CN112334467B - FXR receptor agonists - Google Patents

FXR receptor agonists Download PDF

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CN112334467B
CN112334467B CN201980039625.XA CN201980039625A CN112334467B CN 112334467 B CN112334467 B CN 112334467B CN 201980039625 A CN201980039625 A CN 201980039625A CN 112334467 B CN112334467 B CN 112334467B
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CN112334467A (en
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方文奎
王听中
程静
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Xuanzhu Biopharmaceutical Co Ltd
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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

Abstract

The invention belongs to the technical field of medicines, and in particular relates to a compound shown in a formula (I), pharmaceutically acceptable salt, ester or stereoisomer thereof, R 1 、R 2 、X 1 、X 2 、X 3 M, ar, ring B and L are as defined in the specification; the invention also relates to a preparation method of the compounds, a pharmaceutical preparation and application thereof in preparing medicines for treating and/or preventing related diseases such as alcoholic fatty liver, nonalcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications, malignant tumor and the like mediated by FXR receptors.

Description

FXR receptor agonists
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to FXR (FXR) agonists, pharmaceutically acceptable salts, esters and stereoisomers thereof, pharmaceutical preparations containing the compounds, and application of the compounds, the pharmaceutically acceptable salts, the esters and stereoisomers thereof in preparing medicines for preventing and/or treating related diseases such as non-alcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications and malignant tumors mediated by FXR.
Background
The farnesol X receptor (farnesoid X receptor, FXR) belongs to a family of ligand-activated transcription factor nuclear receptor members with typical nuclear receptor structures, namely the amino-terminal highly conserved DNA Binding Domain (DBD), the carboxy-terminal Ligand Binding Domain (LBD), the amino-terminal ligand independent transcriptional activation domain (AF 1), the carboxy-terminal ligand dependent transcriptional activation domain (AF 2) and the foot chain domain. FXR forms heterodimers with the Retinoid X Receptor (RXR), and when the ligand binds to the LBD region of FXR, the conformation of FXR changes, and the binding domain of DNA binds to FXR response element (IR-1) of the target gene promoter, releasing cofactors (e.g., NCOR) and recruiting cofactors for transcriptional regulation.
FXR is expressed in a variety of organ tissues including adipose tissue, liver, gastrointestinal tract, kidney, etc., where the expression level in liver is most abundant. FXR signaling pathways regulate expression of multiple downstream genes, such as BSEP, SHP, CYP A1, FGFR4, ostα/β, SREBP-1C, and the like, and thus regulate multiple metabolic pathways, such as: triglyceride, cholesterol, blood sugar and energy stability metabolism of cholic acid, and has effects of treating cancer, nonalcoholic fatty liver disease (NAFLD), metabolic disorder, inflammation, etc. Regulating metabolism by inhibiting synthesis, binding and transport of cholic acid is the main regulator of cholic acid balance in vivo.
Some natural cholic acids may agonize FXR, such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), taurine and glycine conjugates of these cholic acids. The natural compounds are removed, the FXR agonist which is developed internationally at present can be mainly divided into two main types, one type is steroid, obeticholic acid (OCA) of Intercet company is used as representative, primary cholangiocarcinoma indication is approved in 5 months of 2016, and the product has adverse reactions such as skin itch and the like during clinical development aiming at nonalcoholic steatohepatitis indication and in clinical stage III; the other is a novel molecular entity, an early developed compound such as GW4604 (WO 2000/037077), which is unstable to light and has low bioavailability, although having strong agonistic activity. Phenex PX-104 (WO 2011020615A 1) is assigned to Gilead, and is currently in phase II clinical research.
Figure GWB0000003591050000031
In addition, GS-9674 developed by Gilead company is in clinical stage II, and the indications are primary biliary cirrhosis, primary sclerosing cholangitis and nonalcoholic steatohepatitis, and the structure is unknown.
Tully et al disclose a class of FXR agonists (see patent application WO2012087519A 1), and specifically disclose compounds 30-70 and 1-1B (LJN-452), LJN-452 currently in clinical stage II, with indications of primary biliary cirrhosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis.
Figure GWB0000003591050000032
At present, a novel FXR receptor agonist with high efficiency, low toxicity and good stability is developed, the variety of medicines is enriched, and the clinical significance is important.
Disclosure of Invention
The present invention relates to compounds having novel molecular entities that are effective in agonizing FXR, increasing the expression levels of BSEP and SHP genes, and simultaneously inhibiting the expression of CYP7A1 genes. In addition, to achieve better therapeutic effects, better meet market demands, it is also desirable to provide FXR receptor agonists that are highly potent, low toxic, and have better stability.
In particular, it is an object of the present invention to provide FXR agonists of novel structure having physicochemical properties, in vitro and in vivo efficacy and/or excellent in vitro and in vivo kinetics superior to known FXR agonists, providing the possibility for use of FXR agonists for the treatment of non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, lipid metabolism disorders, diabetic complications and malignancies.
It is a further object of the present invention to provide a process for the preparation of the FXR receptor agonist described above.
It is another object of the present invention to provide pharmaceutical compositions and formulations containing the above FXR receptor agonists.
It is still another object of the present invention to provide the use of the FXR receptor agonist for the preparation of a medicament for preventing and/or treating diseases such as non-alcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications and malignant tumor.
In one aspect, the invention provides compounds that are FXR agonists.
The invention provides a compound shown in a general formula (I), pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,
Figure GWB0000003591050000041
R 1 selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, 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 cycloalkyl C 1-6 Alkyl, 3-8 membered cycloalkyl C 1-6 Alkoxy, 3-8 membered heterocyclyl C 1-6 Alkyl or 3-8 membered heterocyclic C 1-6 An alkoxy group;
X 1 、X 2 、X 3 independently selected from N, NH, O, S or CR 3 R 4 ；R 3 、R 4 Independently selected from hydrogen, halogen atom, hydroxy, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy or C 1-6 An alkylamino group;
R 2 selected from- (CH) 2 ) n -COOR 5 ，R 5 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, 3-8 membered cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclyl or 3-8 membered heterocyclyl C 1-6 An alkyl group;
m is selected from C 1-6 Alkylene group, said C 1-6 Any carbon atom of the alkylene group is optionally replaced by a heteroatom or group selected from N, NH, O, CO, S, SO or SO 2 ；
Ring B is selected from the group consisting of optionally one or more Q 1 Substituted 6-10 membered aryl, 5-10 membered heteroaryl, 3-14 heterocyclyl or 3-8 membered cycloalkyl;
each Q 1 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfinyl, 3-8 membered cycloalkyl C 1-6 Alkyl, 3-8 membered cycloalkyl C 1-6 Alkoxy, 3-8 membered heterocyclyl C 1-6 Alkyl or 3-8 membered heterocyclic C 1-6 An alkoxy group;
l is selected from the group consisting of absence or C 1-6 Alkylene group, said C 1-6 Any carbon atom of the alkylene group is optionally replaced by a heteroatom or group selected from N, NH, O, CO, S, SO or SO 2 ；
Ar is selected from the group consisting of optionally one or more Q 2 Substituted 6-10 membered aryl, 6-10 membered aryl C 1-6 Alkyl, 6-10 membered aryl C 1-6 Alkoxy, 5-10 membered heteroarylC 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
each Q 2 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 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 C 1-6 Alkyl, 3-8 membered cycloalkyl C 1-6 Alkoxy, 3-8 membered heterocyclyl C 1-6 Alkyl or 3-8 membered heterocyclic C 1-6 An alkoxy group;
n is selected from 0, 1 or 2.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-1),
Figure GWB0000003591050000051
a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-2),
Figure GWB0000003591050000052
a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-3),
Figure GWB0000003591050000053
A pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-4),
Figure GWB0000003591050000054
a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-5),
Figure GWB0000003591050000061
a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-6),
Figure GWB0000003591050000062
a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-7),
Figure GWB0000003591050000063
a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments, the compounds of formula (I) further have a structure represented by formula (I-2),
Figure GWB0000003591050000064
a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof.
In certain embodiments of the foregoing description,
R 1 selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, 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 cycloalkyl C 1-4 Alkyl, 3-6 membered cycloalkyl C 1-4 Alkoxy, 3-6 membered mono-heterocyclyl C 1-4 Alkyl or 3-6 membered mono-heterocyclic C 1-4 An alkoxy group;
X 1 、X 2 independently selected from NH, O, S or CR 3 R 4 ；R 3 、R 4 Independently selected from hydrogen, halogen atom, hydroxy, amino, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy or C 1-4 An alkylamino group;
R 2 selected from- (CH) 2 ) n -COOR 5 ，R 5 Selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, 3-6 membered cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclyl or 3-6 membered heterocyclyl C 1-4 An alkyl group;
m is selected from C 1-4 Alkylene group, said C 1-4 Any carbon atom of the alkylene group is optionally replaced by a heteroatom or group selected from N, NH, O, CO, S, SO or SO 2 ；
Ring B is selected from the group consisting of optionally 1 to 2Q 1 Substituted 8-10 membered fused heteroaryl or 7-14 membered fused heterocyclyl containing 1-3 heteroatoms or groups independently selected from N, NH, O, S, SO or SO 2 ；
Each Q 1 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkylcarbonyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfinyl, 3-6 membered cycloalkyl C 1-4 Alkyl, 3-6 membered cycloalkyl C 1-4 Alkoxy, 3-6 membered mono-heterocyclyl C 1-4 Alkyl or 3-6 membered mono-heterocyclic C 1-4 An alkoxy group;
l is selected from the group consisting of absence or C 1-4 Alkylene group, said C 1-4 Any carbon atom of the alkylene group is optionally replaced by a heteroatom or group selected from NH, O, CO, S, SO or SO 2 ；
Ar is selected from optionally 1 to 3Q 2 Substituted 6-8 membered monocyclic aryl, 8-10 fused aryl, 6-8 membered monocyclic aryl C 1-4 Alkyl, 8-10 membered thick aryl C 1-4 Alkyl, 6-8 membered monocyclic aryl C 1-4 Alkoxy, 8-10 membered fused aryl C 1-4 Alkoxy, 5-7 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl, 5-7 membered monocyclic heteroaryl C 1-4 Alkyl, 8-10 membered fused heteroaryl C 1-4 Alkyl, 5-7 membered monocyclic heteroaryl C 1-4 Alkoxy, 8-10 membered fused heteroaryl C 1-4 Alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
each Q 2 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, 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 C 1-4 Alkyl, 3-6 membered cycloalkyl C 1-4 Alkoxy, 3-6 membered mono-heterocyclyl C 1-4 Alkyl or 3-6 membered mono-heterocyclic C 1-4 An alkoxy group;
n is selected from 0, 1 or 2.
In some of the above aspects, the method comprises, among other things,
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 the group consisting of optionally 1 to 2Q 1 Substituted 9-10 membered fused heteroaryl groups containing 1-2 heteroatoms or groups independently selected from N, NH, O, S, SO, SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, ring B is bound to L or X via a ring carbon atom 3 Are connected;
each Q 1 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy, 3-6 membered cycloalkyl C 1-4 Alkyl, 3-6 membered cycloalkyl C 1-4 Alkoxy, 3-6 membered mono-heterocyclyl C 1-4 Alkyl or 3-6 membered mono-heterocyclic C 1-4 An alkoxy group;
l is selected from the group consisting of absence or C 1-2 Alkylene group, said C 1-2 Any carbon atom in the alkylene group is optionally replaced by a heteroatom or group selected from NH, O, S or CO.
In certain embodiments of the foregoing description,
ring B is selected from the group consisting of optionally 1 to 2Q 1 Substituted 9-membered fused heteroaryl groups containing 1-2 heteroatoms or groups independently selected from N, NH, O, S, SO, SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, ring B is bound to L or X via a ring carbon atom 3 Are connected;
each Q 1 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy, 3-6 membered cycloalkyl C 1-4 Alkyl, 3-6 membered cycloalkyl C 1-4 Alkoxy, 3-6 membered mono-heterocyclyl C 1-4 Alkyl or 3-6 membered mono-heterocyclic C 1-4 An alkoxy group.
In some of the above aspects, the method comprises, among other things,
R 1 selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy C 1-4 Alkyl, 3-4 membered cycloalkyl C 1-4 Alkyl, 3-4 membered cycloalkyl C 1-4 Alkoxy, 3-4 membered mono-heterocyclyl C 1-4 Alkyl or 3-4 membered mono-heterocyclic C 1-4 An alkoxy group;
ar is selected from optionally 1-2Q 2 Substituted phenyl, phenyl C 1-4 Alkyl, phenyl C 1-4 Alkoxy, 5-6 membered monocyclic heteroaryl C 1-4 Alkyl or 5-6 membered monocyclic heteroaryl C 1-4 An alkoxy group;
each Q 2 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl or C 1-4 An alkylamino group.
In certain embodiments of the foregoing description,
R 1 selected from halogen atoms, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy, epoxyethyl, epoxyethylmethyl, aziridinyl, oxetanyl or azetidinyl;
R 2 selected from- (CH) 2 ) n -COOH；
X 1 、X 2 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 group consisting of optionally 1 to 2Q 1 Substituted as follows:
Figure GWB0000003591050000081
each Q 1 Independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl, 2-difluoroethyl, 3-trifluoropropyl, 1-trifluoromethylethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy, cyclopentyl, cyclohexyl, epoxyethyl, epoxyethylmethyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, piperazinyl or morpholinyl;
L is selected from the absence;
ar is selected from optionally 1-2Q 2 Substituted phenyl, phenylmethyl, phenylethyl, phenylmethoxy, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl; each Q 2 Independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl or ethoxymethyl;
n is selected from 0 or 1.
In some of the above-described aspects of the present invention,
R 1 selected from halogen atoms, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy,Ethoxy, propoxy, isopropoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy, epoxyethyl, epoxyethylmethyl, aziridinyl methyl, oxetanyl or azetidinyl.
In certain embodiments of the foregoing description,
R 1 selected from cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy, epoxyethyl, epoxyethylmethyl, aziridinyl methyl, oxetanyl or azetidinyl;
preferably, R 1 Selected from cyclopropyl or cyclobutyl.
In certain embodiments of the foregoing description,
X 1 、X 2 each independently selected from NH, O or S;
preferably, X 1 、X 2 All are O.
In certain embodiments of the foregoing description,
m is selected from-CH 2 -、-CH 2 -CH 2 -or-CH 2 -CH 2 -CH 2 -。
In certain embodiments described above, a compound of formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein,
ring B is selected from optionally substituted 1Q 1 Substituted as follows:
Figure GWB0000003591050000101
Figure GWB0000003591050000102
preferably, ring B is bound to L or X via a ring carbon atom 3 Are connected;
preferably, ring B is selected from the group consisting of optionally 1Q 1 Substituted as follows:
Figure GWB0000003591050000103
preferably, ring B is bound to L or X via a ring carbon atom 3 Are connected;
Q 1 selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-difluoroethyl, 1, 2-difluoroethyl 2, 2-difluoroethyl, 2-trifluoroethyl, 3-trifluoropropyl, 1-trifluoromethylethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropylmethyl cyclopropylethyl, cyclopropylmethoxy, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylmethoxy, cyclopentyl, cyclohexyl, epoxyethyl, epoxyethylmethyl, aziridinyl methyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, piperazinyl or morpholinyl;
Preferably, Q 1 Selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, propoxy or isopropoxy;
more preferably, Q 1 Meta to the carboxyl group in the general structure;
l is selected from the absence.
In certain embodiments of the foregoing description,
ar is selected from optionally 1-2Q 2 Substituted phenyl, phenylmethyl, phenylethyl, phenylmethoxy, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridyl or pyrimidinyl; each Q 2 Independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, methoxymethylMethoxyethyl or ethoxymethyl.
In certain embodiments of the foregoing description,
ar is selected from optionally 1-2Q 2 Substituted phenyl or 6 membered monocyclic heteroaryl;
preferably Ar is selected from the group consisting of optionally 1-2Q 2 Substituted phenyl, pyridyl, pyrimidinyl; each Q 2 Independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, or ethoxymethyl;
Preferably, each Q 2 Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy, methoxy or ethoxy.
In certain embodiments of the foregoing description,
R 1 selected from cyclopropyl or cyclobutyl;
X 1 、X 2 all are O;
ar is selected from phenyl optionally substituted with 1-2Q 2; each Q2 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy, 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:
Figure GWB0000003591050000111
wherein R is 1 、X 1 、X 2 、X 3 M, ar have the meaning defined in some of the schemes described above.
The embodiments and the features related to the embodiments can be arbitrarily combined, and the obtained technical schemes are described herein, and belong to the technical scheme of the invention.
Partial Compounds of the invention
Figure GWB0000003591050000112
Figure GWB0000003591050000121
In another aspect, the present invention relates to pharmaceutical formulations comprising a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or (I-7), a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents, which may be formulated into any pharmaceutically acceptable dosage form. Is administered orally, parenterally, rectally, or pulmonary, etc., to a patient in need of such treatment. For oral administration, conventional solid preparations such as tablet, capsule, pill, granule, etc. can be prepared; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, it can be formulated into injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, it can be made into suppository. For pulmonary administration, the composition can be formulated into inhalant or spray.
In another aspect, the invention also relates to the use of a compound of general formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or (I-7), a pharmaceutically acceptable salt thereof or a stereoisomer thereof for the preparation of a medicament for the prophylaxis and/or treatment of FXR mediated diseases and related disorders.
The diseases include:
(1) 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.), liver cirrhosis (primary biliary cirrhosis, etc.), hepatitis (chronic hepatitis, non-viral hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, etc.), liver failure, cholestasis (benign intrahepatic cholestasis, progressive familial intrahepatic cholestasis, extrahepatic cholestasis conditions, etc.), cholelithiasis, myocardial infarction, stroke, thrombosis, etc.; acute liver failure, cholelithiasis, and/or inflammatory bowel disease.
(2) Clinical complications of type I or type II diabetes include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other observed consequences of clinically overt long-term diabetes.
(3) Non-malignant hyperproliferative diseases 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 neoplastic diseases.
In the description and claims of the present application, compounds are named according to chemical structural formulas, and if the same compound is represented, the naming of the compound does not conform to the chemical structural formulas, the chemical structural formulas or chemical reaction formulas are used as references.
In this application, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the definitions and explanations of some of the relevant terms are provided below. In addition, when the definition and interpretation of terms provided herein are inconsistent with the meaning commonly understood by those skilled in the art, the definition and interpretation of terms provided herein controls.
Detailed Description
"halo" as used herein means substituted with "halogen atoms" as used herein including fluorine, chlorine, bromine and iodine.
"C" as described in the present invention 1-6 Alkyl "means straight-chain or branched alkyl having 1 to 6 carbon atoms and includes, for example," C 1-5 Alkyl "," C 1-4 Alkyl radicals "、“C 1-3 Alkyl "," C 1-2 Alkyl "," C 2-4 Alkyl "," C 2-3 Alkyl "," C 3-4 Alkyl ", and the like, specific examples include, but are 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-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" as described in the present invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
"halogenated C" according to the invention 1-6 Alkyl "means that one or more halogen atoms are substituted for C 1-6 A radical derived from one or more hydrogen atoms on an alkyl radical, said "halogen atom" and "C 1-6 Alkyl "is as defined above. "halogenated C" according to the invention 1-4 Alkyl "means halo C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
The invention relates to a hydroxy C 1-6 Alkyl "means one or more hydroxy-substituted C 1-6 A radical derived from one or more hydrogen atoms on an alkyl radical, said "C 1-6 Alkyl "is as defined above. The invention relates to a hydroxy C 1-4 Alkyl "means hydroxy C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
The invention relates to an amino C 1-6 Alkyl "means one or more amino substituted C 1-6 A radical derived from one or more hydrogen atoms on an alkyl radical, said "C 1-6 Alkyl "is as defined above. The invention relates to an amino C 1-4 Alkyl "means amino C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
"C" as described in the present invention 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, C 1-6 Alkylsulfonyl groupRadical, C 1-6 Alkylsulfinyl "means an alkyl group of the formula 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-S (O) -linked groups, wherein "C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkylcarbonyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfinyl "refers to a specific example in which the alkyl group of the above example contains 1 to 4 carbon atoms.
"halogenated C" according to the invention 1-6 Alkoxy "means that one or more halogen atoms are substituted for C 1-6 Groups derived from one or more hydrogen atoms on an alkoxy group, said "halogen atom" and "C 1-6 Alkoxy "is as defined above. "halogenated C" according to the invention 1-4 Alkoxy "means halo C 1-6 Specific examples of the alkoxy group include those having 1 to 4 carbon atoms.
"C" as described in the present invention 1-6 Alkoxy C 1-6 Alkyl "means one or more C 1-6 Alkoxy substituted C 1-6 A radical derived from one or more hydrogen atoms on an alkyl radical, said "C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkoxy C 1-4 Alkyl "means C 1-6 Alkoxy C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
The invention relates to CR 3 R 4 "means R 3 、R 4 Groups formed by respectively replacing two hydrogen atoms on methylene, and the specific connection mode is that
Figure GWB0000003591050000141
"C" as described in the present invention 1-6 Alkylene "refers to a linear alkane containing 1 to 6 carbon atoms that is derived from the removal of two hydrogens not on the same carbon atom, including" C 1-5 Alkylene "," C 1-4 Alkylene "," C 1-3 Alkylene "," C 1-2 Alkylene group "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 -and the like.
"C" as described in the present invention 1-6 Any carbon atom in the alkylene group optionally substituted by a heteroatom or group "means" C 1-6 Any one of the carbon atoms in the alkylene group "may optionally be replaced by a heteroatom or group, and may be C 1-6 The carbon atoms in the alkylene group are not replaced by any heteroatoms or groups; may also be C 1-6 One carbon atom in the alkylene group is replaced by a heteroatom or group; may also be C 1-6 Any two carbon atoms in the alkylene are replaced by two heteroatoms or groups, which may be the same or different; may also be C 1-6 Any of the multiple carbon atoms in the alkylene group is replaced by a corresponding plurality of identical or different heteroatoms or groups; said hetero atoms or groups being selected from N, NH, O, CO, S, SO or SO 2 。
"3-8 membered cycloalkyl" as used herein refers to a monocyclic saturated cyclic alkyl group containing 3-8 carbon atoms and includes, for example, "3-6 membered cycloalkyl", "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. Specific examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. "3-6 membered cycloalkyl" refers to a saturated cyclic alkyl group containing 3 to 6 carbon atoms. "3-4 membered cycloalkyl" refers to a saturated cyclic alkyl group containing 3-4 carbon atoms.
"3-14 membered heterocyclic group" as used herein refers to a saturated or partially saturated monocyclic or fused ring compound containing 3-14 ring atoms and containing at least one heteroatom and/or group (e.g., 1, 2, 3, 4, or 5 heteroatoms and/or groups) from which one hydrogen atom is removed. The heteroatoms and/or groups are selected from N, NH, O, S, CO, SO or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the The term "fused ring" refers to a group formed by two or more cyclic structures sharing two adjacent atoms with each other. Including, for example, "3-12 membered heterocyclic group", "3-10 membered heterocyclic group", "3-8 membered heterocyclic group", "3-7 membered heterocyclic group", "3-6 membered mono-heterocyclic group", "3-4 membered mono-heterocyclic group", "4-7 membered mono-heterocyclic group", "4-6 membered mono-heterocyclic group", "5-6 membered mono-heterocyclic group", "7-10 membered condensed heterocyclic group", "7-14 membered condensed heterocyclic group", etc. The method specifically comprises the following steps: "5-12 membered heterocyclyl containing 1-2N, O and/or S atoms", "containing 1-2N, O, S and/or SO 2 A 9-10 membered partially saturated fused heterocyclic group of an atom. The 3-14 membered partially saturated heterocyclic group refers to a cyclic group containing a double bond and a heteroatom. The 3-14 membered saturated heterocyclic group means a heteroatom-containing cyclic group having all saturated bonds. Specific examples include, but are not limited to: oxirane, aziridine, diazacyclopropyl, oxetanyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, chromanyl, benzo1, 4-dioxanyl, benzo1, 3-dioxanyl, benzotetrahydropyridinyl, benzodioxanyl, benzotetrahydropyrazinyl, 1,2,3, 4-tetrahydroquinazolinyl, 1,2,3, 4-tetrahydrocinnolinyl, tetrahydronaphtalenyl, and the like. The "3-6 membered heterocyclic group" means a specific example in which 3-14 membered heterocyclic groups contain 3-6 ring atoms. The "3-4 membered mono-heterocyclic group" refers to a specific example of a monocyclic heterocyclic group having 3 to 4 ring atoms in the 3-14 membered heterocyclic group.
The invention relates to a 3-8 membered cycloalkyl C 1-6 Alkyl, 3-8 membered cycloalkyl C 1-6 Alkoxy "refers to 3-8 membered cycloalkyl substituted C 1-6 Alkyl, C 1-6 Groups derived from hydrogen atoms in alkoxy groups, said "3-8 membered cycloalkyl", "C 1-6 Alkyl "," C 1-6 Alkoxy "is as defined above.
The invention relates to a 3-8 membered heterocyclic group C 1-6 Alkyl, 3-8 membered heterocyclyl C 1-6 Alkoxy "refers to 3-8 membered heterocyclyl substituted C 1-6 Alkyl, C 1-6 Groups derived from hydrogen atoms in alkoxy groups, said "3-8 membered heterocyclic groups", "C 1-6 Alkyl "," C 1-6 Alkoxy "is as defined above.
The invention relates to a 3-6 membered cycloalkyl C 1-4 Alkyl, 3-4 membered cycloalkyl C 1-4 Alkyl, 3-6 membered mono-heterocyclic C 1-4 Alkyl, 3-4 membered mono-heterocyclic C 1-4 Alkyl "means 3-6 membered cycloalkyl, 3-4 membered cycloalkyl, 3-6 membered mono-heterocyclyl, 3-4 membered mono-heterocyclyl substituted C 1-4 A group derived from a hydrogen atom in an alkyl group, said "3-6 membered cycloalkyl", "3-4 membered cycloalkyl", "3-6 membered mono-heterocyclyl", "3-4 membered mono-heterocyclyl", "C 1-4 Alkyl "is as defined above.
The invention relates to a 3-6 membered cycloalkyl C 1-4 Alkoxy, 3-4 membered cycloalkyl C 1-4 Alkoxy, 3-6 membered mono-heterocyclic C 1-4 Alkoxy, 3-4 membered mono-heterocyclyl C 1-4 Alkoxy "means 3-6 membered cycloalkyl, 3-4 membered cycloalkyl, 3-6 membered mono-heterocyclyl, 3-4 membered mono-heterocyclyl substituted C 1-4 Groups derived from hydrogen atoms in alkoxy groups, said "3-6 membered cycloalkyl", "3-4 membered cycloalkyl", "3-6 membered mono-heterocyclyl", "3-4 membered mono-heterocyclyl", "C 1-4 Alkoxy "is as defined above.
As used herein, "6-10 membered aryl" refers to an aromatic monocyclic or polycyclic group containing 6 to 10 ring carbon atoms. Examples include "6-8 membered monocyclic aryl", "6-7 membered monocyclic aryl", "8-10 membered fused aryl", and the like. The term "fused aryl" refers to a group having aromatic properties 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 "6-8 membered monocyclic aryl group" means a specific example of a monocyclic ring having 6 to 8 ring carbon atoms in the 6-10 membered aryl group. The "6-7 membered monocyclic aryl group" means a specific example of a monocyclic ring having 6 to 7 ring carbon atoms in the 6-10 membered aryl group. The "8-to 10-membered fused aryl group" is a specific example of a polycyclic group having 8 to 10 ring carbon atoms in the 6-to 10-membered aryl group.
"5-to 10-membered heteroaryl" as used herein refers to an aromatic monocyclic or polycyclic group containing 5 to 10 ring atoms, at least one of which is a heteroatom, and includes mono-and fused heteroaryl groups. The heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom. The "monocyclic heteroaryl" refers to a monocyclic aromatic group; the term "fused ring heteroaryl" refers to a group having aromaticity, wherein two or more cyclic structures share two adjacent atoms. Including, for example, "5-7 membered monocyclic heteroaryl", "5-6 membered monocyclic heteroaryl", "6 membered mono heteroaryl", "7-10 membered fused heteroaryl", "8-10 membered fused heteroaryl", "9-10 membered fused heteroaryl". Specific embodiments include, but are not limited to: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzisothiofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, and the like. By "5-6 membered monocyclic heteroaryl" is meant a specific example of a monocyclic ring containing 5-6 ring atoms in a 5-10 membered heteroaryl. The term "7-to 10-membered fused heteroaryl", "8-to 10-membered fused heteroaryl" and "9-to 10-membered fused heteroaryl" refer to specific examples of polycyclic groups having 7 to 10, 8 to 10 and 9 to 10 ring atoms in the 5-to 10-membered heteroaryl group.
The invention relates to' 6-10 membered aryl C 1-6 Alkyl, 5-10 membered heteroaryl C 1-6 Alkyl "means a 6-10 membered aryl, a 5-10 membered heteroaryl substituted C 1-6 A group derived from a hydrogen atom in an alkyl group. The said "6-10 membered aryl", "5-10 membered heteroaryl", "C 1-6 Alkyl "is as described above.
The invention relates to' 6-10 membered aryl C 1-6 Alkoxy, 5-to 10-membered heteroaryl C 1-6 Alkoxy "means a 6-10 membered aryl group,5-to 10-membered heteroaryl substituted C 1-6 A group derived from a hydrogen atom in an alkoxy group. The said "6-10 membered aryl", "5-10 membered heteroaryl", "C 1-6 Alkoxy "is as described above.
The invention relates to' 6-8 membered monocyclic aryl C 1-4 Alkyl, 8-10 membered thick aryl C 1-4 Alkyl, 6 membered monocyclic aryl C 1-4 Alkyl, 5-7 membered monocyclic heteroaryl C 1-4 Alkyl, 8-10 membered fused heteroaryl C 1-4 Alkyl "means 6-8 membered monocyclic aryl, 8-10 membered fused aryl, 6 membered monocyclic aryl, 5-7 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl substituted C 1-4 And a group derived from a hydrogen atom in the alkyl group. Wherein "6-8 membered monocyclic aryl", "8-10 membered fused aryl", "6 membered monocyclic aryl", "5-7 membered monocyclic heteroaryl", "8-10 membered fused heteroaryl", "C 1-4 Alkyl "is as defined above.
The invention relates to' 6-8 membered monocyclic aryl C 1-4 Alkoxy, 8-10 membered fused aryl C 1-4 Alkoxy, 6 membered monocyclic aryl C 1-4 Alkoxy, 5-7 membered monocyclic heteroaryl C 1-4 Alkoxy, 8-10 membered fused heteroaryl C 1-4 Alkoxy "means 6-8 membered monocyclic aryl, 8-10 membered fused aryl, 6 membered monocyclic aryl, 5-7 membered monocyclic heteroaryl, 8-10 membered fused heteroaryl substituted C 1-4 And a group derived from a hydrogen atom in the alkoxy group. Wherein "6-8 membered monocyclic aryl", "8-10 membered fused aryl", "6 membered monocyclic aryl", "5-7 membered monocyclic heteroaryl", "8-10 membered fused heteroaryl", "C 1-4 Alkoxy "is as defined above.
The term "L is selected from the absence" as used herein means that when L is absent, the rings B and X 3 Directly connected through chemical bond. The virtual bond in the formulae or groups of the present invention refers to the presence or absence of, for example,
Figure GWB0000003591050000171
is meant to include
Figure GWB0000003591050000172
Figure GWB0000003591050000173
Both cases.
The "cis" or "trans" shown in the structural formula of the compound of the present invention means a bridge having no substituent in the 8-membered bridged ring in the structure and passing through X 2 Positional relationship between the attached substituents. Taking compound 1 as an example, compound 1 has a cis structure, and the specific structural formula is as follows:
Figure GWB0000003591050000174
it indicates that compound 1 is a racemate comprising two enantiomers of the formula:
Figure GWB0000003591050000181
In the structural nomenclature of the compounds of the present invention, "(1 rs,4rs,5 sr)" means that it is a racemate containing two enantiomers whose absolute configurations are "1r,4r,5s" and "1s,4s,5r", respectively.
"optional" as used herein means that it may or may not be present. For example, "ring B" as described herein is selected from the group consisting of optionally one or more Q 1 Substitution "includes the case where ring B is not substituted with any Q1, as well as ring B with one or more Q' s 1 Substitution case.
As used herein, "partially saturated" means that the relevant group contains at least one double bond or one triple bond.
The present invention also provides a process for the preparation of compounds of formula (I) including, but not limited to, the following process routes:
the definitions represented by the abbreviations are as follows:
DMF: n, N-dimethylformamide; DMA: n, N-dimethylacetamide; THF: tetrahydrofuran; DCM: dichloromethane; TFA: trifluoroacetic acid; EA: ethyl acetate; PE: petroleum ether; meOH: methanol.
Figure GWB0000003591050000182
R 1 、R 2 、X 1 、X 2 、X 3 Ring B and Ar are as previously described, X, X' are independently selected from Cl or Br.
Specific exemplary steps are as follows:
1. preparation of intermediate 1
Adding the raw material 2, potassium tert-butoxide, 18-crown-6 and KI into an organic solvent, adding the raw material 1, reacting at 25-60 ℃, concentrating the reaction solution after the reaction is finished, and purifying by column chromatography to obtain an intermediate 1. Among them, tetrahydrofuran is preferable as the organic solvent.
2. Preparation of intermediate 2 (Compound of formula I')
Slowly adding the intermediate 1 into a solution containing acidic substances for reaction, adjusting the pH to 7-8 by using an alkaline solution after the reaction is completed, spin-drying the system, and concentrating to obtain the intermediate 2 or directly concentrating after the reaction is completed, wherein the crude product is directly used for the next reaction. Among them, the solution containing an acidic substance is preferably ethanol hydrochloride solution, methylene chloride solution containing trifluoroacetic acid, or the like, and the alkaline solution is preferably saturated sodium bicarbonate solution.
3. Preparation of the Compound of formula (I)
Adding the intermediate 2, the intermediate 3 and cesium carbonate into an organic solvent, carrying out microwave reaction or heating reaction, and purifying by column chromatography after the reaction is finished to obtain the compound shown in the formula (I). Wherein the organic solvent is preferably DMA or DMF.
4. Preparation of Compounds of formula (I)
Adding the intermediate 2, the intermediate 3' and cesium carbonate into an organic solvent, carrying out microwave reaction or heating reaction, and purifying by column chromatography after the reaction is finished to obtain an intermediate 4. Wherein the organic solvent is preferably DMA or DMF.
The intermediate 4 is added into an organic solvent, and then an aqueous solution containing an alkaline substance is added, and the reaction is heated. After the reaction is finished, regulating the pH to 4-6 by using an acidic substance solution, spin-drying the solvent, and purifying by column chromatography to obtain the compound shown in the formula (I). Wherein the organic solvent is preferably methanol/tetrahydrofuran mixed solution, the alkaline substance is preferably lithium hydroxide, sodium hydroxide and the like, and the acidic solution is preferably hydrochloric acid.
The raw materials 1 and 2 of the invention can be self-made or commercially available.
The "pharmaceutically acceptable salts" of the compounds of formula (I) of the present invention refer to salts of the acidic functional groups present in the compounds of formula (I) with suitable inorganic or organic cations (bases), including salts with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts of basic functional groups (e.g., -NH2, etc.) present in the compounds of formula (I) with suitable inorganic or organic anions (acids), including with inorganic acids, with organic carboxylic acids.
The term "ester" of the compound represented by the formula (I) in the present invention means an ester which is formed by esterification with an alcohol when the compound of the formula (I) has a carboxyl group, and an ester which is formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like when the compound of the formula (I) has a hydroxyl group. The esters can undergo hydrolysis in the presence of an acid or base to form the corresponding acid or alcohol.
"stereoisomers" are classified into conformational isomers and configurational isomers, which may also be classified into cis-trans isomers and optical isomers (i.e., optical isomers). Conformational isomerism refers to a stereoisomerism phenomenon that an organic molecule with a certain configuration makes each atom or atomic group of the molecule generate different arrangement modes in space due to rotation or twisting of carbon and carbon single bonds, and commonly has a structure of alkane and naphthene compounds, such as a chair-type conformation and a boat-type conformation, which occur in a cyclohexane structure. "cis-trans isomer" refers to the cis-or trans-isomer produced when a compound contains a functional group that cannot rotate freely, such as a c=c double bond, c≡c triple bond, c=n double bond, n=n double bond, or alicyclic ring, and according to the international unified "order rule", when two preferred groups are cis-isomers on the same side of pi bond or alicyclic ring, and when two preferred groups are trans-isomers on the opposite side of pi bond or alicyclic ring, and specifically to the present invention, the compound contains a bridged ring or bridged heterocyclic ring, cis-or trans-meaning that the group of the bridged ring (or bridged heterocyclic ring) to which the non-substituted bridge is attached to X2 is on the same side or opposite side of the bridged ring (or bridged heterocyclic ring). "optical isomers" means that when a compound of the present invention contains one or more asymmetric centers, it is useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The compounds of the invention have asymmetric centers, each of which produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogen through displacement of one or more double bonds. For example, the ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds of formula (I) are included within the scope of the present invention.
The compound of the invention has the following advantages:
(1) The compound, the pharmaceutically acceptable salt and the stereoisomer thereof have excellent FXR receptor agonistic activity, and can be safely used for treating and/or preventing non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications, malignant tumor and other related diseases;
(2) The compound, the pharmaceutically acceptable salt and the stereoisomer thereof show good metabolic stability, longer action and high bioavailability.
(3) The compound, the pharmaceutically acceptable salt and the stereoisomer thereof show lower toxicity, good drug resistance and high safety.
Experimental protocol
Exemplary protocols for some of the compounds of the present invention are provided below to demonstrate the beneficial activity and beneficial technical effects of the compounds of the present invention. It should be understood that the following experimental schemes are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure. Those skilled in the art, having the benefit of this disclosure, will appreciate that many changes can be made to the invention so described without departing from the spirit and scope thereof.
Experimental example 1: effect of the inventive Compounds on the relative expression level of BSEP mRNA in HepG2 cells
1. Test article: the chemical names and the preparation methods of the compounds are shown in the preparation examples of the respective compounds.
Control: the compound 1-1B is prepared according to the prior art method, and the structure of the compound is shown in the background technology.
2. The experimental method comprises the following steps:
(1) Cell culture, compound treatment and cell collection
Using pancreatin to digest and collect cells, and measuring the cell concentration; based on the counting results, cells were resuspended to 7.5X10 5 cell/mL density; 6-well cell culture plates, 2mL of cells were inoculated per well; the plates were placed in an incubator at 37℃with 5% CO 2 The culture was carried out for 24 hours.
The test compounds were diluted to 0.3 and 3mM using DMSO; the stock solutions obtained in the previous dilution were taken and added to 5mL of medium, respectively, in 5. Mu.L. The working fluid concentrations obtained were 0.3 and 3. Mu.M, respectively. The control group medium was formulated using equal volumes of DMSO instead of stock solution; removing the cell culture plate from the incubator, removing the culture medium, and adding the working fluid and the control culture medium; the plates were returned to the incubator at 37℃with 5% CO 2 The culture was carried out for 24 hours.
After 24 hours of treatment, the cell culture plates were removed from the incubator, the medium was removed, and the cells were rinsed 3 times with pre-chilled (4 ℃) PBS (phosphate buffer); 200. Mu.L of pancreatin was added to each well (preheated to 37 ℃) and gently swirled to allow the pancreatin to cover the plate bottom evenly. The plates were returned to the incubator for incubation until the cells were detached from the bottom of the plates. Digestion was stopped by adding 1mL of medium. After gently pipetting several times, all material in the wells was aspirated into 1.5mL Rnase-free centrifuge tubes and centrifuged at 200 Xg for 5 min; the supernatant was removed and a cell sample was collected.
(2) Cellular RNA sample extraction and purification
Cell lysis: fresh RNA lysate (1 mL lysate plus 10. Mu.L 2-mercaptoethanol) was prepared; adding 600 μl of lysate to the cell sample; vortex vigorously for 1-2 min to allow complete cell lysis; cell lysates were centrifuged at 12,000Xg for 5 min; the supernatant was transferred to a 1.5mL centrifuge tube of RNase-free.
And (3) RNA extraction and purification: adding an equal amount of 70% ethanol to the cell lysate; violently vibrating the centrifuge tube, fully mixing, and dispersing possible formed particle sediment after adding ethanol as much as possible; the adsorption column was placed on a collection tube and the mixture was transferred to the adsorption column. At most 700 μl transferred per time; centrifuge at 12,000Xg for 15 seconds at room temperature. Discarding the solution in the collecting pipe, and placing the adsorption column on the collecting pipe again; the remaining mixture was transferred entirely to an adsorption column. Adding 700 mu L of eluent I to the adsorption column; centrifuge at 12,000Xg for 15 seconds at room temperature. Placing the adsorption column on a new collecting pipe; adding 500 mu L of eluent II to the adsorption column; centrifuge at 12,000Xg for 15 seconds at room temperature. Discarding the solution in the collecting pipe, and placing the adsorption column on the collecting pipe again; adding 500 mu L of eluent II to the adsorption column; centrifuging at room temperature of 12,000Xg for 1-2 min, and placing the adsorption column on an RNA collecting tube; adding 50 mu L of RNase-free water to the central position of the adsorption column, and incubating for 1 minute at room temperature; the RNA was eluted into the collection tube by centrifugation at 14,000Xg for 2 minutes at room temperature.
The concentration and quality of the extracted RNA were measured. RNA was stored at-80 ℃.
(3) Reverse transcription of RNA into cDNA
The RNA extracted in the previous step was denatured by incubating at 70℃for 5 minutes. Placing the sample on ice after treatment; RNA samples were diluted to 200 ng/. Mu.L using RNAse-free water; 10. Mu.L of reverse transcription solution was prepared and mixed with 10. Mu.L of denatured RNA according to the following table. The total amount of RNA in the reverse transcription reaction was 2. Mu.g. During the experiment, all reagents were placed on ice.
Figure GWB0000003591050000211
Figure GWB0000003591050000221
Reverse transcription was performed on a G-Storm GS1 thermal cycler PCR thermocycler. The reverse transcription process is set as follows: 25℃for 10 min, 37℃for 120 min, 85℃for 5 min, 4℃for infinity. The reverse transcription product (cDNA) was stored at-20 ℃.
(4) Sample qPCR experiment
Based on qPCR amplification efficiency, a suitable cDNA concentration was selected for qPCR experiments on the samples. In the third step, cDNA sample was reverse transcribed, and 10. Mu.L of the cDNA sample was diluted 7-fold with 60. Mu.L of RNase-free water.
80. Mu.L of the reaction mixture was prepared according to the following table, and 20. Mu.L to 96-well PCR plates were pipetted into 3 replicates (7. Mu.L of 100ng per well) of cDNA samples.
Figure GWB0000003591050000222
qPCR was performed on an ABI7500 real-time quantitative PCR instrument with the following program settings: 50℃for 2 minutes, 95℃for 10 minutes, 95℃for 15 seconds, 60℃for 60 seconds, wherein 40 cycles are provided between 95℃for 15 seconds and 60℃for 60 seconds.
(5) Experimental results and conclusions:
TABLE 1 detection results of the relative expression level of BSEP mRNA in HepG2 cells by the inventive Compound
Figure GWB0000003591050000223
Note that: the relative expression amount data is the relative expression amount (%) of the compound at the concentration, taking the expression amount of the control drug at 3uM as 100% and the ratio of the other expression amounts to the expression amount of the control drug at 3 uM.
Conclusion:
as shown in Table 1, the 15 specific compounds in the specific embodiment part have better agonism on BSEP mRNA in HepG2 cells, the BSEP is a direct downstream gene of FXR and plays an important role in regulating bile acid generation, excretion and the like, the expression condition of the BSEP mRNA directly reflects the agonism activity of the FXR, and the BSEP mRNA is an index of better agonism activity of the primary screening compound on the FXR, and the research of the FXR agonist has important significance for treating the non-alcoholic fatty liver.
Experimental example 2: experiments on the metabolic stability of the liver microsomes of the Compounds of the present invention in different species
Test article: compounds 1,1-1 and 3 of the invention, their chemical names and methods of preparation are given in the examples of preparation of the respective compounds.
Control: the compounds 30-70 are prepared according to the prior art method, and the structure of the compounds is shown in the background art.
Experimental materials:
mixed liver microsomes from Beagle dogs were purchased from XenoTech and had a liver microsome protein concentration of 20 mg.mL -1 。
The experimental initiation factor β -NADPH was purchased from Roche company, usa. Phosphate Buffer (PBS) pH7.4 was prepared by the present laboratory.
Sample solution preparation:
accurately weighing a proper amount of sample powder, adding a proper amount of dimethyl sulfoxide (DMSO) to dissolve to 1mM, and diluting with methanol to 20 times to 50 μm working solution.
The experimental method comprises the following steps:
TABLE 2 composition of liver microsome metabolic stability experiment incubation System
Figure GWB0000003591050000231
The experimental operation steps are as follows:
(1) According to the above Table 2 "constitution of the experimental incubation System", 100mM PBS 6mL,20mM MgCl was taken for each compound 2 Solution 0.6mL and H 2 O3.66 mL, a mixed solution 1 of the incubation system (without microsomes, test sample and. Beta. -NADPH) was prepared.
(2) Liver microsomes (20 mg protein/mL) were removed from the-80℃refrigerator and pre-incubated for 3min on a 37℃water bath thermostated shaker.
(3) 1.88mL of the incubation system mixture 1 was taken for each species of the compound, and 55. Mu.L of microsomes of different species were added to prepare an incubation system mixture 2 (containing no test sample and. Beta. -NADPH).
(4) Sample group (containing microsomes and β -NADPH): mu.L of the mixed solution 2 of the incubation system was taken, 14. Mu.L of the working solution of the test sample having a concentration of 50. Mu.M was added, and 70. Mu.L of the working solution of 10mM of beta-NADPH was added. Mixing, and repeating. Sampling time points are 0min,5min,10min,20min,30min and 60min.
(5) Control group (microsome-containing, beta-NADPH-free, water instead of beta-NADPH): 264. Mu.L of the mixed solution 2 of the incubation system was added with 6. Mu.L of the working solution of the test sample having a concentration of 50. Mu.M, and 30. Mu.L of water was added. Mixing, and repeating. Sampling time points were 0min and 60min.
(6) At each predetermined time point 50 μl was sampled from the incubation sample tube and added to the stop sample tube (300 μl of cold stop containing internal standard tolbutamide 50ng/mL acetonitrile solution), vortexed, and the reaction stopped.
(7) After vortexing for 10min, centrifugation was carried out for 5min (12000 rpm).
(8) 100 μl of the supernatant was taken, 100 μl of water was added, mixed well by vortexing, and analyzed by LC-MS/MS.
Data analysis:
the ratio of the test sample to the internal standard peak area is converted into the residual percentage by the following formula.
Figure GWB0000003591050000241
Experimental results:
TABLE 3 results of hepatic microsomal stability of the compounds of the invention
Figure GWB0000003591050000242
Conclusion of experiment:
as shown in Table 3, the compounds of the present invention, particularly 15 specific compounds of the specific embodiment part, have good liver microsome stability in canine liver microsomes, are favorable for better pharmacological action in vivo, and have a metabolic stability degree in canine liver microsomes significantly superior to that of a control.
Experimental example 3: in vivo pharmacokinetic experiments in beagle dogs of the Compounds of the invention
Test article: the compound 3 of the invention is self-made, and the chemical name and the preparation method are shown in the preparation examples of the compounds.
Control: the compounds 1-1B, prepared by reference to the prior art methods, have structures as described in the background.
Test animals: male beagle dogs, 3 animals/route of administration/compound, body weight 8-12 kg/animal.
Preparation of drug solution for administration of test and control:
the dissolution scheme is as follows:
IV (intravenous) administration: 5% DMSO+5% PEG400+90% (28% HP-beta-CD)
PO (oral) administration: 2% HPC+0.1% Tween 80
Preparation of blank vehicle 1:
the preparation method of the 28% HP-beta-CD solution comprises the following steps: HP-beta-CD (hydroxypropyl betacyclodextrin) (14 g) is weighed, a proper amount of purified water is added for ultrasonic dissolution, the volume of the purified water is fixed to 50mL, and the mixture is uniformly mixed by vortex to obtain 28% HP-beta-CD solution.
Preparation of blank solvent 2:
formulation of 2% hpc+0.1% tween 80: HPC (hydroxypropyl cellulose) (20 g) is weighed, slowly added into 50mL of stirred purified water, then added with 1mL of Tween 80, and the purified water is used for constant volume to 1000mL, and stirred until the mixture is clear and transparent, thus obtaining the HPC. The preparation method comprises the following steps:
control:
(1) the control (21.96 mg) is weighed, DMSO (dimethyl sulfoxide) (2.1 mL) is added, vortex and ultrasonic dissolution are carried out, PEG400 (polyethylene glycol 400) (2.1 mL) is added, vortex and mixing are carried out uniformly, blank solvent 1 (37.9 mL) is added, vortex and mixing are carried out uniformly, and uniform solution is obtained, and the uniform solution is used as the control beagle IV drug administration liquid medicine 1.
(2) The control (43.11 mg) is weighed and placed in a tissue grinder, blank solvent 2 (20.7 mL) is added, grinding is carried out uniformly at a rotating speed of 1000rpm to obtain 2mg/mL uniform suspension, the uniform suspension is diluted by the blank solvent 2 to a final volume of 207mL, and the final concentration of 0.2mg/mL uniform suspension is obtained and is used as the control beagle PO administration liquid medicine 2.
Test article:
(1) taking compound 3 (20.05 mg), adding DMSO (1.961 mL), vortex and ultrasonic dissolving, adding PEG400 (1.961 mL), vortex uniformly, finally adding blank solvent 1 (35.296 mL), vortex uniformly mixing, placing in a constant-temperature water bath at 50 ℃ for heat preservation for 20min to obtain uniform solution, and taking the uniform solution as a sample beagle IV drug administration liquid 1.
(2) Placing compound 3 (20.24 mg) in a tissue grinder, adding blank solvent 2 (39.6 mL), and grinding at 1000rpm to obtain 0.5mg/mL uniform suspension mother liquor; taking out the mother solution (38.75 mL), adding into a beaker, adding blank solvent 2 (155 mL), and stirring to obtain uniform suspension of 0.1mg/mL, wherein the uniform suspension is used as the sample beagle PO administration liquid medicine 2.
Experimental method
Administration:
the reference substance and the liquid medicine of the test sample are administrated according to the following table method:
Figure GWB0000003591050000251
Figure GWB0000003591050000261
blood collection time point:
IV dosing group: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h after administration
PO dosing group: 0.167, 0.5, 1, 2, 4, 6, 8, 24h after administration
At each time point, about 400 mu L of whole blood is collected through a forelimb vein, placed into an anticoagulant tube containing EDTA-K2 anticoagulant, and a whole blood sample is centrifuged at 8000 rpm for 6 minutes at 4 ℃ to obtain a plasma sample, and placed into a refrigerator at-80 ℃ for freezing. Plasma sample analysis:
the protein precipitation method is adopted: plasma was taken at 20. Mu.L, 200. Mu.L of an internal standard (acetonitrile solution containing 50ng/mL of tolbutamide) was added, vortexed for 10 minutes, and centrifuged at 4000 rpm for 20 minutes, 100. Mu.L of the supernatant was taken, 100. Mu.L of water was added, and after vortexing and mixing for 3 minutes, LC-MS/MS analysis was performed.
Experimental results
Table 4 beagle PK evaluation results (IV)
Figure GWB0000003591050000262
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TABLE 5 beagle PK evaluation results (PO)
Figure GWB0000003591050000263
AUC 0-24h The area under the curve representing the medicine time is 0-24 h; CL represents clearance; v (V) ss Representing a steady state apparent distribution volume; t (T) max Represents peak time of blood concentration; c (C) max Representing the peak concentration of the blood drug concentration; t (T) 1/2 Represents half-life; f% represents absolute bioavailability.
Conclusion of the experiment
From the experimental results in tables 4 and 5, it is apparent that the compounds of the present invention have good pharmacokinetic properties, and have a longer half-life and higher exposure in the test animals than the control. After PO administration, the bioavailability is higher.
Example 4: NASH model test
The effect of the compounds of the present invention on the improvement of model lipids was examined mainly on the high fat feeding (HFD/DIO) model, and specific examination indexes include serum LDL, liver TG, and NASH activity scores, etc.
Detailed Description
The above-described aspects of the present invention will be described in further detail with reference to the following embodiments. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Example 1: preparation of 2- ((1 rs,4rs,5 sr) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2-2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid (compound 1)
Figure GWB0000003591050000271
1. Preparation of (1 rs,4rs,5 sr) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
Figure GWB0000003591050000272
(1 RS,4RS,5 SR) -5-hydroxy-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester (0.2 g,0.88 mmol) and potassium tert-butoxide (140 mg,1.25 mmol), 18-crown ether-6 (330 mg,1.25 mmol) were dissolved in THF (20 mL), 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (300 mg,0.99 mmol) and KI (120 mg,0.8 mmol) were added, heated to 25℃for 6 hours, water (50 mL) and ethyl acetate (20 mL) were added to separate, the aqueous layer was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give the desired product (260 mg, 60.5%).
Preparation of 2.4- ((((1 rs,4rs,5 sr) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole
Figure GWB0000003591050000281
Tert-butyl ((1 rs,4rs,5 sr) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylate (0.25 g,0.51 mmol) was added to dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at 0 ℃, reacted for 16 hours at 0 ℃, and concentrated to give the crude product which was used directly in the next reaction.
3.2 preparation of methyl- ((1 rs,4rs,5 sr) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylate
Figure GWB0000003591050000282
4- ((((1 rs,4rs,5 sr) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (crude), methyl 2-bromobenzo [ d ] thiazole-6-carboxylate (140 mg,0.51 mmol) and cesium carbonate (0.6 g,1.84 mmol) were added to DMF (2 mL), heated to 80 ℃ for reaction for 1 hour, filtered, and the filtrate concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give the desired product (0.11 g, 37.2% in two steps).
4.2- ((1 rs,4rs,5 sr) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid preparation
Figure GWB0000003591050000283
Methyl 2- ((1 rs,4rs,5 sr) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-yl) benzo [ d ] thiazole-6-carboxylate (100 mg,0.17 mmol), dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), added with aqueous sodium hydroxide solution (0.5 mL,1mmol,2 m), stirred at 25 ℃ for 16 hours, ph=6 added with sodium dihydrogen phosphate, filtered, the filtrate concentrated, and the residue purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give the target product (60 mg, 61.2% yield).
The molecular formula: c (C) 28 H 25 Cl 2 N 3 O 4 S molecular weight: 569.1 LC-MS (m/z): 570.1 (M+H) + )
1 H-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).
Example 2: preparation of 2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid (Compound 1-1)
Figure GWB0000003591050000291
1. Preparation of (1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
Figure GWB0000003591050000292
Tert-butyl (1S, 4S, 5R) -5-hydroxy-2-azabicyclo [2.2.2] octane-2-carboxylate (387 mg,1.7 mmol), 18 crown 6 (898 mg,3.4 mmol), potassium tert-butoxide (383mg, 3.4 mmol) were added to THF (50 mL), reacted at 25℃for half an hour, and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (770 mg,2.55 mmol) and potassium iodide (423 mg,2.55 mmol) were added and reacted at 60℃for 2 hours. The system was dried by spin-drying and column chromatography on silica gel (PE: ea=3:1) to give the product (629 mg, 75.0% yield).
Preparation of 2.4- ((((1S, 4S, 5R) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole
Figure GWB0000003591050000293
(1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester (550 mg,1.1 mmol) was added to DCM (5 mL) and TFA (2 mL) was added and reacted at 25℃for 2 hours, and the system was dried directly for the next step.
3.2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid methyl ester
Figure GWB0000003591050000301
4- ((((1S, 4S, 5R) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (crude), methyl 2-bromobenzo [ d ] thiazole-6-carboxylate (370 mg,1.36 mmol), cesium carbonate (668mg, 2.04 mmol) was added to DMA (20 mL) and reacted at 120℃for 3 hours. The temperature was reduced to 25℃and the system was extracted with ethyl acetate (100 mL) and water (80 mL) and the organic phase was chromatographed on a spin-dry silica gel column (PE: EA=4:1) to give the product (410 mg, two-step yield 63.8%).
4.2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid preparation
Figure GWB0000003591050000302
Methyl 2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylate (410 mg,0.70 mmol) was added to methanol (5 mL) and THF (5 mL), then an aqueous solution (2 mL) containing lithium hydroxide monohydrate (118 mg,2.8 mmol) was added, and then heated to 50℃for reaction for 12 hours. The temperature was reduced to 25℃and the pH of the system was adjusted to 4 with 1N HCl and the spin-dried solvent was chromatographed on silica gel (DCM: meOH=50:1) to give the product (370 mg, 92.6% yield).
The molecular formula: c (C) 28 H 25 Cl 2 N 3 O 4 S molecular weight: 569.1 LC-MS (m/z): 569.8 (M+H) + )
1 H-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).
Example 3: preparation of 2- ((1R, 4R, 5S) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid (Compound 1-2)
Figure GWB0000003591050000311
1. Preparation of (1R, 4R, 5S) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
Figure GWB0000003591050000312
(1R, 4R, 5S) -5-hydroxy-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester (500 mg,2.2 mmol), 18 crown 6 (1.16 mg,4.4 mmol), potassium tert-butoxide (493 mg,4.4 mmol) were added to THF (50 mL), and the mixture was reacted at 25℃for half an hour, followed by 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (997 mg,3.3 mmol) and potassium iodide (268 mg,3.3 mmol) and reacted at 60℃for 2 hours. The system was spin-dried and purified by silica gel column chromatography (PE: ea=3:1) to give the product (800 mg, 73.7% yield).
Preparation of 2.4- ((((1R, 4R, 5S) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole
Figure GWB0000003591050000313
(1R, 4R, 5S) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester (800 mg,1.6 mmol) was added to DCM (8 mL) and TFA (3 mL) was added and reacted at 25℃for 2 hours, and the system was dried directly for the next step.
Preparation of methyl 2- ((1R, 4R, 5S) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylate
Figure GWB0000003591050000321
4- ((((1R, 4R, 5S) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (crude), methyl 2-bromobenzo [ d ] thiazole-6-carboxylate (523 mg,1.9 mmol) was added to DMA (20 mL), and reacted at 120℃for 3 hours. The temperature was reduced to 25℃and the system was extracted with ethyl acetate (100 mL) and water (80 mL) and the organic phase was chromatographed on a spin-dry silica gel column (PE: EA=4:1) to give the product (700 mg, 74.8% in two steps).
Preparation of 2- ((1R, 4R, 5S) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid
Figure GWB0000003591050000322
Methyl 2- ((1 r,4r,5 s) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylate (700 mg,1.20 mmol) was added to methanol (6 mL) and THF (6 mL), then an aqueous solution (3 mL) containing lithium hydroxide monohydrate (201 mg,4.8 mmol) was added, followed by heating to 50 ℃ for reaction for 12 hours. The temperature was reduced to 25℃and the pH of the system was adjusted to 5 with 1N HCl, then EA (100 mL) and saturated aqueous sodium chloride (80 mL) were added to extract the fractions, and the organic phase was dried by spin-on-silica gel column chromatography (DCM: meOH=40:1) to give the product (580 mg, 84.7% yield).
The molecular formula: c (C) 28 H 25 Cl 2 N 3 0 4 S molecular weight: 569.1 LC-MS (m/z): 569.8 (M+H) + )
1 H-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).
Example 4: preparation of 2- ((1 rs,4rs,5 rs) -5- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) benzo [ d ] thiazole-6-carboxylic acid (compound 2)
Figure GWB0000003591050000331
The preparation method is described in example 1.
The molecular formula: c (C) 28 H 25 Cl 2 N 3 O 4 S molecular weight: 569.1 LC-MS (m/z): 570.1 (M+H+)
1 H-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).
Example 5: preparation of 2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) -4-fluorobenzo [ d ] thiazole-6-carboxylic acid (Compound 3)
Figure GWB0000003591050000332
1. Preparation of tert-butyl (1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylate
Figure GWB0000003591050000333
The compound 4- (bromomethyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole (330 mg,0.91 mmol), tert-butyl (1S, 4S, 5R) -5-hydroxy-2-azabicyclo [2.2.2] octane-2-carboxylate (207 mg,0.91 mmol), potassium tert-butoxide (152 mg,1.36 mmol), 18-crown-6 (319 mg,1.36 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 35℃for 3 hours. After the reaction was completed, the reaction mixture was concentrated, extracted three times with dichloromethane (50 ml×3) after adding water (50 mL), and the organic phase was concentrated by drying, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether=1:5) to give a product (300 mg, yield 65.0%).
Preparation of 2.4- ((((1S, 4S, 5R) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole
Figure GWB0000003591050000341
The compound tert-butyl (1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] octane-2-carboxylate (300 mg,0.59 mmol) and trifluoroacetic acid (2 mL) was added to dichloromethane (10 mL) and reacted at 20℃for 15 hours. After the reaction was completed, the solvent was concentrated, and the residue was used in the next reaction without purification.
3. Preparation of methyl 2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -2-heterobicyclo [2.2.2] oct-2-yl) -4-fluorobenzo [ d ] thiazole-6-carboxylate
Figure GWB0000003591050000342
The compound 4- ((((1S, 4S, 5R) -2-azabicyclo [2.2.2] oct-5-yl) oxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole crude, methyl 2-bromo-4-fluorobenzo [ d ] thiazole-6-carboxylate (135 mg,0.59 mmol) and cesium carbonate (769 mg,2.36 mmol) obtained in the above step were dissolved in N, N-dimethylacetamide (20 mL) and reacted at 50℃for 3 hours. After the reaction was completed, the reaction solution was poured into ice water (80 mL), suction filtration was performed, and the cake was washed with water and dried to obtain a product (240 mg, two-step yield 65.9%).
4.2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) -4-fluorobenzo [ d ] thiazole-6-carboxylic acid preparation
Figure GWB0000003591050000343
The compound methyl 2- ((1S, 4S, 5R) -5- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -2-azabicyclo [2.2.2] oct-2-yl) -4-fluorobenzo [ d ] thiazole-6-carboxylate (240 mg,0.39 mmol), lithium hydroxide monohydrate (49 mg,1.17 mmol) was dissolved in a mixed solvent of tetrahydrofuran/water (10 mL/2 mL) and reacted at 35℃for 15 hours. After the reaction was completed, the reaction solution was concentrated, the reaction solution was adjusted to ph=7 with 1M diluted hydrochloric acid, water (50 mL) was added, dichloromethane was extracted three times (60 ml×3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol=30:1) to obtain a product (150 mg, yield 63.8%).
The molecular formula: c (C) 29 H 25 F 4 N 3 O 5 S molecular weight: 603.6 LC-MS (m/z): 604.2 (M+H) + )
1 H-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).
The corresponding starting materials were selected and the corresponding compounds 4 to 13 were prepared according to the methods described in examples 1 to 5.

Claims (13)

1. A compound of the general formula (I):
Figure FDA0004239294410000011
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from cyclopropyl or cyclobutyl;
X 1 、X 2 all are O;
X 3 is N;
R 2 selected from- (CH) 2 ) n -COOR 5 ，R 5 Is hydrogen;
m is-CH 2 -；
Ring B is selected from optionally substituted 1Q 1 Substituted
Figure FDA0004239294410000012
Ring B is bound to L or X via a ring carbon atom 3 Are connected;
each Q 1 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group;
l is selected from the absence;
ar is selected from the group consisting of optionally one or more Q 2 A substituted phenyl group;
each Q 2 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 An alkylamino group;
n is selected from 0, 1 or 2.
2. The compound according to claim 1, which has a structure represented by the following formula (I-4), (I-5), (I-6) or (I-7):
Figure FDA0004239294410000013
Figure FDA0004239294410000021
or a pharmaceutically acceptable salt thereof.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein,
Each Q 1 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 An alkylamino group;
l is selected from the absence;
ar is selected from optionally 1 to 3Q 2 A substituted phenyl group;
each Q 2 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl or C 1-4 An alkylamino group;
n is selected from 0 or 1.
4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein,
ring B is selected from optionally substituted 1Q 1 Substituted
Figure FDA0004239294410000022
Ring B is bound to L or X via a ring carbon atom 3 Are connected;
each Q 1 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy or C 1-4 An alkoxy group;
l is selected from the absence.
5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein,
ar is selected from optionally 1-2Q 2 A substituted phenyl group;
each Q 2 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl or C 1-4 An alkylamino group.
6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein,
R 1 selected from cyclopropyl;
R 2 selected from- (CH) 2 ) n -COOH；
X 1 、X 2 All are O;
m is-CH 2 -；
Ring B is selected from optionally substituted 1Q 1 Substituted as follows:
Figure FDA0004239294410000031
ring B is bound to L or X via a ring carbon atom 3 Are connected;
each Q 1 Independently selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-difluoroethyl 1, 2-difluoroethyl, 2-trifluoroethyl, 3-trifluoropropyl, 1-trifluoromethylethyl, trifluoromethoxy, methoxy, ethoxy, propoxy or isopropoxy;
l is selected from the absence;
ar is selected from optionally 1-2Q 2 A substituted phenyl group; each Q 2 Independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, or ethoxymethyl;
n is 0.
7. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein,
R 1 Selected from cyclopropyl;
ring B is selected from optionally substituted 1Q 1 Substituted as follows:
Figure FDA0004239294410000032
ring B is bound to L or X via a ring carbon atom 3 Are connected;
Q 1 selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, propoxy or isopropoxy;
ar is selected from optionally 1-2Q 2 A substituted phenyl group; each Q 2 Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure FDA0004239294410000033
Figure FDA0004239294410000041
9. a pharmaceutical formulation comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable form, comprising one or more pharmaceutically acceptable carriers and/or diluents.
10. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated by FXR, selected from atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fibrosis-related diseases, fatty liver, cirrhosis, hepatitis, liver failure, cholestasis, cholelithiasis, myocardial infarction, stroke, thrombosis, clinical complications of type I or type II diabetes, hyperproliferative diseases and inflammatory bowel diseases.
11. The use of claim 10, wherein the disease is selected from alcoholic fatty liver, non-alcoholic fatty liver, primary biliary cirrhosis, chronic hepatitis, non-viral hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, benign intrahepatic cholestasis, progressive familial intrahepatic cholestasis, drug-induced cholestasis, gestational cholestasis, cholestasis associated with gastrointestinal nutrition, extrahepatic cholestasis conditions, hypercholesterolemia, neonatal jaundice, nuclear jaundice, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed consequences of clinically significant long-term diabetes thereof, hepatocellular carcinoma, colon adenoma, polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, esophageal cancer and other forms of gastrointestinal and liver neoplastic disease.
12. A compound of formula (I') or a pharmaceutically acceptable salt thereof:
Figure FDA0004239294410000051
wherein R is 1 Selected from the group consisting ofCyclopropyl or cyclobutyl;
X 1 、X 2 all are O;
X 3 is N;
m is-CH 2 -；
Ar is selected from the group consisting of optionally one or more Q 2 A substituted phenyl group;
each Q 2 Independently selected from halogen atoms, hydroxy groups, amino groups, cyano groups, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 An alkylamino group.
13. A process for the preparation of a compound of formula (I) according to claim 1, comprising the steps of:
Figure FDA0004239294410000061
R 2 is- (CH) 2 )n-COOR 5 ，
R 5 ＝H
(1) Dissolving the raw material 2 in an organic solvent, and reacting with the raw material 1 in the presence of potassium tert-butoxide, 18-crown ether-6 and potassium iodide to obtain an intermediate 1;
(2) Adding the intermediate 1 into a solution containing hydrochloric acid or trifluoroacetic acid for reaction to obtain an intermediate 2;
(3) Reacting the intermediate 2 with the intermediate 3 under cesium carbonate conditions to obtain a compound of formula (I); wherein R is 1 、R 2 、X 1 、X 2 、X 3 L, M, ring B and Ar are as defined in claim 1, X, X' is independently selected from Cl or Br;
or, reacting the intermediate 2 with the intermediate 3' under cesium carbonate condition to obtain an intermediate 4, and reacting the intermediate 4 under alkaline condition to obtain a compound of formula (I); wherein R is 1 、X 1 、X 2 、X 3 L, M, ring B and Ar are as defined in claim 1X, X' is independently selected from Cl or Br, R 2 Is- (CH) 2 )n-COOR 5 ，R 5 H.
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