CN109320509A - FXR receptor stimulating agent - Google Patents

FXR receptor stimulating agent Download PDF

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CN109320509A
CN109320509A CN201710644314.9A CN201710644314A CN109320509A CN 109320509 A CN109320509 A CN 109320509A CN 201710644314 A CN201710644314 A CN 201710644314A CN 109320509 A CN109320509 A CN 109320509A
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amino
alkoxy
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CN109320509B (en
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史澂空
陈博
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Xuanzhu Biopharmaceutical Co Ltd
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Hainan Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The invention belongs to pharmaceutical technology fields, and in particular to formula (I) compound represented, its pharmaceutically acceptable salt, ester or its stereoisomer, R1、R2、R3、R4, W, A, Z, E, X, Y, n be as defined in specification and claims；The invention further relates to the preparation method of these compounds, pharmaceutical preparation and it is being used to prepare treatment and/or is preventing the application in the drug by related diseases such as the receptor-mediated nonalcoholic fatty liver of FXR, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and malignant tumours.

Description

FXR receptor agonists
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an FXR agonist, pharmaceutically acceptable salts and stereoisomers thereof, a pharmaceutical preparation containing the compounds, and application of the compounds, the pharmaceutically acceptable salts and the stereoisomers thereof in preparation of medicines for preventing and/or treating related diseases such as non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications, malignant tumors and the like mediated by FXR.
Background
FXR receptors (farnesoid X receptors) belong to members of the nuclear receptor family of ligand-activated transcription factors and have the typical nuclear receptor structure, i.e., an amino-terminal highly conserved DNA Binding Domain (DBD), a carboxy-terminal Ligand Binding Domain (LBD), an amino-terminal ligand-independent transcriptional activation domain (AF1), a carboxy-terminal ligand-dependent transcriptional activation domain (AF2), and a foot chain domain. FXR forms heterodimers with Retinoid X Receptor (RXR), and when ligand binds to the LBD region of FXR, conformation of FXR is changed, and a binding domain of DNA binds to FXR-responsive element (IR-1) of a target gene promoter, releasing a co-repressor (e.g., NCOR), recruiting a co-activator, and thereby exerting a transcription regulatory effect.
FXR is expressed in a plurality of organ tissues, including adipose tissues, liver, gastrointestinal tract, kidney and the like, wherein the expression level in the liver is the most abundant, an FXR signal pathway can directly or indirectly regulate the expression of a plurality of downstream genes, such as BSEP, SHP, CYP7A1, FGFR4, OST α/β, SREBP-1C and the like, further regulate a plurality of metabolic pathways, such as triglyceride, cholesterol, blood sugar and metabolism of energy-stable metabolic bile acid, has the function of treating diseases such as cancer, non-alcoholic fatty liver disease (NAFLD), metabolic disorder, inflammation and the like, and is a main regulator of in vivo bile acid balance by inhibiting the synthesis, combination and transportation of the bile acid and regulating the metabolism.
Some natural cholic acid compounds can stimulate FXR receptors, such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and taurine and glycine conjugates of these cholic acids. Except natural compounds, FXR agonists which are researched and developed internationally at present can be mainly divided into two main classes, one class is steroids, Obeticholic acid (OCA) of Intercept company is taken as a representative, primary biliary cirrhosis indications are approved in 2016 and 5 months, and the FXR agonists are in clinical stage III aiming at nonalcoholic steatohepatitis indications, and have adverse reactions such as skin itch and the like during clinical research and development; the other class is a novel molecular entity, an early developed compound such as GW4604(WO2000/037077), which although having strong agonistic activity, is photolabile and less bioavailable. PX-104 from Phoenex corporation (WO2011020615A1) is assigned to Gilead corporation and is currently in phase II clinical studies.
In addition, GS-9674 developed by Gilead and LJN-452 developed by Novartis are both in the clinical stage II, and the indications are primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic steatohepatitis, and the structures of the indications are unknown.
The invention related to the patent is a compound with a novel molecular entity, and the compound can effectively excite an FXR receptor, improve the expression level of BSEP and SHP genes and simultaneously effectively inhibit the expression of CYP7A1 genes. In order to achieve better therapeutic effect and better meet the market demand, the development of FXR receptor agonists with high efficiency, low toxicity and good stability is expected. The invention provides the FXR receptor stimulant with a novel structure, finds that the compound with the structure has good drug effect, and provides possibility for the FXR receptor stimulant to be used for treating non-alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, lipid metabolism disorder, diabetic complication and malignant tumor.
Disclosure of Invention
The invention aims to provide FXR agonists with good in vivo and in vitro drug effects and dynamic characteristics, which can be used for treating related FXR-mediated diseases such as non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications, malignant tumors and the like.
In one aspect, the invention provides compounds as FXR agonists, according to a specific technical scheme as follows:
scheme 1, a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein,
R1、R2each independently selected from hydrogen atom, cyano group, halogen atom, nitro group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylthio radical, C1-6Alkylcarbonyl, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, di-C1-6Alkylaminosulfonyl radical, C1-6Alkylsulfonylamino group, C1-6Alkylsulfonyloxy, C2-8Alkenyl or C2-8An alkynyl group;
R3selected from hydrogen atoms, C optionally substituted by P1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl radical, C1-6Alkylsulfonylamino group, C1-6Alkylsulfonyloxy, 6-14 membered fused ring, 5-12 membered bridged ring or 5-12 membered spiro ring, wherein the carbon atom of said 6-14 membered fused ring, 5-12 membered bridged ring or 5-12 membered spiro ring is optionally substituted with N, O, S, SO and/or SO2Replacement;
p is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonyl radical, C2-8Alkenyl or C2-8An alkynyl group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, carboxyl C1-6Alkyl, carboxyl oxy C1-6Alkyl, carboxy amino C1-6Alkyl, amino C1-6Alkyl, aminocarbonyl C1-6Alkyl radical, C1-6Alkoxy, hydroxy C1-6Alkoxy, halo C1-6Alkoxy, carboxyl C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylcarbonylamino, C1-6Alkylsulfonyl or C1-6An alkylaminosulfonyl group;
w is selected from CH2、NH、O、S、SO、SO2Or CO;
a is selected from NH, O or S;
z is selected from heterocyclyl or cycloalkyl optionally substituted with 1-4Q;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C2-8Alkenyl or C2-8An alkynyl group;
e is selected from C, CH2、N、NH、O、S、SO、SO2Or CO;
x is selected from C, CH or N;
y is selected from C, CH and CH2N, NH, CO, O or S;
E. x, Y are each independently selected from single or double bonds;
n is an integer of 0 to 4.
A compound of scheme 2, scheme 1, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
wherein,
R1、R2each independently selected from hydrogen atom, cyano group, halogen atom, nitro group, amino group, hydroxyl group, carboxyl group, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylthio radical, C1-4Alkylcarbonyl, halo C1-4Alkyl, halo C1-4Alkoxy or C1-4Alkoxy radical C1-4An alkyl group;
R3selected from 3-6 membered cycloalkyl or 3-6 membered heterocyclyl optionally substituted with P;
p is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1-4Alkyl, hydroxy C1-4Alkyl, halo C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl oxy C1-4Alkyl, carboxy amino C1-4Alkyl, amino C1-4Alkyl, aminocarbonyl C1-4Alkyl radical, C1-4Alkoxy, hydroxy C1-4Alkoxy, halo C1-4Alkoxy, carboxyl C1-4Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylcarbonyl group, C1-4Alkoxycarbonyl group, C1-4Alkylcarbonylamino, C1-4Alkylsulfonyl or C1-4An alkylaminosulfonyl group;
w is selected from CH2、NH、O、S、SO、SO2Or CO;
a is selected from NH, O or S;
z is selected from 3-8 membered heterocyclic group or 3-8 membered cycloalkyl group optionally substituted with 1-4Q;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
e is selected from C, CH2N, NH, CO, O or S;
x is selected from C, CH or N;
y is selected from C, CH and CH2N, NH, O, CO or S;
E. x, Y are each independently selected from single or double bonds;
n is an integer of 0 to 4.
A compound of scheme 3, scheme 2, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
R1、R2each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a methoxy group, a methylamino group, a dimethylamino group, an acetyl group, a trifluoromethyl group, a trifluoroethyl group or a trifluoromethoxy group;
R3selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, ethoxycarbonyl group, trifluoromethyl group, trifluoromethoxy group, ethynyl group, methylamino group, ethylamino group, acetyl group, acetamido group, methylsulfonyl group or dimethylamino group;
n is an integer of 0 to 2;
z is selected from saturated 5-6-membered heterocyclic group containing O, S and/or N atoms optionally substituted by 1-2Q, or saturated 5-6-membered cycloalkyl;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
E. x, Y together with the benzene ring form the following structure:
a compound of scheme 4, scheme 3, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
R1、R2each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, a butyl group, a methoxy group, a methylamino group, an acetyl group, a trifluoromethyl group or a trifluoromethoxy group;
R3selected from cyclopropyl, cyclobutyl, cyclopentyl;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, ethoxycarbonyl group, trifluoromethyl group, trifluoromethoxy group, acetyl group or acetylamino group;
w is selected from NH, O or S;
a is selected from NH, O or S;
n is an integer of 0 to 2;
z is selected from cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydropyrazolyl, tetrahydroimidazolyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl optionally substituted with 1-2Q;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
E. x, Y together with the benzene ring form the following structure:
a compound of scheme 5, scheme 4, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
R1、R2each independently selected from hydrogen atom, cyano group, fluorine atom, chlorineAtom, methyl, ethyl, propyl;
R3selected from cyclopropyl, cyclobutyl, cyclopentyl;
R4selected from the group consisting of hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, ethoxycarbonyl group;
w is selected from NH, O or S;
a is selected from NH, O or S;
n is an integer of 0 to 1;
z is selected from cyclohexyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl optionally substituted with 2Q;
q is selected from C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
E. x, Y together with the benzene ring form the following structure:
a compound of scheme 6, scheme 5, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
z is selected from optionally substituted with 2Q
Q is selected from methyl, ethyl, n-propyl, isopropyl, butyl, methoxy and ethoxy;
E. x, Y together with the benzene ring form the following structure:
the above embodiments and the features of the embodiments can be arbitrarily combined, and the technical solutions obtained are described herein and belong to the technical solution of the present invention.
Part of the Compounds of the invention
In another aspect, the present invention relates to a pharmaceutical formulation comprising a compound represented by formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents, which may be formulated into any pharmaceutically acceptable dosage form. Administered to a patient in need of such treatment by oral, parenteral, rectal, or pulmonary administration. When the composition is administered orally, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.
On the other hand, the invention also relates to application of the compound shown in the general formula (I), pharmaceutically acceptable salt, ester or stereoisomer thereof in preparing medicaments for preventing and/or treating FXR mediated diseases and related diseases.
The diseases comprise:
(1) lipid or lipoprotein disorders including atherosclerosis, bile acid disorders, benign intrahepatic cholestasis, progressive familial intrahepatic cholestasis, primary biliary cirrhosis, primary sclerosing cholangitis, cholesterol gallstones, dyslipidemia, fibrosis-related diseases, chronic hepatitis, non-viral hepatitis, inflammatory bowel disease, intestinal flora disorders, liver transplantation, fatty liver, cirrhosis, hepatitis, liver failure, cholestasis, cholelithiasis, non-alcoholic fatty liver disease, myocardial infarction, stroke, thrombosis, and the like.
(2) Clinical complications of type I or type II diabetes mellitus include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other observed outcomes of their clinically overt long-term diabetes.
(3) Non-malignant hyperproliferative or hyperproliferative diseases, including hepatocellular carcinoma, colon adenoma and polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, esophageal cancer and other forms of gastrointestinal and hepatic neoplastic diseases.
In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name of a compound does not match the chemical structural formula when the same compound is represented, the chemical structural formula or chemical reaction formula is the standard.
In the present application, unless otherwise indicated, scientific and technical terms used herein have the meanings that are commonly understood by those of skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
Detailed Description
The "halogen atom" in the present invention includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
"C" according to the invention1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C1-4Alkyl group "," C1-3Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 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" according to the invention2-8Alkenyl "means a straight or branched chain or cyclic alkenyl group of 2 to 8 carbon atoms containing at least one double bond, including, for example," C2-6Alkenyl group "," C2-4Alkenyl group "," C2-3Alkenyl group "," C3-6Cycloalkenyl "and the like, specific examples include, but are not limited to: vinyl group, 1-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-dimethyl-2-propenyl group, 1-ethyl-2-propenyl group, 2-hexenyl group, 3-hexenyl group, 2-methyl-1-pentenyl group, 3-methyl-1-pentenyl group, 1-methyl-2-pentenyl group, 3-methyl-2-pentenyl group, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-1-butenyl, 2-ethyl-3-butenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 4-octenyl, 1, 3-butadienyl, 1-pentenyl, 3-pentenyl, 2-dimethyl-3-butenyl, 2, 3-heptenyl, 4-heptenyl, 2, 4-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl, 1, 5-heptadienyl, 2, 6-octadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, and cyclohexenyl,1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, and the like.
"C" according to the invention2-8Alkynyl refers to a straight or branched chain alkynyl group of 2-8 carbon atoms containing a triple bond, including, for example, "C2-6Alkynyl group "," C2-4Alkynyl group "," C2-3Alkynyl "and the like, specific examples include, but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptynyl, 3-heptynyl, 4-methyl-2-hexynyl, 2-ethyl-2-propynyl, 3-pentynyl, 1-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, 2-methyl-3-hexynyl, 5-methyl-3-hexynyl, 2-methyl-4-hexynyl, 4-methyl-5-hexynyl, 2-octynyl, 3-octynyl, 4-methyl-2-heptynyl, 5-methyl-3-heptynyl, 6-methyl-3-heptynyl, 2-methyl-4-heptynyl, 2-methyl-5-heptynyl, 3-methyl-6-heptynyl and the like.
"C" according to the invention1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl radical, C1-6Alkylsulfonylamino group, C1-6Alkylsulfonyloxy "means a compound represented by formula C1-6alkyl-O-, C1-6alkyl-NH-, (C)1-6Alkyl radical)2-N-、C1-6alkyl-S-, C1-6alkyl-C (O) -, C1-6alkyl-C (O) -O-, C1-6alkyl-SO2-、C1-6alkyl-NH-SO2-、(C1-6Alkyl radical)2-N-SO2-、C1-6alkyl-SO2-NH-、C1-6alkyl-SO2A group formed by the formula-O-, in which "C" is1-6Alkyl "is as defined above.
"C" according to the invention1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylthio radical, C1-4Alkylcarbonyl group, C1-4Alkylcarbonyloxy, C1-4Alkylsulfonyl radical, C1-4Alkylaminosulfonyl, (C)1-4Alkyl radical)2Aminosulfonyl "means a radical represented by C1-4alkyl-O-, C1-4alkyl-NH-, (C)1-4Alkyl radical)2-N-、C1-4alkyl-S-, C1-4alkyl-C (O) -, C1-4alkyl-C (O) -O-, C1-4alkyl-SO2-、C1-4alkyl-NHSO2-、(C1-4Alkyl radical)2-N-SO2A group formed in the formula (I) wherein "C1-4Alkyl "is as defined above.
The "halo C" of the present invention1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl C1-6Alkoxy, carboxyloxy C1-6Alkyl, carboxy amino C1-6Alkyl, aminocarbonyl C1-6Alkyl "refers to one or more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, hydroxyl, amino, sulfonyl, carboxyl, carboxyloxy, carboxyamino, aminocarbonyl, C1-6Alkoxy radicals each being substituted for C1-6Alkyl radical, C1-6A group formed by a hydrogen atom in an alkoxy group.
The "halo C" of the present invention1-4Alkyl, hydroxy C1-4Alkyl, carboxyl C1-4Alkyl, amino C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkoxy, carboxyl C1-4Alkoxy, carboxyloxy C1-4Alkyl, carboxy amino C1-4Alkyl, aminocarbonyl C1-4Alkyl "means one to more than one, for example, 1 to 4, 1 to 3,1 to 2 halogen atoms, hydroxyl group, amino group, sulfonyl group, carboxyl group, carboxyloxy group, carboxyamino group, aminocarbonyl group, C1-4Alkoxy radicals each being substituted for C1-4Alkyl radical, C1-4A group formed by a hydrogen atom in an alkoxy group.
The "cycloalkyl group" refers to a saturated or partially saturated monocyclic cycloalkyl group derived from an alkane moiety of carbon atoms by removing one hydrogen atom, and includes, for example, "3-6-membered cycloalkyl group", "3-8-membered cycloalkyl group", "4-7-membered cycloalkyl group", "4-6-membered cycloalkyl group", "5-6-membered cycloalkyl group", and the like. Examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl and the like.
"Heterocyclyl" refers to a saturated or partially saturated monocyclic heterocyclic compound containing at least one heteroatom (e.g., 1,2, 3,4, or 5 heteroatoms) and having one hydrogen atom removed therefrom. The heteroatom is selected from N, S and/or O. Including, for example, "3-to 8-membered heterocyclic group", "3-to 7-membered heterocyclic group", "3-to 6-membered heterocyclic group", "3-to 5-membered heterocyclic group", "4-to 7-membered heterocyclic group", "4-to 6-membered heterocyclic group", "5-to 6-membered heterocyclic group", 6-to 7-membered heterocyclic group "," 6-to 8-membered heterocyclic group ", etc. The method specifically comprises the following steps: "a 3-to 5-membered heterocyclic group containing 2O, S and/or N atoms", "a 6-to 8-membered heterocyclic group containing 1-2O, S and/or N atoms", "a 4-to 6-membered heterocyclic group containing 1-2O, S and/or N atoms", "a 4-to 5-membered heterocyclic group containing 2O, S and/or N atoms", "a 6-to 7-membered heterocyclic group containing 1-2O, S and/or N atoms", "a 5-membered heterocyclic group containing 2O, S and/or N atoms", "a 6-membered heterocyclic group containing 1-2O, S and/or N atoms", "a 5-membered heterocyclic group containing 2N atoms", "a 6-membered heterocyclic group containing 1-2N atoms", "a 5-membered heterocyclic group containing 2O atoms", "a 6-membered heterocyclic group containing 1-2O atoms".
The "saturated 5-to 6-membered heterocyclic group" in the present invention is preferably a cyclopentyl group, a cyclohexyl group, a tetrahydropyrrolyl group, a tetrahydropyrazolyl group, a tetrahydroimidazolyl group, a tetrahydrofuryl group, a piperidyl group, a piperazinyl group or a morpholinyl group, and particularly preferably a piperidyl group.
The "6-to 14-membered fused cyclic group" as referred to herein means a fused cyclic structure of 6 to 14 ring atoms formed by two or more cyclic structures sharing two adjacent atoms (i.e., sharing one bond) linked to each other, the ring atoms being selected from C, N, S and/or O, and includes, for example, "8-to 11-membered fused cyclic group", "6-to 11-membered fused heterocyclic group", "6-to 10-membered fused heterocyclic group", "7-to 10-membered fused heterocyclic group", "9-to 10-membered fused heterocyclic group", "6-to 10-membered nitrogen-containing fused heterocyclic group", and the like. Specific examples include, but are not limited to: naphthalene, 3-azabicyclo [3.1.0] hexane, 3, 6-diazabicyclo [3.2.0] heptane, 3, 8-diazabicyclo [4.2.0] octane, 3, 7-diazabicyclo [4.2.0] octane, octahydropyrrolo [3,4-c ] pyrrole, octahydropyrrolo [3,4-b ] [1,4] oxazine, octahydro-1H-pyrrolo [3,4-c ] pyridine, octahydro-1H-pyrrolo [3,4-b ] pyridine, octahydro-1H-pyrido [3,4-b ] [1,4] oxazine, decahydro-2, 6-naphthalene, tetrahydroimidazo [4,5-c ] pyridyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, Benzo [ d ] [1,3] dioxolyl, 1, 3-dihydroisobenzofuranyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, and the like.
The "5-12-membered bridged ring group" refers to a bridged ring structure containing 5-12 ring atoms, wherein any two rings share two non-adjacent atoms, and the ring atoms are selected from C, N, S and/or O. Examples thereof include "7-to 11-membered bridged ring group", "6-to 11-membered bridged heterocyclic group", "6-to 9-membered bridged heterocyclic group", "7-to 10-membered bridged heterocyclic group", "7-to 9-membered nitrogen-containing bridged heterocyclic group", "7-to 8-membered bridged heterocyclic group", "8-membered nitrogen-containing bridged heterocyclic group", and the like. Specific examples thereof include, but are not limited to:
and the like.
The 5-12-membered spirocyclic group in the invention refers to a spirocyclic structure containing 5-12 ring atoms, wherein at least two rings share one atom, and the ring atoms are selected from C, N, S and/or O and the like. Examples thereof include "7-11-membered spiro ring group", "6-11-membered spiro heterocyclic group", "7-11-membered nitrogen-containing spiro heterocyclic group", "7-10-membered spiro heterocyclic group", "7-9-membered spiro heterocyclic group", "7-8-membered spiro heterocyclic group" and the like. Examples include, but are not limited to: and the like.
The term "heteroatom" as used herein means N, O, S, SO and/or SO2Etc., preferably N, O, S.
In the general formulae (I) and (II) of the present inventionRefers to a single or double bond.
The term "partially saturated" as used herein means that the relevant group contains at least one double bond.
The present invention also provides a process for the preparation of compounds of formula (I), including, but not limited to, the following process schemes:
the definitions represented by the abbreviations are as follows:
THF: tetrahydrofuran; EA: ethyl acetate; PE: petroleum ether; MeOH: methanol.
R1、R2、R3、R4W, A, Z, E, X, Y, n As mentioned above, a' represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Specific exemplary steps are as follows:
1. raw material 1: purchased or prepared.
2. Raw material 2: purchased or prepared.
3. Preparation of intermediate 1
The raw material 2 is acidified by acid, and then dissolved in an organic solvent together with the raw material 1 to react at 100 ℃ for 12 hours, and the mixture is concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to obtain an intermediate 1. Wherein the acid is preferably hydrochloric acid and the organic solvent is preferably isopropanol.
4. Preparation of intermediate 2
Dissolving the intermediate 3 in an organic solvent, slowly adding sodium borohydride at 0 ℃, then reacting for 1 hour at 25 ℃, adding water, extracting with dichloromethane, drying an organic phase with anhydrous sodium sulfate, concentrating, and directly using for next reaction or silica gel plate separation (mobile phase is PE: EA). Wherein the organic solvent is tetrahydrofuran, and the fluidity is PE: EA ═ 3: 1.
5. Preparation of Compounds of formula (I)
Adding the intermediate 2, raw materials 3, potassium tert-butoxide and 18-crown-6 into tetrahydrofuran, reacting at 80 ℃ for 10 hours, cooling, filtering, concentrating the filtrate, purifying by silica gel column chromatography (PE: EA ═ 2:1), adding the purified substance and lithium hydroxide monohydrate into a mixed solution of methanol, THF and water, stirring and reacting at 25 ℃ for 5 hours, adjusting the pH value to 5 by using dilute hydrochloric acid, extracting by using ethyl acetate, concentrating, and carrying out reverse phase preparation to obtain the compound shown in the formula (I).
"pharmaceutically acceptable salts" of the compounds of formula (I) according to the invention are salts of acidic functions present in the compounds of formula (I) with suitable inorganic or organic cations (bases), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compounds of formula (I) (e.g. -NH)2Etc.) with suitable inorganic or organic anions (acids), including inorganic acids, and organic carboxylic acids.
The "ester" of the compound represented by the formula (I) of the present invention means an ester which can be formed by esterification with an alcohol when a carboxyl group is present in the compound of the formula (I), or an ester which can be formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like when a hydroxyl group is present in the compound of the formula (I). The ester can be hydrolyzed in the presence of acid or alkali to generate corresponding acid or alcohol.
"stereoisomerism" is classified into conformational isomerism and configurational isomerism, and conformational isomerism may also be classified into cis-trans isomerism and optical isomerism (i.e. optical isomerism), and conformational isomerism refers to a stereoisomerism phenomenon in which organic molecules having a certain configuration are rotated or twisted by carbon and carbon single bonds to generate different arrangements of atoms or groups of atoms in a space, and is commonly seen in the structures of alkanes and cycloalkanes, such as chair conformation and boat conformation that occur in cyclohexane structure. "stereoisomers" refers to compounds of the invention when they contain one or more asymmetric centers and thus can be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the invention. All enantiomers, diastereomers, racemates, meso-isomers, 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 agonism activity, and can be safely used for treating and/or preventing related diseases such as non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorder, diabetic complication, malignant tumor and the like;
(2) the compound, the pharmaceutically acceptable salt and the stereoisomer thereof have good metabolic stability, longer action and high bioavailability.
(3) The compound, the pharmaceutically acceptable salt and the stereoisomer thereof have low toxicity, good drug resistance and high safety.
Experimental protocol
An exemplary experimental protocol for a portion of the compounds of the invention is provided below to show the beneficial activity and beneficial technical effects of the compounds of the invention. It should be understood, however, that the following experimental protocols are only 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 the teachings of this specification, will be able to make appropriate modifications or alterations to the teachings of this invention without departing from the spirit or scope thereof.
Experimental example 1: the compounds of the invention are relatively aligned to HepG2 cell and BSEP mRNA of human hepatocyteInfluence of the amount of expression
(1) Test article: the chemical names and preparation methods of the compounds of the present invention are shown in the preparation examples of the respective compounds.
PBS: phosphate buffer.
(2) The experimental method comprises the following steps:
1. plating cells, adding compounds and collecting cells
Digesting and collecting cells by using pancreatin, and measuring the cell concentration; resuspending the cells to a density of 7.5e5 cells/mL according to the counting results; 6-well cell culture plates, each well inoculated with 2mL of cells; the plates were placed in an incubator at 37 ℃ with 5% CO2The culture was conditioned for 24 hours.
Compounds were diluted to 3, 0.3mM using DMSO; 5ul of the stock solution obtained from the previous dilution was added to 5ml of the medium, respectively. The concentrations of the resulting working solutions were 3, 0.3. mu.M, respectively.
A control group culture medium is prepared by using DMSO with the same volume instead of a stock solution; removing the culture medium of the cell culture plate, and adding the working solution and the control culture medium; the plates were returned to the incubator at 37 ℃ with 5% CO2The culture was conditioned for 24 hours.
After 24 hours of treatment, the cell culture plate was removed from the medium and the cells were rinsed 3 times with pre-cooled (4 ℃) PBS; add 200. mu.L of pancreatin per well (preheat to 37 ℃) and gently shake to allow the pancreatin to cover the plate bottom evenly. The plate was returned to the incubator and incubated until the cells were detached from the plate bottom. Digestion was stopped by adding 1mL of medium. After gently blowing and beating for several times by using a pipette, sucking all substances in the holes into a centrifugal tube of 1.5mL RNase-free, and centrifuging for 5 minutes at 200 Xg; the supernatant was removed and a cell sample was collected.
2. Extraction and purification of RNA from cell samples
Cell lysis: fresh RNA lysate (1mL lysate plus 10. mu.L 2-mercaptoethanol); add 600. mu.L of lysate to the cell sample; vortexing vigorously for 1-2 min to lyse the cells completely; the cell lysate was centrifuged at 12,000 Xg for 5 minutes; the supernatant was transferred to a 1.5mL RNase-free centrifuge tube.
RNA extraction and purification: adding an equal amount of 70% ethanol to the cell lysate; violently shaking the centrifugal tube, fully mixing, and dispersing particle precipitates possibly formed 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. Transferring at most 700 μ L each time; centrifuge at room temperature for 15 seconds. The collection tube was discarded and the remaining mixture was transferred to the adsorption column in its entirety. Adding 700 μ L of eluent I into the adsorption column; centrifuge at room temperature for 15 seconds. Adding 500 μ L of eluent II into the adsorption column; centrifuge at room temperature for 15 seconds. Discarding the solution in the collection tube, and adding 500 μ L of eluent II into the adsorption column; centrifuging at room temperature for 1-2 min, and placing the adsorption column on the RNA collection tube; adding 50 μ L RNase-free water to the central position of the adsorption column, and incubating for 1 min at room temperature; centrifuge at room temperature for 2 minutes, elute RNA into collection tubes.
The concentration and mass of the extracted RNA were measured. RNA was stored at-80 ℃.
3. Reverse transcription of RNA into cDNA
The RNA extracted in the second step was incubated at 70 ℃ for 5 minutes to denature the RNA. After treatment, the samples were placed on ice; RNA samples were diluted to 200 ng/. mu.L with RNAse-free water; mu.L of the reverse transcription solution was prepared according to the following table and mixed with 10. mu.L of denatured RNA. The total amount of RNA in the reverse transcription reaction was 2. mu.g. During the experiment, all reagents were placed on ice.
Reverse transcription was performed on a G-Storm GS1thermal cycler PCR thermal cycler. The reverse transcription process was set up as follows:
10 minutes at 25 ℃ → 120 minutes at 37 ℃ → 5 minutes at 85 ℃ → 4 ℃. infinity. The reverse transcription product (cDNA) was stored at-20 ℃.
4. Sample qPCR experiment
And selecting proper cDNA concentration to perform qPCR experiment of the sample according to the qPCR amplification efficiency. And a third step of taking 10 mu L of cDNA sample obtained by reverse transcription and adding 60 mu L of RNase-free water to dilute the cDNA sample by 7 times.
mu.L of the reaction mixture was prepared according to the following table, and 20. mu.L was pipetted into a 96-well PCR reaction plate, and 3 replicates (7. mu.L of 100ng in each reaction well) of the cDNA sample were added.
qPCR in QuantstudioTMThe real-time quantitative PCR of Dx is carried out on a PCR instrument, and the program is set as follows: 50 ℃ for 2 min → 95 ℃ for 10min → 95 ℃ for 15 sec → 60 ℃ for 60 sec, with 40 cycles set between 95 ℃ for 15 sec and 60 ℃ for 60 sec.
(3) Experimental results and conclusions:
TABLE 1 detection of the relative expression of BSEP mRNA in HepG2 cells treated with the Compounds of the invention
(3) And (4) experimental conclusion:
as can be seen from Table 1, the compound of the invention has better expression effect on BSEP mRNA in HepG2 cells and has important significance for treating non-alcoholic fatty liver disease.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1: 2- ((2R,4R,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylic acid
Preparation of (2R,6S) -1-benzyl-2, 6-dimethylpiperidin-4-one
3-carbonyl glutaric acid (40.0g,0.28mol) and 40% acetaldehyde (60.5g,1.37mol) were stirred at 25 ℃ for 10min, then benzylamine (30mL,0.28mol) was slowly added, the reaction solution was stirred at 25 ℃ for 78h, 1N hydrochloric acid was added to adjust the pH to 2, and further stirred for 1h, then a saturated sodium bicarbonate solution was used to adjust the pH to 7, dichloromethane was extracted, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 9:1) to obtain the cis-form title compound (2g, yield: 3.4%).
Preparation of (2R,6S) -2, 6-dimethylpiperidin-4-one
(2R,6S) -1-benzyl-2, 6-dimethylpiperidin-4-one (2g,9.2mol) and 20% palladium hydroxide (2g) were added to methanol (30mL), reacted under a hydrogen atmosphere for 10 hours, filtered, and concentrated to obtain the title compound (1.07g, yield: 91.3%).
Preparation of ethyl 2- ((2R,6S) -2, 6-dimethyl-4-oxopiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl 2-chloro-benzo [ d ] thiazole-6-carboxylate (362mg,1.5mol) was acidified with hydrochloric acid gas and (2R,6S) -2, 6-dimethylpiperidin-4-one (127mg,1.0mmol) was dissolved in isopropanol (30mL), reacted at 100 ℃ for 12 hours, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (80mg, yield: 24.1%).
Preparation of ethyl 2- ((2R,4R,6S) -4-hydroxy-2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl 2- ((2R,6S) -2, 6-dimethyl-4-oxopiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate (80mg,0.24mmol) was dissolved in THF (10mL), sodium borohydride (14mg,0.37mmol) was added slowly at 0 ℃, followed by reaction at 25 ℃ for 1 hour, water was added and extraction with dichloromethane was performed, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by preparative silica gel plate (petroleum ether: ethyl acetate ═ 3:1) to give 36mg, yield 44.8%.
Preparation of ethyl 2- ((2R,4R,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl 2- ((2R,4R,6S) -4-hydroxy-2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate (36mg,0.11mmol), 4-chloromethyl-5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (39mg,0.13mmol), potassium tert-butoxide (18mg,0.16mmol) and 18-crown-6 (42mg,0.16mmol) were added to 20mL of tetrahydrofuran, reacted at 80 ℃ for 10 hours, cooled, filtered, the filtrate was concentrated, and silica gel column chromatography (PE: EA ═ 2:1) was performed to obtain the title compound (30mg, yield 46.8%). 6.2- ((2R,4R,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-
Preparation of yl) benzo [ d ] thiazole-6-carboxylic acid
2- ((2R,4R,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d]Ethyl thiazole-6-carboxylate (30mg,0.05mmol), lithium hydroxide monohydrate (11mg,0.25mmol) were added to a mixed solution of methanol (5mL), THF (5mL), and water (2mL), the reaction was stirred at 25 ℃ for 5 hours, the pH was adjusted to 5 with dilute hydrochloric acid, concentration was carried out to precipitate a white solid, and the objective product was obtained by suction filtration (20mg, yield 70.2%). The molecular formula is as follows: c28H27Cl2N3O4S molecular weight: 571.1LC-MS (m/z): 572.2(M + H)+)
1H NMR(400MHz,CDCl3)δ:8.32(s,1H),8.03(d,1H),7.53(d,1H),7.43-7.28(m,3H),4.42-4.36(m,4H),3.78-3.71(m,1H),2.28-2.15(m,1H),1.96-1.81(m,4H),1.55-1.38(m,4H),1.35-1.15(m,4H),0.98-0.81(m,2H).
Example 2: 2- ((2R,4S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperazin-1-yl) benzo [ d ] thiazole-6-carboxylic acid
Preparation of ethyl 2- ((2R,4S,6S) -4-hydroxy-2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl 2- ((2R,6S) -2, 6-dimethyl-4-oxopiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate preparation method as in example 1, ethyl 2- ((2R,6S) -2, 6-dimethyl-4-oxopiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate (80mg,0.24mmol) was dissolved in THF (10mL), sodium borohydride (14mg,0.37mmol) was slowly added at 0 ℃, followed by reaction at 25 ℃ for 1 hour, water was added and extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and concentrated, and silica gel plate separation (petroleum ether: ethyl acetate 3:1) was performed to obtain 22mg, yield 27.5%.
Preparation of ethyl 2- ((2R,4S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl 2- ((2R,4S,6S) -4-hydroxy-2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate (22mg,0.06mmol), 4-chloromethyl-5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (24mg,0.079mmol), potassium tert-butoxide (11mg,0.099mmol) and 18-crown-6 (26mg,0.099mmol) were added to 20mL of tetrahydrofuran, reacted at 80 ℃ for 10 hours, cooled, filtered, the filtrate was concentrated, and purified by silica gel column chromatography (PE: EA ═ 2:1) to give the title compound (18mg, yield 50%).
3.2- ((2R,4S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperazine-1-
Preparation of yl) benzo [ d ] thiazole-6-carboxylic acid
2- ((2R,4S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d]Thiazole-6-carboxylic acid ethyl ester (18mg, 0.0)3mmol), lithium hydroxide monohydrate (6mg,0.15mmol) was added to a mixed solution of methanol (5mL), THF (5mL), and water (2mL), stirred at 25 ℃ for 5 hours, adjusted to pH 5 with dilute hydrochloric acid, concentrated, and a white solid precipitated, which was filtered off with suction and then reversed-phase to obtain the desired product (8mg, yield 47%). The molecular formula is as follows: c28H27Cl2N3O4S molecular weight: 571.1LC-MS (m/z): 572.2(M + H)+)
1H NMR(400MHz,CDCl3)δ:8.05(s,1H),8.03(d,1H),7.52(d,1H),7.51-7.34(m,3H),5.36(t,1H),5.30(s,1H),4.52-4.49(m,1H),4.44(s,1H),3.91-3.81(m,1H),2.30-2.28(m,1H),2.21-2.16(m,1H),2.12-2.01(m,2H),1.95-1.86(m,2H),1.75-1.60(m,1H),1.49-1.46(m,6H),1.35-1.15(m,2H).
Example 3: 2- ((2S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylic acid
Preparation of (2S,6S) -1-benzyl-2, 6-dimethylpiperidin-4-one
3-carbonyl glutaric acid (40.0g,0.28mol) and 40% acetaldehyde (60.5g,0.55mol) were stirred at 25 ℃ for 10min, then benzylamine (30mL,0.28mol) was slowly added, the reaction solution was stirred at 25 ℃ for 78h, 1N hydrochloric acid was added to adjust the pH to 2, and further stirred for 1h, then a saturated sodium bicarbonate solution was used to adjust the pH to 7, dichloromethane was extracted, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 9:1) to obtain the trans title compound (10g, yield: 16.8%).
Preparation of (2S,6S) -2, 6-dimethylpiperidin-4-one
(2S,6S) -1-benzyl-2, 6-dimethylpiperidin-4-one (3.2g,14.7mmol) and 20% palladium hydroxide (3.2g) were added to methanol (50mL), reacted under a hydrogen atmosphere for 10h, filtered, and concentrated to give the title compound (1.78g, yield: 95.1%).
Preparation of ethyl 2- ((2S,6S) -2, 6-dimethyl-4-oxopiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl 2-chloro-benzo [ d ] thiazole-6-carboxylate (362mg,1.5mmol) was acidified with hydrochloric acid (gas), and (2S,6S) -2, 6-dimethylpiperidin-4-one (127mg,1.0mmol) was dissolved in isopropanol (30mL), reacted at 100 ℃ for 12 hours, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (53mg, yield: 16.1%).
Preparation of ethyl 2- ((2S,6S) -4-hydroxy-2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl 2- ((2S,6S) -2, 6-dimethyl-4-oxopiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate (53mg,0.16mmol) was dissolved in THF (10mL), sodium borohydride (9mg,0.24mmol) was added slowly at 0 ℃, followed by reaction at 25 ℃ for 1 hour, extraction with dichloromethane after addition of water, and the organic phase was dried over anhydrous sodium sulfate, concentrated and used directly in the next reaction.
Preparation of ethyl 2- ((2S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylate
Ethyl (2S,6S) -2, 6-dimethyl-4-hydroxypiperidinylbenzo [ d ] thiazole-6-carboxylate (53mg,0.16mmol), 4-chloromethyl-5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (57.5mg,0.19mmol), potassium tert-butoxide (27mg,0.24mmol) and 18-crown-6 (63mg,0.24mmol) were added to 20mL of tetrahydrofuran, reacted at 80 ℃ for 10 hours, cooled, filtered, the filtrate was concentrated, and purified by silica gel column chromatography (PE: EA ═ 2:1) to give the title compound (9mg, yield 9%). Preparation of 2- ((2S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d ] thiazole-6-carboxylic acid
2- ((2S,6S) -4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2, 6-dimethylpiperidin-1-yl) benzo [ d]Ethyl thiazole-6-carboxylate (9mg,0.015mmol), lithium hydroxide monohydrate (3mg,0.075mmol) were added to a mixed solution of methanol (3mL), THF (3mL), and water (1mL), the reaction was stirred at 25 ℃ for 5 hours, pH was adjusted to 5 with dilute hydrochloric acid, extracted with ethyl acetate, and concentrated to afford the desired product (5mg, 58% yield) by reverse phase. The molecular formula is as follows: c28H27Cl2N3O4S molecular weight: 571.1LC-MS (m/z): 572.2(M + H)+)
1H NMR(400 MHz,CDCl3)δ:8.32(s,1H),8.03(d,1H),7.53(d,1H),7.46(d,2H),7.36-7.28(m,1H),5.36(t,1H),4.36(s,2H),4.31-4.26(m,1H),4.12-4.05(m,1H),3.91-3.86(m,1H),2.30-2.28(m,1H),2.21-2.16(m,1H),2.12-2.01(m,2H),1.95-1.86(m,2H),1.75-1.60(m,1H),1.49-1.46(m,6H),1.35-1.15(m,2H).

Claims (10)

1. A compound shown in a general formula (I), pharmaceutically acceptable salt, ester or stereoisomer thereof,
wherein,
R1、R2each independently selected from hydrogen atom, cyano group, halogen atom, nitro group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylthio radical, C1-6Alkylcarbonyl, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, di-C1-6Alkylaminosulfonyl radical, C1-6Alkylsulfonylamino group, C1-6Alkylsulfonyloxy, C2-8Alkenyl or C2-8An alkynyl group;
R3selected from hydrogen atoms, C optionally substituted by P1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C1-6Alkylsulfonyl radical, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl radical, C1-6Alkylsulfonylamino group, C1-6Alkylsulfonyloxy, 6-14 membered fused ring, 5-12 membered bridged ring or 5-12 membered spiro ring, wherein the carbon atom of said 6-14 membered fused ring, 5-12 membered bridged ring or 5-12 membered spiro ring is optionally substituted with N, O, S, SO and/or SO2Replacement;
p is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonyl radical, C2-8Alkenyl or C2-8An alkynyl group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, carboxyl C1-6Alkyl, carboxyl oxy C1-6Alkyl, carboxy amino C1-6Alkyl, amino C1-6Alkyl, aminocarbonyl C1-6Alkyl radical, C1-6Alkoxy, hydroxy C1-6Alkoxy, halo C1-6Alkoxy, carboxyl C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylcarbonylamino, C1-6Alkylsulfonyl or C1-6An alkylaminosulfonyl group;
w is selected from CH2、NH、O、S、SO、SO2Or CO;
a is selected from NH, O or S;
z is selected from heterocyclyl or cycloalkyl optionally substituted with 1-4Q;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C2-8Alkenyl or C2-8An alkynyl group;
e is selected from C, CH2、N、NH、O、S、SO、SO2Or CO;
x is selected from C, CH or N;
y is selected from C, CH and CH2N, NH, CO, O or S;
E. x, Y are each independently selected from single or double bonds;
n is an integer of 0 to 4.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof: wherein R is1、R2Each independently selected from hydrogen atom, cyano group, halogen atom, nitro group, amino group, hydroxyl group, carboxyl group, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylthio radical, C1-4Alkylcarbonyl, halo C1-4Alkyl, halo C1-4Alkoxy or C1-4Alkoxy radical C1-4An alkyl group;
R3selected from 3-6 membered cycloalkanes optionally substituted by PA group or a 3-6 membered heterocyclic group;
p is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1-4Alkyl, hydroxy C1-4Alkyl, halo C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl oxy C1-4Alkyl, carboxy amino C1-4Alkyl, amino C1-4Alkyl, aminocarbonyl C1-4Alkyl radical, C1-4Alkoxy, hydroxy C1-4Alkoxy, halo C1-4Alkoxy, carboxyl C1-4Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylcarbonyl group, C1-4Alkoxycarbonyl group, C1-4Alkylcarbonylamino, C1-4Alkylsulfonyl or C1-4An alkylaminosulfonyl group;
w is selected from CH2、NH、O、S、SO、SO2Or CO;
a is selected from NH, O or S;
z is selected from 3-8 membered heterocyclic group or 3-8 membered cycloalkyl group optionally substituted with 1-4Q;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
e is selected from C, CH2N, NH, CO, O or S;
x is selected from C, CH or N;
y is selected from C, CH and CH2N, NH, O, CO or S;
E. x, Y are each independently selected from single or double bonds;
n is an integer of 0 to 4.
3. The compound of claim 2, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
R1、R2each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a methoxy group, a methylamino group, a dimethylamino group, an acetyl group, a trifluoromethyl group, a trifluoroethyl group or a trifluoromethoxy group;
R3selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, ethoxycarbonyl group, trifluoromethyl group, trifluoromethoxy group, ethynyl group, methylamino group, ethylamino group, acetyl group, acetamido group, methylsulfonyl group or dimethylamino group;
n is an integer of 0 to 2;
z is selected from saturated 5-6-membered heterocyclic group containing O, S and/or N atoms optionally substituted by 1-2Q, or saturated 5-6-membered cycloalkyl;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
E. x, Y together with the benzene ring form the following structure:
4. the compound of claim 3, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
R1、R2each independently selected from a hydrogen atom, a cyano group, a fluorine atom,Chlorine atom, methyl group, ethyl group, propyl group, butyl group, methoxy group, methylamino group, acetyl group, trifluoromethyl group, or trifluoromethoxy group;
R3selected from cyclopropyl, cyclobutyl, cyclopentyl;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, ethoxycarbonyl group, trifluoromethyl group, trifluoromethoxy group, acetyl group or acetylamino group;
w is selected from NH, O or S;
a is selected from NH, O or S;
n is an integer of 0 to 2;
z is selected from cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydropyrazolyl, tetrahydroimidazolyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl optionally substituted with 1-2Q;
q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
E. x, Y together with the benzene ring form the following structure:
5. the compound of claim 4, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
R1、R2each independently selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl group, ethyl group, propyl group;
R3selected from cyclopropyl, cyclobutyl, cyclopentyl;
R4selected from the group consisting of hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, ethoxycarbonyl group;
w is selected from NH, O or S;
a is selected from NH, O or S;
n is an integer of 0 to 1;
z is selected from cyclohexyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl optionally substituted with 2Q;
q is selected from C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino, halogeno C1-4Alkyl or halo C1-4An alkoxy group;
E. x, Y together with the benzene ring form the following structure:
6. the compound of claim 5, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof:
z is selected from optionally substituted with 2Q
Q is selected from methyl, ethyl, n-propyl, isopropyl, butyl, methoxy and ethoxy;
E. x, Y together with the benzene ring form the following structure:
7. the compound, pharmaceutically acceptable salt thereof, ester thereof, or stereoisomer thereof of claim 1, wherein the compound is selected from:
8. a pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, together with one or more pharmaceutically acceptable carriers and/or diluents.
9. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof for the manufacture of a medicament for the treatment and/or prevention of FXR mediated diseases and related diseases including atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fibrosis related diseases, fatty liver, 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.
10. The use according to claim 9, wherein, the disease is selected from the group consisting of alcoholic fatty liver, non-alcoholic fatty liver, primary biliary cirrhosis, chronic hepatitis, non-viral hepatitis, alcoholic fatty hepatitis, non-alcoholic fatty hepatitis, benign intrahepatic cholestasis, progressive familial intrahepatic cholestasis, extrahepatic cholestatic conditions, drug-induced cholestasis, gestational cholestasis, gastrointestinal nutrition-related cholestasis, extrahepatic cholestatic conditions, hypercholesterolemia, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other observed outcomes of clinically overt long-term diabetes thereof, hepatocellular carcinoma, colon adenoma, polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, esophageal cancer, and other forms of gastrointestinal and hepatic neoplastic diseases.
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