Figure PCTCN2019091482-appb-000050
将4-((((1R,4R,5S)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(粗品)，2-溴基苯并[d]噻唑-6-甲酸甲酯(523mg,1.9mmol)，碳酸铯(940mg,2.88mmol)加入到DMA(20mL)中，120℃下反应3小时。降至25℃，体系加入乙酸乙酯(100mL)和水(80mL)萃取分液，有机相旋干硅胶柱层析(PE:EA＝4:1)，得产物(700mg,两步产率74.8％)。
4. 2-((1R,4R,5S)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸的制备
Figure PCTCN2019091482-appb-000051
将2-((1R,4R,5S)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸甲酯(700mg,1.20mmol)加入到甲醇(6mL)和THF(6mL)中，然后加入含氢氧化锂一水合物(201mg,4.8mmol)的水溶液(3mL)，然后加热至50℃反应12小时。降至25℃，体系用1N HCl调节pH至5，再加入EA(100mL)和饱和氯化钠水溶液(80mL)萃取分液，有机相旋干经硅胶柱层析(DCM:MeOH＝40:1)，得产物(580mg,产率84.7％)。
分子式：C 28H 25Cl 2N 3O 4S        分子量：569.1        LC-MS(m/z):569.8(M+H +)
1H-NMR(400MHz,CDCl 3)δ:8.35(s,1H),8.08-8.04(m,1H),7.52-7.48(m,1H),7.46-7.39(m,2H),7.37-7.34(m,1H),4.35-4.28(m,2H),3.71-3.68(m,1H),3.65-3.52(m,1H),3.45-3.38(m,1H),2.25-2.19(m,1H),2.15-2.08(m,2H),1.90-1.75(m,2H),1.68-1.58(m,1H),1.49-1.39(m,2H),1.33-1.25(m,2H),1.15-1.09(m,2H).
实施例4：2-((1RS,4RS,5RS)-5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)苯并[d]噻唑-6-羧酸的制备(化合物2)
Figure PCTCN2019091482-appb-000052
其制备方法参考实施例1。
分子式:C 28H 25Cl 2N 3O 4S     分子量:569.1     LC-MS(m/z):570.1(M+H+)
1H-NMR(400MHz,CDCl3)δ:8.49(s,1H),8.07(d,J＝8Hz,1H),7.36-7.56(m,1H),7.27-7.34(m,1H),7.14-7.26(m,2H),4.24-4.35(m,2H),3.66-3.69(m,2H),2.10-2.3(m,2H),1.81-1.90(m,2H),1.70-1.90(m,1H),1.50-1.70(m,3H),1.10-1.40(m,4H).
实施例5：2-((1S,4S,5R)-5-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)-4-氟苯并[d]噻唑-6-羧酸的制备(化合物3)
Figure PCTCN2019091482-appb-000053
1.叔丁基(1S,4S,5R)-5-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-羧酸酯的制备
Figure PCTCN2019091482-appb-000054
将化合物4-(溴甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(330mg，0.91mmol)、叔丁基(1S,4S,5R)-5-羟基-2-氮杂双环[2.2.2]辛烷-2-羧酸酯(207mg，0.91mmol)、叔丁醇钾(152mg,1.36mmol)、18-冠-6(359mg,1.36mmol)溶于四氢呋喃(10mL)中，35℃下搅拌3小时。待反应结束，反应液浓缩，加入水(50mL)后二氯甲烷萃取三次(50mL×3)，有机相干燥浓缩，残留物经硅胶柱层析(乙酸乙酯：石油醚＝1：5)得产品(300mg，产率65.0％)。
2. 4-((((1S,4S,5R)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑的制备
Figure PCTCN2019091482-appb-000055
将化合物叔丁基(1S,4S,5R)-5-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-羧酸酯(300mg,0.59mmol)和三氟乙酸(2mL)加入到二氯甲烷(10mL)中，20℃下反应15小时。待反应结束，溶剂浓缩，残留物未经纯化直接用于下一步反应。
3.甲基2-((1S,4S,5R)-5-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-杂双环[2.2.2]辛烷-2-基)-4-氟苯并[d]噻唑-6-羧酸酯的制备
Figure PCTCN2019091482-appb-000056
将上步所得化合物4-((((1S,4S,5R)-2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑粗品、甲基2-溴-4-氟苯并[d]噻唑-6-羧酸酯(135mg,0.59mmol)和碳酸铯(769mg,2.36mmol)溶于N,N-二甲基乙酰胺(20mL)中，50℃反应3小时。待反应结束，将反应液倒入冰水(80mL)中，抽滤，滤饼用水洗涤，干燥得产品(240mg，两步产率65.9％)。
4. 2-((1S,4S,5R)-5-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)-4-氟苯并[d]噻唑-6-羧酸的制备
Figure PCTCN2019091482-appb-000057
将化合物甲基2-((1S,4S,5R)-5-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-2-氮杂双环[2.2.2]辛烷-2-基)-4-氟苯并[d]噻唑-6-羧酸酯(240mg,0.39mmol)、一水合氢氧化锂(49mg,1.17mmol)溶于四氢呋喃/水(10mL/2mL)的混合溶剂中，35℃反应15小时。待反应结束，反应液浓缩，用1M的稀盐酸将反应液调节至pH＝7，加入水(50mL)，二氯甲烷萃取三次(60mL×3)，有机相经无水硫酸钠干燥、浓缩，残留物经硅胶柱层析(二氯甲烷：甲醇＝30:1)得产品(150mg，产率63.8％)。
分子式：C 29H 25F 4N 3O 5S     分子量：603.6    LC-MS(m/z):604.2(M+H +)
1H-NMR(400MHz,CDCl 3)δ:8.13(s,1H),7.46(d,J＝1.2Hz,1H),7.50-7.60(m,2H),7.36-7.49(m,2H),4.30-4.40(m,2H),3.65-3.72(m,1H),2.18-2.21(m,1H),2.05-2.10(m,3H),1.80-1.98(m,2H),1.57-1.73(m,1H),1.35-1.55(m,2H),1.20-1.32(m,4H),1.05-1.15(m,2H).
参考实施例1-5记载的方法，选取相应的原料进而可制备得到相应化合物4至化合物13。

Claims (15)

  1. 通式(I)所示的化合物，其药学上可接受的盐、其酯或其立体异构体：
    Figure PCTCN2019091482-appb-100001
    其中，
    R 1选自卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、C 1-6烷氧基C 1-6烷基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元环烷基C 1-6烷氧基、3-8元杂环基、3-8元杂环基C 1-6烷基或3-8元杂环基C 1-6烷氧基；
    X 1、X 2、X 3分别独立选自N、NH、O、S或CR 3R 4；R 3、R 4分别独立的选自氢、卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基或C 1-6烷基氨基；
    R 2选自-(CH 2) n-COOR 5，R 5选自氢、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元杂环基或3-8元杂环基C 1-6烷基；
    M选自C 1-6亚烷基，所述的C 1-6亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自N、NH、O、CO、S、SO或SO 2；
    环B选自任选被一个或多个Q 1取代的6-10元芳基、5-10元杂芳基，3-14杂环基或3-8元环烷基；
    每个Q 1独立的选自卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 1-6烷基羰基、C 1-6烷基磺酰基、C 1-6烷基亚磺酰基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元环烷基C 1-6烷氧基、3-8元杂环基、3-8元杂环基C 1-6烷基或3-8元杂环基C 1-6烷氧基；
    L选自不存在或C 1-6亚烷基，所述的C 1-6亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自N、NH、O、CO、S、SO或SO 2；
    Ar选自任选被一个或多个Q 2取代的6-10元芳基、6-10元芳基C 1-6烷基、6-10元芳基C 1-6烷氧基、5-10元杂芳基、5-10元杂芳基C 1-6烷基、5-10元杂芳基C 1-6烷氧基、3-8元环烷基或3-8元杂环基；
    每个Q 2独立的选自卤素原子、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、C 1-6烷基氨基、C 1-6烷基羰基、C 1-6烷基磺酰基、C 1-6烷基亚磺酰基、3-8元环烷基、3-8元环烷基C 1-6烷基、3-8元环烷基C 1-6烷氧基、3-8元杂环基、3-8元杂环基C 1-6烷基或3-8元杂环基C 1-6烷氧基；
    n选自0、1或2。
  2. 如权利要求1所述的化合物，其具有下式(I-1)所示的结构：
    Figure PCTCN2019091482-appb-100002
    或者其药学上可接受的盐、其酯或其立体异构体。
  3. 如权利要求1所述的化合物，其具有下式(I-2)或(I-3)所示的结构：
    Figure PCTCN2019091482-appb-100003
    或者其药学上可接受的盐、其酯或其立体异构体。
  4. 如权利要求1所述的化合物，其具有下式(I-4)、(I-5)、(I-6)或(I-7)所示的结构：
    Figure PCTCN2019091482-appb-100004
    Figure PCTCN2019091482-appb-100005
    或者其药学上可接受的盐、其酯或其立体异构体。
  5. 如权利要求1所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    R 1选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷氧基C 1-4烷基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
    X 1、X 2分别独立选自NH、O、S或CR 3R 4；R 3、R 4分别独立的选自氢、卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基或C 1-4烷基氨基；
    R 2选自-(CH 2) n-COOR 5，R 5选自氢、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元杂环基或3-6元杂环基C 1-4烷基；
    M选自C 1-4亚烷基，所述的C 1-4亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自N、NH、O、CO、S、SO或SO 2；
    环B选自任选被1-2个Q 1取代的含有1-3个杂原子或基团的8-10元稠杂芳基或7-14元稠杂环基，所述杂原子或基团独立的选自N、NH、O、S、SO或SO 2；
    每个Q 1独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷基磺酰基、C 1-4烷基亚磺酰基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
    L选自不存在或C 1-4亚烷基，所述的C 1-4亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自NH、O、CO、S、SO或SO 2；
    Ar选自任选被1-3个Q 2取代的6-8元单环芳基、8-10稠芳基、6-8元单环芳基C 1-4烷基、8-10元稠芳基C 1-4烷基、6-8元单环芳基C 1-4烷氧基、8-10元稠芳基C 1-4烷氧基、5-7元单环杂芳基、8-10元稠杂芳基、5-7元单环杂芳基C 1-4烷基、8-10元稠杂芳基C 1-4烷基、5-7元单环杂芳基C 1-4烷氧基、8-10元稠杂芳基C 1-4烷氧基、3-8元环烷基或3-8元杂环基；
    每个Q 2独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷基磺酰基、C 1-4烷基亚磺酰基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
    n选自0、1或2。
  6. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    M选自-CH 2-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-、-CH 2-NH-、-CH 2-CH 2-O-或-CH 2-NH-CO-；
    环B选自任选被1-2个Q 1取代的含有1-2个杂原子或基团的9-10元稠杂芳基，所述杂原子或基团独立的选自N、NH、O、S、SO、SO 2；优选的，环B通过环碳原子与L或X 3相连；
    每个Q 1独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷氧基、3-6元环烷基、3-6元环烷基C 1-4烷基、3-6元环烷基C 1-4烷氧基、3-6元单杂环基、3-6元单杂环基C 1-4烷基或3-6元单杂环基C 1-4烷氧基；
    L选自不存在或C 1-2亚烷基，所述的C 1-2亚烷基中任一碳原子任选被杂原子或基团所替代，所述的杂原子或基团选自NH、O、S或CO。
  7. 如权利要求1-6任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    R 1选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、C 1-4烷基羰基、C 1-4烷氧基C 1-4烷基、3-4元环烷基、3-4元环烷基C 1-4烷基、3-4元环烷基C 1-4烷氧基、3-4元单杂环基、3-4元单杂环基C 1-4烷基或3-4元单杂环基C 1-4烷氧基；
    Ar选自任选被1-2个Q 2取代的苯基、苯基C 1-4烷基、苯基C 1-4烷氧基、5-6元单环杂芳基、5-6元单环杂芳基C 1-4烷基或5-6元单环杂芳基C 1-4烷氧基；
    每个Q 2独立的选自卤素原子、羟基、氨基、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基或C 1-4烷基氨基。
  8. 如权利要求1-7任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构 体，其中，
    R 1选自卤素原子、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲氨基、乙氨基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基或氮杂环丁基；
    R 2选自-(CH 2) n-COOH；
    X 1、X 2分别独立选自NH、O或S；
    M选自-CH 2-、-CH 2-CH 2-或-CH 2-CH 2-CH 2-；
    环B选自任选被1-2个Q 1取代的如下基团：
    Figure PCTCN2019091482-appb-100006
    每个Q 1独立的选自氟、氯、溴、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、氟代甲基、二氟甲基、三氟甲基、1-氟代乙基、2-氟代乙基、1,1-二氟乙基、1,2-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、3,3,3-三氟丙基、1-三氟甲基乙基、三氟甲氧基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环戊基、环己基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基、氮杂环丁基、四氢呋喃基、吡咯烷基、咪唑烷基、吡唑烷基、噻唑烷基、四氢吡喃基、四氢吡啶基、哌啶基、哌嗪基或吗啉基；
    L选自不存在；
    Ar选自任选被1-2个Q 2取代的苯基、苯基甲基、苯基乙基、苯基甲氧基、呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、吡啶基、嘧啶基；每个Q 2独立的选自氟、氯、溴、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙基氧基、三氟甲氧基、甲基氨基、乙基氨基、甲氧基甲基、甲氧基乙基或乙氧基甲基；
    n选自0或1。
  9. 如权利要求8所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    R 1选自环丙基、环丙基甲基、环丙基乙基、环丙基甲氧基、环丁基、环丁基甲基、环丁基乙基、环丁基甲氧基、环氧乙基、环氧乙基甲基、氮杂环丙基、氮杂环丙基甲基、氧杂环丁基或氮杂环丁基；
    环B选自任选被1个Q 1取代的如下基团：
    Figure PCTCN2019091482-appb-100007
    Q 1选自氟、氯、溴、甲基、乙基、丙基、异丙基、三氟甲基、三氟甲氧基、甲氧基、乙氧基、丙氧基或异丙基氧基；
    Ar选自任选被1-2个Q 2取代的苯基、吡啶基或嘧啶基；每个Q 2独立的选自氟、氯、溴、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、三氟甲基或三氟甲氧基。
  10. 如权利要求1所述的化合物、其药学上可接受的盐、其酯或其立体异构体，所述化合物选自：
    Figure PCTCN2019091482-appb-100008
    Figure PCTCN2019091482-appb-100009
  11. 含有权利要求1-10任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体的药物制剂，其特征在于包含一种或多种药学上可接受的载体和/或稀释剂，所述的药物制剂为药学上可接受的任一剂型。
  12. 权利要求1-10任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体在制备预防和/或治疗由FXR介导的疾病的药物中的用途，所述的疾病包括动脉粥样硬化、胆汁酸紊乱、原发性硬化性胆管炎、胆固醇结石、纤维化相关疾病、脂肪肝、肝硬化、肝炎、肝脏衰竭、胆汁郁积、胆结石病、心肌梗塞、中风、血栓、I型或II型糖尿病的临床并发症、过度增殖性疾病和炎性肠道疾病。
  13. 如权利要求12所述的用途，其中所述疾病选自酒精性脂肪肝、非酒精性脂肪肝、原发性胆汁性肝硬化、原发性胆管性肝硬化、慢性肝炎、非病毒性肝炎、酒精性脂肪肝炎、非酒精性脂肪肝炎、良性肝内胆汁淤积、进行性家族性肝内胆汁淤积、药物诱导的胆汁淤积、妊娠性胆汁淤积、与肠胃营养相关的胆汁淤积、肝外胆汁郁积病症、高胆固醇血症、新生儿黄疸、核黄疸、糖尿病性肾病、糖尿病性神经病变、糖尿病性视网膜病及其临床显性长期糖尿病的其他观察到的结果、肝细胞癌、结肠腺瘤、息肉病、结肠腺癌、乳腺癌、胰腺癌、食管癌和其他形式的胃肠道和肝脏肿瘤性疾病。
  14. 通式(I’)所示的化合物、其药学上可接受的盐、其酯或其立体异构体：
    Figure PCTCN2019091482-appb-100010
    其中，R 1、X 1、X 2、X 3、M和Ar具有权利要求1所定义的含义。
  15. 通式(I)化合物的制备方法，包括下列步骤：
    Figure PCTCN2019091482-appb-100011
    (1)将原料2溶于有机溶剂中，在碱性条件下与原料1反应，得中间体1；
    (2)将中间体1加入含有酸性物质的溶液中反应，得中间体2；
    (3)中间体2与中间体3在碱性条件下反应，得式(I)化合物；其中，R 1、R 2、X 1、X 2、X 3、L、M、环B和Ar如权利要求1中的定义所述，X、X’独立的选自Cl或者Br；
    或者，中间体2与中间体3’在碱性条件下反应得中间体4，中间体4在碱性条件下反应，得式(I)化合物；其中，R 1、X 1、X 2、X 3、L、M、环B和Ar如权利要求1中的定义所述，X、X’独立的选自Cl或者Br，R 2为-(CH 2)n-COOR 5，R 5为H。
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WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
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WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
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